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Vorapaxar for Secondary Prevention in Patients with Prior Myocardial Infarction

Vorapaxar for Secondary Prevention in Patients with Prior Myocardial Infarction . NCT00526474; Trial funded by Merck. Benjamin M. Scirica, MD, MPH On behalf of the TRA 2°P-TIMI 50 Steering Committee and Investigators.

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Vorapaxar for Secondary Prevention in Patients with Prior Myocardial Infarction

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  1. Vorapaxar for Secondary Prevention in Patients with Prior Myocardial Infarction NCT00526474; Trial funded by Merck Benjamin M. Scirica, MD, MPHOn behalf of the TRA 2°P-TIMI 50 Steering Committee and Investigators Clinical Trial UpdateEuropean Society of Cardiology Munich, August 26, 2012

  2. Background • The benefit of adding other antiplatelet drugs to aspirin for long-term 2° prevention in stable patients with prior MI is uncertain • Vorapaxar inhibits platelet activation by antagonizing thrombin-mediated activation of the protease activated receptor (PAR)-1

  3. Trial Design Morrow et al. N Engl J Med 2012ClinicalTrials.gov NCT00526474 Prior MI, CVA, or PAD N=26,449 Prior MI Inclusion: Type 1 MI >2 wks and <12 months before randomization Standard care including oral antipltrx RANDOMIZE 1:1 DOUBLE BLIND Stratified by: Qualifying Disease State Use of thienopyridine Vorapaxar 2.5 mg/d Placebo • Primary Efficacy Analysis: • CVD/MI/Stroke • CVD/MI/Stroke/Urgent Coronary Revasc • Principal Safety EP: • GUSTO Mod/Sev bleeding Follow up VisitsDay 30, Mo 4, Mo 8, Mo 12Q6 months Median F/U 30 Months Final Visit

  4. Background – 1° Efficacy EvaluationOverall Population CV Death, MI, or Stroke N = 26449 Mean f/u: 2.5 years 10.5% Placebo 9.3% Hazard Ratio 0.87 p < 0.001 Vorapaxar GUSTO Mod/Sev at 3 yrs 4.2 v. 2.5%, HR 1.66, p<0.001 Morrow et al. N Engl J Med 2012ClinicalTrials.gov NCT00526474c

  5. MI Cohort Statistical MethodsPrior MI Cohort • Prior MI Cohort • Prospectively defined subgroup of 1° interest • 17,779 patients (67% of total trial population) • Low-bleeding Risk Cohort • Based on prior studies1, we applied previously established criteria to identify patients with a low risk of bleeding who have potential for improved net clinical outcomes with potent antiplatelet Rx: • No hx of stroke/TIA • Weight ≥60 kg • Age <75 yr • -14,909 patients (84% of prior MI cohort) 1 Wiviott SD, et al. NEJM 2007

  6. MI Cohort Baseline CharacteristicsPrior MI Cohort No differences between treatment groups

  7. MI Cohort Primary Efficacy EvaluationPrior MI Cohort CV Death, MI, or Stroke N = 17,779 Mean f/u: 2.5 years Placebo 9.7% Hazard Ratio 0.80; 95% CI 0.72 - 0.89 p < 0.001 8.1% Vorapaxar

  8. MI Cohort Efficacy by Time from Qual MIPrior MI Cohort Time from qualifying MI to Randomizations < 3 months 3 to 6 months >6 months HR 0.78 p = 0.026 HR 0.82 p = 0.011 HR 0.79 p = 0.023 10.4% 9.4% 8.8% 8.9% 7.5% 7.1% N = 7801 N = 5151 N = 4703

  9. MI Cohort Efficacy Early and LatePrior MI Cohort Days 0 to 360 Day 360 to 1080 HR 0.79 p = 0.003 HR 0.82 p = 0.004 6.5% 4.0% 5.5% 3.2%

  10. MI Cohort Efficacy in Key Subgroups Prior MI Cohort

  11. MI Cohort Bleeding EndpointsPrior MI Cohort 3-yr KM rates (%) Net Clinical Outcome GUSTO Moderate / Severe Bleeding (%) HR 1.61p < 0.001 HR 1.49p < 0.001 HR 1.29p = 0.033 HR 1.54p = 0.076 HR 1.56p = 0.30 * TIMI Major/Minor/Requiring medical attention

  12. MI Cohort Bleeding in Select SubgroupsPrior MI Cohort GUSTO Mod/Severe Bleeding Prior Stroke/TIA Any High Risk Feature Age Weight <75 yr >75 yr >60 kg <60 kg No Yes No Yes 3-yr Kaplan-Meier rates (%)

  13. MI Cohort Efficacy EvaluationLow Bleeding Risk Cohort (N= 14,909) CV Death, MI, or Stroke CV Death HR 0.75p < 0.0001 HR 0.73p = 0.02 8.6% 2.0% Placebo 6.8% 1.5% Vorapaxar

  14. MI Cohort Summary • When added to standard of care including aspirin ± thienopyridine in stable pts w/ hx prior MI, vorapaxar significantly: • ↓ CV death, MI, or stroke • ↑ mod & severe bleeding • Improved net clinical outcome • The benefit of vorapaxar was consistent: • Regardless of the timing of MI • Both early (<1 yr) and late (>1 yr from rando.) • With or without thienopyridine use

  15. MI Cohort Conclusions • In appropriately selected patients, our findings demonstrate the benefit of prolonged antiplatelet therapy through inhibition of PAR-1, when added to ASA+ thienopyridine for long-term 2° prevention in patients with prior MI

  16. MI Cohort Now available online www.thelancet.com

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