VORAPAXAR (ZONTIVITY®)



















TRA 2P-TIMI 50 TRIAL - Vorapaxar vs Placebo for Secondary Prevention of CVD, NEJM (2012) [PubMed abstract]
  • The TRA 2P-TIMI 50 trial enrolled 26,449 patients with a history of CVD
Main inclusion criteria
  • History of myocardial infarction, ischemic stroke, or peripheral artery disease (defined as history of intermittent claudication with either an ankle-brachial index of less than 0.85 or previous revascularization for limb ischemia) within previous 2 weeks to 12 months
Main exclusion criteria
  • Planning to undergo a revascularization procedure
  • Receiving ongoing treatment with warfarin
  • Active liver disease
  • Bleeding disorder
Baseline characteristics
  • Median age 61 years
  • Qualifying event: MI - 67% | Stroke - 18% | PAD - 14%
Patients were randomized to one of two groups:
  • Group 1 (13,225 patients) - Vorapaxar 2.5 mg once daily
  • Group 2 (13,244 patients) - Placebo once daily
  • All nonstudy antiplatelet therapy was managed by clinicians at study sites according to their local standards of care
  • Other antiplatelet medications at baseline:
    • Qualifying heart attack: Aspirin - 98%, P2Y12 inhibitors - 78%
    • Qualifying peripheral artery disease: Aspirin - 88%, P2Y12 inhibitors - 37%
    • Qualifying stroke: Aspirin - 81%, P2Y12 inhibitors - 24%, dipyridamole - 20%
Primary outcome: Composite of cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to urgent coronary revascularization
Results

Duration: Median of 30 months
Outcome Vorapaxar
(3-year estimate)
Placebo
(3-year estimate)
Comparisons
Primary outcome 9.3% 10.5% p<0.001
Myocardial infarction 5.2% 6.1% p=0.001
Any stroke 2.8% 2.8% p=0.73
Urgent coronary revascularization 2.5% 2.6% p=0.11
Overall mortality 5.0% 5.3% p=0.41
Moderate or severe bleeding 4.2% 2.5% p<0.001
Intracranial bleeding 1.0% 0.5% p<0.001
CV death, MI, stroke, moderate or severe bleeding 11.7% 12.1% p=0.40
  • After 2 years, the study was stopped early in patients with a history of stroke due to increased risk of intracranial hemorrhage in the vorapaxar group (2.4% vs 0.9%, p<0.001)

Findings: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage.