triton-timi 38 elliott m. antman, md

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TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel. TRITON-TIMI 38 Elliott M. Antman, MD. TRITON-TIMI 38 was supported by Eli Lilly and Daiichi Sankyo. Antiplatelet Therapy for PCI. - PowerPoint PPT Presentation


  • TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with PrasugrelTRITON-TIMI 38 Elliott M. Antman, MD

    TRITON-TIMI 38 was supported by Eli Lilly and Daiichi Sankyo.

  • Antiplatelet Therapy for PCIDual antiplatelet Rx (ASA + thienopyridine) is standard of care: Ticlopidine ClopidogrelClinical need to improve on benefits observed with clopidogrelPrasugrel Novel thienopyridine Efficient generation of active metabolite High levels of IPA achieved rapidly High IPA in clopidogrel hyporesponders Encouraging Phase 2 data

  • Study GoalsTo 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.

  • Study DesignDouble-blindACS (STEMI or UA/NSTEMI) & Planned PCIASAPRASUGREL60 mg LD/ 10 mg MDCLOPIDOGREL300 mg LD/ 75 mg MD1o endpoint: CV death, MI, Stroke2o endpoints:CV death, MI, Stroke, Rehosp-Rec IschCV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies:Pharmacokinetic, GenomicMedian duration of therapy - 12 monthsN= 13,600Wiviott SD et al AHJ 152: 627,2006

  • Enrollment CriteriaInclusion Criteria Planned PCI for : Mod-High Risk UA/NSTEMI (TRS > 3) STEMI: < 14 days (ischemia or Rx strategy) STEMI: Primary PCIMajor Exclusion Criteria:Severe comorbidityIncreased bleeding riskPrior hemorrhagic stroke or any stroke < 3 mosAny thienopyridine within 5 daysNo exclusion for advanced age or renal function

    Known AnatomyWiviott SD et al AHJ 152: 627,2006

  • Baseline Characteristics*P 75 y61 (53,69) y1361 (53, 70) y13Wgt, median (IQR) < 60 kg83 kg (72, 92) 5.384 kg (73, 93) 4.6Female2725*Diabetes2323Prior MI1818CrCl (ml/min) >60
  • Index ProcedureWiviott SD et al NEJM 357: 2001, 2007

    Clopidogrel (N=6795) %Prasugrel (N=6813) %PCI / CABG99 / 199 / 1Any Stent9594BMS4748DES4747Multivessel PCI1414UFH / LMWH / Bival65 / 8 / 366 / 9 / 3GP IIb/IIIa5554LD of Study Rx Pre PCI During PCI Post PCI 25 74 1 26 73 1

  • 0510150306090180270360450HR 0.81 (0.73-0.90) P=0.0004Prasugrel ClopidogrelHR 0.80 P=0.0003HR 0.77 P=0.0001Days Primary Endpoint (%)12.1 (781)9.9 (643)Primary Endpoint CV Death,MI,StrokeNNT= 46ITT= 13,608LTFU = 14 (0.1%)Wiviott SD et al NEJM 357: 2001, 2007

  • 10 Endpoint Events PreventedPost-hoc Analysis # Events25/180 6/189 896701ClopidogrelPrasugrel 1st Event P=0.0004Additional EventsTotal Events P
  • CV Death,MI,StrokeTiming of LD < 1 hr post lab (N=3552)Post PCI in lab (N=3833)During PCI (N=2380)Pre PCI (N=3370)0.512Prasugrel BetterClopidogrel BetterHR0.75 (0.60-0.93)0.76 (0.62-0.93)0.93 (0.73-1.19)0.87 (0.71-1.07)Pint = 0.40TIMI Study Group, Data on File

  • 02468012310306090180270360450HR 0.82 P=0.01HR 0.80 P=0.0035. Primary Endpoint (%)Prasugrel ClopidogrelPrasugrel ClopidogrelLoading DoseMaintenance DoseTiming of Benefit (Landmark Analysis - 3 days)

  • Components of Endpoints ClopidogrelHRPrasugrel12.10.819.92.40.892.19.50.767. uTVRNonfatal StrokeNonfatal MICV DeathCV Death, MI, Stroke0.5123.70.662.5Prasugrel BetterClopidogrel BetterAll Cause Mortality3.20.953.0Stent Thrombosis2.40.481.1HRWiviott SD et al NEJM 357: 2001, 2007

  • Myocardial Infarction 0 - 450 days 02468100306090180270360450Days MI (%)Prasugrel Clopidogrel9.77.4HR 0.76 P
  • Urgent Target Vessel Revascularization 02460306090180270360450HR 0.66 P=0.0001Prasugrel ClopidogrelDaysEndpoint (%)3.7 (233)NNT= 832.5 (156)ITT= 13,608Wiviott SD et al NEJM 357: 2001, 2007Reductions in uTVR with Prasugrel in Landmark Analyses at 3, 30 days

  • Stent Thrombosis(ARC Definite + Probable) 01230306090180270360450HR 0.48 P
  • 0510150306090180270360450HR 0.81 (0.73-0.90) P=0.0004Prasugrel ClopidogrelDaysEndpoint (%)12.19.9HR 1.32 (1.03-1.68) P=0.03Prasugrel Clopidogrel1.82.4 138 events 35 events Balance of Efficacy and SafetyCV Death / MI / StrokeTIMI Major NonCABG Bleeds NNT = 46 NNH = 167Wiviott SD et al NEJM 357: 2001, 2007

  • Bleeding EventsSafety Cohort(N=13,457)% EventsARD 0.6% HR 1.32 P=0.03 NNH=167 ClopidogrelPrasugrelARD 0.5% HR 1.52 P=0.01 ARD 0.2% P=0.23 ARD 0% P=0.74 ARD 0.3% P=0.002 ICH in Pts w Prior Stroke/TIA (N=518)Clop 0 (0) % Pras 6 (2.3)% (P=0.02) Wiviott SD et al NEJM 357: 2001, 2007

  • Net Clinical BenefitDeath, MI, Stroke, Major Bleed (non CABG) 0510150306090180270360450DaysEndpoint (%)HR 0.87 P=0.00413.912.2 Prasugrel ClopidogrelITT= 13,608All Cause MortalityClop 3.2% Pras 3.0 % P=0.64Wiviott SD et al NEJM 357: 2001, 2007

  • BOVERALLNo GPIGPIDESBMSDMNo DM>7565-74 60CrCl < 601420Wiviott SD et al NEJM 357: 2001, 2007

  • Diabetic Subgroup 0246810121416180306090180270360450HR 0.70 P
  • Net Clinical BenefitBleeding Risk Subgroups OVERALL>=60 kg< 60 kg< 75>=75NoYes0.512Prior Stroke / TIAAgeWgtRisk (%)+ 54-16-1-16+3-14-13Prasugrel BetterClopidogrel BetterHRPint = 0.006Pint = 0.18Pint = 0.36Post-hoc analysisWiviott SD et al NEJM 357: 2001, 2007

  • Bleeding Risk SubgroupsTherapeutic ConsiderationsSignificant Net Clinical Benefit with Prasugrel 80%MD 10 mgReduced MD Guided by PK Age > 75 or Wt < 60 kg16%Avoid Prasugrel Prior CVA/TIA4%Wiviott SD et al NEJM 357: 2001, 2007






    Age >=75Wgt < 60 kgNo Bleeding Risks


  • Dose Reduction for Patients ClopidogrelClopidogrelPrasugrel

  • Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MDConclusionsHigher IPA to Support PCINet clinical benefit significantly favored PrasugrelOptimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balanceWiviott SD et al NEJM 357: 2001, 2007

  • Antiplatelet Therapy in ACSSingle Antiplatelet RxDual Antiplatelet RxHigher IPAASAASA + ClopidogrelASA + Prasugrel- 22%- 20%- 19%+ 60%+ 38%+ 32%Reduction in Ischemic EventsIncrease in Major BleedsWiviott SD et al NEJM 357: 2001, 2007

    *Dr. ____Dr.____

    It is an honor and a privilege for me to present the primary results of this study on behalf of the TRITON-TIMI 38 investigators.

    This study was supported by a grant to the Brigham and Womens Hospital from Daiichi Sankyo and Eli Lilly.

    * Dual antiplatelet therapy using aspirin and a thienopyridine is the standard of care for pts undergoing PCI. Because of better tolerability, clopidogrel replaced ticlopidine as the preferred thienopyridine. While it is an effective drug, patients continue to have events and therefore there is a clinical need to improve on the benefits observed with clopidogrel

    Prasugrel is a novel, investigational thienopyridine As compared with clopidogrel there is more efficient generation of the active metabolite through prehepatic and hepatic pathways. As result of this more efficient metabolism: High levels of IPA are achieved rapidly with prasugrel even in clopidogrel hyporesponders Encouraging phase 2 data in stable CAD pts and those undergoing PCI(in the JUMBO-TIMI 26 trial) cemented the decision to move forward with a definitive trial comparing clinical outcomes in pts treated w prasugrel vs clopidogrel

    * Our primary hypothesis was that prasugrel + Aspirin is superior to clopidogrel + aspirin in preventing clinical events in moderate to high risk patients with ACS undergoing PCI.

    In addition, this is the first large-scale trial testing the hypothesis that higher and less variable IPA prevents clinical ischemic events.

    *Patients were candidates for the trial if they were moderate-high risk, had an acute coronary syndrome, and there was a plan to perform PCI. A sample size of 13, 600 was considered necessary to provide at least 90 % power to test the primary hypothesis All patients were to receive ASA.Randomization was stratified by UA/NSTEMI vs STEMIDB study drug therapy consisted either of - standard dosing with clopidogrel with a LD of 300 mg and MD of 75 mg- OR prasugrel with a LD of 60 mg and MD of 10 mgDB study drug was to be given for a median of at least 12 months with a minimum of 6 mos and maximum of 15 monthsThe primary composite EP was CV death, MI, or Stroke through the end of the studyKey secondary EPs are listed here and among these was Stent thrombosis Key safety Eps included: TIMI major (non CABG) bleeds, and life-threatening bleeds Two key substudies are evaluating pharmacokinetics and genomics

    *Since this was designed as a PCI trial it was a requirement that the coronary anatomy was known in the first 2 categories listed here:1. Moderate -high risk UA/NSTEMI pts who had a TIMI Risk Score >= 32. STEMI pts within 14 days of initial medical treatment who were referred for an interventional approach

    3. STEMI patients undergoing primary PCI could receive study drug before diagnostic angiography

    Patients with- severe comorbidity, - increased bleeding risk, -prior hem stroke or any stroke within 3 mos, -or any thienopyridine within the prior 5 days were excluded.

    There were no exclusions for advanced age or renal dysfunction.

    *The baseline characteristics were typical of contemporary trials of ACS and the treatment groups were well matched.

    of the subjects had UA/NSTEMI ; STEMI13% were >= 75 yrs oldAbout 5% weighed less than 60 kgJust over 10% had a CrCl < 60 ml/min

    *99% of subjects underwent PCI

    95% received at least one stent---roughly equally divided between BMS + DES

    Just over 50% of

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