Review Article | Published:

Reversal agents for non-vitamin K antagonist oral anticoagulants

Nature Reviews Cardiology volume 15, pages 273281 (2018) | Download Citation

Abstract

The non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban, and rivaroxaban, which inhibit coagulation factor Xa. Although clinical studies of NOACs were conducted without antidotes, patient outcomes with major bleeding when receiving NOACs were no worse than those in patients treated with a vitamin K antagonist. Nonetheless, in patients with life-threatening bleeding or requiring urgent surgery, the capacity for rapid NOAC reversal is likely to increase patient safety. Three NOAC reversal agents are in various stages of development: idarucizumab, a specific reversal agent for dabigatran; andexanet alfa, which reverses factor Xa inhibitors; and ciraparantag, which is purported to reverse all NOACs. Idarucizumab is licensed in many countries, andexanet is under consideration by regulatory agencies, and ciraparantag is undergoing phase III evaluation. In the absence of licensed reversal agents for the oral factor Xa inhibitors, prothrombin complex concentrates are often used in patients taking these agents who present with life-threatening bleeding. In this Review, we summarize the approved indications for the NOACs, outline how to measure their anticoagulant effects, describe the mechanism of action of the reversal strategies, assess the preclinical and clinical data supporting their use, provide guidance on potential indications for reversal, and offer a management approach for patients treated with NOACs who present with serious bleeding or require urgent surgery.

Key points

  • The non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban, and rivaroxaban, which inhibit factor Xa

  • Three NOAC reversal agents are in various stages of development: idarucizumab is licensed in many countries, andexanet is under consideration by regulatory agencies, and ciraparantag is undergoing phase III evaluation

  • Idarucizumab is approved for dabigatran reversal in patients requiring emergency surgery or urgent procedures and in those with life-threatening or uncontrolled bleeding

  • In the absence of licensed reversal agents for the oral factor Xa inhibitors, prothrombin complex concentrates are increasingly used in patients taking these agents who present with life-threatening bleeding

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Author information

Affiliations

  1. Department of Anesthesiology, Critical Care, and Surgery, Duke University Medical Center, 2301 Erwin Road, 5691H HAFS, Box 3094, Durham, North Carolina 27710, USA.

    • Jerrold H. Levy
  2. Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada.

    • James Douketis
    •  & Jeffrey I. Weitz
  3. Thrombosis and Atherosclerosis Research Institute, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

    • James Douketis
    •  & Jeffrey I. Weitz

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Contributions

J.H.L. researched data for the article, and all the authors discussed its content. J.H.L. and J.I.W. wrote the manuscript, and all the authors reviewed and edited the article before submission.

Competing interests

J.H.L. is on the scientific advisory or steering committees of Boehringer Ingelheim, CSL Behring, Grifols, Instrumentation Laboratories, Janssen, Leading Biosciences, Merck, Octapharma, Pfizer, and Portola. J.D. is on the scientific advisory board of AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Leo Pharma, Pfizer, and Sanofi; and is a consultant for Janssen. J.I.W. served as a consultant and received honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Novartis, and Pfizer.

Corresponding author

Correspondence to Jerrold H. Levy.

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DOI

https://doi.org/10.1038/nrcardio.2017.223