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Comparative Study
. 2015 Dec 30;10(12):e0144856.
doi: 10.1371/journal.pone.0144856. eCollection 2015.

Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis

A T Cohen  1 , M Hamilton  2 , S A Mitchell  3 , H Phatak  2 , X Liu  4 , A Bird  5 , D Tushabe  6 , S Batson  3
Affiliations
Comparative Study

Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis

A T Cohen et al. PLoS One. .

Abstract

Background: Anticoagulation with low molecular weight heparin and vitamin K antagonists is the current standard of care (SOC) for venous thromboembolism (VTE) treatment and prevention. Although novel oral anti-coagulants (NOACs) have been compared with SOC in this indication, no head-to-head randomised controlled trials (RCTs) have directly compared NOACs. A systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of NOACs for the initial and long-term treatment of VTE.

Methods: Electronic databases (accessed July 2014) were systematically searched to identify RCTs evaluating apixaban, dabigatran, edoxaban, and rivaroxaban versus SOC. Eligible patients included adults with an objectively confirmed deep vein thrombosis (DVT), pulmonary embolism (PE) or both. A fixed-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as relative risks (RR) and 95% credible intervals (Crl).

Results: Six Phase III RCTs met criteria for inclusion: apixaban (one RCT; n = 5,395); rivaroxaban (two RCTs; n = 3,423/4,832); dabigatran (two RCTs; n = 2,539/2,568); edoxaban (one RCT; n = 8,240). There were no statistically significant differences between the NOACs with regard to the risk of 'VTE and VTE-related death. Apixaban treatment was associated with the most favourable safety profile of the NOACs, showing a statistically significantly reduced risk of 'major or clinically relevant non-major (CRNM) bleed' compared with rivaroxaban (0.47 [0.36, 0.61]), dabigatran (0.69 [0.51, 0.94]), and edoxaban (0.54 [0.41, 0.69]). Dabigatran was also associated with a significantly lower risk of 'major or CRNM bleed' compared with rivaroxaban (0.68 [0.53, 0.87]) and edoxaban (0.77 [0.60, 0.99]).

Conclusions: Indirect comparisons showed statistically similar reductions in the risk of 'VTE or VTE-related death for all NOACs. In contrast, reductions in 'major or CRNM bleed' for initial/long-term treatment were significantly better with apixaban compared with all other NOACs, and with dabigatran compared with rivaroxaban and edoxaban. Results from the current analysis indicate that the NOACs offer clinical benefit over conventional therapy while highlighting relative differences in their bleeding profile.

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Conflict of interest statement

Competing Interests: The authors have the following interests. This study was funded by Bristol Myers Squibb and Pfizer. Hamilton M. and Phatak H. are employed by Bristol Myers Squibb., Liu X. and Bird A. by Pfizer Ltd, Batson S. by Abacus International and Tushabe D. by TUSH-D UK LTD. At the time of this study, Claflin A. was a paid contractor of Pfizer Ltd. Cohen A. is a paid clinical consultant to Bristol Myers Squibb and Pfizer. Fowler H., Mitchell S.A., and Batson S. are paid consultants to Bristol Myers Squibb and Pfizer Ltd. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1
Fig 1. Systematic review flow diagram.
The flow diagram indicates inclusion and exclusion of publications at each stage of the systematic review process.
Fig 2
Fig 2. Network of evidence for the meta-analysis.
†Primary and sensitivity analyses used pooled data from the EINSTEIN DVT and EINSTEIN PE trials [28].
See this image and copyright information in PMC

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