DOACs and bleeding: the role of antidotes

The use of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) is associated with the risk of bleeding complications. To manage severe and life-threatening bleeding, specific antidotes have become available that can effectively restore haemostasis [1].

Major bleeding in patients with AF medicated with factor Xa (FXa) and factor IIa (FIIa) inhibitors remain a concern. The major limitation was the lack of specific reversal agents. However, antidotes have now become available and Dr Kaveshree Govender (Milpark Hospital, South Africa) reviewed their role in managing bleeding complications [1].

The 2018 EHRA practical guideline on AF provides guidance on managing bleeding episodes in DOAC-treated patients [2]. Andexanet alpha was approved as a reversal agent for rivaroxaban and apixaban, while idarucizumab is used as a specific reversal for dabigatran.

Andexanet alfa is a recombinant modified FXa. FXa inhibitors bind to andexanet alfa with the same affinity as to endogenous FXa. Consequently, endogenous FXa is partially freed to contribute to effective haemostasis. The efficacy of 400-800 mg bolus and 480-960 mg infusion dose andexanet alpha in patients with acute major bleeding was shown by Connolly et al. in 2019 [3].

Idarucizumab is a monoclonal antibody fragment developed to reverse the anticoagulant effect of dabigatran. Its efficacy was shown in the RE-VERSE AD study (NCT02104947). Idarucizumab rapidly reversed anticoagulation in 98% of patients after a single dose of 5 g, as assessed by activated partial thromboplastin time, thrombin time, ecarin clotting time, and activated clotting time.

Specific agents are recommended for life-threatening bleeding, bleeding into critical organs, and other uncontrolled major bleeding, as well as for urgent invasive procedures in DOAC-treated patients. The limitations of the use of these specific agents are cost, availability, and possible thrombogenicity [1,2].

Also recommended by the 2018 EHRA guideline to help control bleeding are non-specific agents [2]. Anti-fibrinolytic agents are readily available at lower costs and have shown a low risk of thrombosis. However, their use is not well supported by good-quality clinical studies.

Alternatively, off-label use of haemostatic agents could be considered: activated prothrombin complex concentrate (APCC) for dabigatran-associated bleeding and 4-factor prothrombin complex concentrate (4FPCC) for FXa inhibitor-associated bleeding [1].

Dr Govender concluded that specific antidotes have shown efficacy in DOAC-associated bleeding and are recommended in patients with severe bleeding. If unavailable, non-specific agents are best considered in severe bleeding, but there is a lack of evidence for both safety and efficacy.

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      1. Govender K. Oral anticoagulant and bleeding: role of antidotes. EHRA 2021 Congress, 23–25 April.
      2. Steffel J, et al. Eur. Heart J. 2018;39(16):1330–1393.
      3. Connolly S, et al. N Eng J Med 2019;380:1326–1335.

 

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Posted on 16 June 202129 February 2024