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C. Michael Gibson, M.S., M.D.

C. Michael Gibson, M.S., M.D. Chief, Clinical Research, Beth Israel Deaconess CV Division Chairman, PERFUSE Study Group Chairman of the Board of WikiDoc Foundation, www.wikidoc.org The World’s Largest Textbook of Medicine with 1,800 contributors. Platelet Mediated Thrombosis.

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C. Michael Gibson, M.S., M.D.

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  1. C. Michael Gibson, M.S., M.D. Chief, Clinical Research, Beth Israel Deaconess CV Division Chairman, PERFUSE Study Group Chairman of the Board of WikiDoc Foundation, www.wikidoc.org The World’s Largest Textbook of Medicine with 1,800 contributors

  2. Platelet Mediated Thrombosis Adhesion to subendothelial collagen and vWF via integrin receptors Activation via ADP, collagen, thrombin and other factors Aggregation to form platelet-rich thrombus (“white clot”) Activation Aggregation Adhesion

  3. Platelet Mediated Thrombosis Targets Abciximab, Eptifibatide, Tirofiban TRA cAMP /PDE inhibition: Cilostazol, Dipyridamole ARC1779 Clopidogrel, Ticlopidine Aspirin No currently approved anti-platelet agents specifically target Adhesion Most approved anti-platelets affect different aspects of platelet Activation GP IIb/IIIa inhibitors inhibit the “final common pathway” Aggregation

  4. Positive Feedback Loops Thrombin ADP P2Y12 Inhib P2Y12 Receptor ADP ADP “Amplification” “Burst” “Cascade” “Activation” ADP

  5. Nadia Comaneci 1976: First Perfect Score of 10 In Olympics ACS management is like a balance beam performance Both efficacy and safety are important, and if you fail to balance efficacy and safety, the patient gets hurt

  6. TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel TRITON-TIMI 38

  7. Active Metabolite Formation:Prasugrel and Clopidogrel

  8. Intersubject Variability with Prasugrel at 24 hours (Healthy Volunteers) IntersubjectVariability Response to Prasugrel 60 mg 100.0 N=64 80.0 60.0 IntersubjectVariability Inhibition of Platelet Aggregation (%) 20 µmol/L ADP 40.0 20.0 0.0 Clopidogrel Responder Clopidogrel Non-responder* -20.0 Response to Clopidogrel 300 mg *Clopidogrel non-responder = < 20% IPA at either the 4 hour or 24 hour time point. ADP=Adenosine Diphosphate; IPA=Inhibition of Platelet Aggregation Adapted from Brandt JT et al. Am Heart J 2007;153:66.e9-e16

  9. Inhibition of Platelet Aggregation (Mean ± SEM, 20 µM ADP) Time Day 1, Hours Days Loading Dose Maintenance Doses 100 * * *P<.001 vsClop 300 mg600 mg and 75 mg * * 10 mg * * * * * * * * 80 ‡ 60 mg ‡ †P <.05 vsClop 300 mg/75 mg ‡ † ‡ * 60 600 mg ‡P <.001 vsClop 300 mg/75 mg 75 mg Inhibition of Platelet Aggregation (%) 40 † 300 mg ADP=adenosine diphosphateClop=clopidogrelPras=prasugrel 20 Clopidogrel Clopidogrel The 600 mg LD of clopidogrelis an off-label dosage 0 Prasugrel 1 2 3 4 5 6 2 3 4 5 6 7 8 9 Jakubowski et al. Cardiovasc Drug Rev 2007;25:357-374.

  10. Study Design and Efficacy End Points R TRITON TIMI 38 Prasugrel 60 mg LD/ 10 mg MD ASA UA/NSTEMI (TIMI Risk Score ≥ 3) & Planned PCI Double-blind treatment 6 - 15 months planned follow-up 14.5 month actual median STEMI (Primary PCI ≤ 12 hours of symptoms or post-STEMI within 14 days) ASA Clopidogrel 300 mg LD/ 75 mg MD Day 3 Day 30 Day 90 Day 450 Primary efficacy end point: a composite of the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke = Key secondary end points at 30 and 90 days included primary efficacy end point and a composite of the rate of death from cardiovascular causes, nonfatal MI, or UTVR = Key safety end point: non-CABG related TIMI Major Bleeding ASA=Acetylsalicylic Acid; CABG=Coronary Artery Bypass Graft; LD=Loading Dose; MD=Maintenance Dose; MI=Myocardial Infarction; NSTEMI=Non-ST-Elevation Myocardial Infarction; PCI=Percutaneous Coronary Intervention; R=Randomization; STEMI=ST-Elevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable Angina; UTVR=Urgent Target Vessel Revascularization Wiviott SD et al. Am Heart J 2006;152:627-635 Wiviott SD et al. NEJM 2007;357:2001-2015

  11. Key Enrollment Criteria TRITON TIMI 38 Inclusion Criteria • Moderate-high risk ACS patients with planned PCI: • UA/NSTEMI (TIMI Risk Score ≥ 3) within 72 hours of symptom onset • STEMI: Primary PCI (within 12 hours) • STEMI: Primary PCI not planned (> 12 hours to ≤ 14 days) Exclusion Criteria • Any thienopyridine within 5 days of randomization • Daily treatment with NSAID or Cox-2 inhibitor • Fibrin-specific fibrinolytic therapy < 24 hours • Increased bleeding risk • History of hemorrhagic stroke; or ischemic stroke ≤ 3 months ACS=Acute Coronary Syndrome; NSTEMI=Non-ST-Elevation Myocardial Infarction; PCI=Percutaneous Coronary Intervention; STEMI=ST-Elevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable Angina; NSAID=Non-steroidal Anti-Inflammatory Drug Wiviott SD et al. Am Heart J 2006;152:627-635

  12. Baseline Characteristics TRITON TIMI 38 *P = 0.02 NSTEMI=Non-ST-Elevation Myocardial Infarction; STEMI=ST-Elevation Myocardial Infarction; UA=Unstable Angina 1Wiviott SD et al. NEJM 2007;357:2001-2015 2Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL

  13. Medical History TRITON TIMI 38 CABG=Coronary Artery Bypass Graft Wiviott SD et al. NEJM 2007;357:2001-2015

  14. Index Procedure TRITON TIMI 38 BMS=Bare-Metal Stent; Bival=Bivalirudin; CABG=Coronary Artery Bypass Graft; DES=Drug-Eluting Stent; GP=Glycoprotein; LMWH=Low Molecular Weight Heparin; PCI=Percutaneous Coronary Intervention; UFH=Unfractionated Heparin Wiviott SD et al. NEJM 2007;357:2001-2015

  15. Study Drug and Pharmacotherapies TRITON TIMI 38 *P = 0.03; PCI=Percutaneous Coronary Intervention Wiviott SD et al. NEJM 2007;357:2001-2015

  16. Primary Efficacy End Point TRITON TIMI 38 15 HR 0.77 (0.67-0.88)P < 0.001 12.1(781) Clopidogrel 9.9 (643) 10 Prasugrel Composite of CV Death, MI, Stroke (%) HR 0.81 (0.73-0.90)P < 0.001 HR 0.80 (0.71-0.90)P < 0.001 5 ARR = 2.2% NNT = 46 Intent To Treat = 13,608; Lost to Follow-Up = 14 (0.1%) 0 0 30 60 90 180 270 360 450 Days After Randomization Cumulative Kaplan-Meier estimates of HR and the rates of key study end points during the follow-up period; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT=Number Needed to Treat; ARR=Absolute Risk Reduction Wiviott SD et al. NEJM 2007;357:2001-2015

  17. Landmark Analysis for Primary Efficacy End Point – 3 day TRITON TIMI 38 8 6.9 5.6 5.6 Clopidogrel 6 Clopidogrel 4.7 Composite of CV Death, MI, Stroke (%) 4 Prasugrel Prasugrel 2 HR 0.80 (0.70-0.93)P = 0.003 HR 0.82 (0.71-0.96)P = 0.01 0 3 30 90 180 270 360 450 0 1 2 3 Days after Randomization Days after Randomization Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction Wiviott SD et al. NEJM 2007;357:2001-2015

  18. TRITON TIMI 38 Timing of Benefit: Primary Efficacy End Point (CV Death, MI, or Stroke) 30-Day Landmark Analysis 8 Clopidogrel 7.4 6 5.3 5.7 Prasugrel Clopidogrel 4.5 Primary End Point (%) 4 Prasugrel 2 HR 0.77P = 0.0001 HR 0.87P = 0.089 0 10 5 15 20 25 30 30 60 90 180 270 360 450 0 Early Benefit Late Benefit Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. Trial not powered for the 30-day landmark analyses. CV=Cardiovascular; HR=Hazard Ratio; MI=Non-fatal Myocardial Infarction Days Antman EM 40th Annual NY Symposium; 2007,Dec; New York, NY

  19. End Point (%) Major Efficacy End Points: Overall Cohort at 15 Months TRITON TIMI 38 HR 0.76 P < 0.001 (n=6,795) (n=6,813) HR 0.66 P < 0.001 HR 0.95 P = 0.64 HR 0.89 P = 0.31 HR 0.48 P < 0.001 HR 1.02 P = 0.93 UTVR CV Death All Cause Death Stent Thrombosis Nonfatal Stroke Nonfatal MI HR based on Kaplan-Meier estimates at 15 months; HR=Hazard Ratio; CV=Cardiovascular; MI=Myocardial Infarction; UTVR=Urgent Target Vessel Revascularization Wiviott SD et al. NEJM 2007;357:2001-2015

  20. Prasugrel vs. Clopidogrel: Greater Efficacy in ACS Patients with Planned PCI TRITON TIMI 38 ACS=Acute Coronary Syndrome; CV=Cardiovascular; MI=Myocardial Infarction; PCI=Percutaneous Coronary Intervention Wiviott SD et al. NEJM 2007;357:2001-2015

  21. All ACS Cohort for Follow-up Duration for Major Efficacy End Points* TRITON TIMI 38 P value Risk Reduction % Primary Endpoint 19 < 0.001 CV Death 11 0.31 Nonfatal MI 24 < 0.001 Nonfatal Stroke - 0.93 All cause death 5 0.64 19 < 0.001 CV death / MI / UTVR All cause death / Nonfatal MI / Nonfatal Stroke 17 < 0.001 UTVR 34 < 0.001 CV death / Nonfatal MI / Nonfatal Stroke/ Rehospitalization** 16 < 0.001 Stent thrombosis 52 < 0.001 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 HR Prasugrel Better Clopidogrel Better *Kaplan-Meier Estimates of the rate of the end point at 15 months; **Rehospitalization for ischemia; ACS=Acute Coronary Syndrome; CV=Cardiovascular; MI=Myocardial Infarction; NF=Nonfatal; UTVR=Urgent Target Vessel Revascularization Wiviott SD et al. NEJM 2007;357:2001-2015

  22. Methods: ESC/ACC MI Classification TRITON-TIMI 38 Universal MI Classification • Classification of each MI endpoint (N = 1,218) by reviewers blinded to treatment allocation. • Classification by ESC/ACC MI Type • Type 1: Spontaneous MI • Type 2: Secondary MI • Type 3: SCD due to MI (no biomarkers available) • Type 4a: Peri-PCI • Type 4b: Confirmed stent thrombosis (angio/autopsy) • Type 5: Peri-CABG • Determination of peak CKMB and/or troponin concentration Morrow et al. Eur Heart J 2008; 29: Suppl 1: 746

  23. MI Endpoints Universal MI Classification TRITON-TIMI 38 Universal MI Classification N = 1,218 MI % of MIs Stent Thrombosis N =162 (Type 4b) Peri CABG N = 7 (Type 5) PCI Related N= 603 (Type 4a) Spont. N = 397 (Type 1) Secondary N = 43 (Type 2) SCD N = 6 (Type 3) Morrow et al. Eur Heart J 2008; 29: Suppl 1: 746

  24. TRITON-TIMI 38 Universal MI Classification MI Endpoints: Peak Biomarker N = 1,159 MI with CKMB/cTn data N = 108 N = 69 N = 211 N = 331 N = 440 Morrow et al. Eur Heart J 2008; 29: Suppl 1: 746

  25. Efficacy Analysis: Spontaneous (Type 1) MI TRITON-TIMI 38 Universal MI Classification 5 29% RRR P = 0.0015 4 Clopidogrel 3.4% 3 Cumulative Incidence (%) 2 Prasugrel 2.5% 1 0 0 90 180 270 360 450 Days from randomization Morrow et al. Eur Heart J 2008; 29: Suppl 1: 746

  26. Efficacy Analysis: Procedural MI (Type 4/5) TRITON-TIMI 38 Universal MI Classification 8 Clopidogrel 6.4% 6 Prasugrel 4.9% Cumulative Incidence (%) 4 2 24% HRR P = 0.0002 0 0 90 180 270 360 450 Days from randomization Morrow et al. Eur Heart J 2008; 29: Suppl 1: 746

  27. TRITON-TIMI 38 Universal MI Classification Efficacy Analysis by Universal MI Classification HRR 29%↓ 18%↓ 24%↓ -- -- P 0.0015 0.53 <0.0001 CLOPIDOGREL PRASUGREL 4a Cumulative Incidence (%) 4a 1.7 0.8 4b 4b Spont. Secondary SCD PCI-related Peri-CABG Morrow et al. Eur Heart J 2008; 29: Suppl 1: 746

  28. TRITON-TIMI 38 Universal MI Classification Efficacy Analysis: Peak Biomarker HRR 24%↓ 22%↓ 15%↓ 27%↓ 26%↓ P 0.17 0.33 0.20 0.0077 0.0019 Morrow et al. Eur Heart J 2008; 29: Suppl 1: 746

  29. TRITON-TIMI 38 Universal MI Classification HRR 52%↓ 23%↓ 16%↓ 56%↓ P 0.010 0.016 0.023 <0.0001 Efficacy Analysis by STEMI vs. NSTEMI Non-procedural (Type 1-3) Procedural (Type 4-5) Morrow et al. Eur Heart J 2008; 29: Suppl 1: 746

  30. TRITON TIMI 38 LD/MD Effect: Myocardial Infarction 3-Day Landmark Analysis 6 5.2 Clopidogrel 4.8 4 Clopidogrel Prasugrel 4.3 Myocardial Infarction (%) 3.4 Prasugrel 2 HR 0.81P = 0.008 HR 0.69P < 0.0001 0 3 1 2 3 30 60 90 180 270 360 450 0 Loading Dose Maintenance Dose Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. HR=Hazard Ratio; LD=Loading Dose; MD=Maintenance Dose Days Antman et al. JACC 2008;51:2028-2033

  31. TRITON TIMI 38 Timing of Benefit: Myocardial Infarction 8 6 4 2 0 0 5 10 15 20 25 30 30 60 90 180 270 360 450 30-Day Landmark Analysis 6.4 Clopidogrel HR 0.77P = 0.01 4.8 3.7 Prasugrel Myocardial Infarction (%) Clopidogrel 2.9 HR 0.74P = 0.0001 Prasugrel Early Benefit Late Benefit Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. Trial not powered for the 30 day landmark analyses. HR=Hazard Ratio Days Antman EM 40th Annual NY Symposium; 2007,Dec; New York, NY

  32. TRITON TIMI 38 Overall: Stent Thrombosis (ARC Definite or Probable) 3 2 1 0 0 30 60 90 180 270 360 450 Any Stent at Index PCI n = 12,844 2.4 (n = 142) Clopidogrel 1.1 (n = 68) Stent Thrombosis (%) Prasugrel HR 0.48 (0.36-0.64)P < 0.0001 NNT = 77 Days HR based on Kaplan-Meier estimates at 15 months. ARC=Academic Research Consortium; HR=Hazard Ratio; NNT=Number Needed to Treat; PCI=Percutaneous Coronary Intervention Wiviott et al. Lancet 2008:371:1353-1363

  33. TRITON TIMI 38 LD/MD Effect: Stent Thrombosis (ARC Definite or Probable) 3 2 1 0 3-Day Landmark Analysis Loading Dose Maintenance Dose HR 0.49P = 0.006 HR 0.45P < 0.0001 1.74 Clopidogrel Stent Thrombosis (%) 0.67 Clopidogrel 0.80 Prasugrel Prasugrel 0.33 0 1 2 3 30 60 90 180 270 360 450 3 Days Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period; ARC=Academic Research Consortium; HR=Hazard Ratio; LD=Loading Dose; MD=Maintenance Dose Antman et al. JACC 2008;51:2028-2033

  34. TRITON TIMI 38 Timing of Benefit: Stent Thrombosis(ARC Definite or Probable) 3 2 1 0 0 5 10 15 20 25 30 30 60 90 180 270 360 450 30-Day Landmark Analysis HR 0.60 (0.37-0.97)P = 0.03 HR 0.41 (0.29-0.59)P = 0.0001 1.56 Clopidogrel Stent Thrombosis (%) 0.82 Clopidogrel Prasugrel 0.64 0.49 Prasugrel Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. Trial not powered for the 30 day landmark analyses. ARC=Academic Research Consortium; HR=Hazard Ratio Early Benefit Late Benefit Days Wiviott et al. Lancet 2008:371:1353-1363

  35. TRITON TIMI 38 Overall: Stent Thrombosis with BMS(ARC Definite or Probable) 2.5 2.0 1.5 1.0 0.5 0.0 0 50 100 150 200 250 300 350 400 450 BMS at Index PCI n = 6,461 2.41 (n = 78) Clopidogrel BMS Thrombosis (%) 1.27 (n = 41) Prasugrel HR 0.52 (0.35-0.77) P = 0.0009 Days Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. BMS=Bare Metal Stent; HR=Hazard Ratio ARC=Academic Research Consortium Wiviott et al. Lancet 2008:371:1353-1363

  36. TRITON TIMI 38 Timing of Benefit: Stent Thrombosis with BMS(ARC Definite or Probable) 2.5 2.0 1.5 1.0 0.5 0.0 0 5 10 15 20 25 30 30-Day Landmark Analysis HR 0.45 (0.28-0.73) P = 0.001 HR 0.68 (0.35-1.31) P = 0.24 1.66 Clopidogrel BMS Thrombosis (%) 0.78 Clopidogrel 0.75 Prasugrel 0.53 Prasugrel 30 90 150 210 270 330 390 450 Early Benefit Late Benefit Days Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. Trial not powered for the 30 day landmark analyses. BMS=Bare Metal Stent; HR=Hazard Ratio; ARC=Academic Research Consortium Wiviott et al. Lancet 2008:371:1353-1363

  37. TRITON TIMI 38 Overall: Stent Thrombosis with DES(ARC Definite or Probable) 2.5 2.0 1.5 1.0 0.5 0.0 DES at Index PCI n = 5,743 2.31 (n = 29) Clopidogrel DES Thrombosis (%) 0.84 (n = 24) HR 0.36 (0.22-0.58) P < 0.0001 Prasugrel 50 100 150 200 250 300 350 400 450 0 Days Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. DES=Drug-Eluting Stent; HR=Hazard Ratio ARC=Academic Research Consortium Wiviott et al. Lancet 2008:371:1353-1363

  38. TRITON TIMI 38 Timing of Benefit: Stent Thrombosis with DES(ARC Definite or Probable) 2.5 2.0 1.5 1.0 0.5 0.0 0 5 10 15 20 25 30 30-Day Landmark Analysis HR 0.29 (0.15-0.56) P < 0.0001 HR 0.46 (0.22-0.97) P = 0.04 1.44 Clopidogrel DES Thrombosis (%) 0.91 Clopidogrel 0.42 0.42 Prasugrel Prasugrel 30 90 150 210 270 330 390 450 Early Benefit Late Benefit Days Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. Trial not powered for the 30 day landmark analyses. DES=Drug-Eluting Stent; HR=Hazard Ratio; ARC=Academic Research Consortium Wiviott et al. Lancet 2008:371:1353-1363

  39. TRITON TIMI 38 Overall: Urgent Target Vessel Revascularization 6 4 2 0 0 30 60 90 180 270 360 450 HR 0.66P = 0.0001 3.7(n = 233) Clopidogrel UTVR (%) 2.5(n = 156) Prasugrel Days Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. UTVR=Urgent Target Vessel Revascularization; HR=Hazard Ratio. Antman EM 40th Annual NY Symposium; 2007,Dec; New York, NY

  40. TRITON TIMI 38 LD/MD Effect: UTVR 3 2 1 0 3-Day Landmark Analysis Loading Dose Maintenance Dose 2.97 HR 0.66P = 0.047 HR 0.65P = 0.0003 Clopidogrel UTVR (%) 1.94 Prasugrel 0.83 Clopidogrel 0.54 Prasugrel 0 30 60 90 180 270 360 450 1 2 3 3 Days Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. HR=Hazard Ratio; UTVR=Urgent Target Vessel Revascularization Antman et al. JACC 2008;51:2028-2033

  41. TRITON TIMI 38 Timing of Benefit: UTVR 3 2 1 0 30-Day Landmark Analysis HR 0.79P = 0.07 HR 0.53P = 0.0001 2.16 1.62 Clopidogrel Clopidogrel UTVR (%) 1.66 Prasugrel 0.86 Prasugrel 0 5 10 15 20 25 30 30 60 90 180 270 360 450 Early Benefit Late Benefit Days Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. Trial not powered for the 30 day landmark analyses. HR=Hazard Ratio; UTVR=Urgent Target Vessel Revascularization Antman EM 40th Annual NY Symposium; 2007,Dec; New York, NY

  42. Rates of Key Study End Points TRITON TIMI 38 15 Clopidogrel 12.1(781) Prasugrel CV Death, MI, Stroke 9.9 (643) 10 P < 0.001 ↓138 events End Point (%) ↑ 35 events 5 P = 0.03 Non-CABG TIMI Major Bleeds 2.4 (146) 1.8 (111) 0 0 30 60 90 180 270 360 450 120 Days After Randomization Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period; CABG=Coronary Artery Bypass Graft; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. NEJM 2007;357:2001-2015

  43. TRITON TIMI 38 LD/MD Effect: Non-CABG TIMI Major Bleed 3 2 1 0 0 1 2 3 30 60 90 180 270 360 450 3-Day Landmark Analysis Loading Dose Maintenance Dose HR 1.39P = 0.036 HR 1.22P = 0.35 1.71 Non-CABG TIMI Major Bleed (%) Prasugrel 0.74 1.23 Prasugrel Clopidogrel 0.61 Clopidogrel 3 Days Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. CABG=Coronary Artery Bypass Graft; HR=Hazard Ratio; LD=Loading Dose; MD=Maintenance Dose; TIMI=Thrombolysis In Myocardial Infarction Antman et al. JACC 2008;51:2028-2033

  44. TRITON TIMI 38 Early and Late Risk: Non-CABG TIMI Major Bleed 3 2 1 0 0 5 10 15 20 25 30 30 60 90 180 270 360 450 30-Day Landmark Analysis HR 1.19P = 0.34 HR 1.48P = 0.028 1.42 Non-CABG TIMI Major Bleed (%) 1.03 Prasugrel Prasugrel 0.97 0.87 Clopidogrel Clopidogrel Days Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. TRITON-TIMI 38 was not powered for the 30 day landmark analyses. CABG=Coronary Artery Bypass Graft; HR=Hazard Ratio; TIMI=Thrombolysis In Myocardial Infarction Antman EM 40th Annual NY Symposium; 2007,Dec; New York, NY

  45. TIMI Major Bleeds:Overall Cohort at 15 Months End Point (%) TRITON TIMI 38 P = 0.03 2.4% (n = 6,716) n=146 (n = 6,741) P = 0.01 1.8% 1.6% n=111 n=92 1.1% P = 0.45 n=61 0.7% 0.6% P = 0.51 n=45 n=38 0.2% 0.2% n=12 n=9 Non-CABG TIMI Major TIMI Major Spontaneous TIMI Major Trauma TIMI Major Related to Instrumentation Percentages based on Kaplan-Meier estimates at 15 months Subsets of Non-CABG TIMI Major CABG=Coronary Artery Bypass Graft;HR=Hazard Ratio; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. NEJM 2007;357:2001-2015

  46. Other TIMI Bleeds: Overall Cohort at 15 Months End Point (%) TRITON TIMI 38 Odds Ratio 4.73P < 0.001 13.4% (n=6,716) At risk 24/179 (n=6,741) P = 0.002 P < 0.001 5.0% 3.8% 4.0% n=303 3.2% 3.0% n=244 n=231 At risk 6/189 n=182 Requiring Transfusion CABG-related TIMI Major Bleeding TIMI Major or Minor Percentages based on Kaplan-Meier estimates at 15 months CABG=Coronary Artery Bypass Graft;HR=Hazard Ratio; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. NEJM 2007;357:2001-2015

  47. Life Threatening Bleeds: Overall Cohort at 15 Months TRITON TIMI 38 (n=6,716) (n=6,741) P = 0.01 P = 0.23 1.4% End Point (%) n=85 1.1% 0.9% 0.9% n=64 P = 0.002 n=56 n=51 P = 0.74 0.4% 0.3% 0.3% n=21 0.1% n=19 n=17 n=5 Nonfatal Life-Threatening Fatal Intracranial Subsets of Life threatening Percentages based on Kaplan-Meier estimates at 15 months; HR=Hazard Ratio Wiviott SD et al. NEJM 2007;357:2001-2015

  48. CABG-related TIMI Major or Minor Bleeding Among Prasugrel-treated Patients1

  49. Study Drug Discontinuation Rates and Non-hemorrhagic Serious Adverse Events TRITON TIMI 38 • *Gastrointestinal bleeding preceded diagnosis for 7 prasugrel and 2 clopidogrel cases • † Numbers in parenthesis are numbers of patients where event rates are < 1% Wiviott SD et al. NEJM 2007;357:2001-2015

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