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

BMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j5058 (Published 28 November 2017) Cite this as: BMJ 2017;359:j5058
  1. José A López-López, senior research associate1,
  2. Jonathan A C Sterne, professor12,
  3. Howard H Z Thom, research fellow1,
  4. Julian P T Higgins, professor12,
  5. Aroon D Hingorani, chair3,
  6. George N Okoli, senior research associate1,
  7. Philippa A Davies, senior research associate14,
  8. Pritesh N Bodalia, head of pharmacy56,
  9. Peter A Bryden, senior research associate1,
  10. Nicky J Welton, professor12,
  11. William Hollingworth, professor1,
  12. Deborah M Caldwell, senior lecturer1,
  13. Jelena Savović, senior research fellow14,
  14. Sofia Dias, research fellow1,
  15. Chris Salisbury, professor1,
  16. Diane Eaton, patient group representative7,
  17. Annya Stephens-Boal, patient group representative8,
  18. Reecha Sofat, senior lecturer3
  1. 1Department of Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
  2. 2National Institute for Health Research Bristol Biomedical Research Centre, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
  3. 3Faculty of Population Health Sciences, University College London, London, UK
  4. 4The National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care West (NIHR CLAHRC West) at University Hospitals Bristol NHS Foundation Trust, Bristol, UK
  5. 5University College London Hospitals NHS Foundation Trust, London, UK
  6. 6Royal National Orthopaedic Hospital NHS Trust, London, UK
  7. 7AntiCoagulation Europe, Bromley, Kent, UK
  8. 8Thrombosis UK, Llanwrda, UK
  1. Correspondence to: J A C Sterne jonathan.sterne{at}bristol.ac.uk
  • Accepted 24 October 2017

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.

Footnotes

  • Contributors: JACS, RS, and ADH conceived the project. GNO, PAD, PNB, and JS selected articles for inclusion, extracted data, and assessed the risk of bias. JACS, JPTH, JALL, ADH, and RS selected results for inclusion. JACS, JPTH, SD, NJW, JALL, and DMC planned the statistical analyses. JALL performed the network meta-analyses. NJW, WH, HHZT, and PAB developed and analysed the economic models. HHZT performed the cost effectiveness analyses. ADH, RS, and CS provided clinical expertise. DE and ASB provided a patient perspective. PNB provided pharmaceutical expertise. JALL, JPTH, RS, and HHZT wrote the first draft of the paper and all authors revised it critically for important intellectual content. All authors have approved this version for publication. JACS is the study guarantor.

  • Funding: This research was funded by the National Institute for Health Research (NIHR). Additional time from PAD was supported by the NIHR Collaboration for Leadership in Applied Health Research and Care West (CLAHRC West) at University Hospitals Bristol NHS Foundation Trust. JACS is funded by NIHR Senior Investigator award NF-SI-0611-10168. The funders were not actively involved in the research process at any stage.

  • 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.

  • Ethical approval: Not required.

  • Data sharing: No additional data are available

  • Transparency: The corresponding author, JACS, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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