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Prasugrel—Polit..

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On February 3, 2009, the Cardiovascular and Renal Drugs Advisory Committee to the FDA voted to approve prasugrel (Effient, Eli Lilly), an adenosine diphosphate (ADP) P2Y12 receptor antagonist with a mechanism similar to the thienopyridines clopidogrel and ticlopidine. While the committee meeting minutes lists consensus on each question and had a final vote in favor of prasugrel of 9 to 0, the approval was not without controversy. To begin, the process for approval for this drug has the appearance of tampering. Sanjay Kaul, MD, MPH of Cedar-Sinai Heart Institute who had been critical of approval was disinvited after Eli Lilly representatives reportedly raised allegations of “intellectual bias.” Since the meeting, the director of the Center for Drug Evaluation and Research (CDER) at the FDA and the director of the FDA have each received letters from the consumer group Public Citizen challenging the procedures surrounding the approval of prasugrel.

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The potential benefit of prasugrel as an antiplatelet agent is described in one major clinical trial. Wiviott and colleagues reported the results of the TRITON-TIMI 38 study1 in November 2007. This was a randomized, double-blind comparison of prasugrel (60mg loading dose + 10mg daily maintenance) to clopidogrel (300mg loading dose + 75mg daily maintenance) in 13,608 patients with a wide spectrum of acute coronary syndromes (ACS). Both groups also received low-dose aspirin daily. The primary endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Overall mortality did not significantly differ between groups. The primary safety endpoint was major bleeding. After a treatment of up to 15 months, the primary endpoint was met in 12.1% of the clopidogrel treated patients compared to 9.9% for the prasugrel group. This gives a hazard ratio of 0.81 in favor of prasugrel [95% CI 0.73-0.90]. When preselected subgroups for the primary endpoint were analyzed, prasugrel performed better or there was no difference. However, in the safety endpoints, bleeding events including major, life-threatening, and fatal bleeding were more frequent in the prasugrel group than in the clopidogrel group. The hazard ratio for fatal bleeding with prasugrel was 4.19 [95% CI 1.58-11.1].

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Another potential concern is the cancer signal in the studies done so far. The TRITON study reported 119 new cancers in the prasugrel group and 87 in the clopidogrel group. While TRITON-TIMI 38 was not designed to evaluate cancer risk in patients treated with a thienopyridine, it did not specifically include or exclude patients with cancer. Thus, some patients with pre-existing cancer or risks were likely included. In a review just published and in a recent editorial, Serebruany discusses increased cancer risk with aggressive chronic platelet inhibition.2,3 Since clopidogrel and prasugrel are structurally similar, it is unlikely that prasugrel is a direct carcinogen or is an indirect modulator, but it is possible that its greater inhibition of platelet activity indirectly enhances neoplastic growth. Serebruany reports that platelet activity (biomarkers, hypercoagulation, and impaired fibrinolysis) and tumor progression have been linked previously, so it ...

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