In short Article

Antidotes for direct oral anticoagulants

Several years after the introduction of the direct oral anticoagulants (DOACs), two specific antidotes were authorised. Idarucizumab reverses the action of the direct thrombin inhibitor dabigatran, and andexanet alfa reduces the action of the factor Xa inhibitors rivaroxaban and apixaban. There has been limited research into the efficacy and adverse effects of these agents. Studies show that the antidotes rapidly and almost completely reverse the action of the DOACs. There has also been limited research into prothrombin complex concentrate (PCC), which was the drug of first choice before the specific antidotes had been authorised and is still the preferred drug for certain indications. There have been no studies comparing PCC with the antidotes.

  • The efficacy of idarucizumab and andexanet alfa has not been investigated in randomised studies.
  • Pre-authorisation studies show that both antidotes rapidly and almost completely reverse the effect of DOACs on the coagulation parameters. 
  • Only idarucizumab has been studied and authorised for use in emergency interventions.
  • Since studies directly comparing the two antidotes with PCC are lacking, it is not possible to make a well-founded choice for the treatment of life-threatening or uncontrolled bleeding or for reversing the action of the DOACs in emergency interventions.
  • The high cost of andexanet alfa plays a role in the decision whether or not to apply this treatment.

  1. CBG-MEB Geneesmiddeleninformatiebank. SmPC Pradaxa. Available from:,P0_LANG,P3_RVG1:H,NL,73883. Accessed 05-05-2021.
  2. Testa S, Ageno W, Antonucci E, Morandini R, Beyer-Westendorf J, Paciaroni M, et al. Management of major bleeding and outcomes in patients treated with direct oral anticoagulants: results from the START-Event registry. Intern Emerg Med. 2018 Oct;13(7):1051-1058. doi: 10.1007/s11739-018-1877-z. 
  3. Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x. 
  4. Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015 Aug 6;373(6):511-20. doi: 10.1056/NEJMoa1502000.
  5. Anoniem. Directwerkende orale anticoagulantia. Directe trombineremmer dabigatran. Gebu. 2016;50(3):28-34
  6. Anoniem. Directwerkende orale anticoagulantia. Directe factor Xa-remmers. Gebu. 2016;50(4):41-50
  7. Ersayin A, Thomas A, Seyve L, Thielens N, Castellan M, Marlu R, et al. Catalytically inactive Gla-domainless factor Xa binds to TFPI and restores ex vivo coagulation in hemophilia plasma. Haematologica. 2017 Dec;102(12):e483-e485. doi: 10.3324/haematol.2017.174037.
  8. CBG-MEB Geneesmiddeleninformatiebank. SmPC Ondexxya. Available from:,P0_LANG,P3_RVG1:H,NL,119837. Accessed05-05-2021.
  9. CBG-MEB Geneesmiddeleninformatiebank. SmPC Cofact. Available from:,P0_LANG,P3_RVG1:H,NL,17060. Accessed 05-05-2021.
  10. Ten Cate H, Henskens YM, Lancé MD. Practical guidance on the use of laboratory testing in the management of bleeding in patients receiving direct oral anticoagulants. Vasc Health Risk Manag. 2017 Dec 13;13:457-467. doi: 10.2147/VHRM.S126265.
  11. Nederlandse Internisten Vereniging (NIV). Richtlijn Antitrombotisch beleid – Bloeding of ingreep bij DOAC’s. Beoordeeld 24-03-2021. Available from: Accessed 17-06-2021.
  12. 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 Aug 3;377(5):431-441. doi: 10.1056/NEJMoa1707278.
  13. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573-9. doi: 10.1161/CIRCULATIONAHA.111.029017.
  14. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. ANNEXA-4 Investigators. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019 Apr 4;380(14):1326-1335. doi: 10.1056/NEJMoa1814051.
  15. Green L, Tan J, Antoniou S, Alikhan R, Curry N, Everington T, et al. Haematological management of major bleeding associated with direct oral anticoagulants - UK experience. Br J Haematol. 2019 May;185(3):514-522. doi: 10.1111/bjh.15808.
  16. Dybdahl D, Walliser G, Chance Spalding M, Pershing M, Kincaid M. Four-factor prothrombin complex concentrate for the reversal of factor Xa inhibitors for traumatic intracranial hemorrhage. Am J Emerg Med. 2019 Oct;37(10):1907-1911. doi: 10.1016/j.ajem.2019.01.008.
  17. Sheikh-Taha M. Treatment of apixaban- and rivaroxaban-associated major bleeding using 4-factor prothrombin complex concentrate. Intern Emerg Med. 2019 Mar;14(2):265-269. doi: 10.1007/s11739-018-1977-9.
  18. Schulman S, Gross PL, Ritchie B, Nahirniak S, Lin Y, Lieberman L, et al. Study Investigators. Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study. Thromb Haemost. 2018 May;118(5):842-851. doi: 10.1055/s-0038-1636541. Erratum in: Thromb Haemost. 2018 Dec;118(12):2188.
  19. Majeed A, Ågren A, Holmström M, Bruzelius M, Chaireti R, Odeberg J, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017 Oct 12;130(15):1706-1712. doi: 10.1182/blood-2017-05-782060.
  20. van der Wall SJ, van Rein N, van den Bemt B, Kruip MJHA, Meijer K, Te Boome LCJ, et al. Performance of idarucizumab as antidote of dabigatran in daily clinical practice. Europace. 2019 Mar 1;21(3):414-420. doi: 10.1093/europace/euy220. Erratum in: Europace. 2019 Jul 1;21(7):1000.
  21. CBG-MEB Geneesmiddeleninformatiebank. SmPC Praxbind. Available from:,P0_LANG,P3_RVG1:H,NL,117131. Accessed 05-05-2021.
  22. Informatorium Medicamentorum. Den Haag: KNMP, 2021. Available from: Accessed 24-06-2021.
  23. Ansell J, Laulicht BE, Bakhru SH, Burnett A, Jiang X, Chen L, et al. Ciraparantag, an anticoagulant reversal drug: mechanism of action, pharmacokinetics, and reversal of anticoagulants. Blood. 2021 Jan 7;137(1):115-125. doi: 10.1182/blood.2020007116.
  24. Jourdi G, Gouin-Thibault I, Siguret V, Gandrille S, Gaussem P, Le Bonniec B. FXa-α2-Macroglobulin Complex Neutralizes Direct Oral Anticoagulants Targeting FXa In Vitro and In Vivo. Thromb Haemost. 2018 Sep;118(9):1535-1544. doi: 10.1055/s-0038-1667014.
  25. Thalji NK, Ivanciu L, Davidson R, Gimotty PA, Krishnaswamy S, Camire RM. A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nat Med. 2016 Aug;22(8):924-32. doi: 10.1038/nm.4149.
  26. Parsons-Rich D, Hua F, Li G, Kantaridis C, Pittman DD, Arkin S. Phase 1 dose-escalating study to evaluate the safety, pharmacokinetics, and pharmacodynamics of a recombinant factor Xa variant (FXaI16L ). J Thromb Haemost. 2017 May;15(5):931-937. doi: 10.1111/jth.13673.
  27. Verhoef D, Visscher KM, Vosmeer CR, Cheung KL, Reitsma PH, Geerke DP, et al. Engineered factor Xa variants retain procoagulant activity independent of direct factor Xa inhibitors. Nat Commun. 2017 Sep 13;8(1):528. doi: 10.1038/s41467-017-00647-9.
  28. Schreuder M, Reitsma PH, Bos MHA. Reversal Agents for the Direct Factor Xa Inhibitors: Biochemical Mechanisms of Current and Newly Emerging Therapies. Semin Thromb Hemost. 2020 Nov;46(8):986-998. doi: 10.1055/s-0040-1709134.


  • Nienke van Rein
  • Mettine H.A. Bos