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Who, when, and how to reverse non-vitamin K oral anticoagulants

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Abstract

Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12–24 h after the last NOAC dose, and/or (c) consideration of hemostatic agents.

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Acknowledgments

This study was supported by National Institutes of Health (Grant No: 1RO1NS070307).

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Authors and Affiliations

  1. Section of General Internal Medicine, Department of Medicine, Boston Medical Center, Boston University, Boston, MA, USA

    Konstantinos N. Aronis & Elaine M. Hylek

  2. Division of Cardiology, Johns Hopkins Hospital, Johns Hopkins University, Zayed 7122, 1800 Orleans St, Baltimore, MD, 21287, USA

    Konstantinos N. Aronis

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Correspondence to Konstantinos N. Aronis.

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Dr. Hylek has served on Advisory Boards for Armetheon, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Medtronic, and Pfizer. Dr. Aronis has no conflict of interest to disclose. The National Institutes of Health has not been involved, directly or indirectly, in the collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

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Aronis, K.N., Hylek, E.M. Who, when, and how to reverse non-vitamin K oral anticoagulants. J Thromb Thrombolysis 41, 253–272 (2016). https://doi.org/10.1007/s11239-015-1297-0

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