Combined antiplatelet therapy: still a sweeping combination in cardiology

Platelets play a key role in the pathogenesis of atherothrombosis, involved in both the development and progression of atherosclerotic heart disease, and the attendant acute thrombotic complications. Antiplatelet therapy constitutes a mainstay therapy for patients with acute coronary syndromes and generally high-risk patients with atherothrombosis. Until recently, dual antiplatelet therapy (DAPT) for the treatment and prevention of the complications of atherothrombotic disease was traditionally limited to aspirin plus clopidogrel. However, a most important pertaining issue emerged, that of the occurrence of drug-resistance or tolerance observed in some patients for both these antithrombotic agents, which limited the efficacy and applicability of this combined therapy.The availability of the newer thienopyridine, prasugrel, and the cyclopentyl-triazolopyrimidine, ticagrelor, represents an important addition to the physician's armamentarium. Dual antiplatelet therapy with aspirin and clopidogrel or one of the newer agents interferes with platelet activation in complementary, but separate pathways. Aspirin irreversibly inhibits cyclooxygenase, thus preventing the production of thromboxane A2, which is a prothrombotic and vasoconstrictive substance. Thienopyridines (clopidogrel/prasugrel) irreversibly and ticagrelor reversibly prevent and inhibit platelet activation by blocking one of the three known adenosine 5'-diphosphate (ADP) receptors (the P2Y12 receptor) on the platelet surface, thus interfering with platelet activation, degranulation and aggregation. Each of these antiplatelet agents has a protective effect against adverse vascular events; classical DAPT with aspirin and clopidogrel has an even stronger antiplatelet effect compared with either agent alone, however DAPT combining aspirin with one of the newer more potent agents translates into superior antithrombotic protection in atherothrobotic vascular disease, albeit at an increased, though not inordinately, risk for bleeding complications. A number of randomized clinical trials have demonstrated and confirmed the incremental benefit and efficacy of DAPT with use of either classical or newer agents, above and beyond that of each antiplatelet agent alone. Data have also been obtained from studies where indications for the use of DAPT continue to expand into other patient groups, rendering and maintaining DAPT a sweeping combination in Cardiology. This article is a comprehensive review of all these data and the landmark trials on the two classical and also the newer antiplatelet agents, the issues involved and the current recommendations for their use in patients with atherosclerotic heart disease and other cardiovascular disorders and procedures.