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Reversal agents for non-vitamin K antagonist oral anticoagulants

Nature Reviews Cardiology volume 15, pages 273–281 (2018)Cite this article

Subjects

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

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.

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Figure 1: Reversal agents for non-vitamin K antagonist oral anticoagulants.

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References

  1. Yeh, C. H., Gross, P. L. & Weitz, J. I. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood 124, 1020–1028 (2014).

    Article  CAS  Google Scholar 

  2. Ruff, C. T. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383, 955–962 (2014).

    Article  CAS  Google Scholar 

  3. Levy, J. H., Spyropoulos, A. C., Samama, C. M. & Douketis, J. Direct oral anticoagulants: new drugs and new concepts. JACC Cardiovasc. Interv. 7, 1333–1351 (2014).

    Article  CAS  Google Scholar 

  4. Chan, N. C., Eikelboom, J. W. & Weitz, J. I. Evolving treatments for arterial and venous thrombosis: role of the direct oral anticoagulants. Circ. Res. 118, 1409–1424 (2016).

    Article  CAS  Google Scholar 

  5. Sherwood, M. W. et al. Gastrointestinal bleeding in patients with atrial tibrillation treated with rivaroxaban or warfarin: ROCKET AF trial. J. Am. Coll. Cardiol. 66, 2271–2281 (2015).

    Article  CAS  Google Scholar 

  6. Myers, B. & Webster, A. Heavy menstrual bleeding on rivaroxaban — comparison with apixaban. Br. J. Haematol. 176, 833–835 (2017).

    Article  Google Scholar 

  7. Weitz, J. I. & Harenberg, J. New developments in anticoagulants: past, present and future. Thromb. Haemost. 117, 1283–1288 (2017).

    Article  Google Scholar 

  8. Levy, J. H. et al. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J. Thromb. Haemost. 14, 623–627 (2016).

    Article  CAS  Google Scholar 

  9. Cohen, A. T., Harrington, R. A. & Gibson, C. M. Betrixaban in acutely ill medical patients. N. Engl. J. Med. 375, e50 (2016).

    Article  Google Scholar 

  10. Reiffel, J. A. et al. NOAC monitoring, reversal agents, and post-approval safety and effectiveness evaluation: a cardiac safety research consortium think tank. Am. Heart J. 177, 74–86 (2016).

    Article  Google Scholar 

  11. Samuelson, B. T. & Cuker, A. Measurement and reversal of the direct oral anticoagulants. Blood Rev. 31, 77–84 (2017).

    Article  CAS  Google Scholar 

  12. Ebner, M. et al. Emergency coagulation assessment during treatment with direct oral anticoagulants: limitations and solutions. Stroke 48, 2457–2463 (2017).

    Article  Google Scholar 

  13. Dale, B. J., Chan, N. C. & Eikelboom, J. W. Laboratory measurement of the direct oral anticoagulants. Br. J. Haematol. 172, 315–336 (2016).

    Article  Google Scholar 

  14. Gouin-Thibault, I. et al. Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays. A multicentre French GEHT study. Thromb. Haemost. 111, 240–248 (2014).

    Article  CAS  Google Scholar 

  15. Cuker, A., Siegal, D. M., Crowther, M. A. & Garcia, D. A. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J. Am. Coll. Cardiol. 64, 1128–1139 (2014).

    Article  CAS  Google Scholar 

  16. Konigsbrugge, O. et al. Anti-coagulation assessment with prothrombin time and anti-Xa assays in real-world patients on treatment with rivaroxaban. Ann. Hematol. 94, 1463–1471 (2015).

    Article  Google Scholar 

  17. Pollack, C. V. Jr et al. Idarucizumab for dabigatran reversal — full cohort analysis. N. Engl. J. Med. 377, 431–441 (2017).

    Article  CAS  Google Scholar 

  18. van Ryn, J. et al. Dabigatran etexilate — a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb. Haemost. 103, 1116–1127 (2010).

    Article  CAS  Google Scholar 

  19. Jaffer, I. H. et al. Comparison of the ecarin chromogenic assay and diluted thrombin time for quantification of dabigatran concentrations. J. Thromb. Haemost. 15, 2377–2387 (2017).

    Article  CAS  Google Scholar 

  20. Cuker, A. Laboratory measurement of the non-vitamin K antagonist oral anticoagulants: selecting the optimal assay based on drug, assay availability, and clinical indication. J. Thromb. Thrombolysis 41, 241–247 (2016).

    Article  CAS  Google Scholar 

  21. Ikeda, K. & Tachibana, H. Clinical implication of monitoring rivaroxaban and apixaban by using anti-factor Xa assay in patients with non-valvular atrial fibrillation. J. Arrhythm. 32, 42–50 (2016).

    Article  Google Scholar 

  22. Glund, S. et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb. Haemost. 113, 943–951 (2015).

    Article  Google Scholar 

  23. Glund, S. et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet 386, 680–690 (2015).

    Article  CAS  Google Scholar 

  24. Glund, S. et al. Effect of age and renal function on idarucizumab pharmacokinetics and idarucizumab-mediated reversal of dabigatran anticoagulant activity in a randomized, double-blind, crossover phase Ib study. Clin. Pharmacokinet. 56, 41–54 (2017).

    Article  CAS  Google Scholar 

  25. Pollack, C. V. Jr et al. Idarucizumab for dabigatran reversal. N. Engl. J. Med. 373, 511–520 (2015).

    Article  CAS  Google Scholar 

  26. Pollack, C. V. Jr et al. Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb. Haemost. 114, 198–205 (2015).

    Article  Google Scholar 

  27. Crowther, M. & Crowther, M. A. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler. Thromb. Vasc. Biol. 35, 1736–1745 (2015).

    Article  CAS  Google Scholar 

  28. Ghadimi, K., Dombrowski, K. E., Levy, J. H. & Welsby, I. J. Andexanet alfa for the reversal of factor Xa inhibitor related anticoagulation. Expert Rev. Hematol. 9, 115–122 (2016).

    Article  CAS  Google Scholar 

  29. Siegal, D. M. et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N. Engl. J. Med. 373, 2413–2424 (2015).

    Article  CAS  Google Scholar 

  30. Crowther, M. et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors [abstract]. Blood 124, 4269 (2014).

    Google Scholar 

  31. Crowther, M. et al. Reversal of betrixaban-induced anticoagulation in healthy volunteers by andexanet alfa [abstract]. Blood 128, 143 (2016).

    Google Scholar 

  32. Lu, G. et al. Preclinical safety and efficacy of andexanet alfa in animal models. J. Thromb. Haemost. 15, 1747–1756 (2017).

    Article  CAS  Google Scholar 

  33. Connolly, S. J. et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N. Engl. J. Med. 375, 1131–1141 (2016).

    Article  CAS  Google Scholar 

  34. Sullivan, D. W. Jr, Gad, S. C., Laulicht, B., Bakhru, S. & Steiner, S. Nonclinical safety assessment of PER977: a small molecule reversal agent for new oral anticoagulants and heparins. Int. J. Toxicol. 34, 308–317 (2015).

    Article  CAS  Google Scholar 

  35. Ansell, J. E. et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N. Engl. J. Med. 371, 2141–2142 (2014).

    Article  Google Scholar 

  36. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03172910 (2017).

  37. Eerenberg, E. S. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 124, 1573–1579 (2011).

    Article  CAS  Google Scholar 

  38. Levy, J. H. & Levi, M. New oral anticoagulant-induced bleeding: clinical presentation and management. Clin. Lab. Med. 34, 575–586 (2014).

    Article  Google Scholar 

  39. Song, Y. et al. Reversal of apixaban anticoagulation by 4-factor prothrombin complex concentrates in healthy subjects: a randomized 3-period crossover study. J. Thromb. Haemost. 15, 2125–2137 (2017).

    Article  CAS  Google Scholar 

  40. Zahir, H. et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 131, 82–90 (2015).

    Article  CAS  Google Scholar 

  41. Levy, J. H. et al. Rivaroxaban reversal with prothrombin complex concentrate or tranexamic acid in healthy volunteers. J. Thromb. Haemost. http://dx.doi.org/10.1111/jth.13894 (2017).

  42. Majeed, A. et al. Management of rivaroxaban or apixaban associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 130, 1706–1712 (2017).

    Article  CAS  Google Scholar 

  43. Varadi, K. et al. Pro- and anticoagulant factors facilitate thrombin generation and balance the haemostatic response to FEIBA® in prophylactic therapy. Haemophilia 22, 615–624 (2016).

    Article  CAS  Google Scholar 

  44. Goodnough, L. T. & Levy, J. H. The judicious use of recombinant factor VIIa. Semin. Thromb. Hemost. 42, 125–132 (2016).

    Article  CAS  Google Scholar 

  45. Marlu, R. et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb. Haemost. 108, 217–224 (2012).

    Article  CAS  Google Scholar 

  46. Perzborn, E., Heitmeier, S., Laux, V. & Buchmuller, A. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb. Res. 133, 671–681 (2014).

    Article  CAS  Google Scholar 

  47. Fukuda, T., Honda, Y., Kamisato, C., Morishima, Y. & Shibano, T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb. Haemost. 107, 253–259 (2012).

    Article  CAS  Google Scholar 

  48. Halim, A. B., Samama, M. M. & Mendell, J. Ex vivo reversal of the anticoagulant effects of edoxaban. Thromb. Res. 134, 909–913 (2014).

    Article  CAS  Google Scholar 

  49. Dibu, J. R., Weimer, J. M., Ahrens, C., Manno, E. & Frontera, J. A. The role of FEIBA in reversing novel oral anticoagulants in intracerebral hemorrhage. Neurocrit. Care 24, 413–419 (2016).

    Article  CAS  Google Scholar 

  50. Mao, G., King, L., Young, S. & Kaplan, R. Factor eight inhibitor bypassing agent (FEIBA) for reversal of target-specific oral anticoagulants in life-threatening intracranial bleeding. J. Emerg. Med. 52, 731–737 (2017).

    Article  Google Scholar 

  51. Mayer, S. A. et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N. Engl. J. Med. 358, 2127–2137 (2008).

    Article  CAS  Google Scholar 

  52. Mayer, S. A. et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N. Engl. J. Med. 352, 777–785 (2005).

    Article  CAS  Google Scholar 

  53. Tanaka, K. A., Szlam, F., Dickneite, G. & Levy, J. H. Effects of prothrombin complex concentrate and recombinant activated factor VII on vitamin K antagonist induced anticoagulation. Thromb. Res. 122, 117–123 (2008).

    Article  CAS  Google Scholar 

  54. Levi, M., Levy, J. H., Andersen, H. F. & Truloff, D. Safety of recombinant activated factor VII in randomized clinical trials. N. Engl. J. Med. 363, 1791–1800 (2010).

    Article  CAS  Google Scholar 

  55. Wang, X. et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am. J. Cardiovasc. Drugs 14, 147–154 (2014).

    Article  Google Scholar 

  56. Ollier, E. et al. Effect of activated charcoal on rivaroxaban complex absorption. Clin. Pharmacokinet. 56, 793–801 (2017).

    Article  CAS  Google Scholar 

  57. Raval, A. N. et al. Management of patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a Scientific Statement from the American Heart Association. Circulation 135, e604–e633 (2017).

    Article  CAS  Google Scholar 

  58. Levy, J. H. et al. Antifibrinolytic therapy and perioperative considerations. Anesthesiology http://dx.doi.org/10.1097/ALN.0000000000001997 (2017).

  59. Levy, J. H. Antifibrinolytic therapy: new data and new concepts. Lancet 376, 3–4 (2010).

    Article  Google Scholar 

  60. Witt, D. M. What to do after the bleed: resuming anticoagulation after major bleeding. Hematol. Am. Soc. Hematol. Educ. Program 2016, 620–624 (2016).

    Article  Google Scholar 

  61. Kuramatsu, J. B. et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 313, 824–836 (2015).

    Article  CAS  Google Scholar 

  62. Nielsen, P. B., Larsen, T. B., Skjoth, F. &, Lip, G. Y. Outcomes associated with resuming warfarin treatment after hemorrhagic stroke or traumatic intracranial hemorrhage in patients with atrial fibrillation. JAMA Intern. Med. 177, 563–570 (2017).

    Article  Google Scholar 

  63. Majeed, A. et al. Optimal timing of vitamin K antagonist resumption after upper gastrointestinal bleeding: a risk modelling analysis. Thromb. Haemost 117, 491–499 (2017).

    Article  Google Scholar 

  64. Eikelboom, J. W. & Weitz, J. I. New anticoagulants. Circulation 121, 1523–1532 (2010).

    Article  Google Scholar 

  65. Heidbuchel, H. et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 17, 1467–1507 (2015).

    Article  Google Scholar 

  66. Seyve, L., Richarme, C., Polack, B. & Marlu, R. Impact of four direct oral anticoagulants on rotational thromboelastometry (ROTEM). Int. J. Lab. Hematol. http://dx.doi.org/10.1111/ijlh.12744 (2017).

  67. Taune, V. et al. Whole blood coagulation assays ROTEM and T-TAS to monitor dabigatran treatment. Thromb. Res. 153, 76–82 (2017).

    Article  CAS  Google Scholar 

  68. Ansell, J. E. et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb. Haemost. 117, 238–245 (2017).

    Article  Google Scholar 

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Authors and 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, L8S 4L8, Ontario, Canada

    James Douketis & Jeffrey I. Weitz

  3. Thrombosis and Atherosclerosis Research Institute, 237 Barton Street East, Hamilton, L8L 2X2, Ontario, Canada

    James Douketis & Jeffrey I. Weitz

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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.

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Correspondence to Jerrold H. Levy.

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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.

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Levy, J., Douketis, J. & Weitz, J. Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol 15, 273–281 (2018). https://doi.org/10.1038/nrcardio.2017.223

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