Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombosis

Transcription

1 Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombosis NCT ; Trial funded by Merck David A. Morrow, MD, MPH On behalf of the TRA 2 P-TIMI 50 Steering Committee and Investigators ACC 2012, Chicago, March 24, 2012

2 Protease-activated receptor (PAR)-1 Thrombin Vorapaxar C C C C Vorapaxar is an oral, potent, and selective antagonist of PAR-1 Metabolism by CYP3A4 enzymes No meaningful renal clearance Long half-life (T1/2 > 100 hrs) X Signal Shape Change Activation Aggregation Adapted from Vu TH et al. Cell 1991;64:

3 TRA (Vorapaxar) Program NSTEACS 12,944 TRA Program (38,500 pts) 2º Prevention ~26,500 pts Vorapaxar Placebo Vorapaxar Placebo Median F/U 1.4 years Median F/U 2.5 years CV Death, MI, Stroke, Hosp for ischemia, Urgent Coronary Revasc. HR 0.92 (0.85, 1.01), p=0.072 CV Death, MI, Stroke HR 0.89 (0.81, 0.98), p=0.018 Tricoci et al. N Engl J Med 2012;366:20-33

4 Primary Objective Primary Objectives To test the hypothesis that vorapaxar will atherothrombotic events in stable pts w/ atherosclerosis treated for 1 yr in addition to standard therapy. Parallel Scientific Objectives To test the hypotheses that 1. antagonism of PAR-1 is a valuable novel target 2. adding a new antiplatelet agent to ASA is effective for long-term 2 prevention in stable pts

5 TIMI Study Group Eugene Braunwald (Chair) BM Scirica, MP Bonaca Polly Fish Worldwide Monitoring Teams Covance Jennifer Mead ICON Jeroen Kleijne Sponsor: Merck John Strony Ann Killian Trial Organization David A. Morrow (PI) Stephen D. Wiviott (CEC) Sabina A. Murphy (Statistics) WCT Lucy Bennett Merck Monitoring Gail Berman/Leslie Lipka Xuan Liu, Weili He Data Safety Monitoring Board Robert Frye (Chair) Kent R. Bailey J. Donald Easton Judith Hochman P. Gabriel Steg Freek Verheught

6 Steering Committee Argentina S Ameriso/ E Paolasso Australia P Aylward/G Hankey Austria M Pichler Belgium F van de Werf Brazil J Nicolau Canada P Teal/P Theroux Chile R Corbolan Colombia D Isaza Czech Republic J Spinar Denmark P Grande Finland M Nieminen France JP Bassand Germany C Diehm/H Diener Hungary R Kiss Israel H Hod Italy D De Ferrari/P Merlini Japan S Goto/Y Shinohara Netherlands T Oude Ophius New Zealand H White Norway D Nilsen/L Thomassen Poland M Tendera Portugal J Morais South Africa A Dalby Spain A Betriu Sweden M Dellborg Switzerland H Bounameaux United Kingdom K Fox/R Wilcox United States M Alberts/M Creager P Gurbel/J P Mohr D Moliterno/J Olin K M Welch

7 Trial Design Prior MI, CVA, or PAD Standard care including oral antiplt rx Key Inclusion: 1) Type 1 MI: 2 wks - 12 mo 2) Ischemic CVA: 2 wk - 12 mo 3) PAD: claudication + abnl ABI or prior revasc Vorapaxar 2.5 mg/d RANDOMIZE 1:1 DOUBLE BLIND Stratified by: 1) Qualifying athero 2) Use of thienopyridine Placebo Follow up Visits Day 30, Mo 4, Mo 8, Mo 12 Q6 months Final Visit Minimum of 1 year of follow-up Event Driven Design

8 Endpoints Efficacy: hierarchical testing 1. Cardiovascular (CV) death, MI, or stroke 2. CV death, MI, stroke, or urgent coronary revascularization 3. CV death or MI Bleeding endpoints of primary interest: GUSTO moderate or severe bleeding TIMI Clinically Significant Bleeding: TIMI major, TIMI minor, or bleeding requiring medical attention (medical/surgical rx, lab eval)

9 DSMB Action January, 2011, the DSMB announced that based on its ongoing review of safety: ICH with vorapaxar in pts w/ a prior stroke D/C all pts with a prior stroke Trial should continue in pts without a hx of stroke Analyses 1 st line analysis in all patients, including stroke 2 nd line analysis (new): pts w/out prior stroke Special interest in patients who qualified w/ MI

10 Enrollment Enrolled 9/ /2009: 32 countries, 1032 sites, patients 32 (0.1%) lost to F/U 2.0% withdrew consent for F/U

11 Baseline Characteristics Age (yrs, median) 75 yrs (%) Female (%) Qualifying Atherosclerosis MI (n = 17779, %) PAD (n = 3787, %) Stroke (n = 4883, %) Any CAD (%) Any prior stroke (%) Diabetes (%) Current smoker (%) egfr <60 ml/min/1.73 m 2 Placebo (N = 13224) 61 (53, 69) Vorapaxar (N = 13225) 61 (53, 69)

12 Background Therapy Antiplatelet Therapy, % Qualifying MI Aspirin Thienopyridine Placebo (N = 13224) Vorapaxar (N = 13225) PAD Aspirin Thienopyridine (28% DAPT) Stroke Aspirin Thienopyridine Dipyridamole (8% DAPT) Other Medications at Enrollment Lipid-lowering agent (%) ACEI or ARB (%) Beta-blocker (qualifying MI)

13 Event Rate (%) Primary Efficacy Evaluation CV Death, MI, or Stroke 12% 10% N = Median f/u 2.5 years Placebo Vorapaxar 10.5% 9.3% 8% 6% 4% 2% 0% Days since randomization Hazard Ratio 0.87; 95% CI 0.80 to 0.94 p < 0.001

14 Event Rate (%) Event Rate (%) Additional Major Efficacy Outcomes CV death, MI, Stroke, or Urgent Coronary Revascularization CV death or MI 14% 12% 10% Placebo 12.4% 9% 8% 7% 6% Placebo 8.2% 8% 6% Vorapaxar 11.2% 5% 4% Vorapaxar 7.3% 4% 2% 0% Hazard Ratio 0.88; 95% CI 0.82 to 0.95 p = Days since randomization 3% 2% 1% 0% Hazard Ratio 0.86; 95% CI 0.78 to 0.94 p = Days since randomization

15 Selected Efficacy Outcomes Overall Population 3-yr KM rate (%) Placebo (N = 13224) Vorapaxar (N = 13225) HR p-value CV death, MI, stroke <0.001 CV death MI Any Stroke Ischemic stroke Urgent coronary revascularization CVD, MI, Stroke, UCR, vascular hosp <0.001 All-cause mortality UCR = recurrent ischemia leading to urgent coronary revascularization

16 Efficacy Outcomes No History of Stroke (N= 20,699) 3-yr KM rate (%) Placebo (N = 10344) Vorapaxar (N = 10335) HR p-value CV death, MI, stroke <0.001 CV death MI Any Stroke Ischemic stroke CVD, MI, Stroke, urg coronary revasc <0.001 CV death or MI CVD, MI, Stroke, UCR, vascular hosp <0.001 UCR = recurrent ischemia leading to urgent coronary revascularization

17 Subgroup total no. CV Death, MI, or Stroke in Major Subgroups CV Death, MI, or Stroke Hazard Ratio (95% CI) Overall (0.80, 0.94) Age 0.54 < (0.78, 0.94) >= (0.75, 1.10) Body weight >=60kg (0.78, 0.92) <60kg (0.88, 1.69) Qualifying Athero MI (0.72, 0.89) PAD (0.78, 1.14) Stroke (0.85, 1.25) History of Stroke 0.22 No (0.76, 0.93) Yes (0.80, 1.11) Thienopyridine at Rando 0.76 Yes (0.79, 0.98) No (0.74, 0.98) Interaction p-value No interaction by sex, or region Vorapaxar Better Vorapaxar Worse

18 Bleeding Endpoints Overall Population 3-yr KM rate (%) GUSTO Moderate or Severe TIMI Clinically Significant TIMI Non-CABG Major Intracranial Placebo (N = 13166) Vorapaxar (N = 13186) HR p-value <0.001 <0.001 <0.001 <0.001 Fatal No significant heterogeneity in GUSTO Mod/Sev bleeding across any of major subgroups

19 Major Bleeding Endpoints yr KM rate (%) Placebo Vorapaxar Prior Stroke n = 5746 No Hx of Stroke n = TIMI Non- CABG Major ICH Fatal TIMI Non- CABG Major ICH 0.3 Fatal ARD 2.0% HR 1.87 P<0.001 ARD 1.5% HR 2.55 P<0.001 ARD 0.2% HR 1.48 P=0.46 ARD 0.7% HR 1.35 P=0.005 ARD 0.2% HR 1.55 P=0.049 ARD 0.1% HR 1.44 P=0.30

20 GUSTO Moderate or Severe Bleeding in Major Subgroups yr KM rate (%) Placebo Vorapaxar 8.4 Age Weight Qual Athero Age 75 y Age <75 y Wt <60kg Wt 60kg Stroke PAD MI ARD HR 2.9% % % % % % % 1.61 P-interact

21 Net Clinical Outcome HR VORA PLAC RRR (%) All pts (Including Stroke) CV death, MI, stroke, UCR, GUSTO mod/sev bleed Death, MI, stroke, GUSTO severe bleed P =0.20 P = No Hx Stroke n = 20,699 CV death, MI, stroke, UCR, GUSTO mod/sev bleed Death, MI, stroke, GUSTO severe bleed P =0.16 P = No Hx Stroke/TIA Wgt 60kg n = 18,966 CV death, MI, stroke, UCR, GUSTO mod/sev bleed Death, MI, stroke, GUSTO severe bleed P =0.004 P < Vorapaxar Better Vorapaxar Worse

22 Summary When added to standard of care, including aspirin & thienopyridine, in stable pts w/ hx atherothrombosis, vorapaxar significantly CV death, MI, or stroke mod & severe bleeding, including ICH In addition, our findings indicate significant in thrombosis adding to standard rx, including ASA, for long-term rx in pts with prior MI unacceptable ICH risk in pts with prior stroke uncertain benefit in pts with PAD

23 1. PAR-1 antagonism is an effective approach to reducing recurrent atherothrombosis Conclusions 2. More intensive antiplatelet therapy for long-term 2 prevention reduces recurrent thrombosis in patients with prior MI 3. Patient selection is necessary to balance the antithrombotic benefit vs. risk of bleeding

24 Events / 1000 Pts For Every 1000 Pts Treated with Vorapaxar No History of Stroke/TIA; Wgt 60 kg (n = 18,966) CVD, MI or Stroke P<0.001 MI P<0.001 CV Death P=0.033 Stroke P<0.001 Fatal Bleed P=NS ICH P=0.15 *excluding ICH *GUSTO Mod/Sev P<0.001