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Am Fam Physician. 2019;100(7):405-406

Author disclosure: No relevant financial affiliations.

Clinical Question

Are factor Xa inhibitors as effective and safe as vitamin K antagonists in the prevention of embolic events in patients with atrial fibrillation (AFib)?

Evidence-Based Answer

Treatment of AFib with a factor Xa inhibitor results in a decrease in the combined end point of stroke and embolic events (odds ratio [OR] = 0.89; 95% CI, 0.82 to 0.97), as well as a decrease in intracranial hemorrhage (OR = 0.50; 95% CI, 0.42 to 0.59) and all-cause mortality (OR = 0.89; 95% CI, 0.83 to 0.95) compared with warfarin (Coumadin) therapy.1 (Strength of Recommendation: A, based on consistent, good-quality patient-oriented evidence.)

Practice Pointers

AFib affects 2.7 to 6.1 million Americans. Patients with AFib have a four- to fivefold increased risk of embolic stroke vs. those without.24 In addition to rate control, a mainstay of AFib treatment focuses on anticoagulation to prevent thrombus formation and decrease stroke risk. Before the introduction of factor Xa inhibitors, the vitamin K antagonist warfarin was the anticoagulant used most often. Use of warfarin, however, requires laborator y monitoring and dietar y restrictions that are challenging for patients and clinicians. The authors of this review examined the effectiveness and safety of factor Xa inhibitors compared with warfarin in preventing stroke and embolic events in patients with AFib.

This review included 13 randomized controlled trials with 67,688 participants with mean and median ages ranging from 65 to 74 years.1 These trials directly compared factor Xa inhibitors with dose-adjusted warfarin. Seven factor Xa inhibitors were represented in the trials, but studies looking at apixaban (Eliquis), edoxaban (Savaysa), and rivaroxaban (Xarelto) contributed 90% of the data. Factor Xa inhibitors significantly decreased the incidence of the primary outcome, all strokes and systemic embolic events, compared with warfarin (OR = 0.89; 95% CI, 0.82 to 0.97; 13 studies; n = 67,477). Age-related subgroup analysis revealed that all strokes and systemic embolic events were significantly decreased in patients 75 years and older who were treated with factor Xa inhibitors compared with warfarin (OR = 0.76; 95% CI, 0.66 to 0.88; four studies; n = 21,885).

Secondary outcomes included adverse events such as intracranial hemorrhage, all-cause death, and major or nonmajor bleeding as defined by the International Society on Thrombosis and Haemostasis criteria. The use of factor Xa inhibitors significantly reduced the risk of intracranial hemorrhage (OR = 0.50; 95% CI, 0.42 to 0.59; 12 studies; n = 66,259) and the number of all-cause deaths (OR = 0.89; 95% CI, 0.83 to 0.95; 10 studies; n = 65,624). Bleeding, both major and nonmajor, was not statistically different between groups. There were no significant differences between factor Xa inhibitors and warfarin with respect to disabling or fatal strokes, ischemic strokes, myocardial infarction, or hepatotoxicity.

The 2014 American College of Cardiology/American Heart Association guidelines for the management of patients with AFib state that antithrombotic therapy should be based on shared decision-making, risk, and patient preference.5 These guidelines, as well as the 2016 European Society of Cardiology guidelines, include factor Xa inhibitors as initial and/or suitable anticoagulant treatment options, although they are not endorsed over other options such as warfarin.5,6 Although direct medical costs incurred through the use of factor Xa inhibitors are significantly greater than those with warfarin ($7.43 to $14.60 per pill vs. $0.36 for warfarin),7 there are also indirect cost savings to consider, including decreases in laboratory equipment use, testing, patient visits, associated patient travel costs, and adverse events requiring hospitalization and treatment. Furthermore, the findings in the age-related subgroup analysis suggest that patients 75 years and older achieve the greatest benefit and stroke prevention from factor Xa inhibitor use compared with warfarin. If available and indicated, factor Xa inhibitors are a safe alternative to warfarin and may be preferred in some populations.

The practice recommendations in this activity are available at

The views expressed in this article are the authors' and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences, the Department of Defense, or the U.S. government.

These are summaries of reviews from the Cochrane Library.

This series is coordinated by Corey D. Fogleman, MD, assistant medical editor.

A collection of Cochrane for Clinicians published in AFP is available at

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