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Specific Antidotes for Direct Oral Anticoagulants in Life-Threatening Bleeding

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Review presents data on medicines from the new group of cardiovascular drugs, direct oral anticoagulants (DOACs) inhibitors, as antidotes for DOAC when stopping life-threatening bleeding. DOAC therapy is accorded by hemorrhages with lower frequency than therapy by indirect anticoagulants, but really exist. New antidotes for DOACs are idarucizumab, andexanet, ciraparantag. The need in antidotes for DOAC may suddenly appear in spontaneous bleeding, during surgical operation, invasive procedure, due to trauma, in patients with stroke, kidney or liver failure. Data is given on the frequency of the main types of bleeding while taking new oral anticoagulants. Information concerning use of antidotes for DOACs in bleedings as well as use of non-specific therapy are reviewed.


About the Authors

A. B. Sumarokov
National Medical Research Centre of Cardiology
Russian Federation
MD, PhD, Senior Researcher, Research Institute of Clinical Cardiology n.a. A. L. Myasnikov

L. I. Buryachkovskaya
National Medical Research Centre of Cardiology
Russian Federation
MD, PhD, Leading Researcher, Institute of Experimental Cardiology

N. V. Lomakin
Central Clinical Hospital of the Presidential Administration of the Russian Federation
Russian Federation
MD, PhD, Head of Cardioreanimatology Department


1. Connolly S.J., Ezekowitz M.D., Yusuf S. et al., the RE-LY Steering Committee and Investigators. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139-51. doi:10.1056/NEJMoa0905561.

2. Patel M.R., Mahaffey K.W., Garg J. et al., ROCKET AF Steering Commetee for the ROCKET AF Investigators. Rivaroxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2011;365:883-91. doi:10.1056/NEJMoa09055612.

3. Grangler C.B., Alexander J.H., McMurray J.J.V. et al. for the ARISTOTLE Committees and Investigators. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2011; 365(11):981-92. doi:10.1056/NEJMoa1107039.

4. Guigliano R.P., Ruff C.T., Braunwald E. et al. for the ENGAGE AF-TIMI 48 Investigators.Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2013;369(22):2093-104. doi:10.1056/NEJMoa1310907.

5. Eikelboom J., Merli G. Bleeding with Direct Oral Anticoagulants vs Warfarin: Clinical Experience. Am J Med. 2016;129 Suppl:S33-S40. doi:10.1016/j.amjmed.2016.06.003.

6. Chai-Adisaksopha C., Crowther M., Isayama T., Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124(15):2450-8. doi:10.1182/blood-2014-07-590323.

7. Villines T.D., Peacock W.F. Safety of Direct Oral Anticoagulants: Insight from Postmarketing Studies. Am J Med. 2016;129(11S):S41-S46. doi:10.1016/j.amjmed.2016.06.004.

8. Rose D., Bar B. Direct Oral Anticoagulant Agents: Pharmacologic Profile, Indications, Coagulation Monitiring, and Reversal Agents. J Stroke Cerebrovasc Dis. 2018;27(8):2049-58. doi:10.1016/j. jstrokecerebrovasdis.2018.04.004.

9. Gibson M.C., Nafee T., Megan K. et al. Symptomatic event reduction with extended-duration betrixaban in acute medically ill hospitalized patients. Am Heart J. 2018;198:84-90. doi:10.1016/j.ahj. 2017.12.015.

10. Milner J., Cunha A., Gamboa-Cruz C. et al. Recent major advances in cardiovascular pharmacotherapy. Eur J Clin Pharmacol. 2018;74(7):853-862. doi:10.1007/s00228-018-2453-1.

11. Pollack C.V., Reilly P.A., van Ryn J. et al. Idarubicizumab for dabigatran reversal - full cohort analysis. N Engl J Med. 2017;337:431-41. doi:10.1056/NEJMoa1707278.

12. Baker D.E. Coagulation Factor Xa (Recombinant), Inactivated-zhzo (Andexanet Alfa).Hosp Pharm. 2018;53(5):286-291. doi:10.1177/0018578718788840.

13. Levy J.H. Discontinuation and Management of Direct-Acting Anticoagulants for Emergency Procedures. Am J Med. 2016;129 Suppl:S47-S53. doi:10.1016/j.amjmed.2016.06.005.

14. ten Cate H., Henskens Y., Lance M.D. Practical guidance on the use of laboratory testing in management of bleeding in patients receiving direct oral аnticoagulants. Vascular Health and Risk Management. 2017;13:457-67. doi:10.2147/VHRM.S126265.

15. Eikelboom J.W., Quilan D.J., Hirsh J. et al. Laboratory Monitiring of Non-Vitamin K Antagonist Oral Anticoagulant Use in Patient With Atrial Fibrillation. A Review. JAMA Cardiol. 2017;2(5):566-74. doi:10.1001/jamacardio.2017.0364.

16. Takatsuki S., Kimura K., Sugimoto K. et al. Real-world monitoring of effect direct oral anticoagulants in clinic and hospitalisation settings. Sage Open Medicine. 2017(5):1-9. doi:10.1177/ 2050312117734773.

17. Schiele F., van Ryn J., Canada K. et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013: 121 (18):3554-62. doi:10.1182/blood-2012-11-468207.

18. Pollack C.V. Evidence Supporting Idarubicizumab for the Reversal of Dabigatran. Am J Med. 2016;129 Suppl:S73-S79. doi:10.1016/j.ajem.2016.09.051.

19. Glund S., Stangier J., van Ryn J. 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;56:41-54. doi:10.1007/ s40262-016-0417-0.

20. Kaur U., Chakrabarti S.S., Manna S., Gambhir I.S. Severe haematuria of lower urinary tract origin with low dose dabigatran use in three Indian elderly patients: unresolved issues in the safety of novel oral oral anticoagulants. Ther Adv Drug Safety. 2018;9(1):89-91. doi:10.1177/ 2042098617742344.

21. Reilly P.A., van Ryn J., Grottke O. et al. Idarucizumab, a Specific Reversal Agent for Dabigatran: Mode of Action, Pharmacokinetics and Pharmacodynamics, Safety and Efficacy in Phase I Subjects. Am J Med. 2016;129 Suppl:S64-S72. doi:10.1016/j.amjmed.2016.06.007.

22. Glund S., Stangier J., van Ryn J. et al. Restarting Dabigatran Etexilate 24 h After Reversal With Idarubicizumab in Healthy Volunteers. JACC. 2016;67(13):1653-9. doi:10.1016/j.jacc.2016.01.043.

23. Glund S., Stangier J., Schmohl M. et al. Safety, tolerability, and efficacy of idarubicizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomized, placebo controlled, double-blind phase 1 trial. Lancet. 2015;386:680-90. doi:10.1016/S0140-6736(15)60732-2.

24. Tirely D., He J., Nordling M.M., Wienecke T. Systemic Thrombolysis in Acute Ischemic Stroke after Dabigatran Etexilate Reversal with Idarubicizumab - A Case Report. J Stroke Cerebrovasc Dis. 2017;26(7):e123-e125. doi:10.1016/j.jstrokecerebrovasdis.2017.03.039.

25. Connolly S.J., Milling T.J., Eikelboom J.W. et al., for the ANNEXA-4 Investigators. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016;375(12):1131-41. doi:10.1056/NEJMoa1607887.

26. Siegal D., Curnutte J.T., Connolly S.J. et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373:2413-24. doi:10.1056/NEJMoa1510991.

27. Ansell J.E., Bakhru S.H., Laulicht B.E. et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost. 2017;117(2):238-245. doi:10.1160/TH16-03-0224.

28. Martsevich S.Y., Lukina Y.V. Warfarin and its significance in new oral anticoagulant era. Problems of efficacy and safety control. Rational Pharmacotherapy in Cardiology. 2017;13(5):699-705. (In Russ.) doi:10.20996/1819-6446-2017-13-5-699-705.

29. Steffel J., Verhamme P., Potpara T.S. et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39:1330-93. doi:10.1093/eurheartj/ehj136.

30. Kirchhof P., Benussi S., Kotecha D. et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893-962. doi:10.1093/eurheartj/ehw210.

31. Eikelboom J.W., Kozek-Langenecker S., Exadaktilos A. et al. Emergency care of patients receiving non-vitamin K antagonists oral anticoagulants. J Thromb Thrombolysis. 2017;43(3):306-17. doi:10.1007/s11239-017-1476-2.

32. Di Fusco S.A., Luca F., Benvenuto M. et al. Maior bleeding with old and novel anticoagulants: How to manage it. Focus on reversal agents. Int J Cardiol. 2018;268:75-79. doi:10.1016/j.ijcard. 2018.05.060.

33. Engelbart J.M., Zepeske A., Galet A. et al. Safety and effectiveness of Factor Eight Inhibitir Bypassing Activity for direct oral anticoagulants-related hemorrhage reversal. Am J Emerg Med. 2018 May 17. pii: S0735-6757(18)30400-5. doi:10.1016/j.ajem.2018.05.023.

34. Schenk B., Goerke S., Beer R. et al. Four-factor prothrombin concentrate improves thrombin generation and protrombine time in patients with bleeding complications releted to rivaroxaban: a singlecenter pilot trial. Thromb J. 2018;16:1. doi:10.1186/s12959-017-0158-9.

35. Kumar V., Allencherril J., Bracey A. et al. Therapeutic Plasma Exchange for Urgent Rivaroxaban Reversal. Texas Heart Institute Journal. 2018;45(2):96-8. doi:10.14503/THIJ-17-6229.

36. Horev N.G., Momot A.P., Kon’kova V.O. Antidotes for new direct oral anticoagulants. Angiologia and Vascular Surgery. 2016;22(3):173-9. (In Russ.)

For citation:

Sumarokov A.B., Buryachkovskaya L.I., Lomakin N.V. Specific Antidotes for Direct Oral Anticoagulants in Life-Threatening Bleeding. Rational Pharmacotherapy in Cardiology. 2018;14(6):944-950.

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ISSN 1819-6446 (Print)
ISSN 2225-3653 (Online)