Evaluating the Risk-Benefit Profile of the Direct-Acting P2Y12 Inhibitor Ticagrelor in Acute Coronary Syndromes

Ticagrelor is a direct-acting, oral, reversibly binding P2Y(12) receptor antagonist. As a cyclopentyltriazolopyrimidine, ticagrelor represents a new chemical class of agents that do not require metabolic activation and have consistent ability to inhibit platelet aggregation. The phase 3 PLATelet Inhibition and Patient Outcomes (PLATO) trial (NCT00391872) evaluated ticagrelor compared with clopidogrel in I 8 624 patients with acute coronary syndromes (ACS), and demonstrated a significant reduction in the risk of death from vascular causes/myocardial infarction (MI)/stroke with ticagrelor (9.8% vs 11.7% with clopidogrel [hazard ratio, 0.84; 95% confidence interval, 0.77-0.92]; P < 0.001) without a significant increase in PLATO-defined major bleeding (11.6% vs 11.2%, respectively; P = 0.43). Myocardial infarction and death from vascular causes were separately significantly reduced, and death from any cause and stent thrombosis reductions achieved nominal statistical significance. Ticagrelor showed benefit over clopidogrel in almost all patient subgroups, including patients who had previously received clopidogrel, patients with both planned invasive or noninvasive treatment, patients with ST-segment elevation MI (STEMI) referred for primary percutaneous coronary intervention, patients with non-STEMI, and patients who underwent bypass surgery. Hence, the PLATO population reflected specifically those patients who would ordinarily receive thienopyridine-based antiplatelet therapy in a clinical setting. Although there are limitations in directly translating trial findings to clinical practice, the findings of PLATO suggest that for every 1000 ACS patients admitted to hospital, using ticagrelor instead of clopidogrel for 12 months would result in 14 fewer deaths or 11 fewer MIs. This review places the PLATO data in context, and assesses the role that ticagrelor may play in treating patients with ACS.