Platelet inhibitor therapy: Current perspectives and emerging novel agents: Introduction

The observation that platelets play a pivotal role in the pathophysiology of acute coronary syndromes (ACS) and complications after percutaneous coronary intervention (PCI) has led to the development of antiplatelet agents as the cornerstone of treatment in these clinical scenarios. Dual antiplatelet therapy was first explored in the emerging clinical setting of coronary stenting, but the failure to identify a safe and efficacious antithrombotic drug regimen in the initial era of coronary stenting significantly limited the growth of coronary interventions. Thienopyridines are a class of oral agents that inhibit platelet aggregation by blocking the adenosine 5′-diphosphate (ADP)-dependent activation of platelets mediated by the ADP P2Y12 receptor on platelets. Landmark clinical trials have confirmed that cardiovascular outcomes in patients with ACS and undergoing PCI are significantly improved by combined thienopyridine and aspirin treatment.1, 2, 3, 4, 5, 6 Ticlopidine is a first-generation thienopyridine, which enhances platelet inhibition in combination with aspirin because of the additive effects achieved with the blockade of the P2Y12 and cyclooxygenase 1 pathways. Although there have been clinical advantages associated with the use of ticlopidine, its significant side effect profile subsequently led to its replacement by clopidogrel as the thienopyridine of choice. Thus, clopidogrel in combination with aspirin is the currently recommended standard of care for reducing the number of cardiovascular events related to PCI in patients with stable coronary artery disease and in patients presenting with ACS.

Despite the important short-term and long-term clinical benefits conferred by current antiplatelet agents, there are a number of significant limitations associated with these agents. For example, shortcomings associated with clopidogrel include individual variability in response, delayed platelet inhibition, drug resistance or hyporesponsiveness, and a prolonged time course of recovery of platelet function.7 Furthermore, a considerable number of patients continue to experience cardiovascular events despite dual antiplatelet therapy, including myocardial infarction and coronary stent thrombosis. These events have been attributed to poor antiplatelet drug response in some patients. New agents with more potent and consistent inhibition of platelet function are clearly needed. Consequently, there has been considerable effort in clinical cardiology directed to the development of antiplatelet therapies with clinical profiles superior to those of current standards of care.

In this supplement, we describe the benefits and limitations of current antiplatelet therapies and present an overview of the pharmacology and recent clinical trial results for novel platelet inhibitors in advanced clinical testing. Emerging antiplatelet agents that will be discussed include prasugrel (CS-747; LY-640315), ticagrelor (AZD6140), cangrelor (ARC-69931MX), and SCH 530348. Prasugrel (CS-747; LY-640315) is a third-generation oral thienopyridine that is a specific, irreversible antagonist of the platelet ADP P2Y12 receptor. Cangrelor and ticagrelor are reversible inhibitors of the platelet ADP P2Y12 receptor, whereas SCH 530348 is a novel thrombin receptor antagonist. Results of phase II studies and ongoing phase III trials have shown favorable safety and efficacy profiles for these promising antiplatelet therapies that have the potential to overcome the limitations of current antiplatelet agents and provide improved clinical outcomes in patients who have ACS and/or are undergoing PCI.