1. TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel TRITON-TIMI 38 TRITON-TIMI 38 Elliott M. Antman, MD TRITON-TIMI 38 was supported by Eli Lilly and Daiichi Sankyo.

2. Antiplatelet Therapy for PCI Dual antiplatelet Rx (ASA + thienopyridine) is standard of care: Ticlopidine ClopidogrelDual antiplatelet Rx (ASA + thienopyridine) is standard of care: Ticlopidine Clopidogrel Clinical need to improve on benefits observed with clopidogrelClinical 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 dataPrasugrel Novel thienopyridine Efficient generation of active metabolite High levels of IPA achieved rapidly High IPA in clopidogrel “hyporesponders” Encouraging Phase 2 data

3. 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.

4. Study Design Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1 o endpoint: CV death, MI, Stroke 2 o 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 Median duration of therapy - 12 months N= 13,600 Wiviott SD et al AHJ 152: 627,2006

5. 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 Wiviott SD et al AHJ 152: 627,2006

6. Clopidogrel (N=6795) % Prasugrel (N=6813) % UA/NSTEMI74 STEMI26 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 Female2725* Diabetes23 Prior MI18 CrCl (ml/min) >60 <60 88 12 89 11 Baseline Characteristics *P<0.05 Wiviott SD et al NEJM 357: 2001, 2007

7. Clopidogrel (N=6795) % Prasugrel (N=6813) % PCI / CABG99 / 1 Any Stent9594 BMS4748 DES47 Multivessel PCI14 UFH / LMWH / Bival65 / 8 / 366 / 9 / 3 GP IIb/IIIa5554 LD of Study Rx Pre PCI During PCI Post PCI 25 74 1 26 73 1 Index Procedure Wiviott SD et al NEJM 357: 2001, 2007

8. 0 5 10 15 0306090180270360450 HR 0.81 (0.73-0.90) P=0.0004 Prasugrel Clopidogrel HR 0.80 P=0.0003 HR 0.77 P=0.0001 Days Primary Endpoint (%) 12.1 (781) 9.9 (643) Primary Endpoint CV Death,MI,Stroke NNT= 46 ITT= 13,608 LTFU = 14 (0.1%) Wiviott SD et al NEJM 357: 2001, 2007

9. 1 0 Endpoint Events Prevented Post-hoc Analysis # Events # Events 25/1806/189 896 896 701 ClopidogrelPrasugrel 1st Event P=0.0004 Additional Events Total Events P<0.0001 -138 -195 ITT N= 13,608 TIMI Study Group, Data on File

10. CV Death,MI,Stroke Timing of LD < 1 hr post lab (N=3552) Post PCI in lab (N=3833) During PCI (N=2380) Pre PCI (N=3370) 0.512 Prasugrel Better Clopidogrel Better HR 0.75 (0.60-0.93) 0.76 (0.62-0.93) 0.93 (0.73-1.19) 0.87 (0.71-1.07) P int = 0.40 TIMI Study Group, Data on File

11. 0 2 4 6 8 0123 1 0 306090180270360450 HR 0.82 P=0.01 HR 0.80 P=0.003 5.6 4.7 6.9 5.6 Days Primary Endpoint (%) Prasugrel Clopidogrel Prasugrel Clopidogrel Loading DoseMaintenance Dose Timing of Benefit (Landmark Analysis - 3 days)

12. Components of Endpoints Clopidogrel HR Prasugrel 12.1 0.81 9.9 2.4 0.89 2.1 9.5 0.76 7.3 1.0 1.02 1.0 uTVR Nonfatal Stroke Nonfatal MI CV Death CV Death, MI, Stroke 0.512 3.7 0.66 2.5 Prasugrel BetterClopidogrel Better All Cause Mortality 3.2 0.95 3.0 Stent Thrombosis 2.4 0.48 1.1 HR Wiviott SD et al NEJM 357: 2001, 2007

13. Myocardial Infarction 0 - 450 days 0 2 4 6 8 10 0306090180270360450 Days MI (%) Prasugrel Clopidogrel 9.7 7.4 HR 0.76 P<0.0001 TIMI Study Group-- Data on file Significant reductions in : Landmark Analyses at 3, 30 days Peri-Procedural MI’s Spontaneous MI’s during followup New development of STEMI CV Death after MI

14. Urgent Target Vessel Revascularization 0 2 4 6 0306090180270360450 HR 0.66 P=0.0001 Prasugrel Clopidogrel Days Endpoint (%) 3.7 (233) NNT= 83 2.5 (156) ITT= 13,608 Wiviott SD et al NEJM 357: 2001, 2007 Reductions in uTVR with Prasugrel in Landmark Analyses at 3, 30 days

15. Stent Thrombosis (ARC Definite + Probable) 0 1 2 3 0306090180270360450 HR 0.48 P <0.0001 Prasugrel Clopidogrel 2.4 (142) NNT= 77 1.1 (68) Days Endpoint (%) Any Stent at Index PCI N= 12,844 Wiviott SD et al NEJM 357: 2001, 2007 Significant reductions both with BMS, DES Significant reductions in early and late stent thromboses

16. 0 5 10 15 0306090180270360450 HR 0.81 (0.73-0.90) P=0.0004 Prasugrel Clopidogrel Days Endpoint (%) 12.1 9.9 HR 1.32 (1.03-1.68) P=0.03 Prasugrel Clopidogrel 1.8 2.4 138 events 35 events Balance of Efficacy and Safety CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167 Wiviott SD et al NEJM 357: 2001, 2007

17. Bleeding Events Safety Cohort (N=13,457) % Events ARD 0.6% HR 1.32 P=0.03 NNH=167 Clopidogrel Prasugrel ARD 0.5% HR 1.52 P=0.01 ARD 0.2% P=0.23 ARD 0% P=0.74 ARD 0.3% P=0.002 ICH in Pts w Prior Stroke/TIA (N=518) ICH in Pts w Prior Stroke/TIA (N=518) Clop 0 (0) % Pras 6 (2.3)% (P=0.02) Wiviott SD et al NEJM 357: 2001, 2007

18. Net Clinical Benefit Death, MI, Stroke, Major Bleed (non CABG) 0 5 10 15 0306090180270360450 Days Endpoint (%) HR 0.87 P=0.004 13.9 12.2 Prasugrel Clopidogrel ITT= 13,608 Events per 1000 pts MI Major Bleed (non CABG) + All Cause Mortality Clop 3.2% Pras 3.0 % P=0.64 Wiviott SD et al NEJM 357: 2001, 2007

19. B OVERALL No GPI GPI DES BMS DM No DM >75 65-74 <65 Female Male STEMI UA/NSTEMI 0.5 12 Prasugrel BetterClopidogrel Better HR Age Reduction in risk (%) 18 21 12 25 14 6 30 20 18 21 16 19 21 P inter = NS CV Death, MI, Stroke Major Subgroups CrCl > 60 CrCl < 60 14 20 Wiviott SD et al NEJM 357: 2001, 2007

20. Diabetic Subgroup 0 2 4 6 8 10 12 14 16 18 0306090180270360450 HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 21 N=3146 17.0 12.2 Prasugrel Clopidogrel Prasugrel Clopidogrel 2.6 2.5 Wiviott SD et al NEJM 357: 2001, 2007

21. Net Clinical Benefit Bleeding Risk Subgroups OVERALL >=60 kg < 60 kg < 75 >=75 No Yes 0.512 Prior Stroke / TIA Age Wgt Risk (%) + 54 -16 -16 +3 -14 -13 Prasugrel BetterClopidogrel Better HR P int = 0.006 P int = 0.18 P int = 0.36 Post-hoc analysis Wiviott SD et al NEJM 357: 2001, 2007

22. Bleeding Risk Subgroups Therapeutic Considerations Significant Net Clinical Benefit with Prasugrel 80% MD 10 mg Reduced MD Guided by PK Age > 75 or Wt < 60 kg 16% Avoid Prasugrel Prior CVA/TIA 4% Wiviott SD et al NEJM 357: 2001, 2007

23. Dose Reduction for Patients <60kg or ≥75 yrs Decreased Exposure Time Concentration Risk of Bleeding Decreased Risk Efficacy Retain Efficacy AUC (ng*hr/mL) 050100150200250300 0 20 40 60 80 100 MPA AUC Maintain PD > Clopidogrel Clopidogrel Prasugrel

24. 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 Thrombosis52% uTVR 34% MI 24% 2. An early and sustained benefit 3. Across ACS spectrum Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD Conclusions Higher IPA to Support PCI Net clinical benefit significantly favored Prasugrel Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balance Wiviott SD et al NEJM 357: 2001, 2007

25. Antiplatelet Therapy in ACS Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA ASA ASA + Clopidogrel ASA + Prasugrel - 22% - 20% - 19% + 60% + 38% + 32% Reduction in Ischemic Events Increase in Major Bleeds Wiviott SD et al NEJM 357: 2001, 2007