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TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel

TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel. TRITON-TIMI 38 AHA 2007 Orlando, Florida.

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TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel

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  1. TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel TRITON-TIMI 38AHA 2007Orlando, 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 VolunteerCrossover Study 100 N=66 80 InterpatientVariability 60 IPA at 24 hours (%) 40 InterpatientVariability 20 Clopidogrel Responder 0 Clopidogrel Non-responder -20 Response to Prasugrel 60 mg Response to Clopidogrel 300 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

  6. 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 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 bleedsKey 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 KnownAnatomy

  8. Enrollment: Nov 2004 - Jan 2007N = 13,608 (ITT) 30 Countries 707 Sites LTFU = 14 (0.1%)

  9. Baseline Characteristics *P<0.05

  10. Index Procedure

  11. Primary EndpointCV 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 0.80P=0.0003 HR 0.77P=0.0001 5 NNT= 46 LTFU = 14 (0.1%) ITT= 13,608 0 0 30 60 90 180 270 360 450 Days

  12. Timing of Benefit(Landmark Analysis) 8 6.9 Clopidogrel Clopidogrel 5.6 5.6 6 Primary Endpoint (%) 4.7 4 Prasugrel Prasugrel HR 0.82P=0.01 HR 0.80P=0.003 2 1 0 0 1 2 3 0 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 0.48P <0.0001 NNT= 77 0 0 30 60 90 180 270 360 450 Days

  14. Balance of Efficacy and Safety 15 138 events Clopidogrel HR 0.81(0.73-0.90)P=0.0004 12.1 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 0 NNH = 167 0 30 60 90 180 270 360 450 Days

  15. Bleeding EventsSafety 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 1.32P=0.03NNH=167 ARD 0.5%HR 1.52P=0.01 ARD 0.2%P=0.23 ARD 0.3%P=0.002 ARD 0%P=0.74

  16. Net Clinical BenefitDeath, MI, Stroke, Major Bleed (non CABG) Events per 1000 pts + Major Bleed(non CABG) MI 15 Clopidogrel 13.9 ITT= 13,608 12.2 HR 0.87P=0.004 Prasugrel 10 Endpoint (%) All CauseMortality 5 Clop 3.2%Pras 3.0 %P=0.64 0 0 30 60 90 180 270 360 450 Days

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

  18. Diabetic Subgroup N=3146 18 Clopidogrel 17.0 16 CV Death / MI / Stroke 14 12.2 12 HR 0.70P<0.001 Endpoint (%) Prasugrel 10 NNT = 21 8 6 TIMI Major NonCABG Bleeds Clopidogrel 4 2.6 2.5 2 Prasugrel 0 0 30 60 90 180 270 360 450 Days

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

  20. Bleeding Risk SubgroupsTherapeutic Considerations Reduced MDGuided by PKAge > 75 or Wt < 60 kg Avoid PrasugrelPrior CVA/TIA 16% 4% Significant Net Clinical Benefit with Prasugrel80% MD 10 mg

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

  22. ConclusionsHigher IPA to Support PCI Efficacy 1. A significant reduction in: CV Death/MI/Stroke19% Stent Thrombosis 52% uTVR 34%       MI 24% 2. An early and sustained benefit 3. Across ACS spectrum Safety Significant increase in serious bleeding(32%increase)Avoid in pts with prior CVA/TIA Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD 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 Reduction inIschemicEvents - 22% - 20% - 19% Increase in Major Bleeds + 32% + 38% + 60% Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA

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

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