Transcript Amber Malik
Slide 1
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 2
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 3
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 4
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 5
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 6
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 7
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 8
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 9
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 10
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 11
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 12
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 13
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 14
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 15
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 16
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 17
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 18
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 19
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 20
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 21
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 22
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 23
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 24
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 25
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 26
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 27
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 28
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 29
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 30
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 31
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 32
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 33
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 34
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 35
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 36
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 37
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 38
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 39
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 40
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 41
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 42
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 43
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 44
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 45
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 46
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 47
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 48
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 49
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 50
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 51
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 52
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 53
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 54
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 55
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 56
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 57
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 58
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 59
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 60
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 61
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 62
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 63
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 64
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 65
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 66
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 67
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 68
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 69
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 70
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 71
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 72
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 73
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 74
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 75
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 76
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 77
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 78
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 79
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 80
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
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•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 81
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 82
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 2
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 3
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 4
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 5
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 6
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 7
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 8
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 9
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 10
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 11
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 12
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 13
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 14
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 15
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 16
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 17
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 18
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 19
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 20
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 21
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 22
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 23
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 24
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 25
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 26
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 27
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 28
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 29
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 30
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 31
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 32
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 33
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 34
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 35
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 36
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 37
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 38
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 39
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 40
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 41
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 42
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 43
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 44
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 45
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 46
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 47
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 48
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 49
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 50
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 51
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 52
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 53
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 54
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 55
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 56
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 57
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 58
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 59
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 60
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 61
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 62
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 63
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 64
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 65
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 66
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 67
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 68
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 69
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 70
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 71
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 72
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 73
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 74
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 75
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 76
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 77
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
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•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 78
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 79
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 80
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 81
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU
Slide 82
Amber Malik
Director Cath Lab Services
Shaikh Zayed Hospital, Lahore
Platelet
aggregation contributes to
atherothrombosis which in turn is
associated with Acute Coronary
Syndromes
ACS
often precipitates cardiovascular
death
Acute coronary syndrome
No ST elevation
Partial
flow
ST elevation
Complete
obstruction
UA/NSTEMI
STEMI
Antithrombin Rx
Antiplatelet Rx
X
Xa
Prothrom
Va
Ca++
VIIIa
IXa
Thrombin
Plt
FGN
FGN
XI
TF/ VIIa
FGN
Fibrin
Platelet activation:
Release of contents,
surface receptor expression
Inactive
platelet
GP
Ia/IIa
GP
VI
Collagen fibrils
RBCs
Endothelial cells
Ca++
ADP
Collagen
AA release
Thrombin
Epinephrine
Tx A2
COX
PGG2-PGH2
Tx Syn
Serotonin
Tx A2
Tx A2
IIb/IIIa
Thrombin
FGN
Collagen
ADP
Epinephrine
GP IIb/IIIa
receptor
activation
Tx A2
Serotonin
Shear forces
IIb/IIIa
inhibitor
Risk
during and after ACS can be
reduced by optimal anticoagulation and
antiplatelet treatment in conservatively
treated as well as revascularised patients
In
PCI with stents effective AP inhibition
is highly mandatory as the processes
themselves are thrombogenic and add to
the risk
X
Xa LMWH, pentasaccharide
UFH
Va,Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
inhibitor
LMWH
UFH
DTIs
DAPT
( aspirin and clopidogrel) for
NSTEMI for 1 year (CURE trial )
DAPT
for STEMI for at least 30 days
(CLARITY- TIMI 28 trial )
DAPT mandatory post
• BMS at least 1 month
• DES at least 1 year
PCI with stents
Even
though CURE shows a RRR of 20%
of composite end point which occurred in
9.3% vs 11.4 % on placebo .
The
9.35 % event rate is still quite high
inspite of DAPT, which rose to 16.3%
when recurrent ischemia was included.
Hence
the desire to improve outcome
even further
Cox
inhibitors :
Aspirin
ADP receptor antagonist :
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor(AZD6140)
Phosphodiesterase
inhibitors :
Cilostazol
Dipyridamole
Thrombin inhibitor :
Bivalirudin
Glycoprotein IIb/IIIA inhibitors :
Abciximab
Eptifibatide
Tirofiban
COOCH3
N
S
N
S
Cl
Cl
Ticlopidine
Clopidogrel
(1st generation)
(2nd generation)
Prasugrel (CS-747) (LY640315)
O
(3rd generation)
C H3
N
O
O
S
F
Slow onset: requires prolonged
pretreatment for PCI efficacy
Optimal interval from delivery to max
drug effect is >15 hrs
Bleeding (especially related to CABG)
Modest levels of platelet inhibition
Variability of response is upto 30%
depending on the measure of platelet
aggregation used
ESC guidelines recommend 300mg loading dose
> 6 hrs pre PCI
Reality is very different
Common practise CAG is often followed by ad
hoc PCI with very little time for optimal dosing
etc and exposing patients to an increased risk of
bleeding
PRAGUE 8 concluded that non selective
treatment of pts with high dose clopidogrel
should not be routinely undertaken
Lesser Response
Failure of Therapy
Successful Therapy
Greater Response
Failure of Therapy = Drug Resistance
Sem Vasc Med 3:113, 2003
O
C
Sankyo Ann Report 51:1,1999
O CH3
O
Pro-drug
N
S
O
Cl
O
C
CH3
Clopidogrel
N
S
F
Prasugrel
Hydrolysis
85% Inactive
Metabolites
(Esterases)
O
Esterases
O
O
C
O CH3
S
(Cytochrome P450)
Cl
O
O
C
N
S
F
Oxidation
N
S
N
Cl
O CH3
O
HOOC
* HS
O
OCH3
HOOC
* HS
N
Cl
Active Metabolite
N
F
Active Metabolite
60.0
40.0
20.0
0.0
-20.0
Interpatient Variability
80.0
Interpatient
Variability
Inhibition of Platelet Aggregation (%)
100.0
Clopidogrel Responder
Clopidogrel Non-responder
Response to
Clopidogrel
*Responder = 25% IPA at 4 and 24 h
Response to
Prasugrel
Brandt, Payne, Wiviott et al AHJ 2007
PRASUGREL
Faster and more potent IPA :
• Less dependent on CYP450 for metabolism
• More extensively metabolised to its active metabolite
• Reaches higher concentrations with a 60mg LD and 10mg
MD vs 300mgLD and 75mg MD as well as high dose
600mg LD and 150 mg MD clopidogrel
Less variabilty of response
Benefits demonstrated in both healthy volunteers
and CAD pts.
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and
Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
NEJM 357: 2001-2015, 2007
www.NEJM.org
Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:
Ticlopidine
Clopidogrel
Clinical need to improve on benefits observed with clopidogrel
Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of IPA achieved rapidly
High IPA in clopidogrel “hyporesponders”
Encouraging Phase 2 data
1. To test the hypothesis that higher and
less variable IPA prevents clinical
ischemic events.
2. To evaluate the safety of a regimen that
produces higher IPA.
These goals were achieved by evaluating
the efficacy and safety of prasugrel
compared to clopidogrel in mod/high risk
patients with ACS undergoing PCI on a
background of ASA.
Trial Leadership: TIMI Study Group
Eugene Braunwald,Chairman, Elliott M. Antman,PI,
Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,
Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly
J. Anthony Ware, Jeffrey Riesmeyer, William Macias,
James Croaning, Govinda Weerakkody, Francis Plat,
Tomas Bocanegra
Data Center and Site Management: Quintiles Inc
Data Safety Monitoring Board
David Williams (Chair) , Christophe Bode, Spencer King,
Ulrich Sigwart, David DeMets
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
STEMI: < 14 days (ischemia or Rx
Anatomy
strategy)
STEMI: Primary PCI
•Major Exclusion Criteria:
– Severe comorbidity
– Increased bleeding risk
– Prior hemorrhagic stroke or any stroke < 3 mos
– Any thienopyridine within 5 days
– No exclusion for advanced age or renal function
Argentina (195)
Finland (116)
New Zealand (49)
Australia (217)
France (146)
Poland (1938)
Austria (182)
Germany (999)
Portugal (67)
Belgium (287)
Hungary (695)
Slovakia (140)
Brazil (225)
Iceland (10)
South Africa (404)
Canada (251)
Israel (1219)
Spain (178)
Chile (114)
Italy 782)
Sweden (154)
Czech Rep (340)
Latvia (21)
Switzerland (136)
Denmark (33)
Lithuania (54)
United Kingdom (73)
Estonia 134)
Netherlands (390)
United States (4059)
30 Countries
707 Sites
LTFU = 14 (0.1%)
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Female
27
25*
Diabetes
23
23
Prior MI
18
18
88
12
89
11
CrCl (ml/min)
>60
<60
*P<0.05
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
Multivessel PCI
14
14
UFH / LMWH / Bival
65 / 8 / 3
66 / 9 / 3
GP IIb/IIIa
55
54
LD of Study Rx
Pre PCI
During PCI
Post PCI
25
74
1
26
73
1
Primary Endpoint
CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
12.1
(781)
180
270
LTFU = 14 (0.1%)
360
450
This
was primarily driven by a reduction
in the rate of non-fatal MI 7.3 vs 9.5%;
p<0.0001 at 6- 15 months
There
was no significant difference
between the incidence of rates of CV
death or nonfatal stroke
Prasugrel
compared to clopidogrel
reduces the incidence of recurrent MI
Also
reduces the severity of recurrent MI
• Overall MI
• MI followed by death
RRR – 24%
RRR - 42%
The
rapid onset time of prasugrel upto 30
mins means that the physician can afford
to take the time to determine coronary
anatomy ( rule out urgent CABG), yet still
have time to achieve high levels of IPA for
?proceed PCI
• LD and day 3
• MD and day 450
RRR 19 %
RRR 31%
Timing of Benefit
(Landmark Analysis)
8
Primary Endpoint (%)
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
Loading Dose
2
Days
3
0
30 60 90
180
270
360
Maintenance Dose
450
3
Any Stent at Index PCI
N= 12,844
2.4
(142)
Clopidogrel
Endpoint (%)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
Days
180
270
360
450
Balance of
Efficacy and Safety
15
Endpoint (%)
Clopidogrel
10
CV Death / MI /
Stroke
Prasugrel
138
events
12.1 HR 0.81
(0.73-0.90)
P=0.0004
9.9
NNT = 46
5
TIMI Major
NonCABG Bleeds
Prasugrel
Clopidogrel
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
P=0.03
0
0 30 60 90
180
Days
270
360
450
NNH = 167
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
% Events
2.4
2
1.8
1.4
0.9
0.9
1.1
0.4
0.1
0.3
0.3
0
TIMI Major
Bleeds
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Life
Threatening
ARD 0.5%
HR 1.52
P=0.01
Nonfatal
ARD 0.2%
P=0.23
Fatal
ARD 0.3%
P=0.002
ICH
ARD 0%
P=0.74
15
Clopidogrel
ITT= 13,608
13.9
12.2
Prasugrel
10
Endpoint (%)
HR 0.87
P=0.004
Events per 1000 pts
10
+
6
5
0
5
-5
-10
-15
-20
-25
-23
Major Bleed
(non CABG)
MI
0
0
30 60 90
Days
180
270
360
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64
450
CV Death, MI, Stroke
Major Subgroups
UA/NSTEMI
STEMI
Reduction in risk (%)
18
21
B
Male
Female
21
12
<65
Age 65-74
>75
25
14
6
No DM
DM
14
30
BMS
DES
20
18
GPI
No GPI
21
16
CrCl < 60
CrCl > 60
14
20
19
OVERALL
0.5
Prasugrel Better
1
HR
Pinter =
NS
Clopidogrel Better
2
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
+ 37
Yes
No
Pint = 0.006
-1
>=75
-16
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
Pint = 0.36
>=60 kg
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke
Stent Thrombosis
uTVR
MI
2. An early and sustained benefit
3. Across ACS spectrum
19%
52%
34%
24%
Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the
benefit : risk balance
Prasugrel compared with clopidogrel significantly reduced
the incidence of ischemic events , both in the acute and long
term
The increased efficacy of prasugrel was associated with an
increased risk of bleeding.
The balance of efficacy and safety revealed an early and
sustained net clinical benefit over the entire spectrum of
ACS investigated
Avoid in pts with prior stroke / TIA
Very old and low body weight may require reduced dose
Patients
with DM and AMI derived the
greatest net clincal benefit from
prasugrel as compared to clopidogrel
STEMI
Primary
PCI
Secondary PCI
Baseline
3534 pts
2438(69%)
1094(31%)
characteristics well matched
More frequent use of Gp 11b111a
inhibitorswith clopidogrel due to bail out
Benefit
of prasugrel across the overall
spectrum of ACSs but particularly
pronounced in STEMI pts.
Primary
end point significant reduction
• 6.5 vs 9.5%; p=0.002
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction
6
Clopidogrel
5.24
Clopidogrel
4
Prasugrel
MI (%)
4.79
4.27
3.40
Prasugrel
2
0
HR 0.81
(0. 70-0.95)
P = 0.008
0
1
2
Loading dose
HR 0.69
(0.58-0.83)
P < 0.0001
3
60
180
270
360
450
Maintenance dose
Time (days)
Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.
Secondary
end point of CV death, MI and
UTVR at 30 days was reduced
6.7%vs
8.8% p=0.02
Benefit
persisted through 15 months
Multivariate
analyses were performed to
identify predictors of CV death, MI and
UTVR
Common indicators of high risk
remained the same :
• Gp11b111a use , BMS, multivessel PCI, prior MI
>75yrs age.
Only
factor that reduced HR was
treatment with prasugrel
Efficacy
profile
Reduced rate of :
• single end points of all cause death , MI and
stent thromboses
• Dual end points of CV death and MI
• Non significant trend towards a reduced rate of
UTVR
Efficacy
profile was maintained
throughout 15 months
Safety
profile :
• After 15 months rate of TIMI major non- CABG
bleed in prasugrel and clopidogrel was similar
• 30 day incidence was higher with clopidogrel
due to increased Gp2b3a use.
Net
clinical benefit analysis
CV
death , MI, non fatal stroke, or TIMI
major non CABG bleed after 15 months
of treatment with prasugrel vs
clopidogrel significant benefit
12.2
vs 14.6% p=0.02
N=3146
18
Clopidogrel
17.0
16
CV Death / MI /
Stroke
Endpoint (%)
14
12.2
12
HR 0.70
P<0.001
NNT = 21
Prasugrel
10
8
6
TIMI Major
NonCABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
Days
180
270
360
450
The
primary end point was again driven by
a reduction in the rate of MI in pts treated
with Prasugrel
• 8.2 vs 13.2% p<0.001
A
total of 21 pts with DM would need to be
treated with prasugrel to avoid one case of
the primary end point if the pt was treated
with clopidogrel
In
the overall study population the
efficacy of prasugrel is at the expense of
an increased risk of bleeding.
In
this analysis in the DM subset
prasugrel did not significantly increase
the risk of non CABG bleed
Multiple
sub group analysis showed that
the reductions in the rate of stent
thrombosis were in favour of prasugrel
as compared with clopidogrel in every
instance
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94%)
BMS Only
6461 (47%)
DES Only
5743 (42%)
Both BMS/DES
640 (5%)
PES Only
2766 (20%)
SES Only
2454 (18%)
Other/Mixed
523 (4%)
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Blinded CEC review of using source documents incl imaging reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of
the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory w/o angiographic
confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
HR 13.1 (9.8 – 17.5) P<0.0001
30
% of Subjects
25
CLOPIDOGREL
Clopidogrel
25.9
25.9
20
15
10
2.6
2.6
5
0
Stent Thrombosis
Stent thrombosis
N=210
No Stent Thrombosis
No SAT
N=12634
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0.5
0
0
50
100
150
200 250
DAYS
300
350
400
450
% of Subjects
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
40%
1
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0
30
DAYS
0.49%
90
150
210
270
330
390
450
STENT ANALYSIS
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.310.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
PRAS
B
STEMI
UA/NSTEMI
B
B
B
Stent > 20 mm
Stent <= 20 mm
B
No Bifurcation Stent
Bifurcation Stent
B
B
CrCl >=60
CrCl< 60
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
0.1
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
1.6
1.0
CLO
P
2.8
2.2
1.4
0.9
2.9
1.9
53%
52%
1.1
1.4
2.2
4.6
50%
69%
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
2
RISK
CLOPIDOGREL
BETTER
(%)
42%
57%
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
CLOPIDOGREL
% of Subjects
2
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75% 0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Intensive antiplatelet therapy with PRASUGREL in
stented patients compared to CLOPIDOGREL:
•Substantial reduction in ST:
•Regardless of stent type or ST definition
•Early and Late
•A broad range of clinical/procedural
characteristics
•Fewer ischemic events, more major bleeding
Events per 1000 patients treated
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA
w/o ST
+5
TIMI Major
Non CABG
bleed
-12
-15
STENT ANALYSIS
www.thelancet.com
•Stent Thrombosis is a rare, but devastating complication of PCI associated with a
high mortality. Efforts to reduce ST have focused on compliance w/ and duration of
ASA/clopidogrel
•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of
platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a
broad array of clinical procedural characteristics
STENT ANALYSIS
In
addition to reducing ST prasugrel also
reduced the primary end point , in the
stented population, the BMS pop, and the
DES pop.
STENT ANALYSIS
Net Clinical Benefit
HR 0.86
(0.77-0.95)
p=0.002
13.7
HR 0.88
(0.77-1.01)
p=0.07
13.6
% of Subjects
12
Any
N=12844
12.3
HR 0.84
0.84
HR
(0.72-0.98)
P=0.025
p=0.025
13.4
11.4
BMS
DES
N=6461
N=5743
STENT ANALYSIS
CVD/MI/CVA
HR 0.81
(0.720.90)
p=0.0001
HR 0.80
(0.690.93)
p=0.003
MAJOR BLEEDING
HR 0.82
(0.690.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
HR 1.19
(0.95-1.99) (0.83-1.72)
p=0.09
p=0.34
Prasugrel
as compared to clopidogrel
significantly reduced :
• Incidence of combined end point of CV death,
MI and nonfatal stroke
• NNT 46; p<0.0001
This
benefit came at the cost of an
increase in major non-CABG bleeds
• NNH 167; p=0.03
Prasugrel is more effective than clopidogrel for
the prevention of ischemic events including
stent thrombosis, in ACS pts undergoing PCI esp
high risk e.g STEMI, diabetic and stent pop.
The reduction is primarily MI prevention
driven
Safety profile is comparable to that of
clopidogrel in this high risk subset
ASA
ASA +
Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
Increase
in
Major
Bleeds
+ 60%
Placebo
Single
Antiplatelet Rx
APTC
+ 38%
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON-TIMI 38
Higher
IPA
ACS
can lead to CV death
Post PCI – SAT , death, MI or UTVR
Clopidogrel is not enough
PRASUGREL
• Pharmacokinetics
• Pharmacodynamics
• Good clinical impact as it reduces MI
Prasugrel better
Bleeding risk ????
THANKYOU