Dipyridamole exerts its effect by inhibition of platelet phosphodiesterase E5, increasing cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP).33 By inhibiting its uptake and metabolism by erythrocytes, dipyridamole also increases the availability of adenosine within blood vessels, promoting inhibition of platelet aggregation and local vasodilatation.34 Dipyridamole may also inhibit cAMP phosphodiesterase in platelets, which further increases cAMP levels35 and may enhance endothelial nitric oxide production, contributing to its antithrom-botic effect. Existing trials of dipyridamole in stroke have focused on secondary prevention and will be discussed briefly.

The European Stroke Prevention Study 2 (ESPS-2) trial examined four treatment arms—extended-release dipyridamole (ER-DP) 200 mg twice daily alone, aspirin 25 mg twice daily alone, ER-DP 200 mg twice daily + aspirin 25 mg twice daily, or placebo.36 In comparison with placebo the overall reduction in stroke risk was 16% with ER-DP alone and 18% with aspirin alone. The combination of ER-DP and aspirin led to a 37% reduction in stroke risk compared to placebo. Compared with aspirin alone, the combination of ER-DP with aspirin reduced the risk of stroke by 23%.

The European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT)37 confirmed the finding of ESPS 2, showing that the combination of aspirin and dipyridamole is more effective than aspirin alone in the prevention of new vascular events in patients with nondisabling cerebral ischaemia of presumed arterial origin. Adding the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or MI of 0.82 (95% CI 0.74-0.91).

PROFESS is an ongoing large randomized trial examining combination ER-DP plus aspirin therapy compared with clopidogrel (each group also with or without telmisartan, an angiotensin receptor antagonist) for the secondary prevention of early and late recurrent stroke, and other vascular events.

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