Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50 - TRA 2°P–TIMI 50

Description:

The goal of the trial was to evaluate treatment with the novel antiplatelet agent protease-activated receptor (PAR-1) antagonist, vorapaxar, compared with placebo among patients with stable atherosclerosis. PAR-1 is the major thrombin receptor on platelets.

Contribution to the Literature: The TRA 2°P–TIMI 50 trial showed that vorapaxar reduced adverse events, but increased major bleeding among patients with stable atherosclerosis.

 

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel
  • Stratified

Patient Populations:

  • Patients with prior MI (within 2 weeks to 12 months), ischemic stroke (within 2 weeks to 12 months), or PAD (claudication and ankle-brachial index <0.85 or prior revascularization)

    Number of enrollees: 26,449
    Duration of follow-up: Median 30 months
    Mean patient age: 61 years
    Percentage female: 24%

Exclusions:

  • Anticipated revascularization procedure
  • Bleeding abnormality
  • Treatment with warfarin
  • Active hepatobiliary disease

Primary Endpoints:

  • CV death, MI, or stroke

Secondary Endpoints:

  • CV death, MI, stroke, or urgent revascularization
  • CV death or MI
  • GUSTO moderate or severe bleeding
  • TIMI clinically significant bleeding

Drug/Procedures Used:

Patients with prior atherothrombotic disease treated with standard therapy were randomized to vorapaxar 2.5 mg daily (n = 13,224) vs. placebo (n = 13,225).

Concomitant Medications:

Among patients with prior myocardial infarction (MI), the use of aspirin/thienopyridine was 98%/78%; among those with prior stroke, the use of aspirin/thienopyridine was 81%/24%; and among those with peripheral artery disease (PAD), the use of aspirin/thienopyridine was 81%/37%, respectively.

Principal Findings:

Overall, 26,449 patients were randomized. The median age was 61 years, 24% were women, 26% had diabetes, and qualifying diagnosis was MI in 67%, stroke in 18%, and PAD in 14%.

In January 2011, the Data and Safety Monitoring Board recommended discontinuation of vorapaxar in patients with prior stroke due to an increased risk of intracranial hemorrhage. The study drug was continued in other patients.

The primary composite outcome of cardiovascular (CV) death, MI, or stroke occurred in 9.3% of the vorapaxar group vs. 10.5% of the placebo group (p < 0.001). Vorapaxar did not improve outcomes among patients that weighed <60 kg. Among those with a qualifying diagnosis of MI within the previous 2 weeks to 12 months and no stroke/transient ischemia attack (TIA), vorapaxar vs. placebo similarly reduced CV death, MI, or stroke among those with planned thienopyridine (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.70-0.91; p < 0.01) and among those with no planned thienopyridine (HR, 0.75; 95% CI, 0.60-0.94; p = 0.011; p for interaction = 0.67).

- CV death, MI, stroke, or urgent revascularization: 11.2% vs. 12.4% (p = 0.001), respectively for vorapaxar vs. placebo
- CV death or MI: 7.3% vs. 8.2% (p = 0.002), respectively for vorapaxar vs. placebo

- GUSTO moderate or severe bleeding: 4.2% vs. 2.5% (p < 0.001), respectively for vorapaxar vs. placebo
- TIMI clinically significant bleeding: 15.8% vs. 11.1% (p < 0.001), respectively for vorapaxar vs. placebo
- Intracranial hemorrhage: 1.0% vs. 0.5% (p < 0.001), respectively for vorapaxar vs. placebo. Bleeding (including intracranial hemorrhage) was magnified by vorapaxar among patients with prior ischemic stroke.

There was no net clinical benefit (defined as CV death, MI, stroke, urgent revascularization, or GUSTO moderate/severe bleeding [p = 0.20] or defined as CV death, MI, stroke, or GUSTO moderate/severe bleeding [p = 0.40]) with vorapaxar.

A prespecified subgroup analysis examined patients with a qualifying diagnosis of MI within the previous 2 weeks to 12 months (n = 17,779):

- CV death, MI, or stroke: 8.1% vs. 9.7% (p < 0.0001), respectively for vorapaxar vs. placebo
- GUSTO moderate/severe bleeding: 3.4% vs. 2.1% (p < 0.0001), respectively for vorapaxar vs. placebo
- TIMI clinically significant bleeding: 15.1% vs. 10.4% (p < 0.0001), respectively for vorapaxar vs. placebo
- Intracranial hemorrhage: 0.6% vs. 0.4% (p = 0.076), respectively for vorapaxar vs. placebo

A prespecified subgroup analysis examined patients with diabetes and prior MI (n = 3,623):

- CV death, MI, or stroke: 11.4% vs. 14.3% (p = 0.002), respectively for vorapaxar vs. placebo
- GUSTO moderate/severe bleeding: 4.4% vs. 2.6% (p < 0.0001), respectively for vorapaxar vs. placebo
- TIMI clinically significant bleeding: 17.1% vs. 11.4% (p < 0.0001), respectively for vorapaxar vs. placebo
- Intracranial hemorrhage: 0.9% vs. 0.7% (p = 0.65), respectively for vorapaxar vs. placebo

In another prespecified subgroup analysis examining patients with symptomatic PAD (n = 3,787), acute limb ischemia occurred at a rate of 1.3% per year. In 56%, acute limb ischemia was due to surgical graft thrombosis, while in 27% it was due to native vessel thrombosis.

- Acute limb ischemia: 2.0% with vorapaxar vs. 3.3% with placebo (p = 0.007)

- GUSTO moderate or severe bleeding: 6.6% with vorapaxar vs. 4.5% with placebo (p = 0.003)

Interpretation:

Among patients with stable atherosclerosis, the novel antiplatelet agent, vorapaxar, reduced ischemic events at a cost of increased bleeding. There was increased bleeding, including intracranial hemorrhage among patients with prior ischemic stroke. Converging lines of evidence are highlighting the increased risk of intracranial hemorrhage with potent antiplatelet therapy among patients with prior stroke. Results were similar among patients with a qualifying diagnosis of MI (regardless of diabetic status or thienopyridine use). Among patients with symptomatic PAD, vorapaxar reduced acute limb ischemia at a cost of increased moderate or severe bleeding.

References:

Bonaca MP, Gutierrez JA, Creager MA, et al. Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease: Results From TRA2°P-TIMI 50. Circulation 2016;Jan 29:[Epub ahead of print].

Bohula EA, Aylward PE, Bonaca MP, et al. Efficacy and Safety of Vorapaxar With and Without a Thienopyridine for Secondary Prevention in Patients With Previous Myocardial Infarction and No History of Stroke or Transient Ischemic Attack: Results from TRA 2°P-TIMI 50. Circulation 2015;132:1871-9.

Cavender MA, Scirica BM, Bonaca MP, et al. Vorapaxar in Patients With Diabetes and Prior MI: Findings From the TRA 2°P-TIMI 50 Trial. Circulation 2015;Feb 13:[Epub ahead of print].

Morrow DA, Braunwald E, Bonaca MP, et al., on behalf of the TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012;366:1404-13.

Scirica BM, Bonaca MP, Braunwald E, et al., on behalf of the TRA 2°P-TIMI 50 Steering Committee and Investigators. Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial. Lancet 2012;380:1317-24.

Presented by Dr. Benjamin Scirica at the European Society of Cardiology Congress, Munich, August 26, 2012.

Presented by Dr. David Morrow at ACC.12 & ACC-i2 with TCT, Chicago, IL, March 24, 2012.

Clinical Topics: Vascular Medicine

Keywords: Stroke, Atherosclerosis, Follow-Up Studies, Platelet Aggregation Inhibitors, Ankle Brachial Index, Receptors, Proteinase-Activated, Clinical Trials Data Monitoring Committees, Receptors, Thrombin, Ticlopidine, Pyridines, Blood Platelets, Intracranial Hemorrhages, Lactones, Diabetes Mellitus, Peripheral Arterial Disease


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