New developments in oral antiplatelet therapy

Abstract

Oral antiplatelet therapy is central to the treatment of patients with thrombotic diseases. Yet, despite the proven efficacy of currently available agents such as aspirin and the P2Y12 receptor antagonist clopidogrel, and their advocacy in treatment guidelines, their efficacy and utilization remain suboptimal. This has prompted the search for more efficacious oral antiplatelet agents. Drug classes that have been, or continue to be, investigated include thromboxane A2/prostaglandin H2 (TXA2/PGH2; TP) receptor antagonists, protease-activated receptor (PAR) antagonists, and newer P2Y12 receptor antagonists. TP receptors are G-protein-coupled receptors that, on agonist binding, activate the phospholipase C signalling cascade, resulting in platelet activation. The success of TP receptor antagonists has been limited to date; the majority of agents have been discontinued at phase I/II clinical trials following efficacy and safety concerns. However, S-18886 (terutroban) remains in development. Results from preclinical investigations demonstrate S-18886 to have comparable antiplatelet effects to clopidogrel, while data from phase II studies appear promising. Inhibiting the actions of thrombin on platelets represents an emerging area of antiplatelet research, and compounds that target the PAR1 receptor are in early development. These include the PAR1-selective antagonist SCH 530348, which is currently being evaluated in phase III studies in patients with acute coronary syndromes (ACS), prior myocardial infarction, stroke, and existing peripheral arterial disease. The P2Y12 G protein receptor is predominately located on platelets and is involved in the amplification of platelet activation. Owing to limitations of first- and second-generation thienopyridine P2Y12 antagonists such as clopidogrel, new antagonists are being evaluated. The irreversible thienopyridine P2Y12 antagonist prasugrel is currently in phase III development and has the potential to provide additional benefits over clopidogrel, including faster onset of action with improved inhibition of ADP-induced platelet aggregation and fewer non-responders. The differences in response are thought to be due to the more efficient generation of the active metabolite of prasugrel. The phase II JUMBO-TIMI 26 trial, which compared prasugrel with clopidogrel in patients undergoing elective or urgent percutaneous coronary intervention (PCI), reported low rates of bleeding with both drugs and a trend towards a reduction in ischaemic events with prasugrel relative to clopidogrel. However, the trial was not powered to show clinical outcomes. Reversible, non-thienopyridine P2Y12 receptor antagonists are a further class of antiplatelet agents undergoing evaluation in clinical trials and include cangrelor, an ATP analogue. Cangrelor is a fast- and direct-acting, intravenous antiplatelet agent which has completed phase II clinical trials for the acute treatment of patients with ACS undergoing PCI. AZD6140 is a CPTP (cyclo-pentyl-triazolo-pyrimidine), and the first oral reversible antiplatelet agent in development for use in patients with ACS. Unlike the irreversible thienopyridines, AZD6140 does not require cytochrome P450 metabolic activation to exert its inhibitory effects on platelet aggregation. Data from the phase II DISPERSE trial demonstrates AZD6140 to have a more rapid onset of action and a significantly greater and more consistent inhibition of platelet aggregation when compared with clopidogrel in stable patients with atherosclerotic disease. Publication of the full analysis from the second phase II trial, DISPERSE2, is pending while recruitment is underway for the phase III PLATO (study of PLATelet inhibition and patient Outcomes). PLATO is a head-to-head outcomes study investigating the use of AZD6140 vs. clopidogrel for ACS in patients treated with medical therapy, PCI, or coronary artery bypass graft, with a planned recruitment of 18 000 patients worldwide. Data from ongoing phase II and III clinical trials on the emerging antiplatelet agents are eagerly awaited. If these agents offer improvements over those currently available in terms of patient response to therapy, safety, and convenience, they are likely to influence the current prescribing patterns and guidelines.