Reversal of direct oral anticoagulants: Highlights from the Anticoagulation Forum guidelines

Reversal of direct oral anticoagulants: Highlights from the Anticoagulation Forum guidelines

Haeshik S. Gorr, MD, Lucy Yun Lu, PharmD, MS and Eric Hung, PharmD, CACP, AE-C 
Cleveland Clinic Journal of Medicine February 2021, 88 (2) 98-103.

• Direct oral anticoagulants (DOACs) have many benefits in comparison to warfarin
• More patients are now being treated with DOACs, causing an increase in major and life-threatening DOAC-associated bleeding
• There is a need for clear guidelines for the reversal of DOAC-associated bleeding
• Reversal agents of DOACs are now available and have been shown to be efficient
• The cost and risk associated with these agents calls for comprehensive reversal guidelines

Direct oral anticoagulants (DOACs) have been used over the past few years to treat chronic oral anticoagulation (Moreno et al, 2018). While several DOACs indicate a favourable benefit-risk balance in their safety and efficacy profiles on conditions such as thromboembolism as shown in clinical trials (Moreno et al, 2018) they have also been associated with serious bleeding which often requires reversal of the anticoagulant effects (Cuker et al 2019). For this purpose, two agents have been FDA approved and currently been used, namely idarucizumab (for dabigatran-associated bleeding) and andexanet alfa (for factor Xa inhibitor-associated bleeding) (Cuker et al 2019).

The Anticoagulation Forum guideline provided instructions on how to use these two agents for reversing the side effects of DOACs (Cuker 2019). However, a very recent review discussed here provided highlights from the forum guideline (Haeshik et al, 2021).

Which DOACs have been approved and for what indications?

Dabigatran (an inhibitor of thrombin (factor IIa)) and rivaroxaban, apixaban, edoxaban and betrixaban (four direct factor Xa inhibitors) have all been approved for several applications (Table 1). DOACs have also been shown to be non-inferior to warfarin and more so, more beneficial than warfarin. For example, they do not require routine blood monitoring, cause less intracranial bleeding and more rapid onset of action (Connolly, 2009; Patel et al, 2011; Granger et al, 2011). However, a greater demand DOACs leads to more serious bleeding events, therefore, guidelines are required on how to reverse this serious side effect.

Table 1. Approved indications for direct oral anticoagulants.

AF, atrial fibrillation; DVT, deep vein thrombosis; PE, pulmonary embolism; CAD, coronary artery disease; PAD, peripheral artery disease.

What are the main recommendations of the guidelines?

The guideline covers information for the two FDA-approved reversal agents, idarucizumab and andexanet alfa but also off-label use of hemostatic agents. They do not recommend routinely using reversal agents for DOAC but only when their use is critical, or bleeding would otherwise be life-threatening.

The recommended dosage varies depending on the type of DOAC administered and concerns remain on their use due to the costs and risk of severe side effects.   

What are the differences with earlier guidelines?

The Anticoagulation Forum guidelines discussed here provide a clinical approach to treating bleeding associated with DOACs. Previous guidelines were published on anticoagulant reversal strategies (Tomaselli et al, 2017; Steffel et al, 2018), however, the Anticoagulation Forum guidelines were published after andexanet alfa was FDA approved and include information that previous guidelines lacked. More so, these guidelines will be very valuable when health systems need to establish evidence-based practice guidelines in anticoagulation management that include reversal strategies.

Summary

The Anticoagulation Forum guidelines set out clear guidance on how to use the two approved reversal agents, idarucizumab and andexanet alfa, as well as other alternatives used off-label if these two are not available. Finally, it offers strategies for managing stewardship programs on anticoagulation at the health system level.

References

Adam Cuker  Allison Burnett  Darren Triller  Mark Crowther  Jack Ansell  Elizabeth M. Van Cott  Diane Wirth  Scott Kaatz. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Mar 27; 94(6): 697-709. https://doi.org/10.1002/ajh.25475

Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361(12):1139–1151. doi:10.1056/NEJMoa0905561

Franco Moreno AI, Martín Díaz RM, García Navarro MJ. Direct oral anticoagulants: An update. Med Clin (Barc). 2018 Sep 14;151(5):198-206. English, Spanish. doi: 10.1016/j.medcli.2017.11.042. Epub 2017 Dec 30. PMID: 29295790.

Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365(11):981–992. doi:10.1056/NEJMoa1107039

Haeshik S. Gorr, MD, Lucy Yun Lu, PharmD, MS and Eric Hung, PharmD, CACP, AE-C.

Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365(10):883–891. doi:10.1056/NEJMoa1009638
Reversal of direct oral anticoagulants: Highlights from the Anticoagulation Forum guideline. Feb 21; 88(2): 98-103. DOI: https://doi.org/10.3949/ccjm.88a.19133

Steffel J, Verhamme P, Potpara TS, et al. 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 2018; 39(16):1330–1393. doi:10.1093/eurheartj/ehy136

Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017; 70(24):3042–3067. doi:10.1016/j.jacc.2017.09.1085