New antiplatelet therapies in development

Abstract

The efficacy and safety of new antiplatelet therapies, as well as antiplatelet therapies in development, are reviewed. Variability in the response to treatment with aspirin has been recognized for more than 40 years. Thienopyridine antiplatelet agents are now a standard pharmacologic component in the management of patients undergoing percutaneous coronary intervention (PCI) and stent placement. However, investigators have recently described wide inter-individual variability in the level of platelet inhibition following treatment with the thienopyridine clopidogrel, with a small number of patients classified as "non-responders" or "resistant." Such variability in response is likely to have important clinical implications, because antiplatelet therapy plays a key role in the prevention and treatment of cardiovascular disease, For example, recent studies have demonstrated that diminished response to clopidogrel may be associated with increased cardiac events after PCI. Even with larger-than-approved loading doses, clopidogrel requires several hours to reach a steady-state effect, and therapy must be discontinued for several days prior to surgery in order to avoid major bleeding events. Clinical trials of prasugrel, a new oral thienopyridine with a more rapid onset of platelet inhibition, have demonstrated significant reductions in adverse cardiovascular outcomes and stent thrombosis; however, there is an increased risk for major bleeding events with prasugrel in some subgroups of the study populations. These limitations have led to development of agents that may potentially overcome such clinical challenges. AZD6140, a novel, potent oral P2Y12 antagonist, demonstrated more effective platelet inhibition versus clopidogrel in a large randomized trial of patients with acute coronary syndrome. However, patients taking AZD6140 reported dyspnea significantly more frequently than those taking clopidogrel. Cangrelor, a novel intravenous P2Y(12) receptor antagonist with a rapid onset of action and complete reversibility of platelet inhibition within 20-50 minutes of administration, may offer advantages over currently approved antiplatelet therapies. A new oral antiplatelet thrombin-receptor antagonist, TRA-SCH 530348, is in early clinical trials. Unlike currently available drugs, TRA-SCH 530348 effectively prevents thrombin-induced activation of platelets. Each new class of antiplatelet therapies has the potential for specific benefits and adverse effects in clinical use.