Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety

Abstract

Dual antiplatelet therapy, composed of aspirin plus a P2Y12 -receptor antagonist, is the cornerstone of treatment for patients with acute coronary syndrome (ACS). A number of U.S. Food and Drug Administration-approved P2Y12 -receptor antagonists are available for treating patients with ACS, including the thienopyridine compounds clopidogrel and prasugrel. Ticagrelor, the first of a new class of antiplatelet agents, is a noncompetitive, direct-acting P2Y12 -receptor antagonist. Unlike the thienopyridine compounds, ticagrelor does not require metabolism for activity. Also, whereas clopidogrel and prasugrel are irreversible inhibitors of the P2Y12 receptor, ticagrelor binds reversibly to inhibit receptor signaling and subsequent platelet activation. In pharmacodynamic studies, ticagrelor demonstrated faster onset and more potent inhibition of platelet aggregation than clopidogrel. These properties of ticagrelor may contribute to reduced rates of thrombotic outcomes compared with clopidogrel, as demonstrated in a phase III clinical trial. However, in addition to bleeding, distinctive adverse effects of this new chemical entity have not been reported with the thienopyridine P2Y12 -receptor inhibitors. Although ticagrelor represents an advancement in P2Y12 -receptor inhibition therapy, a thorough understanding of this compound as an antiplatelet therapy remains to be elucidated.

Keywords: ACS; CAD; P2Y12 inhibitors; acute coronary syndrome; antiplatelets; coronary artery disease; ticagrelor.

Figure 1

Chemical structures of the thienopyridine compounds prasugrel and clopidogrel.

Figure 2

Chemical structures of adenosine triphosphate (ATP), ticagrelor, and cangrelor.

Figure 3

Final inhibition of platelet aggregation in patients with stable coronary artery disease who received ticagrelor (180-mg loading dose followed by a 90 mg twice/day maintenance dose), clopidogrel (600-mg loading dose followed by a 75-mg/day maintenance dose), or placebo for 6 weeks in the ONSET/OFFSET study. *p<0.0001; ^†p<0.005; ^‡p<0.05.

Figure 4

Maximum inhibition of platelet aggregation (IPA) in patients with stable coronary artery disease who were clopidogrel nonresponders (41 patients; panel A) and clopidogrel responders (57 patients; panel B) and were randomized to either ticagrelor (180-mg loading dose followed by 90 mg twice/day) or clopidogrel (600-mg loading dose followed by 75 mg once/day) for 14 days (period 1), then switched treatments (period 2; all nonresponders; half of responders). ADP = adenosine diphosphate. *p<0.0001; ^†p<0.001; ^‡p<0.05.