Physicians' Academy for Cardiovascular Education

Vorapaxar in post-MI patients

Literature -

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

Scirica BM, Bonaca MP, Braunwald E, et al; for the TRA 2°P-TIMI 50 Steering Committee Investigators.

Lancet. 2012 Aug 24. [Epub]

 

Background

Patients with a history of myocardial infarction are at substantial risk of recurrent thrombotic events, despite secondary prevention [1]. The efficacy and safety of vorapaxar, a potent and selective antagonist of protease-activated receptor 1, were studied in the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P-TIMI 50) trial [2]. In the overall trial, which randomized 26,449 patients with a history of MI, ischemic stroke, or peripheral arterial disease to either vorapaxar or placebo in addition to standard therapy, the rate of CV death, MI, or stroke was significantly reduced by vorapaxar, but the rate of intracranial bleeding was doubled.

As long-term antiplatelet therapy might have different benefits in patients with myocardial infarction [3] compared with patients with stroke and peripheral arterial disease [4-6], the subgroup of 17.779 patients with a history of MI was analyzed in this study.

 

Main results

After 2.5 years of follow-up, the rate of CV death, MI, or stroke was significantly reduced in the vorapaxar group compared to the placebo group, although vorapaxar was also associated with an increased risk of bleeding, but not intracranial bleeding:

  • Primary endpoint: 8.1% versus 9.7%, HR 0.80, CI 0.72-0.89, p<0.0001
  • Moderate or severe bleeding:3.4% versus 2.1%, HR 1.61, CI 1.31-1.97, p<0.0001
  • Intracranial hemorrhage: 0.6% versus 0.4%, p=0.076
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Conclusion

Vorapaxar reduced the risk of cardiovascular death or ischaemic events. As vorapaxar increased the risk of dangerous bleeding, clinicians will need to carefully assess which groups of patients will benefit from the treatment. Vorapaxar might be beneficial in a population with a history of MI but with no history of stroke or TIA, age below 75, and weight over 60 kg, where the cardiovascular advantages of long-term treatment are likely to outweigh the adverse health risks to the patient associated with a higher likelihood of bleeding.

Editorial comment [7]
“The results of this work give further support for the benefit of adding more potent long term anti thrombotic therapy for patients who have previously had a heart attack. However, the challenge – as with all strategies of this type – is to weigh the benefit against the increased bleeding risk.

References

1. Steg PG, Bhatt DL, Wilson PW, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297: 1197–206.
2. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012;366:1404–13.
3. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49: 1982–88.
4. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364: 331–37.
5. Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 2010;303: 841–48.
6. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238–51
7. James S, Held C. Improving long-term outcome after myocardial infarction. Lancet. 2012 Aug 24. [Epub ahead of print]


Abstract

Background:
Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial.

Methods:
In TRA 2°P-TIMI 50-a randomised, placebo-controlled, parallel trial-we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2•5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474).

Findings:
17 779 of 26 449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2•5 years (IQR 2•0-2•9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8•1%vs 9•7%, HR 0•80, 95% CI 0•72-0•89; p<0•0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3•4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2•1%, 3-year Kaplan-Meier estimate], HR 1•61, 95% CI 1•31-1•97; p<0•0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0•6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0•4%, 3-year Kaplan-Meier estimate) with placebo (p=0•076). Other serious adverse events were equally distributed between groups.

Interpretation:
For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding

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