Aggrenox: a fixed-dose combination of aspirin and dipyridamole

To describe the pharmacology, pharmacokinetics, efficacy, and safety of a fixed-dose combination of aspirin and extended-release (ER) dipyridamole indicated for the secondary prevention of stroke.

Published articles and abstracts were identified from a MEDLINE search (1966-December 1999) using the search terms dipyridamole, aspirin, antiplatelet, antiaggregation, and stroke prevention. Pertinent articles written in English were considered for review. Additional articles were identified from the references of retrieved literature.

Studies including a combination of aspirin/dipyridamole in human subjects were evaluated. Emphasis was placed on randomized, controlled trials.

Aspirin is a platelet inhibitor that works by inhibiting platelet cyclooxygenase, which reduces the production of thromboxane A2. Dipyridamole is a platelet inhibitor that is thought to work in part by inhibiting platelet cyclic-3',5'-adenosine monophosphate and cyclic-3',5'-guanosine monophosphate phosphodiesterase. The active metabolite of aspirin, salicylic acid, is highly bound to plasma protein and has a plasma half-life of two to three hours. Dipyridamole is also highly bound to plasma proteins, and the ER formulation has a plasma half-life of 13 hours. The first European Stroke Prevention Study (ESPS-1) found the combination of aspirin/dipyridamole to be superior to placebo in the prevention of stroke and transient ischemic attack (TIA). The ESPS-1, however, did not include an aspirin-only treatment arm. Therefore, it was unclear whether the combination of aspirin/dipyridamole was superior to aspirin alone. As a result, a second trial was conducted that included treatment arms of aspirin alone, ER dipyridamole alone, combination therapy, and placebo. The combination of aspirin 25 mg plus ER dipyridamole 200 mg twice daily was shown in the ESPS-2 to be significantly better than either agent given individually in preventing stroke and TIAs (p < 0.001).

The American College of Chest Physicians (ACCP) recommends aspirin 50-325 mg/d to be the initial antiplatelet of choice for the prevention of atherothrombotic cerebral ischemic events. However, with the favorable results of the ESPS-2, it may be appropriate to substitute aspirin/ER dipyridamole for aspirin alone as the drug of choice. This combination appears to have a favorable adverse effect profile. The relative effectiveness of aspirin/ER dipyridamole compared with clopidogrel and ticlopidine has yet to be determined. If alternative antiplatelet therapy is needed, the ACCP recommends clopidogrel rather than ticlopidine because of its lower incidence of adverse effects. The ACCP further states that the combination of aspirin plus dipyridamole may be more effective than clopidogrel; these agents have a similarly favorable adverse effect profile.