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Combination antiplatelet agents with multiple mechanisms of action are being used with increasing frequency for vascular disorders, including cerebrovascular disease. Limited data exist regarding the efficacy of combination antiplatelet therapy in the primary or secondary prevention of cerebral ischemia, and combination therapies are often used without adequate evidence of efficacy. However, over the last few years, several cerebrovascular and cardiovascular trials have provided some preliminary information on the effectiveness of various combination therapies in preventing cerebral ischemic disease. This article reviews recently completed cerebrovascular and cardiovascular trials that tested a combination antiplatelet regimen against aspirin alone, and that assessed cerebral ischemia as an outcome measure. Controversies pertaining to these trials and to the use of the various combination antiplatelet regimens are discussed. Based on cardiovascular studies, clopidogrel in combination with aspirin has not been proven superior to aspirin alone for the primary prevention of cerebral ischemia. No data exists regarding the combination of clopidogrel and aspirin for the secondary prevention of cerebrovascular disease. The combination of aspirin plus extended-release dipyridamole (xrDP) appears to be superior to aspirin alone in the secondary prevention of cerebral ischemia, but may compromise cardiovascular protection in patients with coexisting coronary artery disease. Combination therapy with aspirin and clopidogrel seems to increase the risk of major hemorrhages, whereas aspirin plus xrDP does not. Ongoing trials are expected to clarify the role of various combination antiplatelet regimens.

Background: Two recent cerebrovascular studies, Clopidogrel (Clo) in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT), have purportedly demonstrated the superiority of early dual antiplatelet therapy (DAPT), using aspirin (ASA) plus Clo, in comparison to ASA alone following the occurrence of acute minor cerebral infarction or transient ischemic attack. However, limitations to these trials exist that may not have been adequately explored and presented in the literature, and which may impact the overall efficacy and benefit of DAPT in these situations. Herein we provide a detailed and extensive critique of these 2 trials and of a combined analysis, with particular attention to study data and analyses pertaining to hemorrhagic complications. Summary: DAPT may be superior to ASA alone in preventing recurrent cerebral ischemic events, but exclusively during the first 7–10 days of treatment, and probably only in the presence of acute infarction on cerebral imaging. The impact of minor hemorrhages, which are often clinically consequential and which frequently lead to permanent DAPT discontinuation, has not been adequately considered in the available analyses. Based on data from the trials, DAPT use causes more major and minor hemorrhages than ASA use alone or Clo alone, and Clo use results in fewer hemorrhages than the use of ASA alone. Analyses that include hemorrhage data from the period of Clo alone use as part of the DAPT data may provide inaccurate and erroneous conclusions regarding the relative safety and overall net benefit of DAPT use over ASA alone. [ABSTRACT FROM AUTHOR]