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Original research article
Extended treatment of venous thromboembolism: a systematic review and network meta-analysis
  1. Kang-Ling Wang1,2,
  2. Nick van Es3,
  3. Chris Cameron4,
  4. Lana A Castellucci5,
  5. Harry R Büller3,
  6. Marc Carrier5
  1. 1 General Clinical Research Center, Taipei Veterans General Hospital, Taipei, Taiwan
  2. 2 School of Medicine, National Yang-Ming University, Taipei, Taiwan
  3. 3 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
  4. 4 Cornerstone Research Group Inc, Burlington, Ontario, Canada
  5. 5 Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
  1. Correspondence to Dr Marc Carrier, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada; mcarr001{at}


Objective To evaluate efficacy and safety of oral anticoagulant regimens and aspirin for extended venous thromboembolism (VTE) treatment.

Methods We searched MEDLINE, Embase, CENTRAL and conference proceedings for randomised controlled trials studying vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or aspirin for secondary prevention of VTE beyond 3 months. ORs (95% credible intervals) between treatments were estimated using random-effects Bayesian network meta-analysis.

Results Sixteen studies, totaling more than 22 000 patients, were included. Compared with placebo or observation and with aspirin, respectively, the risk of recurrent VTE was lower with standard-intensity VKAs (0.15 (0.08 to 0.24) and 0.23 (0.09 to 0.54)), low-dose factor Xa inhibitors (0.16 (0.06 to 0.38) and 0.25 (0.09 to 0.66)), standard-dose factor Xa inhibitors (0.17 (0.08 to 0.33) and 0.27 (0.11 to 0.65)) and the direct thrombin inhibitor (0.15 (0.04 to 0.37) and 0.23 (0.06 to 0.74)) although the risk of major bleeding was higher with standard-intensity VKAs (4.42 (1.99 to 12.24) and 4.14 (1.17 to 18.86)). Effect estimates were consistent in male patients and those with index pulmonary embolism or with unprovoked VTE and in sensitivity analyses. In addition, compared with placebo or observation, the risk of all-cause mortality was reduced with standard-intensity VKAs (0.44 (0.20 to 0.87)) and low-dose factor Xa inhibitors (0.38 (0.12 to 0.995)).

Conclusions Standard-intensity VKAs and DOACs are more efficacious than aspirin for extended VTE treatment. Despite a higher risk of major bleeding, standard-intensity VKAs was associated with a lower risk of all-cause mortality. Since overall efficacy and safety of standard-intensity VKAs and DOACs are in equipoise, patient factors, costs and patient preferences should be considered when recommending extending anticoagulation treatment.

  • thromboembolic pulmonary vascular disease
  • pulmonary vascular disease

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  • K-LW and NE contributed equally.

  • Contributors The study was conceived and designed by K-LW, NvE, HRB and MC. The data were analysed by all authors. The first draft of the manuscript was prepared by KLW and NvE, which was edited with inputs from CC, LAC, HRB and MC. All authors gave final approval of the version to be published and have contributed to the manuscript. K-LW, NvE and MC are guarantors.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests K-LW reports honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Orient EuroPharm, Novartis and Tanabe. NvE reports a personal fee from Daiichi-Sankyo and Pfizer. CC reports being a partner at Cornerstone Research Group Inc, which consults for various pharmaceutical and medical device companies. LAC reports honoraria from Bayer, Bristol-Myers Squibb, Leo Pharma and Pfizer. HRB reports research support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, IONIS, Novartis, Pfizer, Roche and Sanofi and is a consultant for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, IONIS, Novartis, Pfizer, Roche, Sanofi and Thrombogenics. MC reports research funding from Bristol-Myers Squibb and LEO Pharma and honoraria from Bayer, Bristol-Myers Squibb, Leo Pharma, Pfizer and Sanofi.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement We do not have any additional data.