Reversal agents for oral anticoagulant-associated major or life-threatening bleeding
Oral anticoagulants (OA) are effective drugs for treating and preventing the formation of blood clots in patients with atrial fibrillation, mechanical heart valves and venous thromboembolism but their therapeutic effect is always counterbalanced by an increased risk of bleeding. Direct oral anticoagulants (DOACs) have brought advantages in the management of many patients, with evidence of a lower risk of intracranial bleeding in comparison to vitamin K antagonists (VKAs). However, due to the increased number of anticoagulated patients worldwide, major and life threatening OA-related bleeding is also increasing, and effective reversal strategies are needed. We reviewed the reversal strategies for both VKAs and DOACs in the light of the latest evidence and recent guidelines, taking into account non-specific methods with fresh frozen plasma (FFP), prothrombin complex concentrate (PCC) or four factor PCC, as well as specific reversal antidotes that are already approved or in approval phase. Most published studies on OA reversal have drawbacks, such as lacking a control arm or data on clinically relevant outcomes, and current guidelines’ recommendations are mainly based on panellists’ judgment. There is an urgent need for well-designed studies in this field. In the meanwhile, to improve the correct use of available resources and patients’ outcomes, we suggest a seven-element bundle for an optimal management of OA-associated major bleeding, including the implementation of fast turnaround time for laboratory tests in emergency, i.e. INR and DOAC plasma levels, and to build up a ‘bleeding team’ that includes experts of hemostasis, lab, trauma, emergency medicine, endoscopy, radiology, and surgery in every hospital.
KeywordsBleeding Idarucizumab Andexanet Prothrombin concentrate complex Direct oral anticoagulant Vitamin K antagonist
This article was independently developed by the authors following an advisory board meeting sponsored by Daiichi Sankyo SpA.
Compliance with ethical standards
Conflict of interest
Alessandro Squizzato received fees for lectures and advisory board meetings from Daiichi Sankyo, Pfizer, Bristol Myers Squibb, Bayer, Boehringer Ingelheim. Marco Moia received fees for lectures from Bayer, Daiichi Sankyo, Pfizer, Werfen.
Statements on human and animal rights
This article does not contain any studies with human participants or animals performed by any of the authors.
For this type of study formal consent is not required.
- 1.Schulman S, Beyth RJ, Kearon C, Levine MN (2008) Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 133(6 Suppl):257S–298S. https://doi.org/10.1378/chest.08-0674 CrossRefPubMedGoogle Scholar
- 2.Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, Haeusler KG, Oldgren J, Reinecke H, Roldan-Schilling V, Rowell N, Sinnaeve P, Collins R, Camm AJ, Heidbüchel H, ESC Scientific Document Group (2018) The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 39(16):1330–1393CrossRefGoogle Scholar
- 4.Witt DM, Nieuwlaat R, Clark NP, Ansell J, Holbrook A, Skov J, Shehab N, Mock J, Myers T, Dentali F, Crowther MA, Agarwal A, Bhatt M, Khatib R, Riva JJ, Zhang Y, Guyatt G (2018) American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2(22):3257–3291CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Sarode R, Milling TJ Jr, Refaai MA et al (2013) Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 128(11):1234–1243CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific, and Standardization Committee of the International Society on Thrombosis, and Haemostasis (2005) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 3(4):692–694CrossRefPubMedGoogle Scholar
- 9.Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI (2017) Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med 377(5):431–441CrossRefPubMedGoogle Scholar
- 12.Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M, ANNEXA-4 Investigators (2016) Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 375(12):1131–1141CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Demchuk AM, Pallin DJ, Concha M, Goodman S, Leeds J, Souza S, Siegal DM, Zotova E, Meeks B, Ahmad S, Nakamya J, Milling TJ Jr, ANNEXA-4 Investigators (2019) Full study report of andexanet alfa for bleeding associated with factor Xa Inhibitors. N Engl J Med 380(14):1326–1335CrossRefPubMedPubMedCentralGoogle Scholar