Stroke Prevention in Patients With Atrial Fibrillation: A Systematic Review Update

Purpose of Review

To update a previous review in patients with atrial fibrillation/atrial flutter (AF) to determine the best assessment tools for predicting risk of stroke and bleeding, as well as the best treatment options to prevent stroke. Current treatments include new antithrombotic strategies, devices, and oral anticoagulants (oral direct thrombin inhibitors, factor Xa inhibitors).

Key Messages

• CHADS2, CHA2DS2-VASc, and ABC risk scores have the best evidence to support prediction of stroke events.
• HAS-BLED has the best evidence to support prediction of bleeding risk.
• Imaging tools for stroke prediction require further evidence.
• Dabigatran (150 mg dose) is superior to warfarin in preventing stroke or systemic embolism, with no evidence for a difference in major bleeding. There may also be no evidence for a difference in myocardial infarction or all-cause mortality.
• Apixaban is superior to warfarin in preventing stroke or systemic embolism. Apixaban also has less risk for major bleeding and may also decrease all-cause mortality compared to warfarin.
• Rivaroxaban may be similar to warfarin in preventing stroke or systemic embolism and in risk of major bleeding. Rivaroxaban is most likely similar to warfarin in the rate of all-cause mortality. However, inconsistent with the randomized controlled trial (RCT) findings, observational studies showed rivaroxaban may better prevent stroke or systemic embolism and may have a higher risk of major bleeding.
• Edoxaban is most likely similar to warfarin in preventing stroke or systemic embolism and also most likely has less risk for major bleeding and hemorrhagic stroke than warfarin.
• Further RCTs directly comparing oral anticoagulants, including thrombin inhibitors and individual Xa inhibitors, are needed.

Structured Abstract

Objectives. This review updates previous reviews regarding the optimal risk stratification tools for stroke and bleeding prediction, and treatment options for stroke prevention in patients with atrial fibrillation.

Data sources. We searched PubMed®, Embase®, and the Cochrane Database of Systematic Reviews for relevant English-language comparative studies published from January 1, 2000, to February 14, 2018.

Review methods. 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.

Results. Our review included 320 articles (185 unique studies). This included 61 studies relevant to predicting thromboembolic risk, 38 relevant to predicting bleeding risk, and 117 relevant to interventions for preventing thromboembolic (TE) events. Data suggest that the CHADS2, CHA2DS2-VASc, and ABC risk scores have the best evidence predicting TE risk (moderate strength of evidence [SOE] for limited prediction ability of each score) and that the HAS-BLED score has the best evidence to predict bleeding risk (moderate SOE).

We found that a thrombin inhibitor (dabigatran 150 mg) was superior to warfarin in preventing stroke (including hemorrhagic) or systemic embolism (relative risk [RR] 0.66; 95% confidence interval [CI] 0.53 to 0.82), with no statistically significant difference in the occurrence of major bleeding (RR 0.93; 95% CI 0.81 to 1.07) (high SOE for both outcomes). The Xa inhibitor apixaban was superior to warfarin in preventing stroke or systemic embolism (hazard ratio [HR] 0.79; 95% CI 0.66 to 0.95; high SOE), major bleeding (HR 0.69; 95% CI 0.60 to 0.80; high SOE), and all-cause mortality (HR 0.89; 95% CI 0.80 to 0.998; low SOE). Apixaban was also superior to aspirin in preventing stroke or systemic embolism (HR 0.45; 95% CI 0.32 to 0.62), with similar risk for major bleeding (HR 1.13; 95% CI 0.74 to 1.75) in patients who are not suitable for warfarin (moderate SOE for both outcomes). The Xa inhibitor edoxaban reduced hemorrhagic stroke and major bleeding compared to warfarin (moderate SOE for both outcomes) but had no evidence of a difference in stroke or systemic embolism (moderate SOE) or myocardial infarction (moderate SOE). The Xa inhibitor rivaroxaban was similar to warfarin in preventing stroke or systemic embolism (HR 0.88, 95% CI 0.74 to 1.03; moderate SOE), with similar rates of major bleeding (low SOE) and death (moderate SOE). Low SOE for major bleeding was due to a trend toward an increase in risk of major bleeding with rivaroxaban seen in observational studies. Comparative effectiveness findings for stroke prevention were limited by the direct comparisons between individual direct oral anticoagulants. Evidence regarding nonpharmacologic interventions was sparse, but left atrial appendage (LAA) closure devices showed a trend toward benefit over warfarin for strokes, major bleeding, and all-cause mortality that did not reach statistical significance. Higher adverse events (excessive bleeding or procedure-related complications) were observed with LAA (low SOE).

Conclusions. Overall, we found that CHADS2, CHA2DS2-VASc, and ABC scores have similar evidence regarding their ability to predict stroke risk in patients with atrial fibrillation, whereas HAS-BLED has the best evidence to predict bleeding risk. Direct oral anticoagulants (specifically apixaban and dabigatran) demonstrate reductions in stroke events and reductions (apixaban) or similar (dabigatran) rates in bleeding events when compared with warfarin, while rivaroxaban was similar in both benefits and harms to warfarin. Edoxaban reduced hemorrhagic stroke and major bleeding compared to warfarin but had no evidence of a difference in other outcomes. More studies are needed directly comparing oral anticoagulants, including thrombin inhibitors and individual Xa inhibitors.