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TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet InhibitioN with Prasugrel TRITON-TIMI 38 TRITON-TIMI 38 Elliott M. Antman, MD Elliott M. Antman, MD TRITON-TIMI 38 was supported by Eli Lilly and Daiichi Sankyo. TRITON-TIMI 38 was supported by Eli Lilly and Daiichi Sankyo.

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

Text of TRITON-TIMI 38 Elliott M. Antman, MD

  • 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 the subjects were treated with a GP 2b3a inhibitor during the index PCI

    About 25% received the LD prior to PCI , about 74 % during PCI, and 1% after PCI*The findings for the primary end point are shown here.

    PRASUGREL REDUCED THE PRIMARY ENDPINT OF CVDeath /MI/ or stroke from 12.1 % in the clopidogrel group to 9.9% over a median FU of 15 months.

    This 2.2% absolute risk reduction represented a prevention of 138 events with prasugrel and a 19% reduction in the HR with P =0.0004.

    Significant benefit in favor of prasugrel was already evident at 30 and 90 Days (Point)

    ***To evaluate the impact of the LD and MD of prasugrel we performed a landmark analysis of events through 3 days, and from 3 days to the end of the study.As you can see PRASUGREL REDUCED THE PRIMARY ENDPOINT by 18% through 3 days and by 20% from 3 days to the end of the study suggesting that there was a significant benefit of prasugrel compared clopidogrel during both the LD and MD phases of treatment.

    ****This slide depicts the balance of efficacy and safety observed in the trial.At the top is shown the significant reduction in the primary endpoint as presented a few moments ago. The number needed to treat to prevent one event was 46At the bottom is the rate of TIMI major non CABG bleeds--a key safety endpoint-- which was 2.4% with prasugrel and 1.8% with clopidogrela 0.6% Absolute risk increase. The excess of 35 major bleeds with prasugrel corresponded to an HR of 1.32 and P value of 0.03 . The number of subjects who would need to be treated to result in one excess major bleed (NNH) was 167.

    **More details of the bleeding events are shown on this slide.The TIMI major non CABG bleed data are shown in the pair of bar graphs on the left, showing the increase in events with prasugrel

    Life threatening bleeding--another key safety EP ( defined as requiring a 4 unit txn, fluid or inotropic support, surgical intervention, or an ICH) occurred in 0.9 % of clopidogrel and 1.4% of prasugrel subjectsa 0.5% ARI with prasugrel, associated with a P value of 0.01

    Subcategories of life threatening bleeding are shown to the right.

    Fatal bleeding occurred in 0.1% of pts with clopidogrel and was increased to 0.4% of patients with prasugrela 0.3% Absolute risk increase associated with a P value of 0.002.

    There was no difference in ICH overall in the trialoccurring in 0.3% of pts in both groups.Of note, in the subgroup of 518 patients with a history of prior stroke or TIA, no ICHs occurred with clopidogrel while 6 occurred with prasugrela significant difference at the 0.02 level.

    *The balance of efficacy and safety was assessed using a prespecified net clinical benefit composite endpoint of:All cause Death / MI / Stroke/ or Major bleed Through the end of the study this occurred in 13.9% of clopidogrel and 12.2% of prasugrel patients. 109 events were prevented with prasugrel corresponding to a 13% reduction in the HR with P =0.004.

    There was no difference in all cause mortality.(ANIMATE)We estimate that, on average, for every 1000 patients treated with prasugrel compared with clopidogrel 23 MI s would be prevented and 6 more major bleeds would occur.

    *The beneficial effect of prasugrel on the primary end point was consistent across key prespecified major subgroups. Notable observations include:A significant benefit in both the UA/NSTEMI and STEMI cohortsThere was a consistent reduction in events with prasugrel in men and women, pts with and without diabetes, those treated with either a BMS or DESwhether or not a GPI was administered and regardless of the degree of renal function All P values in tests for interaction for the subgroups described were negative.

    Not depicted on the slide are the data showing a reduction in events with prasugrel regardless of the timing of the LD

    **As a result of the discordance between efficacy and safety with prasugrel signficant reductions in events at the cost of a significant increase in bleeding we performed a series of post-hoc exploratory analyses to identify subgroups of patients that did not have a favorable net clinical benefit or who had net harm.

    The group with a prior cerebrovascular event (shown in red) had more primary endpoint events and increased bleeding with prasugrel, resulting in a significant net clinical benefit favoring clopidogrel. Patients without a prior cerebrovascular event, shown in green, had a net clinical benefit favoring prasugrel. The P value for interaction was significant at 0.006.

    Elderly patients and those with a low body weight (shown in yellow) tended to have better efficacy but more bleeding with prasugrel, resulting in a net clinical benefit near unity. The younger patients and those with higher body weights (shown in green) had siginificant net clinical benefit favoring prasugrel. The interaction P values for the elderly and low weight patients did not reach statistical significance.**On the basis of these observations we have formulated several potential therapeutic considerations.

    1. The 4% of patients with a prior stroke, shown in red are at increased risk for bleeding and had worse outcomes--they should not receive prasugrel2.Patients age >= 75 or with a weight < 60 kg, shown in yellow and representing 16% of the trial may benefit from a reduced MD to minimize bleeding.3.The 80% of remaining patients had a significant net clinical benefit with prasugrel at 10 mg MD.*We draw the following conclusions with respect to a test of a regimen producing higher IPA to support PCI.

    *This slide places our findings in the context of prior studies of antiplatelet therapy in ACS.

    The introduction of single antiplatelet therapy with aspirin, as summarized in the APTC report, was associated with a 22% reduction in ischemic events. Moving to dual antiplatelet therapy with clopidogrel + aspirin in CURE produced a further 20% reduction in ischemic events. The higher IPA achieved with the combination of prasugrel and aspirin produced yet a further 19% reduction in ischemic events.

    Each of these advances in antiplatelet therapy was associated with a progressive increase in major bleeds as depicted in the red bars along the bottom.

    In each case, as with TRITON-TIMI 38, the absolute reduction in ischemic events was greater than the increase in major bleeds, resulting in net clinical benefit with increasingly potent oral antiplatelet regimens.