Transcript Document

TRial to Assess Improvement in
Therapeutic Outcomes by Optimizing
Platelet InhibitioN with Prasugrel
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.
Antiplatelet Therapy
for PCI
• 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
Healthy Volunteer
Crossover Study
100
Interpatient
Variability
N=66
60
40
20
Interpatient
Variability
IPA at 24 hours (%)
80
Clopidogrel Responder
0
Clopidogrel Non-responder
-20
Response to
Clopidogrel 300 mg
From Brandt JT AHJ 153: 66e9,2007
Response to
Prasugrel 60 mg
Study Goals
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
Organization
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
Study Design
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
Enrollment Criteria
•Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)
Known
Anatomy STEMI: < 14 days (ischemia or Rx 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
Enrollment: Nov 2004 - Jan 2007
N = 13,608 (ITT)
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%)
Baseline Characteristics
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
Index Procedure
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
Primary Endpoint (%)
15
Clopidogrel
12.1
(781)
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
180
270
Days
LTFU = 14 (0.1%)
360
450
Timing of Benefit
(Landmark Analysis)
Primary Endpoint (%)
8
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
2
Loading Dose
3
0
30 60 90
Days
180
270
360
Maintenance Dose
450
Stent Thrombosis
(ARC Definite + Probable)
3
Any Stent at Index PCI
N= 12,844
Endpoint (%)
Clopidogrel
2.4
(142)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0 30 60 90
180
270
Days
360
450
Balance of
Efficacy and Safety
15
138
events
Clopidogrel
12.1
Endpoint (%)
CV Death / MI / Stroke
9.9
10
HR 0.81
(0.73-0.90)
P=0.0004
NNT = 46
Prasugrel
5
TIMI Major
NonCABG Bleeds
Prasugrel
2.4 HR 1.32
1.8 (1.03-1.68)
Clopidogrel
P=0.03
0
0 30 60 90
180
270
Days
35
events
360
450
NNH = 167
Bleeding Events
Safety Cohort
(N=13,457)
4
ICH in Pts w
Prior Stroke/TIA
(N=518)
% Events
Clopidogrel
Prasugrel
Clop 0 (0) %
Pras 6 (2.3)%
(P=0.02)
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
Life
Threatening
ARD 0.6%
HR 1.32
P=0.03
NNH=167
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
Net Clinical Benefit
Death, MI, Stroke,
Major Bleed (non CABG)
15
Clopidogrel
ITT= 13,608
13.9
Endpoint (%)
12.2
Prasugrel
10
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
180
270
Days
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
Diabetic Subgroup
N=3146
18
Clopidogrel
17.0
Endpoint (%)
16
CV Death / MI / Stroke
14
12.2
12
Prasugrel
10
HR 0.70
P<0.001
NNT = 46
8
6
TIMI Major
NonCABG Bleeds
4
Clopidogrel
2
2.6
2.5
Prasugrel
0
0
30 60 90
180
270
Days
360
450
Net Clinical Benefit
Bleeding Risk Subgroups
Post-hoc analysis
Risk (%)
Prior
Stroke / TIA
Age
Yes
+ 37
No
Pint = 0.006
-1
>=75
Pint = 0.18
< 75
Wgt
-16
-16
+3
< 60 kg
>=60 kg
Pint = 0.36
-14
-13
OVERALL
0.5
1
Prasugrel Better
HR
2
Clopidogrel Better
Bleeding Risk Subgroups
Therapeutic Considerations
16%
4%
MD
10 mg
Significant
Net Clinical Benefit
with Prasugrel
80%
PRINCIPLE – TIMI 44
IPA (%; 20 mM ADP)
N=201
P<0.0001 for each
Comparison with Higher
Dose Clopidogrel
IPA (%; 20 mM ADP)
P<0.0001
Prasugrel 60 mg
Clopidogrel 600 mg
Clopidogrel Prasugrel
150 mg
10 mg
Hours
Wiviott et al Circ 2007 (In Press)
14 Days
Conclusions
Higher IPA to Support PCI
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
Antiplatelet Therapy in ACS
ASA
ASA + Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
+ 60%
Placebo
APTC
Single
Antiplatelet Rx
+ 38%
+ 32%
CURE
TRITON-TIMI 38
Dual
Antiplatelet Rx
Higher
IPA
Increase
in
Major
Bleeds
Publication of Primary Results
NEJM 357: 2001-2015, 2007
www.NEJM.org
Slides and Full Listing of Trial Participants at
www.TIMI.org