Combination Antithrombotic Therapies

Abstract

A therothrombosis is the major pathophysiological process responsible for the occurrence of severe ischemic events in patients with cardiovascular diseases. In the United States, atherothrombosis strongly influenced mortality in 2004: One in 2.8 deaths was due to CVD, 1 in 5 deaths to coronary heart disease, and 1 in 17 deaths to stroke. 1 Because cardiovascular disease is a progressive and systemic disease, long-term antithrombotic therapies that effectively target the entire arterial vasculature and modulate the key components responsible for thrombus generation are essential to improve patient outcomes. Because platelet activation is determined by multiple receptor-mediated signaling pathways, clinical studies have evaluated the efficacy of multidrug administration in the prevention of atherothrombotic complications. 2,3 The major concern with these therapies is the critical balance between anti-ischemic effect and bleeding risk. This review summarizes our understanding of the role of combination antiplatelet therapies in the treatment and prevention of atherothrombosis. Pathophysiology of AtherothrombosisPlatelet activation and aggregation play a pivotal role in the generation of occlusive thrombus at the site of coronary arterial plaque rupture. In addition, platelets influence various endothelial and inflammatory responses during the initiation and progression of atherosclerosis. Under normal conditions, anucleate circulating platelets are in a quiescent state. Healthy vascular endothelium prevents adhesion and activation of platelets by producing antithrombotic factors such as CD39 (ectoADPase), prostaglandin I 2 , nitric oxide, heparin, matrix metalloproteinase-9, protein S, and thrombomodulin. 3,4 Endothelial activation and denudation and frank atherosclerotic plaque rupture expose the subendothelial matrix and release prothrombotic factors during acute coronary syndromes (ACS) and percutaneous interventions. These processes result in localized platelet adhesion and platelet activation. After adhesion to the exposed subendothelial matrix, platelets are activated by shear and the soluble agonists thromboxane A 2 (TxA 2 ), ADP, and thrombin. TxA 2 is produced from arachidonic acid, which originates from membrane phospholipids and binds to Tx receptors; ADP is secreted from dense granules and binds to P2Y 12 and P2Y 1 receptors. These 2 secondary agonists, through an autocrine and paracrine fashion, produce sustained activation of glycoprotein IIb/IIIa receptors, leading to stable platelet-rich thrombus generation. The ADP-P2Y 12 interaction contributes most to ADP-induced aggregation measured by conventional aggregometry. 5 Platelet activation also results in the membrane exposure of phosphatidyl serine, providing binding sites for coagulation factors. The coagulation process results in the generation of thrombin and subsequent platelet-fibrin clot formation. 3 Endogenous phosphodiesterase (PDE) activity that affects intraplatelet cAMP levels also modulates platelet function (the Figure). Finally, isopros...

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