Overview of the 2010 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee Meeting Regarding Ticagrelor

Abstract

Landmark clinical trials established the benefit of the thienopyridine clopidogrel, an irreversibly binding inhibitor of the platelet P2Y12 receptor, in the setting of acute coronary syndromes (ACS).1,–,3 Clopidogrel has thus become a key component of the current standard of care for antiplatelet therapy in the setting of ACS.4,5 Evidence has emerged, however, regarding the inherent limitations of clopidogrel. The concept of “clopidogrel resistance,” or the failure of clopidogrel to inhibit the target of its action,6 is in part due to a wide range of variability in the antiplatelet effect of clopidogrel. Specifically, clopidogrel is a prodrug that requires metabolism by the cytochrome P450 system to generate an active metabolite7,–,9; as such, common variations in genes encoding enzymes that are involved in the metabolism of clopidogrel may affect the level of platelet inhibition.10 Furthermore, high on-treatment platelet reactivity is an emerging risk factor in patients undergoing percutaneous coronary intervention (PCI), and increased doses of clopidogrel only partially ameliorate this difficulty.11 The newly approved thienopyridine prasugrel achieves more rapid and effective platelet inhibition than clopidogrel as a result of more efficient metabolism12; in addition, the effect of prasugrel is not affected by genetic variations in cytochrome P450.13 Although prasugrel appeared to reduce myocardial infarction (MI) and stent thrombosis when compared directly to clopidogrel, this came at the cost of an increase in major bleeding.14 Ticagrelor is the first of a new class of antiplatelet agents, the cyclopentyl-triazolo-pyrimidines, that also target the P2Y12 receptor. Unlike the thienopyridines, however, it is a reversibly binding inhibitor with a half-life of approximately 12 hours.15,16 Furthermore, it does not require metabolic activation, and it achieves greater and more consistent platelet inhibition …