Critical review of prasugrel for formulary decision makers.

BACKGROUND Cardiovascular disease, including acute coronary syndromes (ACS) comprising ST-elevation and non-ST-elevation myocardial infarction (STEMI/NSTEMI) and unstable angina (UA), remains the leading cause of death in the United States. The direct and indirect costs of cardiovascular disease are estimated to surpass $165 billion in 2009. Antiplatelet pharmacotherapy has been shown to reduce ACS-related death and is part of the American College of Chest Physicians (ACCP) and the American College of Cardiology /American Heart Association (ACC/AHA) treatment guideline recommendations. OBJECTIVE To provide formulary decision makers with information on the pharmacokinetics and pharmacodynamics of the thienopyridine antiplatelet agent prasugrel as well as an analysis of available efficacy and safety data and its risk-benefit profile in comparison with clopidogrel. METHODS Literature search for information on prasugrel with a focus on (a) the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial, (b) briefing documents from the FDA available as of March 1, 2009, and (c) ongoing phase III studies of prasugrel. RESULTS TRITON-TIMI 38 was a double blind, randomized superiority study involving 13,608 patients with moderate-to high-risk acute coronary syndromes with scheduled percutaneous coronary intervention (PCI). TRITON-TIMI 38 data were available in a published manuscript and in an FDA review. Study patients were randomized to either prasugrel or clopidogrel once daily. The primary end point (composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in 643 patients (9.9%) in the prasugrel group and 781 patients (12.1%) in the clopidogrel group (HR = 0.82, 95% CI = 0.73-0.93, P = 0.002). Non-coronary artery bypass graft (non-CABG) TIMI major hemorrhage occurred in 146 patients (2.4%) in the prasugrel group compared with 111 patients (1.8%) in the clopidogrel group (HR=1.32, 95% CI=1.03-1.68, P = 0.03). A subanalysis of the TRITON-TIMI 38 trial data revealed a net harm for patients with a prior history of stroke or transient ischemic attack (TIA) when treated with prasugrel (HR = 1.54, 95% CI = 1.02-2.32, P = 0.04). Combination prasugrel and aspirin is currently being studied in comparison with clopidogrel and aspirin for the treatment of UA/NSTEMI patients that are medically managed. CONCLUSIONS For every 1,000 patients treated with prasugrel instead of clopidogrel, a total of 24 end points would be prevented at the cost of 10 additional bleeding events. On February 3, 2009, the FDA Cardiovascular and Renal Drugs Advisory Committee deemed this to be an acceptable riskbenefit profile. The committee recommended a label contraindication for patients with prior history of transient ischemic attack or stroke. Treatment versus time analyses demonstrated both early and sustained benefit for prasugrel compared with clopidogrel. However, prasugrel was associated with fewer cardiovascular events prevented per bleeding case the longer the duration of therapy. The study population of TRITON-TIMI 38 was limited to patients undergoing PCI. Managed care decision makers should consider specific criteria limiting prasugrel use to health plan members with characteristics similar to the study population in TRITON-TIMI 38 that benefited from treatment and avoiding use in patients with prior history of stroke or TIA. More data are needed before prasugrel can be recommended in patient groups not addressed by TRITON-TIMI 38.