Meta-Analyses of Oral Anticoagulants in Atrial Fibrillation

Quick Takes

  • A patient-level network meta-analysis of all phase 3 randomized clinical trials confirms the use of DOACs as first-line for stroke prevention in atrial fibrillation.
  • Use of standard-dose (including renally adjusted) DOACs experienced fewer ischemic and severe bleeding events than warfarin-treated patients.
  • Use of reduced-dose (not for renal adjustment) DOACs did not reduce stroke risk as compared to warfarin therapy.

Study Questions:

What are the efficacy and safety outcomes associated with direct oral anticoagulation (DOAC) use as compared to warfarin for patients with atrial fibrillation?


The authors conducted a patient-level network meta-analysis of the four pivotal randomized clinical trials comparing a DOAC (apixaban, dabigatran, edoxaban, or rivaroxaban) to warfarin for stroke prevention in patients with atrial fibrillation. The authors used a stratified Cox model with random effects to compare standard-dose DOAC, lower-dose DOAC, and warfarin. Covariate-by-treatment interactions were estimated for various comorbidities, age, and sex. Key outcomes assessed included stroke or systemic embolism, death, intracranial hemorrhage, and major bleeding.


A total of 71,683 patients were included (29,362 on standard-dose DOAC, 13,049 on lower-dose DOAC, and 29,272 on warfarin). Compared to warfarin, standard-dose DOACs were associated with a lower hazard for stroke/systemic embolism (3.01% vs. 3.69%, hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.74-0.89), death (7.76% vs. 8.42%, HR, 0.92; 95% CI, 0.87-0.97), and intracranial bleeding (0.63% vs. 1.40%, HR, 0.45; 95% CI, 0.37-0.56) but not for major bleeding (5.05% vs. 5.94%, HR, 0.86; 95% CI, 0.74-1.01). Compared to warfarin, lower-dose DOACs were associated with no statistically different hazard for stroke/systemic embolism (3.96% vs. 3.69%, HR, 1.06; 95% CI, 0.95-1.19) but a lower hazard for intracranial hemorrhage (0.42% vs. 1.40%, HR, 0.28; 95% CI, 0.21-0.37), death (8.29% vs. 8.42%, HR, 0.90; 95% CI, 0.83-0.97), and major bleeding (4.34% vs. 5.94%, HR, 0.62; 95% CI, 0.45-0.88). Treatment effects were consistent across age and sex for the outcomes of stroke/systemic embolism and death. Standard-dose DOACs were favored for patients without prior warfarin use and chronic kidney disease for the outcomes of stroke/systemic embolism and death as well as in patients with low body weight for the outcome of major bleeding.


The authors concluded that when compared to warfarin, DOACs have favorable efficacy and safety profiles among patients with atrial fibrillation.


Major guidelines favor the use of DOACs as first-line therapies to prevent stroke or systemic embolism associated with atrial fibrillation. This patient-level network meta-analysis confirms that the benefit of DOAC therapy over warfarin is consistent across key age, sex, and comorbidity subgroups. While patients using lower-dose DOAC (dabigatran 110 mg twice daily or edoxaban 30 mg daily or 15 mg daily if dose reduction criteria were met) had lower hazards for many bleeding outcomes, that was offset by a lack of reduction in stroke/systemic embolism for this group as compared to warfarin treatment. On the other hand, patients using standard-dose DOACs experienced lower hazards of stroke/systemic embolism, death, fatal bleeding, and intracranial hemorrhage as compared to warfarin therapy. This supports the use of standard-dose (rather than lower-dose) DOACs for most patients with atrial fibrillation who qualify for pharmacologic stroke-reduction therapy.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Novel Agents

Keywords: Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Dabigatran, Embolism, Hemorrhage, Intracranial Hemorrhages, Renal Insufficiency, Chronic, Rivaroxaban, Secondary Prevention, Stroke, Vascular Diseases, Warfarin

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