Expert Review: Acute Coronary Syndrome

Vorapaxar in the secondary prevention of atherothrombotic events

Background

It is established that patients who had an atherosclerotic event such as stroke, myocardial infarction or peripheral artery disease receive secondary prevention medical treatment. This treatment which also comprises antiplatelet therapy using aspirin or thienopyridines has been shown to reduce cardiovascular events.

Knowledge Gap

It is not known whether antiplatelet treatment with a PAR-1 antagonist, inhibiting a different platelet pathway, in addition to standard secondary prevention for atherosclerosis can reduce further cardiovascular events.

Aim of the Study

The authors assessed the safety and efficacy for vorapaxar, a PAR-1 antagonist, to reduce cardiovascular events in patients with a previous atherosclerotic event (myocardial infarction, ischemic stroke or peripheral artery disease).

Methods

This was a multicenter randomized placebo-controlled study enrolling 26,449 patients with a previous myocardial infarction, ischemic stroke or peripheral artery disease event in 1032 sites in 32 countries.

Patients were randomized (1:1) to either 2.5mg vorapaxar or placebo once daily in addition to standard secondary prevention and followed up for a median of 30 months. Ninety-four percent of the patients were treated with aspirin.

The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. The secondary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to urgent coronary revascularization.

Results

The primary endpoint occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 of the placebo group (10.3%, p<0.0001). The secondary endpoint occurred in 1259 vorapaxar patients (11.2%) and 1417 of the placebo group (12.4%, p=0.001). Moderate and severe bleeding was more frequent in the treatment group (4.2% vs. 2.5%, p<0.001) with a higher rate of intracranial hemorrhage in the vorapaxar group which led to premature termination of the study in patients with a previous stroke. The overall prevalence in the net clinical outcome (primary end point plus rates of moderate/severe bleeding) did not differ between the two groups.

Conclusion

Vorapaxar treatment, in addition to standard therapy, reduced the risk for cardiovascular events among patients with stable atherosclerosis. This effect was particularly seen in patients with a previous myocardial infarction. However, reduction in cardiovascular events came at the cost of increased bleeding, including intracranial hemorrhage especially in the group of patients with a previous stroke.

Perspective – Clinical Impact

Although this trial was stopped prematurely in patients with a previous stroke due to increased frequency of intracranial hemorrhage, the results in patients without previous stroke are very encouraging. Especially the cohort with a previous myocardial infarction seems to benefit from additional antiplatelet therapy.

Therefore, inhibition of another platelet pathway in addition to that targeted by standard antiplatelet therapy for secondary prevention may have a role in daily practice. This needs to be confirmed in future studies.

Corresponding Author from the original article : Morror DA, Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA. E-mail: dmorrow@partners.org

Citation: N Engl J Med. 2012 Apr 12;366(15):1404-13. Epub 2012 Mar 24.

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