Antiplatelet agents in stroke prevention. combination therapy: present and future.

Platelets contribute to arterial thrombosis by multiple mechanisms that promote blood clotting, favor vasoconstriction, activate the procoagulant capacity of endothelium, and stimulate inflammation. These activities are augmented by turbulent blood flow. Classic antiplatelet therapy with aspirin to prevent occlusive stroke offers significant clinical benefit (20-25% risk reduction), yet is less effective than in prevention of coronary artery occlusion (up to 50% risk reduction of myocardial infarction in unstable angina). Since aspirin's antiplatelet effects are limited to blocking a single metabolic pathway - namely inhibition of thromboxane A(2) formation -, and aspirin fails to alter platelet adhesion, other antiplatelet agents that target ADP receptors, platelet surface glycoproteins (such as the GPIIb/IIIa complex), or platelet-dependent thrombin generation offer additional clinical benefits by blocking additional separate pathways or the final common pathway of platelet activation. Combinations of antiplatelet agents, such as aspirin/dipyridamole, aspirin/clopidogrel, or aspirin/GPIIb/IIIa inhibitors, have recently been tested for improved efficacy in clinical trials. Soluble recombinant CD39, an ecto-ADPase, protects against stroke in animal models by metabolizing released ADP/ATP to antiplatelet derivatives. In general, combinations of antiplatelet agents promise greater efficacy than single drugs in preventing stroke, since interactions among different antiplatelet mechanisms can be synergistic. However, such combinations may also increase the risk of bleeding, so that precise understanding of risk/benefit ratios that address the possibility of intracranial as well as gastrointestinal bleeding will require careful monitoring in large clinical trials of patients at risk of stroke, with particular attention to the elderly.