Review of prasugrel for the secondary prevention of atherothrombosis

Abstract

Background: The role of platelets in atherothrombotic disease is well established, and antiplatelet therapy is now recommended for the shortand long-term management of patients with acute coronary syndromes (ACS), with and without percutaneous coronary intervention (PCI). The thienopyridine clopidogrel is accepted as a key component of antiplatelet management and is recommended in current treatment guidelines as addon therapy to aspirin in secondary prevention to reduce coronary risk in patients with ACS and/or following PCI. The FDA Cardiovascular and Renal Drugs Advisory Committee met on February 3, 2009, and recommended approval of prasugrel, but with guidance to physicians about increased risk in low-weight or elderly patients and avoidance of use (a) around coronary artery bypass graft (CABG) or other surgical or invasive procedures and (b) in patients with prior or current stroke or transient ischemic attack (TIA).

Objective: To review the published literature examining primarily the clinical efficacy and safety of prasugrel in ACS patients.

Methods: The PubMed database was searched for English language studies involving the use of prasugrel in human subjects published up to April 2009 using the keyword "prasugrel." The review focused on randomized, controlled trials with clinical end points. Abstracts from recent scientific meetings (up to November 2008) were also searched for relevant studies, as was the FDA briefing document prepared in advance of the advisory committee meeting on February 3, 2009.

Results: Of the 124 published papers identified, 28 pertained to research in human subjects: 21 on prasugrel pharmacology and 7 with clinical end points. In the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction (PRINCIPLE-TIMI) 44 trial, a cross-over study of laboratory-determined platelet activity, prasugrel produced significantly greater inhibition of platelet aggregation than clopidogrel after both loading dose (74.8% vs. 31.8% at 6 hours, P < 0.001) and maintenance dose (day 14: 61.3% vs. 46.1%, P < 0.001) in patients with stable coronary artery disease (CAD). In the only end point outcomes study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction [TRITON-TIMI 38]) there was a significant reduction in adverse cardiac outcomes in patients with ACS treated with prasugrel, 94% of whom received at least 1 coronary stent. The incidence of the primary composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke was 9.9% in the prasugrel group versus 12.1% in the clopidogrel group (hazard ratio = 0.81, 95% CI = 0.73-0.90, P < 0.001). However, the risk of a major bleeding event was significantly greater with prasugrel versus clopidogrel, and prasugrel appeared to be of net clinical harm in patients with a history of stroke/TIA. The FDA reviewer recommended that prasugrel use be discouraged in patients aged 75 years or older or those with a history of stroke/TIA.

Conclusion: Available data suggest that prasugrel offers potential as an alternative to clopidogrel with greater efficacy but with increased bleeding risk in patients with ACS who receive PCI. Data are not yet available to define the efficacy and risk-benefit profile of prasugrel in patients not undergoing PCI.