Journal of Thrombosis and Thrombolysis

, Volume 36, Issue 2, pp 195–202 | Cite as

Reversal of target-specific oral anticoagulants

  • Scott Kaatz
  • Mark Crowther


The target-specific oral anticoagulants represent the first new oral anti-thrombotic therapy in over 50 years and have the potential to make therapy easier and hence more accessible to many patients. Like any new therapy, the potential benefits must be weighed against the potential challenges and one of the most concerning aspects of the new target-specific oral anticoagulants is the lack of a proven method to reverse their effect. Unlike the vitamin K antagonist, i.e. warfarin, there is no specific antidote for these medications. This paper will review the limited data on the use of non-specific therapies to reverse anticoagulation for the new agents. We hope to prepare clinicians who are faced with a patient who has serious bleeding or needs emergent surgery while taking dabigatran, rivaroxaban or apixaban.


Reversal Target specific oral anticoagulants Apixaban Dabigatran Rivaroxaban 


  1. 1.
    Dentali F, Marchesi C, Pierfranceschi MG, Crowther M, Garcia D, Hylek E, Witt DM, Clark NP, Squizzato A, Imberti D, Ageno W (2011) Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 106(3):429–438. doi: 10.1160/TH11-01-0052 PubMedCrossRefGoogle Scholar
  2. 2.
    Levi M, Levy JH, Andersen HF, Truloff D (2010) Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 363(19):1791–1800. doi: 10.1056/NEJMoa1006221 PubMedCrossRefGoogle Scholar
  3. 3.
    Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH (2012) Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e152S–e184S. doi: 10.1378/chest.11-2295 PubMedCrossRefGoogle Scholar
  4. 4.
    van Ryn J, Litzenburger T, Waterman A, Canada K, Hauel N, Sarko C, Kroe-Barrett R, Singh S, Park J (2011) Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in in vitro and in vivo models. J Am Coll Cardiol 57(14):E1130CrossRefGoogle Scholar
  5. 5.
    Lu G, Luan P, Hollenbach S, Abe K, DeGuzman F, Siu G, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U (2009) Reconstructed recombinant factor Xa as an antidote to reverse anticoagulation by factor Xa inhibitors. J Thromb Haemost 7(Suppl 2):107Google Scholar
  6. 6.
    Crowther MA, Warkentin TE (2009) Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 7(Suppl 1):107–110. doi: 10.1111/j.1538-7836.2009.03429.x PubMedCrossRefGoogle Scholar
  7. 7.
    Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M (2011) Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 124(14):1573–1579. doi: 10.1161/CIRCULATIONAHA.111.029017 PubMedCrossRefGoogle Scholar
  8. 8.
    Perzborn E, Tinel H (2009) Prothrombin complex concentrate reverses the effects of high-dose rivaroxaban in rats. J Thromb Haemost 7(suppl 2):379Google Scholar
  9. 9.
    Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME (2010) Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood 116(5):693–701. doi: 10.1182/blood-2009-11-253492 PubMedCrossRefGoogle Scholar
  10. 10.
    van Ryn J, Sieger P, Kink-Eiband M, Gansser D, Clemens A (2009) Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro. Blood 114(22):440Google Scholar
  11. 11.
    Stangier J, Rathgen K, Stahle H, Mazur D (2010) Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 49(4):259–268. doi: 10.2165/11318170-000000000-00000 PubMedCrossRefGoogle Scholar
  12. 12.
    Wagner F, Peters H, Formella S, Wiegert E, Moschetti V, Khadzhynov D, Clemens A (2011) Effective elimination of dabigatran with haemodialysis: a phase I single centre study in patients with end-stage renal disease. Circulation 124(21 Suppl):A10956Google Scholar
  13. 13.
    Van Ryn J, Neubauer M, Flieg R, Krause B, Storr M, Hauel N, Priepke H, Clemens A (2010) Successful removal of dabigatran in flowing blood with an activated charcoal hemoperfusion column in an in vitro test system. Haematologica 95:293CrossRefGoogle Scholar
  14. 14.
    Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, Bendszus M, Heiland S, van Ryn J, Veltkamp R (2011) Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 42(12):3594–3599. doi: 10.1161/STROKEAHA.111.624650 PubMedCrossRefGoogle Scholar
  15. 15.
    van Ryn J, Ruehl D, Priepke H, Hauel N, Wienen W (2008) Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor viia or activated prothrombin complex concentrate. Haematologica 93:148Google Scholar
  16. 16.
    van Ryn J, Schurer J, Kink-Eiband M, Clemens A (2011) The successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood 118(21):1004Google Scholar
  17. 17.
    Lambourne MD, Eltringham-Smith LJ, Gataiance S, Arnold DM, Crowther MA, Sheffield W (2012) Prothrombin complex concentrates reduce blood loss in mice rendered coagulopathic by warfarin but not dabigatran etexilate. Transfusion 52:56A–57ACrossRefGoogle Scholar
  18. 18.
    Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G (2012) 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(2):217–224. doi: 10.1160/TH12-03-0179 PubMedCrossRefGoogle Scholar
  19. 19.
    Pragst I, Zeitler SH, Doerr B, Kaspereit FJ, Herzog E, Dickneite G, van Ryn J (2012) Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 10(9):1841–1848. doi: 10.1111/j.1538-7836.2012.04859.x PubMedCrossRefGoogle Scholar
  20. 20.
    Khoo TL, Weatherburn C, Kershaw G, Reddel CJ, Curnow J, Dunkley S (2012) The use of FEIBA(®) in the correction of coagulation abnormalities induced by dabigatran. Int J Lab Hematol. doi: 10.1111/ijlh.12005 Google Scholar
  21. 21.
    Johnson & Johnson Pharmaceutical Research & Development LLC (2009) Advisory Committee briefing book: rivaroxaban for the prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in Patients undergoing hip or knee replacement surgery. Johnson & Johnson Pharmaceutical Research & Development, L.L.C, San DiegoGoogle Scholar
  22. 22.
  23. 23.
    Tinel H, Huetter J, Perzborn E (2006) Partial reversal of the anticoagulant effect of high-dose rivaroxaban—an oral, direct factor Xa inhibitor—by recombinant factor VIIa in rats. Blood 108(11):274AGoogle Scholar
  24. 24.
    Gruber A, Marzec UM, Buetehorn U, Hanson S, Perzborn E (2008) Potential of activated prothrombin complex concentrate and activated factor vii to reverse the anticoagulant effects of rivaroxaban in primates. Blood 112(11):1307Google Scholar
  25. 25.
    Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM, Emmerich J, Marchand-Leroux C, Lecompte T, Samama CM (2012) Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 116(1):94–102. doi: 10.1097/ALN.0b013e318238c036 PubMedCrossRefGoogle Scholar
  26. 26.
    European Medicines Agency SMH Assessment report for Eliquis (2011) European Medicines Agency, Science Medicines Health, LondonGoogle Scholar
  27. 27.
    Escolar GA-RE, Reverter JC, Villalta J, Sanz V, Molina P, Diaz-Ricart M, Galan AM (2012) Reversal of apixaban induced alterations of hemostasis by different coagulation factor concentrates: studies in vitro with circulating human blood. Circulation 126(4):2Google Scholar
  28. 28.
    Miyares MA, Davis K (2012) Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health Syst Pharm 69(17):1473–1484. doi: 10.2146/ajhp110725 PubMedCrossRefGoogle Scholar
  29. 29.
    Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J (2012) Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 87(Suppl 1):S141–S145PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Hospital MedicineHurley Medical CenterFlintUSA
  2. 2. Hamilton Regional Laboratory Medicine Program, Hamilton Health SciencesHamiltonCanada
  3. 3.St Joseph’s HealthcareHamiltonCanada
  4. 4.McMaster UniversityHamiltonCanada

Personalised recommendations