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.

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 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

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.

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

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

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

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 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

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 25 74 1 26 73 1

Primary Endpoint CV Death,MI,Stroke 15 Clopidogrel 12.1 (781) 9.9 (643) 10 Primary Endpoint (%) Prasugrel HR 0.81 (0.73-0.90) 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

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

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

Balance of Efficacy and Safety TIMI Major NonCABG Bleeds 15 138 events Clopidogrel 12.1 HR 0.81 (0.73-0.90) 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 (1.03-1.68) P=0.03 1.8 Clopidogrel NNH = 167 30 60 90 180 270 360 450 Days

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

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

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

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 = 21 8 6 TIMI Major NonCABG Bleeds 4 Clopidogrel 2.6 2.5 2 Prasugrel 30 60 90 180 270 360 450 Days

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

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

Comparison with Higher Dose Clopidogrel IPA (%; 20 mM ADP) IPA (%; 20 mM ADP) N=201 P<0.0001 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

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

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

Publication of Primary Results NEJM 357: 2001-2015, 2007 www.NEJM.org Slides and Full Listing of Trial Participants at www.TIMI.org