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Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials

BMJ 2012; 345 doi: (Published 13 November 2012) Cite this as: BMJ 2012;345:e7498
  1. Benjamin D Fox, visiting professor1,
  2. Susan R Kahn, professor of medicine2,
  3. David Langleben, professor of medicine1,
  4. Mark J Eisenberg, professor of medicine12,
  5. Avi Shimony, visiting scientist12
  1. 1Center for Pulmonary Vascular Disease and Division of Cardiology, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada H3T 1E2
  2. 2Division of Internal Medicine and Department of Medicine, McGill University, Center for Clinical Epidemiology and Community Studies, Lady Davis Institute, Jewish General Hospital, Montreal, QC
  1. Correspondence to: B D Fox{at}
  • Accepted 1 October 2012


Objective To critically review the effectiveness of the novel oral anticoagulants (rivaroxaban, dabigatran, ximelagatran, and apixaban) in the treatment of acute venous thromboembolism.

Design Systematic review and random effects meta-analysis. Data were extracted independently by two investigators. An adjusted indirect comparison was performed to compare between novel oral anticoagulants.

Data sources Medline, Embase, and Cochrane Library (from inception to April 2012). Hand searching of relevant scientific works and contact with experts.

Study selection Randomised controlled trials of novel oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism. Selected outcomes were recurrent events, major bleeding, and all cause mortality.

Results Nine studies met our inclusion criteria, involving 16 701 patients evaluated for efficacy and 16 611 for safety. Data were stratified according to different novel oral anticoagulants. For recurrent acute venous thromboembolism, there were no significant differences in events rates between any of the anticoagulants and conventional treatment (rivaroxaban (four studies): relative risk 0.85, 95% confidence interval 0.55 to 1.31; dabigatran (two studies): 1.09, 0.76 to 1.57; ximelagatran (two studies): 1.06, 0.62 to 1.80; and apixaban (one study): 0.98, 0.20 to 4.79). Rivaroxaban reduced the risk of major bleeding compared with conventional treatment (0.57, 0.39 to 0.84), whereas other novel oral anticoagulants did not (0.76 (0.49 to 1.18) for dabigatran; 0.54 (0.28 to 1.03) for ximelagatran; 2.95 (0.12 to 71.82) for apixaban). For all cause mortality there were no significant differences between the novel oral anticoagulants and conventional treatment (0.96 (0.72 to 1.27) for rivaroxaban; 1.00 (0.67 to 1.50) for dabigatran; 0.67 (0.42 to 1.08) for ximelagatran; 6.89 (0.36 to 132.06) for apixaban). The adjusted indirect comparison between rivaroxaban and dabigatran did not show superiority of either drug over the others for major bleeding (0.75, 0.41 to 1.34) or the other endpoints.

Conclusions Compared with vitamin K antagonists, the novel oral anticoagulants had a similar risk of recurrence of acute venous thromboembolism and all cause mortality, though rivaroxaban was associated with a reduced risk of bleeding.


  • BDF is supported in part by the William Pencer Family Foundation. AS is supported by the Azrieli Foundation and a Susan Raymer cardiology fellowship grant. SRK and MJE are supported by a national investigator award of the Fonds de la recherche en santé du Québec (FRSQ). DL receives support from the Bank of Montreal Center for the Study of Heart Disease in Women, and the Dimitrious Banousis Foundation.

  • Contributors: BDF conceived the study, performed the systematic review, data extraction, and data analysis, and drafted the manuscript. SRK, MJE, and DL conceived the study, analysed the data, and reviewed the manuscript for important intellectual content. AS conceived the study, performed the systematic review, data extraction, and analysis, and reviewed the manuscript for important intellectual content. All authors had full access to the data and take responsibility for the integrity of the data and accuracy of the analysis. BDF is guarantor.

  • Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing:No additional data available.

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