Novel antiplatelet strategies in acute coronary syndromes

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Both prasugrel and clopidogrel are irreversible P2Y 12 receptor blockers. For this reason, one must wait approximately 5 days after the last dose of either medication for generation of a sufficient number of new platelets to allow restoration of normal platelet-mediated hemostasis.

Inhibition of platelet aggregation relative to clopidogrel

In a study among healthy volunteers, inhibition of platelet aggregation was significantly higher after a 60-mg loading dose of prasugrel compared with a 300-mg loading dose of clopidogrel. 13 Further, suboptimal responders to clopidogrel who crossed over to prasugrel had levels of platelet inhibition as high as 80% following prasu­grel administration. The time to peak effect of prasugrel was about 1 hour. Inhibition of platelet aggregation was more consistent following dosing of prasugrel compared with clopidogrel. 13

In a study of 201 patients undergoing cardiac catheterization with planned PCI, Wiviott et al demonstrated better levels of inhibition of platelet aggregation at 6 hours after a 60-mg loading dose of prasugrel than after a 600-mg loading dose of clopidogrel ( P < .0001). 1

Clinical effects relative to clopidogrel: TRITON-TIMI 38

A large phase 3 clinical trial—the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38—was conducted to compare the effects of prasugrel and standard-dose clopidogrel on death and ischemic end points in 13,608 patients with ACS scheduled to undergo PCI. 15 Patients randomized to clopidogrel were given the standard regimen of a 300-mg loading dose followed by a 75-mg daily maintenance dose; those randomized to prasugrel were given a 60-mg loading dose followed by a 10-mg daily maintenance dose. The study drug was typically given immediately before PCI, a time frame that may mimic real-life use but that favored the faster-onset prasugrel over the slower-onset clopidogrel. Both groups also received low-dose aspirin. Approximately half of the patients in each group were treated with a glycoprotein IIb/IIIa inhibitor. The median duration of therapy was approximately 15 months.

Efficacy. The primary end point—a composite of cardiovascular death, MI, or stroke—occurred in 9.9% of patients randomized to prasugrel compared with 12.1% of those randomized to clopidogrel, corresponding to a 19% relative risk reduction ( P = .0004) with prasugrel. Based on these results, 46 patients would need to be treated with prasugrel rather than with clopidogrel to prevent 1 additional cardiovascular death, MI, or stroke. 15

Reprinted, with permission, from New England Journal of Medicine (Wiviott SD, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001–2015), © 2007 Massachusetts Medical Society. All rights reserved.

Figure 2. Cumulative Kaplan-Meier estimates of the rates of the primary efficacy end point (composite of cardio­vascular death, myocardial infarction, or stroke) and the key safety end point (major bleeding not related to coronary artery bypass grafting) with clopidogrel and prasugrel in the 13,608-patient TRITON-TIMI 38 trial. 15

Prasugrel was associated with significant reductions in the occurrence of the primary end point during both the loading-dose phase ( P = .01) and the maintenance-dose phase ( P

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