Antiplatelet agent – vorapaxar

Patients at risk of atherothrombosis are commonly given aspirin or clopidogrel. However, this carries the risk of bleeding complications

A key factor in the development of atherothrombosis is the activation of platelets and at-risk patients are commonly given aspirin or clopidogrel. However, the risk of bleeding complications means this type of therapy is largely restricted to patients at high risk. A new drug being investigated by Merck & Co, vorapaxar, acts via a different mechanism – it is an inhibitor of the protease activated receptor PAR-1 and inhibits thrombin-induced platelet aggregation.1

In a randomised, double blind, placebo-controlled Phase II trial, 1,030 patients aged at least 45 undergoing non-urgent percutaneous coronary intervention (PCI) or coronary angio-graphy with planned PCI were given an oral loading dose of 10, 20 or 40mg of the drug or placebo.2 Those given the active who received PCI continued with an oral maintenance dose of 0.5, 1 or 2.5mg/day, and the placebo group continued receiving placebo, for 60 days. It was generally well tolerated, and did not result in an increase in thrombolysis in myocardial infarction bleeding.

Two large Phase III trials have also been conducted. In one, it was compared with placebo in 12,944 patients with acute coronary syndromes.3 The trial’s primary endpoint was a composite of death from cardiovascular events, myocardial infarction, recurrent ischaemia that required hospitalisation, or urgent coronary revascularisation. After a median follow-up of 502 days, a primary endpoint was reached by 1,031 of the half given vorapaxar, and 1,102 of those given placebo. However, rates of moderate and severe bleeding were higher, at 7.2%, in the active group, compared with 5.2% in the placebo group. Although the drug gave a slight – but not significant – improvement in the primary endpoint, there was a significant increase in the risk of major bleeding events, and follow-up was stopped after a safety review.

In the second Phase III trial, 26,449 patients with a history of myocardial infarction, ischaemic stroke or peripheral artery disease were given 2.5mg daily doses or vorapaxar or placebo, and they were followed for a median 30 months.4 Primary efficacy endpoint was a composite of death from cardiovascular events, myocardial infarction or stroke. After three years, 9.3% of the vorapaxar group and 10.5% of those given placebo had reached a primary endpoint, but moderate or severe bleeding took place in 4.2% of the active group, and 2.5% of the placebo group. There was also an increase in the incidence of intracranial haemorrhage in those given vorapaxar – 1% compared with 0.5% given placebo. The study’s data and safety monitoring board advised the study should be stopped and Merck is now deciding whether to proceed further with development of the drug.


1. S. Chackalamannil et al. J. Med. Chem. 2008, 51, 3061

2. R.C. Becker et al. Lancet 2009, 373, 919

3. P. Tricoci et al. N. Engl. J. Med. 2012, 366, 20

4. D.A. Morrow et al. N. Engl. J. Med. 2012, 366, 1404