Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis

Abstract

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.

Conflict of interest statement

Competing interests: JACS was a former member of the Health Technology Assessment Clinical Trial Board. CS is currently a Health Services and Delivery Research - Researcher Led Board member. NJW, JS, and SD report NIHR and Medical Research Council grants during the conduct of the study, outside the present work. Other authors have no potential conflicts of interest to declare.

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Figures

Fig 1

PRISMA flowchart for review of prevention of stroke in patients with atrial fibrillation

Fig 2

Network plots of stroke or systemic embolism, ischaemic stroke, myocardial infarction, and all-cause mortality outcomes for review of prevention of stroke in patients with atrial fibrillation. Line thickness is proportional to the number of patients that contributed to the comparison
*Doses of direct acting oral anticoagulants (DOACs) that were excluded from the primary analysis owing to not being considered to be of interest to inform health decisions in the UK (eg, warfarin interventions using subtherapeutic INR ranges), the total number of events was zero so they are uninformative, or they did not connect with the other trials in the network.
†Excluded doses of DOACs that were included in sensitivity analyses.
‡Recommended doses of DOACs evaluated in a phase III trial; these are interventions of primary interest.

Fig 3

Network plots of bleeding outcomes for review of prevention of stroke in patients with atrial fibrillation. Line thickness is proportional to the number of patients that contributed to the comparison
*Doses of direct acting oral anticoagulants (DOACs) that were excluded from the primary analysis owing to not being considered to be of interest to inform health decisions in the UK (eg, warfarin interventions using subtherapeutic INR ranges), the total number of events was zero so they are uninformative, or they did not connect with the other trials in the network.
†Excluded doses of DOACs that were included in sensitivity analyses.
‡Recommended doses of DOACs evaluated in a phase III trial; these are interventions of primary interest.

Fig 4

Rankograms for doses of licensed products examined in prevention of stroke in patients with atrial fibrillation

Fig 5

Cost effectiveness acceptability curves. The probability each preferred intervention is most cost effective against willingness to pay for each QALY threshold