Objective To compare the efficacy, safety, and cost effectiveness of
direct acting oral anticoagulants (DOACs) for patients with
atrial fibrillation.Design Systematic review, network meta-analysis, and cost effectiveness analysis. Data sources Medline, PreMedline, Embase, and The Cochrane Library.Eligibility criteria for selecting studies Published randomised trials evaluating the use of a DOAC,
vitamin K antagonist, or
antiplatelet drug for prevention of
stroke in patients with
atrial fibrillation.Results 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with
warfarin dosed to achieve a target INR of 2.0-3.0.
Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94),
dabigatran 150 mg twice daily (0.65, 0.52 to 0.81),
edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and
rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of
stroke or systemic
embolism compared with
warfarin. The risk of
stroke or systemic
embolism was higher with
edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and
rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with
dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with
warfarin.
Apixaban 5 mg twice daily (0.71, 0.61 to 0.81),
dabigatran 110 mg twice daily (0.80, 0.69 to 0.93),
edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and
edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major
bleeding compared with
warfarin. The risk of major
bleeding was higher with
dabigatran 150 mg twice daily than
apixaban 5 mg twice daily (1.33, 1.09 to 1.62),
rivaroxaban 20 mg twice daily than
apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and
rivaroxaban 20 mg twice daily than
edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial
bleeding was substantially lower for most DOACs compared with
warfarin, whereas the risk of gastrointestinal
bleeding was higher with some DOACs than
warfarin.
Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with
warfarin.Conclusions The network meta-analysis informs the choice of DOACs for prevention of
stroke in patients with
atrial fibrillation. Several DOACs are of net benefit compared with
warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis.Systematic review registration PROSPERO CRD 42013005324.