TRial to Assess Improvement in Therapeutic Outcomes by

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TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibitio. N with Prasugrel

TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibitio. N 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

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

Healthy Volunteer Crossover Study 100 Interpatient Variability N=66 60 40 20 Interpatient Variability IPA at 24 hours (%) 80 Clopidogrel Responder 0 -20 Clopidogrel Non-responder Response to Clopidogrel 300 mg From Brandt JT AHJ 153: 66 e 9, 2007 Response to Prasugrel 60 mg

Study Goals 1. To test the hypothesis that higher and less variable IPA prevents

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,

Trial Organization Trial Leadership: TIMI Study Group Eugene Braunwald, Chairman, Elliott M. Antman, PI, Stephen D. Wiviott, Gilles Montalescot, Carolyn H. Mc. Cabe, Sabina A. Murphy, Susan Mc. Hale 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 De. Mets

Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI N= 13, 600 ASA Double-blind

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 1 o endpoint: 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

Enrollment Criteria • Inclusion Criteria Planned PCI for : Mod-High Risk UA/NSTEMI (TRS >

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) Australia

Enrollment: Nov 2004 - Jan 2007 N = 13, 608 (ITT) Argentina (195) Australia (217) Finland (116) France (146) New Zealand (49) Poland (1938) Austria (182) Belgium (287) Germany (999) Hungary (695) Portugal (67) Slovakia (140) Brazil (225) Canada (251) Iceland (10) Israel (1219) South Africa (404) Spain (178) Chile (114) Czech Rep (340) Italy 782) Latvia (21) Sweden (154) Switzerland (136) Denmark (33) Estonia 134) Lithuania (54) Netherlands (390) United Kingdom (73) 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

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 Cr. Cl (ml/min) >60 <60 88 12 89 11 *P<0. 05

Index Procedure Clopidogrel (N=6795) % Prasugrel (N=6813) % PCI / CABG 99 / 1

Index Procedure Clopidogrel (N=6795) % Prasugrel (N=6813) % PCI / CABG 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 10 Prasugrel HR

Primary Endpoint CV Death, MI, Stroke 15 Primary Endpoint (%) Clopidogrel 10 Prasugrel HR 0. 77 P=0. 0001 ITT= 13, 608 0 0 30 60 90 9. 9 (643) HR 0. 81 (0. 73 -0. 90) P=0. 0004 NNT= 46 HR 0. 80 P=0. 0003 5 12. 1 (781) 180 Days 270 LTFU = 14 (0. 1%) 360 450

Timing of Benefit (Landmark Analysis) Primary Endpoint (%) 8 Clopidogrel 6 5. 6 4

Timing of Benefit (Landmark Analysis) Primary Endpoint (%) 8 Clopidogrel 6 5. 6 4 4. 7 5. 6 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,

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 Clopidogrel HR 0. 81 (0. 73 -0. 90)

Balance of Efficacy and Safety 15 Clopidogrel HR 0. 81 (0. 73 -0. 90) P=0. 0004 9. 9 NNT = 46 12. 1 CV Death / MI / Stroke Endpoint (%) 138 events 10 Prasugrel 5 TIMI Major Non. CABG Bleeds Prasugrel 2. 4 HR 1. 32 1. 8 (1. 03 -1. 68) Clopidogrel P=0. 03 0 0 30 60 90 180 Days 35 events 270 360 450 NNH = 167

Bleeding Events Safety Cohort (N=13, 457) ICH in Pts w Prior Stroke/TIA (N=518) Clopidogrel

Bleeding Events Safety Cohort (N=13, 457) ICH in Pts w Prior Stroke/TIA (N=518) Clopidogrel Prasugrel % Events Clop 0 (0) % Pras 6 (2. 3)% (P=0. 02) 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

Net Clinical Benefit Death, MI, Stroke, Major Bleed (non CABG) 15 Clopidogrel ITT= 13,

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 + 5 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 Reduction in risk (%) 18 21 B

CV Death, MI, Stroke Major Subgroups UA/NSTEMI 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 14 20 Cr. Cl < 60 Cr. Cl > 60 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

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 = 21 8 6 TIMI Major Non. CABG Bleeds 4 2 0 Clopidogrel 2. 6 2. 5 Prasugrel 0 30 60 90 180 Days 270 360 450

Net Clinical Benefit Bleeding Risk Subgroups Post-hoc analysis Risk (%) Prior Stroke / TIA

Net Clinical Benefit Bleeding Risk Subgroups Post-hoc analysis Risk (%) Prior Stroke / TIA Age Yes + 54 No Pint = 0. 006 -1 >=75 Pint = 0. 18 < 75 Wgt -16 +3 < 60 kg >=60 kg Pint = 0. 36 -14 -13 OVERALL 0. 5 -16 Prasugrel Better 1 HR Clopidogrel Better 2

Bleeding Risk Subgroups Therapeutic Considerations 16% 4% MD 10 mg Significant Net Clinical Benefit

Bleeding Risk Subgroups Therapeutic Considerations 16% 4% MD 10 mg Significant Net Clinical Benefit with Prasugrel 80% id Avo rel sug Pra rior P /TIA CVA Re Gu du ce i d Ag ed d M W e > by D t < 75 PK 60 o kg r

PRINCIPLE – TIMI 44 IPA (%; 20 m. M ADP) N=201 P<0. 0001 for

PRINCIPLE – TIMI 44 IPA (%; 20 m. M ADP) N=201 P<0. 0001 for each Comparison with Higher Dose Clopidogrel IPA (%; 20 m. M 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/10 mg MD vs Clopidogrel

Conclusions Higher IPA to Support PCI Prasugrel 60 mg LD/10 mg MD vs Clopidogrel 300 mg LD/ 75 mg MD Efficacy Safety 1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% u. TVR 34% MI 24% 2. An early and sustained benefit 3. Across ACS spectrum 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 + Clopidogrel ASA + Prasugrel Reduction in Ischemic Events

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

Publication of Primary Results NEJM 357: 2001 -2015, 2007 www. NEJM. org Slides and

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