Thromb Haemost 2016; 116(06): 1003-1010
DOI: 10.1160/TH16-05-0363
Anticoagulation Education Task Force White Paper
Schattauer Publishers Schattauer

Managing reversal of direct oral anticoagulants in emergency situations

Anticoagulation Education Task Force White Paper
Walter Ageno
1   University of Insubria, Varese, Italy
,
Harry R. Büller
2   Academic Medical Centre, Amsterdam, The Netherlands
,
Anna Falanga
3   Department of Immunohematology & Transfusion Medicine and the Hemostasis and Thrombosis Center, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Werner Hacke
4   Department of Neurology, Heidelberg University, Heidelberg, Germany
,
Jeroen Hendriks
5   Centre for Heart Rhythm Disorders, University of Adelaide, Royal Adelaide Hospital, South Australian Health & Medical Research Institute, Adelaide, Australia
6   Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
,
Trudie Lobban
7   Arrhythmia Alliance and AF Association, Hampshire, UK
,
Jose Merino
8   Arrhythmia Research Unit, Universitario La Paz , Madrid, Spain
,
Ivan S. Milojevic
9   General Hospital Cuprija, Cuprija, Serbia
,
Francisco Moya
10   International Medical Services and Emergency Medicine, Vithas-Xanit International Hospital, Benalmadena, Malaga, Spain
,
H. Bart van der Worp
11   Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
,
Gary Randall
12   Stroke Alliance For Europe (SAFE), London, UK
,
Konstantinos Tsioufis
13   First Cardiology Clinic, Hippokration Hospital, University of Athens, Greece
,
Peter Verhamme
14   University of Leuven, Leuven, Belgium
,
A. John Camm
15   Division of Cardiovascular Sciences, St George’s University of London, London, UK
16   ICMS, Imperial College, London, UK
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 11. Mai 2016

Accepted after major revision: 10. Juli 2016

Publikationsdatum:
09. März 2018 (online)

Summary

Anticoagulation is the cornerstone of prevention and treatment of venous thromboembolism (VTE) and stroke prevention in patients with atrial fibrillation (AF). However, the mechanisms by which anticoagulants confer therapeutic benefit also increase the risk of bleeding. As such, reversal strategies are critical. Until recently, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban lacked a specific reversal agent. This report is based on findings from the Anticoagulation Education Task Force, which brought together patient groups and professionals representing different medical specialties with an interest in patient safety and expertise in AF, VTE, stroke, anticoagulation, and reversal agents, to discuss the current status of anticoagulation reversal and fundamental changes in management of bleeding associated with DOACs occasioned by the approval of idarucizumab, a specific reversal agent for dabigatran, as well as recent clinical data on specific reversal agents for factor Xa inhibitors. Recommendations are given for when there is a definite need for a reversal agent (e.g. in cases of life-threatening bleeding, bleeding into a closed space or organ, persistent bleeding despite local haemostatic measures, and need for urgent interventions and/or interventions that carry a high risk for bleeding), when reversal agents may be helpful, and when a reversal agent is generally not needed. Key stakeholders who require 24–7/around-the-clock access to these agents vary among hospitals; however, from a practical perspective the emergency department is recommended as an appropriate location for these agents. Clearly, the advent of new agents requires standardised protocols for treating bleeding on an institutional level.

 
  • References

  • 1 Lip GY, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest 2012; 142: 1489-1498.
  • 2 Ball J, Carrington MJ, McMurray JJ, Stewart S. Atrial fibrillation: profile and burden of an evolving epidemic in the 21st century. Int J Cardiol 2013; 167: 1807-1824.
  • 3 Chugh SS, Havmoeller R, Narayanan K. et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129: 837-847.
  • 4 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449-1457.
  • 5 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
  • 6 Connolly SJ, Eikelboom J, Joyner C. et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.
  • 7 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
  • 8 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvu-lar atrial fibrillation. N Engl J Med 2011; 365: 883-891.
  • 9 Giugliano RP, Ruff CT, Braunwald E. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093-2104.
  • 10 Larsen TB, Rasmussen LH, Skjoth F. et al. Efficacy and safety of dabigatran etex-ilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013; 61: 2264-2273.
  • 11 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: 157-164.
  • 12 Camm AJ, Amarenco P, Haas S. et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2015 Epub ahead of print.
  • 13 Ageno W, Mantovani LG, Haas S. et al. Safety and effectiveness of oral riva-roxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interven-tional study. Lancet Haematol 2016; 03: e12-21.
  • 14 Garcia DA, Baglin TP, Weitz JI, Samama MM. American College of Chest P. Par-enteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e24S-43S.
  • 15 Warfarin [SmPC]. Taro Pharmaceuticals UK Limited 2013
  • 16 Fasco MJ, Principe LM. R- and S-Warfarin inhibition of vitamin K and vitamin K 2,3-epoxide reductase activities in the rat. J Biol Chem 1982; 257: 4894-4901.
  • 17 Ageno W, Gallus AS, Wittkowsky A. et al. Oral anticoagulant therapy: Anti-thrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e44S-88S.
  • 18 Siegal DM. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis 2015; 39: 395-402.
  • 19 Lange J, Thiel C, Thiel K. et al. Acceration of dabigatran elimination by activated charcoal perfusion and hemodialysis in a pig model. ASH Annual Meeting Abstracts 2012; 120: 2272.
  • 20 Praxbind (Idarucizumab) injection for intravenous use [package insert]. Boehr-inger Ingelheim Pharmaceuticals, Inc. 2015. Ridgefield, CT: October
  • 21 Glund S, Stangier J, Schmohl M. et al. Safety, tolerability, and efficacy of idaruc-izumab 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: 680-690.
  • 22 Pollack Jr. CV, Reilly PA, Eikelboom J. et al. Idarucizumab for Dabigatran Reversal. N Engl J Med 2015; 373: 511-520.
  • 23 Glund S, Moschetti V, Norris S. et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015; 113: 943-951.
  • 24 Glund S, Stangier J, Schmol M. et al. Idarucizumab, a specific antidote for dabi-gatran: immediate, complete and sustained reversal of dabigatran induced anti-coagulation in elderly and renally impaired subjects. Blood 2014; 124: 344.
  • 25 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: 198-205.
  • 26 Siegal DM, Curnutte JT, Connolly SJ. et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med 2015
  • 27 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: 446-451.
  • 28 Crowther M, Levy G, Lu G. et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. 2014. Presented at the 56th annual meeting of the American Society of Hematology; San Francisco: December 6–9
  • 29 Crowther M, Lu G, Conley PB. Reversal of factor Xa inhibitors-induced antico-agulation in healthy subjects by andexanet alfa. Crit Care Med 2014; 42: A1469.
  • 30 Crowther M, Mathur V, Kitt M. et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced antico-agulation in healthy subjects by andexanet alfa (PRT064445), an antidote for Fxa inhibitors. Presented at the 55th annual meeting of the American Society of Hematology; New Orleans: December 7-10.
  • 31 Crowther M, Kittl E, Lorenz T. et al. A phase 2 randomized, double-blind, placebo-controlled trial of PRT064445, a novel, universal antidote for direct and indirect factor Xa inhibitors 20.1. J Thromb Haemost 2013 11. 02 Abstract.
  • 32 Greinacher A, Thiele T, Selleng K. Reversal of anticoagulants: an overview of current developments. Thromb Haemost 2015; 113: 931-942.
  • 33 Ansell JE, Bakhru SH, Laulicht BE. et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371: 2141-2142.
  • 34 Majeed A, Hwang HG, Connolly SJ. et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128: 2325-2332.
  • 35 Levy JH, Ageno W, Chan WC. et al. When and how to use antidotes for the reversal of direct oral anticoagulants: Guidance from the SSC of the ISTH. J Thromb Haemost 2015 in press.
  • 36 Heidbuchel H, Verhamme P, Alings M. et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094-2106.