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

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