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TRITON-TIMI 38 Elliott M. Antman, MD PowerPoint Presentation
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TRITON-TIMI 38 Elliott M. Antman, MD

TRITON-TIMI 38 Elliott M. Antman, MD

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TRITON-TIMI 38 Elliott M. Antman, MD

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  1. TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel 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 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. 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.

  4. Study Design Wiviott SD et al AHJ 152: 627,2006 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

  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 KnownAnatomy Wiviott SD et al AHJ 152: 627,2006

  6. Baseline Characteristics Wiviott SD et al NEJM 357: 2001, 2007 *P<0.05

  7. Index Procedure Wiviott SD et al NEJM 357: 2001, 2007

  8. Primary EndpointCV Death,MI,Stroke 15 Clopidogrel 12.1(781) 9.9 (643) 10 Prasugrel Primary Endpoint (%) 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 Wiviott SD et al NEJM 357: 2001, 2007

  9. 10 Endpoint Events PreventedPost-hoc Analysis Total EventsP<0.0001 896 -195 701 AdditionalEvents # Events 1st EventP=0.0004 -138 Clopidogrel Prasugrel 6/189 25/180 ITT N= 13,608 TIMI Study Group, Data on File

  10. CV Death,MI,StrokeTiming of LD 0.87 (0.71-1.07) Pre PCI (N=3370) 0.93 (0.73-1.19) During PCI (N=2380) Post PCI in lab (N=3833) 0.76 (0.62-0.93) < 1 hr post lab (N=3552) 0.75 (0.60-0.93) 0.5 1 2 Clopidogrel Better Prasugrel Better Pint = 0.40 HR TIMI Study Group, Data on File

  11. Timing of Benefit(Landmark Analysis - 3 days) 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

  12. Components of Endpoints Clopidogrel Prasugrel HR 0.81 12.1 9.9 CV Death, MI, Stroke 0.89 2.1 2.4 CV Death 0.76 9.5 7.3 Nonfatal MI 1.02 1.0 1.0 Nonfatal Stroke 0.95 3.2 3.0 All Cause Mortality 0.66 3.7 2.5 uTVR Stent Thrombosis 2.4 1.1 0.48 0.5 1 2 Prasugrel Better Clopidogrel Better HR Wiviott SD et al NEJM 357: 2001, 2007

  13. Myocardial Infarction 0 - 450 days 9.7 Clopidogrel 10 8 7.4 Prasugrel MI (%) 6 HR 0.76P<0.0001 Significant reductions in :Landmark Analyses at 3, 30 daysPeri-Procedural MI’s Spontaneous MI’s during followupNew development of STEMICV Death after MI 4 2 0 0 30 60 90 180 270 360 450 Days TIMI Study Group-- Data on file

  14. Urgent Target Vessel Revascularization 6 ITT= 13,608 3.7(233) Clopidogrel 4 Endpoint (%) 2.5 (156) 2 Prasugrel HR 0.66P=0.0001 Reductions in uTVR with Prasugrel in Landmark Analyses at 3, 30 days NNT= 83 0 0 30 60 90 180 270 360 450 Days Wiviott SD et al NEJM 357: 2001, 2007

  15. 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 Significant reductions both with BMS, DES Significant reductions in early and late stent thromboses NNT= 77 0 0 30 60 90 180 270 360 450 Days Wiviott SD et al NEJM 357: 2001, 2007

  16. 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 Wiviott SD et al NEJM 357: 2001, 2007

  17. 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 Wiviott SD et al NEJM 357: 2001, 2007

  18. 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 Wiviott SD et al NEJM 357: 2001, 2007

  19. 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 Wiviott SD et al NEJM 357: 2001, 2007

  20. 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 Wiviott SD et al NEJM 357: 2001, 2007

  21. Net Clinical BenefitBleeding Risk Subgroups Post-hoc analysis Risk (%) + 54 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 Wiviott SD et al NEJM 357: 2001, 2007

  22. 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 Wiviott SD et al NEJM 357: 2001, 2007

  23. Dose Reduction for Patients <60kg or ≥75 yrs DecreasedRisk Decreased Exposure Risk of Bleeding 1 0 0 Clopidogrel Maintain PD> Clopidogrel 8 0 Concentration Prasugrel 6 0 MPA 4 0 2 0 0 Time 0 5 0 1 0 0 1 5 0 2 0 0 2 5 0 3 0 0 A U C ( n g * h r / m L ) RetainEfficacy Efficacy AUC

  24. 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 Wiviott SD et al NEJM 357: 2001, 2007

  25. Wiviott SD et al NEJM 357: 2001, 2007 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