Skip to main content
Log in

Current Evidence for Pharmacologic Reversal Using Direct Oral Anticoagulants: What’s New?

  • Leading Article
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Direct oral anticoagulants are increasingly used in clinical practice and have addressed many of the issues related to vitamin K antagonists. However, the lack of reversal in life-threatening situations raises concerns regarding patient safety. Thus, current research is aimed at developing reversal agents that can safely neutralize the effects of anticoagulants. We present the design and mechanisms of action of and the animal models, clinical trials, and current evidence supporting the use of these emerging reversal agents. Idarucizumab is approved in many countries, and andexanet alfa has been approved by the US FDA, whereas others are in clinical trials. In view of the results of clinical studies to date, the problems of safety, price and accessibility remain. Therefore, these antidotes are a significant step towards improving the field of urgent and emergency reversal. From a practical perspective, post-market surveillance will be crucial to monitor the safety and effectiveness of these agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Zhao S, Zhao H, Wang X, Gao C, Qin Y, Cai H, et al. Factors influencing medication knowledge and beliefs on warfarin adherence among patients with atrial fibrillation in China. Patient Prefer Adherence. 2017;11:213–20.

    Article  Google Scholar 

  2. Samuelson BT, Cuker A. Measurement and reversal of the direct oral anticoagulants. Blood Rev. 2017;31(1):77–84.

    Article  CAS  Google Scholar 

  3. DeWald TA, Becker RC. The pharmacology of novel oral anticoagulants. J Thromb Thrombolysis. 2014;37(2):217–33.

    Article  CAS  Google Scholar 

  4. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, 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 (London, England). 2014;383(9921):955–62.

    Article  CAS  Google Scholar 

  5. Makam RCP, Hoaglin DC, McManus DD, Wang V, Gore JM, Spencer FA, et al. Efficacy and safety of direct oral anticoagulants approved for cardiovascular indications: systematic review and meta-analysis. PloS One. 2018;13(5):e0197583.

    Article  Google Scholar 

  6. Weitz JI. Factor XI and factor XII as targets for new anticoagulants. Thromb Res. 2016;141(Suppl 2):S40–5.

    Article  CAS  Google Scholar 

  7. Sherwood MW, Nessel CC, Hellkamp AS, Mahaffey KW, Piccini JP, Suh EY, et al. Gastrointestinal bleeding in patients with atrial fibrillation treated with rivaroxaban or warfarin: ROCKET AF trial. J Am Coll Cardiol. 2015;66(21):2271–81.

    Article  CAS  Google Scholar 

  8. Fang MC, Go AS, Chang Y, Hylek EM, Henault LE, Jensvold NG, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007;120(8):700–5.

    Article  Google Scholar 

  9. Farmakis D, Davlouros P, Giamouzis G, Giannakoulas G, Pipilis A, Tsivgoulis G, et al. Direct oral anticoagulants in nonvalvular atrial fibrillation: practical considerations on the choice of agent and dosing. Cardiology. 2018;140(2):126–32.

    Article  CAS  Google Scholar 

  10. Myers B, Webster A. Heavy menstrual bleeding on rivaroxaban—comparison with apixaban. Br J Haematol. 2017;176(5):833–5.

    Article  Google Scholar 

  11. Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, 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 Eur Pacing Arrhythm Card Electrophysiol. 2015;17(10):1467–507.

    Google Scholar 

  12. Boehringer Ingelheim Inc. Praxbind (idarucizumab) prescribing information: Food and Drug Administration (FDA). 2015. http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Praxbind/Praxbind.pdf. Accessed 16 July 2015.

  13. Portola Pharmaceuticals Inc, Andexxa (andexanet alfa) prescribing information: Food and Drug Administration (FDA). 2018. https://www.fda.gov/downloads/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm606687.pdf. Accessed 3 May 2018.

  14. Costin J, Ansell J, Bakhru S, Laulicht B, Steiner S. The new oral anticoagulants: clinical use and reversal agent development. ISBT Sci Ser. 2015;10(S1):324–31.

    Article  CAS  Google Scholar 

  15. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121(18):3554–62.

    Article  CAS  Google Scholar 

  16. Grottke O, Honickel M, van Ryn J, ten Cate H, Rossaint R, Spronk HM. Idarucizumab, a specific dabigatran reversal agent, reduces blood loss in a porcine model of trauma with dabigatran anticoagulation. J Am Coll Cardiol. 2015;66(13):1518–9.

    Article  Google Scholar 

  17. Glund S, Stangier J, Schmohl M, Moschetti V, Haazen W, De Smet M, et al. Idarucizumab, a specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. Blood. 2014;124(21):344.

    Article  Google Scholar 

  18. Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, 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 (London, England). 2015;386(9994):680–90.

    Article  CAS  Google Scholar 

  19. Glund S, Stangier J, van Ryn J, Schmohl M, Moschetti V, Haazen W, 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. 2017;56(1):41–54.

    Article  CAS  Google Scholar 

  20. Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, et al. Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med. 2017;377(5):431–41.

    Article  CAS  Google Scholar 

  21. Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–20.

    Article  CAS  Google Scholar 

  22. FDA. FDA approves Praxbind® the first reversal agent for the anticoagulant Pradaxa [media release]. http://fda.gov. Accessed 16 Oct 2015.

  23. EMA. EMA Agency, Fast-tracks antidote to anticoagulant Pradaxa [media release]. http://www.ema.europa.eu/. Accessed 25 Sep 2015.

  24. Ghadimi K, Dombrowski KE, Levy JH, Welsby IJ. Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Expert Rev Hematol. 2016;9(2):115–22.

    Article  CAS  Google Scholar 

  25. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation Factor Xa. Nat Med. 2013;19(4):446–51.

    Article  CAS  Google Scholar 

  26. Lu G, Hollenbach SJ, Baker DC, Tan S, Hutchaleelaha A, Curnutte JT, et al. Preclinical safety and efficacy of andexanet alfa in animal models. J Thromb Haemost. 2017;15(9):1747–56.

    Article  CAS  Google Scholar 

  27. Crowther M, Levy GG, Lu G, Leeds J, Lin J, Pratikhya P, 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. Blood. 2014;124(21):4269.

    Article  Google Scholar 

  28. Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet alfa for the reversal of Factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413–24.

    Article  CAS  Google Scholar 

  29. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. Full study report of andexanet alfa for bleeding associated with Factor Xa inhibitors. N Engl J Med. 2019;380(14):1326–35.

    Article  CAS  Google Scholar 

  30. FDA. FDA approves Andexxa®, the first and only antidote for the reversal of factor Xa inhibitors [media release]. http://fda.gov. Accessed 3 May 2018

  31. Bakhru SLB, Jiang X, Chen L, Grosso M, Morishima Y, et al. A synthetic small molecule antidote for anticoagulants. Eur Heart J. 2013;34:1078.

    Article  Google Scholar 

  32. Bakhru SLBJX. A synthetic small molecule which reverses over-dosage and bleeding by the new oral anticoagulants. Circulation. 2013;128:A18809.

    Google Scholar 

  33. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371(22):2141–2.

    Article  Google Scholar 

  34. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso MA, Brown K, et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost. 2017;117(2):238–45.

    Article  Google Scholar 

  35. Ansell JE, Laulicht BE, Bakhru SH, Hoffman M, Steiner SS, Costin JC. Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin. Thromb Res. 2016;146:113–8.

    Article  CAS  Google Scholar 

  36. Ansell J, Zappe S, Jiang X, Chen L, Steiner S, Laulicht B, et al. A novel whole blood point-of-care coagulometer to measure the effect of direct oral anticoagulants and heparins. Semin Thromb Hemost. 2019;45(3):259–63.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peizhi Ma.

Ethics declarations

Funding

This study was funded by Scientific and Technological Research Projects in Henan Province from China to Shujuan Zhao (no. 201702235).

Conflict of interest

Shujuan Zhao, Xuejiao Hong, Jingjing Cao, Jing Zhang, and Peizhi Ma have no conflicts of interest that might be relevant to the contents of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, S., Hong, X., Cao, J. et al. Current Evidence for Pharmacologic Reversal Using Direct Oral Anticoagulants: What’s New?. Am J Cardiovasc Drugs 20, 117–123 (2020). https://doi.org/10.1007/s40256-019-00366-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-019-00366-0

Navigation