Prasugrel A Review of its Use in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention

Prasugrel (Efient (R)) is a potent, selective and irreversible inhibitor of adenosine diphosphate (ADP)-mediated platelet aggregation that is indicated for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS) [comprising unstable angina pectoris/non-ST-segment-elevation myocardial infarction (unstable angina/NSTEMI) and ST-segment-elevation myocardial infarction (STEMI)] undergoing percutaneous coronary intervention (PCI). Oral prasugrel provides rapid, potent inhibition of platelet aggregation and is an effective antiplatelet agent for the management of patients with ACS who are undergoing PCI. In these patients, prasugrel was associated with a significantly lower incidence of ischaemic events than clopidogrel, and was particularly effective in specific subgroups of patients, such as those with diabetes mellitus. However, the efficacy of prasugrel was offset by a higher risk of bleeding than clopidogrel, with patients aged >= 75 years, those weighing <60 kg and those with a history of stroke or transient ischaemic attack at the greatest risk. A lower dose of prasugrel in patients aged >= 75 years and those weighing <60 kg may help to minimize the bleeding risk, although more data are needed to establish this; prasugrel is contraindicated in patients with a history of stroke or transient ischaemic attack. Thus, prasugrel provides a new option for the management of patients with ACS who are undergoing PCI; the risk-benefit ratio should be carefully assessed before intensive antiplatelet therapy with prasugrel is initiated. Pharmacological Properties Prasugrel is a potent thienopyridine antiplatelet agent that selectively and irreversibly inhibits ADP-induced platelet aggregation mediated by the P2Y(12) receptor. Prasugrel is a prodrug that must first undergo biotransformation to its active metabolite via cytochrome P450-mediated hepatic metabolism. In healthy volunteers, patients undergoing PCI and patients with coronary artery disease, greater and more rapid inhibition of platelet aggregation was seen with prasugrel than with clopidogrel. Inhibition of platelet aggregation occurred : 1 hour after administration of prasugrel. Metabolism of prasugrel to the active metabolite occurred rapidly with the peak plasma concentrations of the active metabolite reached within approximate to 30 minutes. Formation of the active metabolite was more rapid and extensive with prasugrel than with clopidogrel, potentially explaining its more rapid onset and greater degree of platelet aggregation inhibition. Therapeutic Efficacy In a large, randomized, double-blind, multicentre, phase III trial known as the TRITON-Thrombolysis In Myocardial Infarction (TIMI) 38, prasugrel was more effective than clopidogrel in the prevention of ischaemic events during long-term follow-up for up to 15 months in patients with ACS who were undergoing scheduled PCI, as well as during the periprocedural period (first 3 days of treatment). The risk of death from cardiovascular causes, nonfatal myocardial infarction and nonfatal stroke (composite primary endpoint) in patients with unstable angina, NSTEMI or STEMI was significantly lower with prasugrel than with clopidogrel. Landmark analyses demonstrated this effect was apparent both during the first 3 days of treatment and from day 3 until the end of the trial. Prasugrel was also significantly more effective than clopidogrel in reducing ischaemic events in various patient subpopulations, including patients who had received at least one coronary stent and patients undergoing PCI for STEMI, while a more pronounced effect was observed in patients with a history of diabetes. The incidence of recurring cardiovascular events were also significantly lower in prasugrel recipients than in clopidogrel recipients. Tolerability Bleeding events were the most frequently reported adverse events associated with prasugrel treatment. The incidence of TIMI major bleeding events not related to coronary artery bypass grafting (CABG) was significantly higher with prasugrel than clopidogrel, including the incidence of life-threatening bleeding and fatal bleeding events. Combined non-CABG-related TIMI major and minor bleeding events were also more frequent in prasugrel recipients than in clopidogrel recipients, while a greater percentage of prasugrel than clopidogrel recipients discontinued treatment because of adverse events related to bleeding. Post hoc analyses showed that patients aged >= 75 years and those weighing <60 kg experienced no net benefit, and those with a history of cerebrovascular events experienced net harm and an increased risk of intracranial bleeding compared with clopidogrel. The frequency of serious adverse events not related to bleeding was generally similar between prasugrel and clopidogrel recipients.