1. TRITON-TIMI 38 AHA 2007 Orlando, Florida
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.

2. 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

3. Healthy Volunteer Crossover Study
100
N=66 80
Interpatient Variability 60
IPA at 24 hours (%) 40
Interpatient Variability 20
Clopidogrel Responder
Clopidogrel Non-responder
-20
Response to Clopidogrel 300 mg
Response to Prasugrel 60 mg
From Brandt JT AHJ 153: 66e9,2007

4. Study Goals
To test the hypothesis that higher and less variable IPA prevents clinical ischemic events.
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.

5. 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 5

6. Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N= 13,600
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint: CV death, MI, Stroke
2o endpoints: 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

7. Enrollment Criteria
Inclusion Criteria Planned PCI for : Mod-High Risk UA/NSTEMI (TRS > 3) 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
Known Anatomy

8. 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%)

9. Baseline Characteristics
Clopidogrel (N=6795) %
Prasugrel (N=6813) %
UA/NSTEMI 74
STEMI 26
Age, median (IQR)
> 75 y
61 (53,69) y 13
61 (53, 70) y
Wgt, median (IQR) < 60 kg
83 kg (72, 92) 5.3
84 kg (73, 93) 4.6
Female 27
25*
Diabetes 23
Prior MI 18
CrCl (ml/min) >60 <60
88 12
89 11
*P<0.05

10. LD of Study Rx Pre PCI During PCI Post PCI
Index Procedure
Clopidogrel (N=6795) %
Prasugrel (N=6813) %
PCI / CABG
99 / 1
Any Stent 95 94
BMS 47 48
DES
Multivessel PCI 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

11. Primary Endpoint CV Death,MI,Stroke15
Clopidogrel
12.1 (781)
9.9 (643) 10
Primary Endpoint (%)
Prasugrel
HR 0.81 ( ) P=0.0004
HR 0.80 P=0.0003
HR 0.77 P=0.0001 5
NNT= 46
ITT= 13,608
LTFU = 14 (0.1%) 30 60 90
180
270
360
450
Days

12. Timing of Benefit (Landmark Analysis)8
6.9
Clopidogrel
Clopidogrel 6
5.6
5.6
Primary Endpoint (%)
4.7 4
Prasugrel
Prasugrel
HR 0.82 P=0.01
HR 0.80 P=0.003 2 1 1 2 3 30 60 90
180
270
360
450
Days
Loading Dose
Maintenance Dose

13. Stent Thrombosis (ARC Definite + Probable)3
Any Stent at Index PCI N= 12,844
2.4 (142)
Clopidogrel 2
Endpoint (%)
1.1 (68) 1
Prasugrel
HR 0.48 P <0.0001
NNT= 77 30 60 90
180
270
360
450
Days

14. Balance of Efficacy and Safety TIMI Major NonCABG Bleeds15
138 events
Clopidogrel
12.1
HR 0.81 ( ) P=0.0004
CV Death / MI / Stroke
9.9 10
NNT = 46
Prasugrel
Endpoint (%) 5
35 events
TIMI Major NonCABG Bleeds
Prasugrel
2.4
HR 1.32 ( ) P=0.03
1.8
Clopidogrel
NNH = 167 30 60 90
180
270
360
450
Days

15. Bleeding Events Safety Cohort (N=13,457)
ICH in Pts w Prior Stroke/TIA (N=518)
Clopidogrel
Prasugrel
Clop 0 (0) % Pras 6 (2.3)% (P=0.02)
% Events
ARD 0.6% HR 1.32 P=0.03 NNH=167
ARD 0.5% HR 1.52 P=0.01
ARD 0.2% P=0.23
ARD 0.3% P=0.002
ARD 0% P=0.74 15

16. Net Clinical Benefit Death, MI, Stroke, Major Bleed (non CABG)15
Clopidogrel
13.9
ITT= 13,608
12.2
HR 0.87 P=0.004
Prasugrel 10
Endpoint (%)
Events per 1000 pts MI
Major Bleed (non CABG) +
All Cause Mortality 5
Clop 3.2% Pras 3.0 % P=0.64 30 60 90
180
270
360
450
Days

17. CV Death, MI, Stroke Major Subgroups
Reduction in risk (%) 18
UA/NSTEMI B 21
STEMI
Male 21
Female 12
<65 25
Age
65-74 14
>75 6
No DM 14 DM 30
BMS 20
DES 18
GPI 21
No GPI 16 14
CrCl < 60 20
CrCl > 60 19
Pinter = NS
OVERALL
0.5 1 2
Prasugrel Better
Clopidogrel Better HR

18. TIMI Major NonCABG Bleeds
Diabetic Subgroup
N=3146 18
Clopidogrel
17.0 16
CV Death / MI / Stroke 14
12.2 12
HR 0.70 P<0.001
Endpoint (%)
Prasugrel 10
NNT = 46 8 6
TIMI Major NonCABG Bleeds 4
Clopidogrel
2.6
2.5 2
Prasugrel 30 60 90
180
270
360
450
Days

19. Net Clinical Benefit Bleeding Risk Subgroups
Post-hoc analysis
Risk (%)
Yes
+ 37
Prior Stroke / TIA
-16 No
Pint = 0.006 -1
>=75
Age
Pint = 0.18
-16
< 75
< 60 kg +3
Wgt
>=60 kg
Pint = 0.36
-14
-13
OVERALL
0.5 1 2
Prasugrel Better
Clopidogrel Better HR

20. Bleeding Risk Subgroups Therapeutic Considerations
Reduced MD Guided by PK Age > 75 or Wt < 60 kg
Avoid Prasugrel Prior CVA/TIA
16% 4%
Significant Net Clinical Benefit with Prasugrel 80%
MD 10 mg 20

21. Comparison with Higher Dose Clopidogrel
IPA (%; 20 mM ADP)
IPA (%; 20 mM ADP)
N=201
P< for each
P<0.0001
Prasugrel 60 mg
Clopidogrel 600 mg
Clopidogrel 150 mg
Prasugrel 10 mg
Hours
14 Days
Wiviott et al Circ 2007 (In Press) 21

22. Conclusions Higher IPA to Support PCI
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Safety
Significant increase in serious bleeding (32% increase) Avoid in pts with prior CVA/TIA
Efficacy
1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%       MI 24%
2. An early and sustained benefit
3. Across ACS spectrum
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balance

23. Antiplatelet Therapy in ACS
ASA
ASA + Clopidogrel
ASA + Prasugrel
- 22%
Reduction in Ischemic Events
- 20%
- 19%
Increase in Major Bleeds
+ 60%
+ 38%
+ 32%
Single Antiplatelet Rx
Dual Antiplatelet Rx
Higher IPA

24. Publication of Primary Results
NEJM 357: , 2007
Slides and Full Listing of Trial Participants at