Optimizing antiplatelet therapy in high-risk patients with atrial fibrillation: insights from Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE A).

In a recent study, investigators of the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE A) enrolled 7554 patients with atrial fibrillation (AF) at high risk of developing vascular events such as stroke, myocardial infarction, systemic embolism, and vascular death.1 These patients, in whom anticoagulation was contraindicated, were randomly assigned to receive either 75 mg clopidogrel or placebo in addition to 75 to 100 mg aspirin daily.1 After a median follow-up period of 3.6 years, a significant 11% reduction in vascular events was observed in those receiving clopidogrel as compared with placebo, contributed primarily by a reduction in the incidence of disabling strokes.1 These benefits, however, come at a high cost of bleeding complications; a 57% higher incidence of major and severe bleeding was observed in those receiving clopidogrel plus aspirin, affecting predominantly the gastrointestinal tract, possibly cancelling the benefit from reduction in vascular events.1 Although the increase in bleeding risks may limit the acceptance of clopidogrel plus aspirin in the thromboprophylaxis of patients with AF, one should not disregard their potential benefits to carefully selected individuals who are predisposed to vascular events but with low bleeding risks. At present, the Cardiac Failure, Hypertension, Age, Diabetes, Stroke (Doubled) (CHADS2) score has been widely used to identify high-risk patients who may benefit from antithrombotic therapy; patients with 2 moderate risk factors (age 75 years, hypertension, diabetes, or heart failure) or one high risk factor (prior stroke, prosthetic heart valve, or mitral stenosis) are at risk of stroke, approximately 3% to 5% per year.2 This score, however, does not take into account structural cardiac features and prothrombotic features (such as elevated D-dimer and von Willebrand factors) that may confer a higher risk of vascular events to individual patients. Therefore, it makes clinical sense to incorporate these additional risk markers to improve on our ability to identify individuals who may be at risk of vascular events more accurately, possibly through the use of data obtained from ACTIVE A. A similar effort should also be extended to help identify patients at high risk of serious bleeding complications. For instance, peptic ulcer disease was not systematically screened for in ACTIVE A. Although patients with documented peptic ulcer disease were excluded from the study, there were no active attempts to exclude the presence of peptic ulcer disease during randomization, which may be a glaring omission given their potential contribution to the excess in bleeding risks. This begs a pertinent question: are there accurate measures to screen patients who may be at higher risk of bleeding? At present, there are limited data to justify the risks of endoscopy (such as aspiration pneumonia and bowel perforation) before the initiation of antiplatelet therapy in an effort to stratify the risks of bleeding better. Further studies are needed to assess cost-effectiveness of routine endoscopy to stratify the risks of gastrointestinal bleeding and the use of morphological gastrointestinal features to predict the risk of gastrointestinal bleeding. The practice of adding proton pump inhibitors to antiplatelets, aimed at reducing the risks of gastrointestinal bleeding, has recently been challenged after in vivo observations of a significant decrease in platelet activation and aggregation effects, potentially leading to treatment failure.3 It is important to emphasize that the present evidence indicates that anticoagulation remains the most efficacious therapy in high-risk patients with AF.4 In a similar study (ACTIVE W) that compared the efficacy of anticoagulation against aspirin and clopidogrel, the trial was stopped early due to the clear superiority of anticoagulation (relative risk, 1.44; 1.18 to 1.76; P 0.001).4 However, the acceptance of anticoagulation in the “real world,” however, is less than