Role of prasugrel, a novel P2Y(12) receptor antagonist, in the management of acute coronary syndromes

Abstract

Prasugrel is a new P2Y(12) receptor antagonist that has been investigated for the treatment of atherothrombosis in patients with cardiovascular disease undergoing percutaneous coronary intervention (PCI). Similar to other thienopyridines, prasugrel is a prodrug that requires biologic conversion to active metabolites. Studies have demonstrated the ability of prasugrel to selectively and irreversibly inhibit ADP-induced platelet aggregation to a greater degree than clopidogrel. In a large randomized, double-blind, double-dummy clinical trial, it was demonstrated that treatment with prasugrel (n = 6813; 60 mg loading dose followed by 10 mg/day) significantly reduced the incidence of a composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke during the median follow-up of 14.5 months, compared with clopidogrel (n = 6795; 300 mg loading dose followed by 75 mg/day) in patients with acute coronary syndromes scheduled to undergo PCI. The number of patients who would need to be treated with prasugrel instead of clopidogrel in order to prevent one primary efficacy outcome was 46. Landmark analyses found that prasugrel not only reduced the incidence of individual clinical endpoints and stent thrombosis during the loading dose phase (randomization to 3 days), but also that these benefits continued throughout the maintenance phase (from 3 days until the end of the trial). Nonsurgical-related Thrombolysis In Myocardial Infarction (TIMI)-major and life-threatening bleeds were significantly more frequent in patients receiving prasugrel compared with clopidogrel. Patients with a history of stroke or transient ischemic attack (TIA) seem to be at especially high risk for bleeding, as well as patients aged >75 years and those weighing <60 kg. A prespecified analysis of net clinical benefit, which took into account the effects on both the primary efficacy and safety endpoints, was conducted. After taking into account the higher bleeding rates, the net clinical benefit still favored prasugrel use compared with clopidogrel. However, patients with prior stroke or TIA, patients older than 75 years, and patients weighing <60 kg did not demonstrate a net clinical benefit with prasugrel use. Prasugrel was approved for use in Europe by the European Commission in February 2009, and is currently available in the UK. In July 2009, the US Food and Drug Administration (FDA) approved the use of prasugrel for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with PCI.