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Reversal of dabigatran-associated bleeding using idarucizumab: review of the current evidence

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Abstract

Major bleeding occurs in about 4% of patients while on treatment with direct oral anticoagulants (DOACs). The case-fatality rate associated with these events is estimated to be about 5%. The specific roles of antidotes, when used with DOACs in reducing the case fatality or improving the overall clinical course of these events, are not thoroughly understood. To this regard, the US Food and Drug Administration as well as European Medicines Agency have recently licensed idarucizumab for the management of patients with life-threatening bleeding or the need for urgent surgery/procedures while on treatment with dabigatran. Specifically, idarucizumab is a humanized monoclonal antibody fragment that rapidly reverses the anticoagulant effect of dabigatran. Two other antidotes, andeXanet and ciraparantag are currently under evaluation for reversal of DOACs. Here, we report on the use of idarucizumab in two patients who experienced life-threatening bleeding while on treatment with dabigatran for atrial fibrillation and provide a review highlighting the need for antidotes use with DOACs.

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References

  1. Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have non valvular atrial fibrillation. Ann Intern Med 146(12):857–867

    Article  PubMed  Google Scholar 

  2. Kearon C, Gent M, Hirsh J et al (1999) A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 340(12):901–907

    Article  CAS  PubMed  Google Scholar 

  3. Ruff CT, Giugliano RP, Braunwald E et al (2014) 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(9921):955–962

    Article  CAS  PubMed  Google Scholar 

  4. Van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR (2014) Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 124(12):1968–1975

    Article  PubMed  Google Scholar 

  5. Kirchhof P, Benussi S, Kotecha D et al (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 37(38):2893–2962

    Article  PubMed  Google Scholar 

  6. Kearon C, Akl EA, Ornelas J et al (2016) Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 149(2):315–352

    Article  PubMed  Google Scholar 

  7. Heidbuchel H, Verhamme P, Alings M et al (2015) 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(10):1467–1507

    Article  PubMed  Google Scholar 

  8. Levy JH, Ageno W, Chan NC et al (2016) 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

    Article  CAS  PubMed  Google Scholar 

  9. Chai-Adisaksopha C, Crowther M, Isayama T, Lim W (2014) The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 124(15):2450–2458

    Article  CAS  PubMed  Google Scholar 

  10. Majeed A, Hwang HG, Connolly SJ et al (2013) Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 128(21):2325–2332

    Article  CAS  PubMed  Google Scholar 

  11. Piccini JP, Garg J, Patel MR et al (2014) ROCKET AF investigators. Management of major bleeding events in patients treated with rivaroxaban vs warfarin: results from the ROCKET AF trial. Eur Heart J 35(28):1873–1880

    Article  CAS  PubMed  Google Scholar 

  12. Connolly SJ, Ezekowitz MD, Yusuf S et al (2009) RE-LY steering committee and investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139–1151

    Article  CAS  PubMed  Google Scholar 

  13. Patel MR, Mahaffey KW, Garg J et al (2011) ROCKET AF investigators. Rivaroxaban versus warfarin in non valvular atrial fibrillation. N Engl J Med 365(10):883–891

    Article  CAS  PubMed  Google Scholar 

  14. Granger CB, Alexander JH, McMurray JJ et al (2011) ARISTOTLE committees and investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365(11):981–992

    Article  CAS  PubMed  Google Scholar 

  15. Giugliano RP, Ruff CT, Braunwald E et al (2013) ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369(22):2093–2104

    Article  CAS  PubMed  Google Scholar 

  16. Agnelli G, Buller HR, Cohen A et al (2013) AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369(9):799–808

    Article  CAS  PubMed  Google Scholar 

  17. Büller HR, Décousus H, Grosso MA et al (2013) Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369(15):1406–1415

    Article  PubMed  Google Scholar 

  18. Prins MH, Lensing AW, Bauersachs R et al (2013) Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 11(1):21

    Article  PubMed  PubMed Central  Google Scholar 

  19. Schulman S, Kakkar AK, Goldhaber SZ et al (2014) RE-COVER II trial investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 129(7):764–772

    Article  CAS  PubMed  Google Scholar 

  20. Becattini C, Franco L, Beyer-Westendorf J et al (2016) Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life. Int J Cardiol 227:261–266

    Article  PubMed  Google Scholar 

  21. Larsen TB, Rasmussen LH, Skjøth F et al (2013) Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 61(22):2264–2273

    Article  CAS  PubMed  Google Scholar 

  22. Ageno W, Mantovani LG, Haas S et al (2016) Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol 3(1):e12–e21

    Article  PubMed  Google Scholar 

  23. Graham DJ, Reichman ME, Wernecke M et al (2015) Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for non valvular atrial fibrillation. Circulation 131(2):157–164

    Article  CAS  PubMed  Google Scholar 

  24. Caldeira D, Rodrigues FB, Barra M et al (2015) Non-vitamin K antagonist oral anticoagulants and major bleeding-related fatality in patients with atrial fibrillation and venous thromboembolism: a systematic review and meta-analysis. Heart 101(15):1204–1211

    Article  CAS  PubMed  Google Scholar 

  25. Beyer-Westendorf J, Förster K, Pannach S et al (2014) Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 124(6):955–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Douketis JD, Spyropoulos AC, Spencer FA et al (2012) American College of Chest Physicians. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e326S–e350S

    Google Scholar 

  27. Douketis JD, Healey JS, Brueckmann M et al. (2017) Urgent surgery or procedures in patients taking dabigatran or warfarin: analysis of perioperative outcomes from the RE-LY trial. Thromb Res 139:77–81

    Article  Google Scholar 

  28. Hanley JP (2004) Warfarin reversal. J Clin Pathol 57(11):1132–1139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chai-Adisaksopha C, Hillis C, Siegal DM et al (2016) Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost 116(5):879–890

    Article  PubMed  Google Scholar 

  30. 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

    Article  CAS  PubMed  Google Scholar 

  31. Cheung YW, Barco S, Hutten BA, Meijers JC, Middeldorp S, Coppens M (2015) In vivo increase in thrombin generation by four-factor prothrombin complex concentrate in apixaban-treated healthy volunteers. J Thromb Haemost 13(10):1799–1805

    Article  CAS  PubMed  Google Scholar 

  32. Brown KS, Wickremasingha P, Parasrampuria DA et al (2015) The impact of a three-factor prothrombin complex concentrate on the anticoagulatory effects of the factor Xa inhibitor edoxaban. Thromb Res 136(4):825–831

    Article  CAS  PubMed  Google Scholar 

  33. Barco S, Whitney Cheung Y, Coppens M, Hutten BA, Meijers JC, Middeldorp S (2016) In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate. Br J Haematol 172(2):255–261

    Article  CAS  PubMed  Google Scholar 

  34. Elg M, Carlsson S, Gustafsson D (2001) Effect of activated prothrombin complex concentrate or recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thromb Res 101(3):145–157

    Article  CAS  PubMed  Google Scholar 

  35. Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski 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

    Article  CAS  PubMed  Google Scholar 

  36. Mao G, King L, Young S, Kaplan R (2016) Factor eight inhibitor bypassing agent (FEIBA) for reversal of target-specific oral anticoagulants in life-threatening intracranial bleeding. J Emerg Med. doi:10.1016/j.jemermed.2016.11.011

    Google Scholar 

  37. Dibu JR, Weimer JM, Ahrens C, Manno E, Frontera JA (2016) The Role of FEIBA in reversing novel oral anticoagulants in intracerebral hemorrhage. Neurocrit Care 24(3):413–419

    Article  CAS  PubMed  Google Scholar 

  38. Schiele F, van Ryn J, Canada K et al (2013) A specific antidote for dabigatran: functional and structural characterization. Blood 121(18):3554–3562

    Article  CAS  PubMed  Google Scholar 

  39. Glund S, Moschetti V, Norris S et al (2015) A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 113(5):943–945

    Article  PubMed  Google Scholar 

  40. Glund S, Stangier J, Schmohl M et al (2015) 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(9994):680–690

    Article  CAS  PubMed  Google Scholar 

  41. Pollack CV Jr, Reilly PA, van Ryn J et al (2017) Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. N Engl J Med. doi: 10.1056/NEJMoa1707278

    Google Scholar 

  42. Dentali F, Marchesi C, Giorgi Pierfranceschi M et al (2011) Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 106(3):429–438

    Article  CAS  PubMed  Google Scholar 

  43. Goldstein JN, Refaai MA, Milling TJ Jr et al (2015) Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 385:2077–2087

    Article  CAS  PubMed  Google Scholar 

  44. Lu G, DeGuzman FR, Hollenbach SJ et al (2013) A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 19(4):446–451

    Article  CAS  PubMed  Google Scholar 

  45. Siegal DM, Curnutte JT, Connolly SJ et al (2015) Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 373(25):2413–2424

    Article  CAS  PubMed  Google Scholar 

  46. Connolly SJ, Milling TJ Jr, Eikelboom JW et al (2016) ANNEXA-4 investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 375(12):1131–1141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sullivan DW Jr, Gad SC, Laulicht B, Bakhru S, Steiner S (2015) Non clinical safety assessment of PER977: a small molecule reversal agent for new oral anticoagulants and heparins. Int J Toxicol 34(4):308–317

    Article  CAS  PubMed  Google Scholar 

  48. Ansell JE, Bakhru SH, Laulicht BE et al (2014) Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 371(22):2141–2142

    Article  PubMed  Google Scholar 

  49. Ansell JE, Laulicht BE, Bakhru SH, Hoffman M, Steiner SS, Costin JC (2016) Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin. Thromb Res 146:113–118

    Article  CAS  PubMed  Google Scholar 

  50. Ansell JE, Bakhru SH, Laulicht BE et al (2017) Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost 26(2):238–245 117

    Google Scholar 

  51. van Ryn J, Stangier J, Haertter S et al (2010) Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103(6):1116–1127

    Article  PubMed  Google Scholar 

  52. Ageno W, Büller HR, Falanga A et al (2016) Managing reversal of direct oral anticoagulants in emergency situations. Anticoagulation Education Task Force White Paper. Thromb Haemost 116(6):1003–1010

    Article  PubMed  Google Scholar 

  53. Stangier J, Rathgen K, Stähle H, Gansser D (2007) Roth W:The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64:292–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Internal Vascular and Emergency Medicine and Stroke Unit, University of Perugia, Via G Dottori 1, 06129, Perugia, Italy

    Michela Giustozzi, Melina Verso, Giancarlo Agnelli & Cecilia Becattini

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  1. Michela Giustozzi
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  2. Melina Verso
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  3. Giancarlo Agnelli
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  4. Cecilia Becattini
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Correspondence to Michela Giustozzi.

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Conflict of interest

Dr. Michela Giustozzi and Dr. Melina Verso have no conflict of interest to declare. Dr. Cecilia Becattini received lectures fees from Bayer HealthCare, Bristol Meyer Squibb, Daiichi Sankyo and Boehringer Ingelheim. Dr. Agnelli received consulting fees from Bayer, Boehringer Ingelheim, and Daiichi Sankyo and lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Sanofi-Aventis.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Giustozzi, M., Verso, M., Agnelli, G. et al. Reversal of dabigatran-associated bleeding using idarucizumab: review of the current evidence. J Thromb Thrombolysis 44, 527–535 (2017). https://doi.org/10.1007/s11239-017-1555-4

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