T hrombin R eceptor A ntagonist in Secondary P revention of Atherothrombosis NCT00526474; Trial funded by Merck On behalf of the TRA 2°P-TIMI 50 Steering Committee and Investigators ** CONFIDENTIAL FINAL DRAFT ** EMBARGOED UNTIL SAT 3/24 10AM
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Protease-activated receptor (PAR)-1 Thrombi Thr bin Vor orap apaxar ar C C C C C C C C X Vorapaxar is an oral, potent, and • Signa gnal selective antagonist of PAR-1 Shape Change • Metabolism by CYP3A4 enzymes Activation No meaningful renal clearance • Aggregation • Long half-life (T1/2 > 100 hrs)
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** TRA (Vorapaxar) Program TRA Program (38,500 pts) 2º Prevention NSTEACS 12,944 ~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 3
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Primary Objectives Primary Objective To test the hypothesis that vorapaxar will ↓ athero- thrombotic 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 PAR1 is a valuable novel target 2. adding a new antiplatelet agent to ASA is effective for long-term 2° prevention in stable pts
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Trial Organization TIMI Study Group Eugene Braunwald (Chair) David A. Morrow (PI) BM Scirica, MP Bonaca Stephen D. Wiviott (CEC) Polly Fish Sabina A. Murphy (Statistics) Worldwide Monitoring Teams Covance – Jennifer Mead WCT – Lucy Bennett ICON – Jeroen Kleijne Merck Monitoring Sponsor: Merck John Strony Gail Berman/Leslie Lipka Ann Killian Xuan Liu, Weili He Data Safety Monitoring Board Robert Frye (Chair) Kent R. Bailey J. Donald Easton Judith Hochman P. Gabriel Steg Freek Verheught
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** National Lead Investigators Argentina Denmark New Zealand S Ameriso/ E Paolasso P Grande H White Australia Finland Norway P Aylward/G Hankey M Nieminen D Nilsen/L Thomassen Austria France Poland M Pichler JP Bassand M Tendera Belgium Germany Portugal F van de Werf C Diehm/H Diener J Morais Brazil Hungary South Africa J Nicolau R Kiss A Dalby Canada Israel Spain P Teal/P Theroux H Hod A Betriu Chile Italy Sweden R Corbolan D De Ferrari/P Merlini M Dellborg Colombia Japan Switzerland D Isaza S Goto H Bounameaux Czech Republic Netherlands United Kingdom J Spinar T Oude Ophius R Wilcox
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Trial Design Prior MI, CVA, or PAD Key Inclusion: 1) MI: 2 wks - 12 mo 2) Ischemic CVA: 2 wk-12 mo Standard care 3) PAD: claudication + abnl including oral antiplt rx ABI or prior revasc RANDOMIZE 1:1 DOUBLE BLIND Stratified by: Vorapaxar Placebo 1) Qualifying athero 2.5 mg/d 2) Use of thienopyridine Follow up Visits Minimum of Day 30, Mo 4, Mo 8, Mo 12 Q6 months 1 year of follow-up Event Driven Design Final Visit
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** 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)
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** 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
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Enrollment Enrolled 9/2007-11/2009: 32 countries, 1032 sites, 26449 patients 32 (0.1%) lost to F/U 2.0% withdrew consent for F/U
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Baseline Characteristics Placebo Vorapaxar (N = 13224) (N = 13225) Age (yrs, median) 61 (53, 69) 61 (53, 69) ≥ 75 yrs (%) 11 11 Female (%) 24 24 Qualifying Atherosclerosis MI (n = 17779, %) 67 67 PAD (n = 3787, %) 14 14 Stroke (n = 4883, %) 19 18 Any CAD (%) 78 78 Any prior stroke (%) 22 22 Diabetes (%) 25 25 Current smoker (%) 21 21 eGFR <60 ml/min/1.73 m 2 15 16
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Background Therapy Placebo Vorapaxar (N = 13224) (N = 13225) Antiplatelet Therapy, % Qualifying MI Aspirin 98 98 Thienopyridine 78 78 PAD Aspirin 88 88 Thienopyridine 37 37 Stroke Aspirin 81 81 Thienopyridine 24 24 Dipyridamole 19 20 Other Medications at Enrollment Lipid-lowering agent (%) 92 91 ACEI or ARB (%) 75 74 Beta-blocker (qualifying MI) 84 84
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Primary Efficacy Evaluation CV Death, MI, or Stroke 12% Placebo N = 26449 10.5% Median f/u Vorapaxar 10% 2.5 years 9.3% 8% Event Rate (%) 6% 4% Hazard Ratio 0.87; 2% 95% CI 0.80 to 0.94 p < 0.001 0% 0 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 Days since randomization
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Additional Major Efficacy Outcomes CV death, MI, Stroke, or Urgent CV death or MI Coronary Revascularization 14% 9% Placebo Placebo 8% 12% 12.4% 8.2% 7% 10% 6% Event Rate (%) Event Rate (%) 8% 5% Vorapaxar Vorapaxar 4% 11.2% 6% 7.3% 3% 4% Hazard Ratio 0.88; 2% Hazard Ratio 0.86; 2% 95% CI 0.82 to 0.95 95% CI 0.78 to 0.94 1% p = 0.001 p = 0.002 0% 0% 0 180 360 540 720 900 1080 0 180 360 540 720 900 1080 Days since randomization Days since randomization
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Selected Efficacy Outcomes Placebo Vorapaxar (N = 13224) (N = 13225) 3- yr KM rate (%) HR p-value CV death, MI, stroke 10.5 9.3 0.87 <0.001 CV death 3.0 2.7 0.89 0.15 MI 6.1 5.2 0.83 0.001 Any Stroke 2.8 2.8 0.97 0.73 Ischemic stroke 2.6 2.2 0.85 0.059 Urgent coronary 2.6 2.5 0.88 0.11 revascularization CVD, MI, Stroke, 14.7 13.1 0.87 <0.001 UCR, vascular hosp. All-cause mortality 5.3 5.0 0.95 0.41 UCR = recurrent ischemia leading to urgent coronary revascularization
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Efficacy Outcomes No History of Stroke (N= 20,699) Placebo Vorapaxar (N = 10344) (N = 10335) 3- yr KM rate (%) HR p-value CV death, MI, stroke 9.6 8.3 0.84 <0.001 CV death 2.8 2.5 0.87 0.13 MI 6.4 5.5 0.84 0.004 Any Stroke 1.7 1.5 0.82 0.11 Ischemic stroke 1.5 1.1 0.72 0.013 CVD, MI, Stroke, urg 11.8 10.6 0.86 <0.001 coronary revasc. CV death or MI 8.4 7.4 0.85 0.002 CVD, MI, Stroke, 14.0 12.3 0.86 <0.001 UCR, vascular hosp. UCR = recurrent ischemia leading to urgent coronary revascularization
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** CV Death, MI, or Stroke in Major Subgroups CV Death, MI, or Interaction Stroke p-value Subgroup total no. Hazard Ratio (95% CI) Overall 26449 0.87 (0.80, 0.94) Age 0.54 <75 23429 0.86 (0.78, 0.94) >=75 3020 0.91 (0.75, 1.10) Body weight 0.033 >=60kg 24546 0.85 (0.78, 0.92) <60kg 1852 1.22 (0.88, 1.69) Qualifying Athero 0.058 MI 17779 0.80 (0.72, 0.89) PAD 3787 0.94 (0.78, 1.14) Stroke 4883 1.03 (0.85, 1.25) History of Stroke 0.22 No 20699 0.84 (0.76, 0.93) Yes 5746 0.95 (0.80, 1.11) Thienopyridine at Rando 0.76 Yes 16442 0.88 (0.79, 0.98) No 10007 0.85 (0.74, 0.98) 0.5 1 2 5 No interaction by sex, or region. Vorapaxar Better Vorapaxar Worse
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Bleeding Endpoints Overall Population Placebo Vorapaxar (N = 13166) (N = 13186) 3- yr KM rate (%) HR p-value GUSTO Moderate or 2.5 4.2 1.66 <0.001 Severe TIMI Clinically 11.1 15.8 1.46 <0.001 Significant TIMI Non-CABG 1.8 2.8 1.46 <0.001 Major Intracranial 0.5 1.0 1.94 <0.001 Fatal 0.2 0.3 1.46 0.19 No significant heterogeneity in GUSTO Mod/Sev bleeding across any of major subgroups
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** Major Bleeding Endpoints by History of Stroke 3- yr KM rate (%) 8 Prior Stroke No Hx of Stroke Placebo 7 n = 5746 n = 20699 Vorapaxar 6 5 4.1 4 3 2.5 2.4 2.1 1.8 2 0.9 0.6 1 0.5 0.4 0.3 0.3 0.2 0 TIMI Non- ICH Fatal TIMI Non- ICH Fatal CABG Major CABG Major ARD 2.0% ARD 1.5% ARD 0.2% ARD 0.7% ARD 0.2% ARD 0.1% HR 1.87 HR 2.55 HR 1.48 HR 1.35 HR 1.55 HR 1.44 P<0.001 P<0.001 P=0.46 P=0.005 P=0.049 P=0.30
** CONFIDENTIAL FINAL DRAFT / EMBARGOED ** GUSTO Moderate or Severe Bleeding in Major Subgroups Placebo Vorapaxar 3- yr KM rate (%) 10 Age Weight Qual Athero 9 8.4 7.7 8 7.4 7 5.5 6 4.5 5 4.2 4.0 3.7 3.7 4 3.4 3 2.4 2.4 2.2 2.1 2 1 0 Age ≥75 y Age <75 y Wt <60kg Wt ≥60kg Stroke PAD MI ARD 2.9% 1.5% 4.0% 1.6% 1.8% 2.9% 1.3% HR 1.69 1.65 1.95 1.64 1.93 1.62 1.61 P-interact 0.87 0.50 0.69
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