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

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 than clopidogrel.16 This drug was examined against clopidogrel in the Study of Platelet Inhibition and Patient Outcomes (PLATO), which showed a mortality benefit of the former in a broad spectrum of ACS patients.17 AstraZeneca (ie, the sponsor) therefore presented efficacy and safety data regarding ticagrelor to the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee (CRDAC) on July 28, 2010, in Adelphi, MD. The sponsor sought approval for the indication of reduction of thrombotic events, including stent thrombosis, in patients with unstable angina, non–ST-segment MI (NSTEMI), and ST-segment elevation MI (STEMI) who are to be managed either medically or invasively (with either PCI or coronary artery bypass grafting). The FDA asked CRDAC to opine on whether the data presented by the sponsor demonstrated a reasonable level of efficacy (in regard to the end point of cardiovascular death, MI, and stroke) and safety, including the adverse events of bleeding, dyspnea, and bradycardia.