Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist.
Ticagrelor (AZD6140) is the first reversibly binding oral P2Y(12) receptor antagonist that blocks ADP-induced platelet aggregation. Unlike thienopyridines, which irreversibly bind to the P2Y(12) receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels. Animal models indicate greater separation between antithrombotic effects and bleeding effects with ticagrelor than with thienopyridines. Unlike the thienopyridines, ticagrelor does not require metabolic activation. It is quickly absorbed and exhibits a rapid antiplatelet effect, with higher and more consistent levels of inhibition of platelet aggregation (IPA) being maintained across the dosing interval than with clopidogrel. IPA levels decline with plasma drug levels after discontinuation of dosing. In the phase II DISPERSE-2 trial of 990 patients with non-ST-elevation acute coronary syndromes (ACS), ticagrelor treatment with 90 mg and 180 mg twice daily showed comparable rates of major and minor bleeding compared with clopidogrel 75 mg while there were numerically fewer myocardial infarctions. Ticagrelor resulted in greater IPA in clopidogrel-naïve patients and produced substantial additional reductions in platelet aggregation activity in patients pretreated with clopidogrel. Ticagrelor treatment was well tolerated in DISPERSE-2, and discontinuation rates were comparable to those observed for clopidogrel. An increased risk of mild to moderate dyspnea and mostly asymptomatic ventricular pauses were observed in phase II studies. The mechanisms for these effects are currently being investigated. The efficacy and safety of ticagrelor are being further evaluated in the phase III PLATO trial, involving approximately 18,000 patients with ACS, including both ST-elevation and non-ST-elevation ACS.
Husted
Steen
S
Department of Medicine and Cardiology, Aarhus University Hospital, DK-8000 Aarhus, Denmark. steehust@rm.dk
van Giezen
J J J
JJ
D054058:Acute Coronary Syndrome / Q000188:drug therapy; D000241:Adenosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy; D002986:Clinical Trials as Topic; D000077144:Clopidogrel; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects
C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine