Disclosures. Dr. Scirica has also served as a consultant for Lexicon, Arena, Gilead, and Eisai.

Transcription

1 Disclosures Benjamin M. Scirica, MD, MPH, is employed by the TIMI Study Group, which has received research grants from Abbott, AstraZeneca, Amgen, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Daichii Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Merck (SPRI), Novartis, Pfizer, Roche Diagnostics, Sanofi-Aventis, and Johnson & Johnson, as well as grant support through Brigham and Women's Hospital from Brahams, Critical Diagnostics, Genzyme, Nanosphere, and Takeda. Dr. Scirica has also served as a consultant for Lexicon, Arena, Gilead, and Eisai. 1

2 for Secondary Prevention in Patients with Prior Myocardial Infarction NCT ; Trial funded by Merck Benjamin M. Scirica, MD, MPH On behalf of the TRA 2 P-TIMI 50 Steering Committee and Investigators Clinical Trial Update European Society of Cardiology Munich, August 26, 2012

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

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

5 Background 1 Efficacy Evaluation Overall Population CV Death, MI, or Stroke 12% 10% N = Mean f/u: 2.5 years 10.5% 9.3% Event Rate (%) 8% 6% 4% 2% Hazard Ratio 0.87 p < GUSTO Mod/Sev at 3 yrs 4.2 v. 2.5%, HR 1.66, p< % Days since randomization Morrow et al. N Engl J Med 2012 ClinicalTrials.gov NCT c

6 Statistical Methods Prospectively defined subgroup of 1 interest 17,779 patients (67% of total trial population) Low-bleeding Risk Cohort Based on prior studies 1, 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

7 Demographics Baseline Characteristics N=17,779 Age, median (IQR) 59 (51-66) Age >=75 years (%) 8 Female (%) 21 Clinical Characteristics Diabetes mellitus (%) 22 Hypertension (%) 63 Hyperlipidemia (%) 85 Current smoker (%) 20 Prior coronary revasc (%) 86 Any cerebrovascular event (%) 5 Baseline Medical Therapy Aspirin (%) 98 Thienopyridine (%) 78 Lipid-lowering therapy (%) 96 No differences between treatment groups

8 Primary Efficacy Evaluation 12% 10% CV Death, MI, or Stroke N = 17,779 Mean f/u: 2.5 years 9.7% Event Rate (%) 8% 6% 4% 2% 0% Hazard Ratio 0.80; 95% CI p < Days since Randomization 8.1% Vora Plac HR P-value CV Death MI <0.001 Stroke

9 Efficacy by Time from Qual MI Time from qualifying MI to Randomizations < 3 months 3 to 6 months >6 months HR 0.82 p = HR 0.79 p = HR 0.78 p = CV Death / MI / Stroke (%) 10% 8% 6% 4% 2% 10.4% 9.4% 8.9% 8.8% 7.5% 7.1% N = 7801 N = 5151 N = % Days since randomization Days since randomization Days since randomization

10 Efficacy Early and Late Days 0 to 360 Day 360 to % HR 0.79 p = % HR 0.82 p = % 6% 6% CV Death / MI / Stroke (%) 5% 4% 3% 2% 4.0% 3.2% 5% 4% 3% 2% 5.5% 1% 1% 0% Days since randomization 0% Days since randomization

11 Yes No Efficacy in Key Subgroups Prior Stent 0.30 Yes No Total no Vora Plac Thienopyridine at randomization Overall HR P for interaction Qualifying MI 0.22 STEMI NSTEMI CV death, MI, Stroke 3-yr. KM% Hazard Ratio Unknown

12 Bleeding Endpoints GUSTO Moderate / Severe Bleeding (%) GUSTO Mod/ Sev TIMI Clinically Significant* TIMI Non- CABG Major 3-yr KM rates (%) ICH Fatal HR 1.61 p < HR 1.49 p < HR 1.29 p = * TIMI Major/Minor/Requiring medical attention HR 1.54 p = HR 1.56 p = 0.30

13 Net Clinical Outcomes 3-yr KM rate (%) N=8880 N=8849 HR p-value All-cause death, MI, stroke, GUSTO Severe bleeding CV Death, MI, Stroke, UCR, GUSTO Mod/Severe bleeding UCR = recurrent ischemia leading to urgent coronary revascularization

14 3-yr Kaplan-Meier rates (%) GUSTO Mod/ Severe Bleeding Age Bleeding in Select Subgroups Weight Prior Stroke/TIA Any High Risk Feature <75 yr >75 yr >60 kg <60 kg No Yes No Yes

15 Efficacy Evaluation Low Bleeding Risk Cohort (N= 14,909) CV Death, MI, or Stroke CV Death 12% 10% HR 0.75 p < % 3% HR 0.73 p = % Event Rate (%) 8% 6% 4% 6.8% Event Rate (%) 2% 1% 1.5% 2% 0% % Days since Randomization Days since Randomization

16 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

17 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

18 Now available online