Ticagrelor - toward more efficient platelet inhibition and beyond

Abstract

Novel antiplatelet drugs, including ticagrelor, are being successively introduced into the therapy of atherothrombotic conditions due to their superiority over a standard combination of clopidogrel with acetylsalicylic acid in patients with acute coronary syndromes (ACS). A P2Y12 receptor antagonist, ticagrelor, is unique among antiplatelet drugs, because ticagrelor inhibits the platelet P2Y12 receptor in a reversible manner, and because it demonstrates a wide palette of advantageous pleiotropic effects associated with the increased concentration of adenosine. The pleiotropic effects of ticagrelor comprise cardioprotection, restoration of the myocardium after an ischemic event, promotion of the release of anticoagulative factors and, eventually, anti-inflammatory effects. Beyond the advantageous effects, the increased concentration of adenosine is responsible for some of ticagrelor's adverse effects, including dyspnea and bradycardia. Large-scale clinical trials demonstrated that both standard 12-month therapy and long-term use of ticagrelor reduce the risk of cardiovascular events in patients with ACS, but at the expense of a higher risk of major bleeding. Further trials focused on the use of ticagrelor in conditions other than ACS, including ischemic stroke, peripheral artery disease and status after coronary artery bypass grafting. The results of these trials suggest comparable efficacy and safety of ticagrelor and clopidogrel in extra-coronary indications, but firm conclusions are anticipated from currently ongoing studies. Here, we summarize current evidence on the superiority of ticagrelor over other P2Y12 antagonists in ACS, discuss the mechanism underlying the drug-drug interactions and pleiotropic effects of ticagrelor, and present future perspectives of non-coronary indications for ticagrelor.

Keywords: P2Y12; acute coronary syndromes; antiplatelet drugs; myocardial infarction; pleiotropism; ticagrelor.

Figure 1

Ticagrelor versus prasugrel – efficiency and safety comparison. Notes: Differences between (A) PLATOs-defined overall primary endpoint risk (myocardial infarction, stroke, death from vascular causes); (B) non-CABG-associated major bleeding risk; (C) PLATO-defined primary endpoint risk in NSTE-ACS patients; (D) PLATO-defined primary endpoint risk in STEMI patients; and (E) PLATO-defined overall mortality risk among PLATO and TRITON TIMI (Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes) 38 studies. Abbreviations: RRR, relative risk reduction; NNT, number needed to treat; RRI, relative risk increase; NNH, number needed to harm; CABG, coronary artery bypass graft; NSTE-ACS, non-ST-elevation acute coronary state; STEMI, ST segment elevation myocardial infarction.

Figure 2

Mechanisms underlying the probable adenosine-dependent and non-adenosine-dependent pleiotropic effects of ticagrelor. Abbreviations: ICaL, L-type Ca(2+) currents in cardiomyocytes; PAI, plasminogen activation inhibitor; EGF, endothelial growth factor; IL-10, interleukin 10; hENT1, human equilibrative nucleoside transporter 1; ATP, adenosine triphosphate; ADP, adenosine diphosphate; VSMC, vascular smooth muscle cells.