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Semin Respir Crit Care Med 2017; 38(01): 040-050
DOI: 10.1055/s-0036-1597831
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Reversal of Direct Oral Anticoagulants: Current Status and Future Directions

Jeffrey I. Weitz
1   Department of Medicine and Biochemistry and Biomedical Sciences, Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
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Publication History

Publication Date:
16 February 2017 (online)

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Abstract

Direct oral anticoagulants (DOACs) are increasingly used for prevention and treatment of venous thromboembolism and for prevention of stroke in patients with nonvalvular atrial fibrillation. In phase III clinical trials that included more than 100,000 patients, the DOACs were at least as effective as vitamin K antagonists (VKAs) and were associated with less serious bleeding, particularly less intracranial bleeding. Real-world evidence supports these outcomes. Despite this, some physicians and patients are concerned about serious bleeding or emergencies unless specific reversal agents for the DOACs are available. However, in clinical trials performed without reversal agents, the outcome of major bleeds was similar or better in patients receiving DOACs than in those taking VKAs. Because of their short half-lives, supportive measures are sufficient to manage most bleeds in patients receiving DOACs. Anticoagulant reversal should only be considered with life-threatening bleeds, with bleeds that fail to respond to usual measures and in patients requiring urgent surgery. Idarucizumab is licensed for dabigatran reversal and andexanet alfa is likely to be soon licensed for reversal of rivaroxaban, apixaban, and edoxaban. To ensure responsible use of these agents, every hospital needs a bleeding management algorithm that identifies patients eligible for reversal and outlines appropriate dosing regimens.

Keywords

andexanet - apixaban - bleeding management - ciraparantag - dabigatran - direct oral anticoagulants - edoxaban - idarucizumab - rivaroxaban
 

  • References

  • 1 Patel MR, Mahaffey KW, Garg J , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
    CrossrefPubMedSearch in Google Scholar
  • 2 Connolly SJ, Ezekowitz MD, Yusuf S , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
    CrossrefPubMedSearch in Google Scholar
  • 3 Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L ; Randomized Evaluation of Long-Term Anticoagulation Therapy Investigators. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363 (19) 1875-1876
    CrossrefPubMedSearch in Google Scholar
  • 4 Connolly SJ, Wallentin L, Yusuf S. Additional events in the RE-LY trial. N Engl J Med 2014; 371 (15) 1464-1465
    CrossrefPubMedSearch in Google Scholar
  • 5 Granger CB, Alexander JH, McMurray JJ , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
    CrossrefPubMedSearch in Google Scholar
  • 6 Giugliano RP, Ruff CT, Braunwald E , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
    CrossrefPubMedSearch in Google Scholar
  • 7 Agnelli G, Buller HR, Cohen A , et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (9) 799-808
    CrossrefPubMedSearch in Google Scholar
  • 8 Büller HR, Décousus H, Grosso MA , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
    CrossrefPubMedSearch in Google Scholar
  • 9 Prins MH, Lensing AW, Bauersachs R , et al; 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 2013; 11 (1) 21
    CrossrefPubMedSearch in Google Scholar
  • 10 Schulman S, Kakkar AK, Goldhaber SZ , et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (7) 764-772
    CrossrefPubMedSearch in Google Scholar
  • 11 Ruff CT, Giugliano RP, Braunwald E , 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 2014; 383 (9921): 955-962
    CrossrefPubMedSearch in Google Scholar
  • 12 Camm AJ, Lip GY, De Caterina R , et al; 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33 (21) 2719-2747
    CrossrefPubMedSearch in Google Scholar
  • 13 January CT, Wann LS, Alpert JS , et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64 (21) e1-e76
    CrossrefPubMedSearch in Google Scholar
  • 14 Verma A, Cairns JA, Mitchell LB , et al; CCS Atrial Fibrillation Guidelines Committee. 2014 focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation. Can J Cardiol 2014; 30 (10) 1114-1130
    CrossrefPubMedSearch in Google Scholar
  • 15 Kearon C, Akl EA, Comerota AJ , et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141: e419S-e494S
    CrossrefPubMedSearch in Google Scholar
  • 16 Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes 2012; 5 (5) 615-621
    CrossrefPubMedSearch in Google Scholar
  • 17 Desai NR, Krumme AA, Schneeweiss S , et al. Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications. Am J Med 2014; 127 (11) 1075-82.e1
    CrossrefPubMedSearch in Google Scholar
  • 18 Weitz JI, Semchuk W, Turpie AG , et al. Trends in prescribing oral anticoagulants in Canada, 2008–2014. Clin Ther 2015; 37 (11) 2506-2514.e4
    CrossrefPubMedSearch in Google Scholar
  • 19 Larsen TB, Gorst-Rasmussen A, Rasmussen LH, Skjøth F, Rosenzweig M, Lip GY. Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation. Am J Med 2014; 127 (7) 650-656.e5
    CrossrefPubMedSearch in Google Scholar
  • 20 Beyer-Westendorf J, Förster K, Pannach S , et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014; 124 (6) 955-962
    CrossrefPubMedSearch in Google Scholar
  • 21 Hess PL, Mirro MJ, Diener HC , et al; Atrial Fibrillation Think-Tank Participants. Addressing barriers to optimal oral anticoagulation use and persistence among patients with atrial fibrillation: Proceedings, Washington, DC, December 3-4, 2012. Am Heart J 2014; 168 (3) 239-247.e1
    CrossrefPubMedSearch in Google Scholar
  • 22 Fang MC, Go AS, Chang Y , et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 2007; 120 (8) 700-705
    CrossrefPubMedSearch in Google Scholar
  • 23 Vanassche T, Hirsh J, Eikelboom JW, Ginsberg JS. Organ-specific bleeding patterns of anticoagulant therapy: lessons from clinical trials. Thromb Haemost 2014; 112 (5) 918-923
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ 2012; 345: e7498
    CrossrefPubMedSearch in Google Scholar
  • 25 van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12 (3) 320-328
    CrossrefPubMedSearch in Google Scholar
  • 26 Castellucci LA, Cameron C, Le Gal G , et al. Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA 2014; 312 (11) 1122-1135
    CrossrefPubMedSearch in Google Scholar
  • 27 Kang N, Sobieraj DM. Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism. Thromb Res 2014; 133 (6) 1145-1151
    CrossrefPubMedSearch in Google Scholar
  • 28 Mantha S, Ansell J. Indirect comparison of dabigatran, rivaroxaban, apixaban and edoxaban for the treatment of acute venous thromboembolism. J Thromb Thrombolysis 2015; 39 (2) 155-165
    CrossrefPubMedSearch in Google Scholar
  • 29 Camm AJ, Amarenco P, Haas S , et al; XANTUS Investigators. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2016; 37 (14) 1145-1153
    CrossrefPubMedSearch in Google Scholar
  • 30 Larsen TB, Rasmussen LH, Skjøth F , et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013; 61 (22) 2264-2273
    CrossrefPubMedSearch in Google Scholar
  • 31 Ageno W, Mantovani LG, Haas S , et al. 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 2016; 3 (1) e12-e21
    PubMedSearch in Google Scholar
  • 32 Vaughan Sarrazin MS, Jones M, Mazur A, Chrischilles E, Cram P. Bleeding rates in veterans affairs patients with atrial fibrillation who switch from warfarin to dabigatran. Am J Med 2014; 127 (12) 1179-1185
    CrossrefPubMedSearch in Google Scholar
  • 33 Fontaine GV, Mathews KD, Woller SC, Stevens SM, Lloyd JF, Evans RS. Major bleeding with dabigatran and rivaroxaban in patients with atrial fibrillation: a real-world setting. Clin Appl Thromb Hemost 2014; 20 (7) 665-672
    CrossrefPubMedSearch in Google Scholar
  • 34 Graham DJ, Reichman ME, Wernecke M , et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015; 131 (2) 157-164
    CrossrefPubMedSearch in Google Scholar
  • 35 Kakkar AK, Mueller I, Bassand JP , et al; GARFIELD Registry Investigators. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry. PLoS ONE 2013; 8 (5) e63479
    CrossrefPubMedSearch in Google Scholar
  • 36 Larsen TB, Skjøth F, Nielsen PB, Kjældgaard JN, Lip GY. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2016; 353: i3189
    PubMedSearch in Google Scholar
  • 37 Caldeira D, Rodrigues FB, Barra M , et al. 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 2015; 101 (15) 1204-1211
    CrossrefPubMedSearch in Google Scholar
  • 38 Majeed A, Hwang HG, Connolly SJ , et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128 (21) 2325-2332
    CrossrefPubMedSearch in Google Scholar
  • 39 Hylek EM, Held C, Alexander JH , et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes. J Am Coll Cardiol 2014; 63 (20) 2141-2147
    CrossrefPubMedSearch in Google Scholar
  • 40 Hart RG, Diener HC, Yang S , et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke 2012; 43 (6) 1511-1517
    CrossrefPubMedSearch in Google Scholar
  • 41 Hankey GJ, Stevens SR, Piccini JP , et al; ROCKET AF Steering Committee and Investigators. Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke 2014; 45 (5) 1304-1312
    CrossrefPubMedSearch in Google Scholar
  • 42 Eikelboom JW, Weitz JI. New anticoagulants. Circulation 2010; 121 (13) 1523-1532
    CrossrefPubMedSearch in Google Scholar
  • 43 Heidbuchel H, Verhamme P, Alings M , et al; European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013; 15 (5) 625-651
    CrossrefPubMedSearch in Google Scholar
  • 44 Healey JS, Eikelboom J, Douketis J , et al; RE-LY Investigators. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 2012; 126 (3) 343-348
    CrossrefPubMedSearch in Google Scholar
  • 45 Eikelboom JW, Quinlan DJ, van Ryn J, Weitz JI. Idarucizumab: the antidote for reversal of dabigatran. Circulation 2015; 132 (25) 2412-2422
    CrossrefPubMedSearch in Google Scholar
  • 46 Glund S, Stangier J, Schmohl M , 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 2015; 386 (9994): 680-690
    CrossrefPubMedSearch in Google Scholar
  • 47 Pollack Jr CV, Reilly PA, Bernstein R , et al. Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost 2015; 114 (1) 198-205
    Thieme ConnectPubMedSearch in Google Scholar
  • 48 Pollack Jr CV, Reilly PA, Eikelboom J , et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373 (6) 511-520
    CrossrefPubMedSearch in Google Scholar
  • 49 Lu G, DeGuzman FR, Hollenbach SJ , et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19 (4) 446-451
    CrossrefPubMedSearch in Google Scholar
  • 50 Yeh CH, Fredenburgh JC, Weitz JI. The real decoy: an antidote for factor Xa-directed anticoagulants. Circ Res 2013; 113 (8) 954-957
    CrossrefPubMedSearch in Google Scholar
  • 51 Crowther M, Kitt M, McLure M , et al. Randomized, double-blind, placebo-controlled single ascending dose pharmacokinetic and pharmacodynamic study of PRT064445, a universal antidote for factor Xa inhibitors. Arterioscler Thromb Vasc Biol 2013; 33: A10
    PubMedSearch in Google Scholar
  • 52 Siegal DM, Curnutte JT, Connolly SJ , et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373 (25) 2413-2424
    CrossrefPubMedSearch in Google Scholar
  • 53 Sullivan Jr DW, Gad SC, Laulicht B, Bakhru S, Steiner S. Nonclinical safety assessment of PER977: a small molecule reversal agent for new oral anticoagulants and heparins. Int J Toxicol 2015; 34 (4) 308-317
    CrossrefPubMedSearch in Google Scholar
  • 54 Costin JC, Laulicht B, Bakhru S, Steiner S. PER977 reverses low molecular weight heparin in addition to IIa and Xa new oral anticoagulants. J Am Coll Cardiol 2015; 65: A2056
    CrossrefPubMedSearch in Google Scholar
  • 55 Ansell JE, Bakhru SH, Laulicht BE , et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371 (22) 2141-2142
    CrossrefPubMedSearch in Google Scholar
  • 56 Laulicht R, Bakhru S, Steinre S , et al. PER977 reverses edoxaban anticoagulation at steady state and has no effect on re-anticoagulation at the next scheduled dose. Eur Heart J 2015; 36: 859-860
    PubMedSearch in Google Scholar
  • 57 Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108 (2) 217-224
    Thieme ConnectPubMedSearch in Google Scholar
  • 58 Khoo TL, Weatherburn C, Kershaw G, Reddel CJ, Curnow J, Dunkley S. The use of FEIBA® in the correction of coagulation abnormalities induced by dabigatran. Int J Lab Hematol 2013; 35 (2) 222-224
    CrossrefPubMedSearch in Google Scholar
  • 59 Körber MK, Langer E, Ziemer S, Perzborn E, Gericke C, Heymann Cv. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost 2014; 20 (7) 735-740
    CrossrefPubMedSearch in Google Scholar
  • 60 Pragst I, Zeitler SH, Doerr B , et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012; 10 (9) 1841-1848
    CrossrefPubMedSearch in Google Scholar
  • 61 Godier A, Miclot A, Le Bonniec B , et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012; 116 (1) 94-102
    CrossrefPubMedSearch in Google Scholar
  • 62 Lambourne MD, Eltringham-Smith LJ, Gataiance S, Arnold DM, Crowther MA, Sheffield WP. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J Thromb Haemost 2012; 10 (9) 1830-1840
    CrossrefPubMedSearch in Google Scholar
  • 63 Perzborn E, Gruber A, Tinel H , et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost 2013; 110 (1) 162-172
    Thieme ConnectPubMedSearch in Google Scholar
  • 64 Martin AC, Le Bonniec B, Fischer AM , et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol 2013; 168 (4) 4228-4233
    CrossrefPubMedSearch in Google Scholar
  • 65 Zhou W, Zorn M, Nawroth P , et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke 2013; 44 (3) 771-778
    CrossrefPubMedSearch in Google Scholar
  • 66 Honickel M, Treutler S, van Ryn J, Tillmann S, Rossaint R, Grottke O. Reversal of dabigatran anticoagulation ex vivo: porcine study comparing prothrombin complex concentrates and idarucizumab. Thromb Haemost 2015; 113 (4) 728-740
    Thieme ConnectPubMedSearch in Google Scholar
  • 67 Honickel M, Braunschweig T, van Ryn J , et al. Prothrombin complex concentrate is effective in treating the anticoagulant effects of dabigatran in a porcine polytrauma model. Anesthesiology 2015; 123 (6) 1350-1361
    CrossrefPubMedSearch in Google Scholar
  • 68 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; 124 (14) 1573-1579
    CrossrefPubMedSearch in Google Scholar
  • 69 Levi M, Moore KT, Castillejos CF , et al. Comparison of three- and four-factor prothrombin complex concentrates on the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost 2014; 12: 1428-1436
    CrossrefPubMedSearch in Google Scholar
  • 70 Nagalla S, Thomson L, Oppong Y, Bachman B, Chervoneva I, Kraft WK. Reversibility of apixaban anticoagulation with a four-factor prothrombin complex concentrate in healthy volunteers. Clin Transl Sci 2016; 9 (3) 176-180
    CrossrefPubMedSearch in Google Scholar
  • 71 Zahir H, Brown KS, Vandell AG , et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 2015; 131 (1) 82-90
    CrossrefPubMedSearch in Google Scholar
  • 72 Piccini JP, Garg J, Patel MR , et al; ROCKET AF Investigators. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J 2014; 35 (28) 1873-1880
    CrossrefPubMedSearch in Google Scholar
  • 73 Baumann Kreuziger LM, Reding MT. Management of bleeding associated with dabigatran and rivaroxaban: a survey of current practices. Thromb Res 2013; 132 (2) e161-e163
    CrossrefPubMedSearch in Google Scholar