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Oral anticoagulation with vitamin K antagonists (VKAs) has long been the gold standard therapy for stroke prevention in nonvalvular atrial fibrillation (AF). Limitations in monitoring and compliance of VKAs have fueled the development of new antithrombotic strategies, devices, and oral anticoagulants, including oral direct thrombin inhibitors and factor Xa inhibitors. This review updates previous reviews, particularly with regard to these newer treatment options and the optimal risk stratification tools for stroke and bleeding prediction.
We searched PubMed®, Embase®, and the Cochrane Database of Systematic Reviews for relevant English-language comparative studies published from January 1, 2000, to August 14, 2012.
Two investigators screened each abstract and full-text article for inclusion, abstracted data, rated quality and applicability, and graded evidence. When possible, random-effects models were used to compute summary estimates of effects.
Our review included 122 articles (92 unique studies), comprising 37 studies relevant to predicting thromboembolic risk, 17 relevant to predicting bleeding risk, 43 relevant to interventions for preventing thromboembolic events, 13 relevant to anticoagulation strategies in patients undergoing invasive procedures, and no studies relevant to strategies for switching between warfarin and novel oral anticoagulants or to stroke prevention after a hemorrhagic event. Across the Key Questions addressing prediction of stroke and bleeding risk, evidence was limited by variability in reporting and in underlying treatment of AF. Data suggest that the continuous CHADS2 (Congestive heart failure, Hypertension, Age ≥75, Diabetes mellitus, prior Stroke/transient ischemic attack [2 points]) and continuous CHA2DS2-VASc (Congestive heart failure/left ventricular ejection fraction ≤40%, Hypertension, Age ≥75 [2 points], Diabetes mellitus, prior Stroke/transient ischemic attack/thromboembolism [2 points], Vascular disease, Age 65–74, Sex category female) scores have the greatest discrimination for stroke risk (c-statistic 0.71 [95% confidence interval (CI), 0.66 to 0.75], and c-statistic 0.70 [95% CI 0.66 to 0.75], respectively; low strength of evidence for both scores) and that the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly [>65 years], Drugs/alcohol concomitantly) score has the greatest discrimination for bleeding risk (moderate strength of evidence).
Evidence evaluating interventions for stroke prevention was limited by the small number of studies for specific comparisons and lack of direct comparisons of novel anticoagulants, although many included studies were good-quality randomized controlled trials involving more than 5,000 patients. We found that a factor IIa inhibitor (dabigatran 150 mg) was superior to warfarin in reducing the incidence of stroke (including hemorrhagic) or systemic embolism (relative risk [RR] 0.66; 95% CI 0.53 to 0.82), with no significant difference in the occurrence of major bleeding (RR 0.93; 95% CI 0.81 to 1.07) (high strength of evidence for both outcomes). The Xa inhibitor rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism (moderate strength of evidence), with similar rates of major bleeding and death (high strength of evidence). The Xa inhibitor apixaban was superior to warfarin in reducing the incidence of stroke or systemic embolism (hazard ratio [HR] 0.79; 95% CI 0.66 to 0.95; high strength of evidence); major bleeding (HR 0.69; 95% CI 0.60 to 0.80; high strength of evidence); and all-cause mortality (HR 0.89; 95% CI 0.80 to 0.998; moderate strength of evidence). Apixaban was also superior to aspirin in reducing the incidence of stroke or systemic embolism (HR 0.45; 95% CI 0.32 to 0.62), with similar hemorrhagic events, including major bleeding (HR 1.13; 95% CI 0.74 to 1.75), in patients who are not suitable for oral anticoagulation (high strength of evidence for both outcomes). However, no studies directly compared the new therapies. Evidence for patients undergoing invasive procedures, switching among anticoagulant therapies, and starting or restarting anticoagulant therapy after previous major bleeding events was insufficient.
Overall, we found that CHADS2 and CHA2DS2-VASc scores have the best discrimination ability for stroke events in patients with AF among the risk scores we reviewed, whereas HAS-BLED provides the best discrimination of bleeding risk. Imaging tools require further evidence in regard to their appropriate use in clinical decisionmaking. Improved evidence of the use of these scores among patients on therapy is also required. Newer anticoagulants show early promise of reducing stroke and bleeding events when compared with warfarin, and apixaban shows safety and efficacy in patients who are not candidates for warfarin. However, further studies are required for key clinical scenarios involving anticoagulation use and procedures, switching or bridging therapies, and when to start anticoagulation after a hemorrhagic event.