Aggrenox® (Extended-Release Dipyridamole and Low-Dose Aspirin in Combination): Protecting Platelets from Excessive Activation in Patients with Vascular Events

Abstract

Aspirin has become an established therapy in patients for preventing recurrent stroke and the incidence of acute coronary events. Aggrenox^®, a novel combination of low-dose aspirin with dipyridamole, represents a safe and promising combination alternative for mild but sustained platelet inhibition and the reduction of occurrences of both arterial and venous thrombi. In a recent, large, well-controlled trial (European Stroke Prevention Study 2; ESPS-2) evaluating antiplatelet agents for stroke prevention, Aggrenox was twice as effective as either aspirin or dipyridamole. Results of experimental studies show that dipyridamole combined with aspirin at ratios of about 10:1 or higher effectively inhibit thrombus formation, whereas a ratio of 1:1 has little effect. Indeed, one of the reasons that the ESPS-2 trial appears so convincing was the fact that a high dose of extended-release dipyridamole was combined with low-dose aspirin at a dose ratio of 8:1. Combination therapy with Aggrenox inhibits platelet aggregation much more strongly than aspirin or dipyridamole alone, and it may gain an additional clinical benefit due to synergic targeting of leukocytes, through an increase in endothelial nitric oxide production. Based on in vitro data showing that platelet adhesivity and aggregation induced by adenosine diphosphate (ADP), adrenaline and collagen is diminished, as well as through measurements of malondialdehyde production (marker of free radical production), it is known that dipyridamole and aspirin indeed exhibit a potentiated synergism as platelet inhibitors. On the other hand, clopidogrel, a novel thienopyridine and a potent ADP receptor blocker, has also been proven to yield a clinical benefit in unstable angina patients and during coronary interventions. Considering recent trends to combine clopidogrel with aspirin, it remains to be seen which combination will better serve various clinical scenarios in the near future. Further well-designed and carefully conducted clinical trials should elucidate possible benefits of Aggrenox during coronary interventions, especially in conjunction with new and aggressive reperfusion techniques. The benefits of Aggrenox in an expanding array of clinical conditions, including ischemic stroke, may be directly related to platelet inhibition. Moreover, marginal clinical benefits and recently reported severe bleeding events in some patients after oral platelet glycoprotein IIb/IIIa therapy may advance Aggrenox as a safe and efficient alternative for patients with vascular disease. This review summarizes the latest and often confusing data on the effects of aspirin, dipyridamole and Aggrenox on platelets and attempts to relate these data to bleeding complications and clinical outcomes.