Letter to the Editor|Articles in Press

Safety of Andexanet Alfa Use in Cardiac Surgery

Published:March 03, 2023DOI:


      To the Editor:
      We read with great interest the letter by Pauls et al (1) regarding the possible risk of andexanet alfa-related heparin resistance and recommendations made in the 2021 Society of Thoracic Surgeons (STS)/Society of Cardiovascular Anesthesiologists (SCA)/American Society of ExtraCorporeal Technology (AmSECT)/Society for the Advancement of Blood Management (SABM) Update to the Clinical Practice Guidelines on Patient Blood Management (2, 3). In the recent Guideline (2), a recommendation is proposed for administration of a specific reversal antidote (i.e., idarucizumab for dabigatran or andexanet alfa for either apixaban or rivaroxaban) to patients requiring emergent cardiac surgery with recent ingestion of a nonvitamin K oral anticoagulant or laboratory evidence of its effect. This Guideline also makes recommendations to avoid bleeding after cardiopulmonary bypass. We agree that the timing of this intervention is important.
      Andexanet alfa, as a factor Xa decoy, interacts with endogenous factor Xa and reverses anticoagulation of Xa inhibitors. Andexanet alfa is approved in the US, Europe, and Japan for adult patients treated with direct factor Xa inhibitors when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding (4, 5). However, andexanet alfa also binds to antithrombin III, reduces the circulating antithrombin III–heparin complexes, and may render heparin ineffective (6). Several reports suggested that the competition between andexanet alfa and heparin or antithrombin III/heparin complex could manifest as heparin resistance (7-10). An unpublished case series suggested andexanet alfa was associated with heparin resistance and thrombus formation during bypass and could preclude adequate anticoagulation if administered before cardiac surgery (11). The European Medicines Agency issued a communication stating that off-label use of andexanet alfa before surgery with heparin anticoagulation may cause unresponsiveness to heparin. Thus, use of andexanet alfa before planned heparinization should be avoided (12).
      The current STS/SCA/AmSECT/SABM Guideline literature search was completed before the publication of these reports. We acknowledge that elective cardiac surgery in patients treated with a nonvitamin K oral anticoagulant should be delayed, allowing for the natural clearance of the drug. In emergent cardiac surgery, administration of andexanet alpha should be delayed until after bypass so that heparin anticoagulation can be safely used. If reversal of anticoagulation must be achieved before bypass, prothrombin complex concentrates may be considered, as guided with viscoelastic testing. (Figure 1)
      For the patient who has received andexanet alfa and demonstrates heparin resistance, administration of antithrombin III may be an alternative approach (8). Bivalirudin anticoagulation may also be considered in this setting. A third option is the removal of nonvitamin K oral anticoagulants using device-based hemoadsorption during bypass, but this approach has not yet been approved in the US (13). (Figure 1) There are currently no prospective clinical trials or retrospective studies describing andexanet alfa use in cardiac surgery. As stronger evidence accumulates, the STS/SCA/AmSECT/SABM guideline writing group will take this new evidence into considerations for the next guideline update.
      Declaration of interests
      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


      • 1
        Pauls LA, Rathor R, Pennington BT. Andexanet Alfa-Induced Heparin Resistance Missing From SCA Blood Management in Cardiac Surgery Guidelines. J Cardiothorac Vasc Anesth. 2022;36:4557-4558.
      • 2
        Tibi P, McClure RS, Huang J, et al. STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management. J Cardiothorac Vasc Anesth. 2021;35:2569-2591.
      • 3
        Huang J, Firestone S, Moffatt-Bruce S, et al. 2021 Clinical Practice Guidelines for Anesthesiologists on Patient Blood Management in Cardiac Surgery. J Cardiothorac Vasc Anesth. 2021;35:3493-3495.
      • 4
        Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding
      • Associated with Factor Xa Inhibitors. N Engl J Med. 2019;380:1326-35.
      • 1
        Matejic-Spasic M, Hassan K, Thielmann M, et al. Management of perioperative bleeding risk in patients on antithrombotic medications undergoing cardiac surgery-a systematic review. J Thorac Dis. 2022;14:3030-3044.
        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;19:446-51.
      • 2
        Eche IM, Elsamadisi P, Wex N, et al. Intraoperative unfractionated heparin unresponsiveness during endovascular repair of a ruptured abdominal aortic aneurysm following administration of andexanet alfa for the reversal of rivaroxaban. Pharmacotherapy. 2019;39:861-5.
      • 3
        Apostel HJCL, Winckers K, Bidar E, et al. Successful antithrombin administration in andexanet alfa-associated heparin resistance. J Cardiothorac Vasc Anesth. 2021;35:904-7.
      • 4
        Flaherty D, Connors JM, Singh S, et al. Andexanet alfa for urgent reversal of apixaban before aortic surgery requiring cardiopulmonary bypass: a case report. A A Pract. 2019;13:271-3.
      • 5
        Kainz M, Bsuchner P, Schellongowski P, et al. Intraoperative off-label reversal of apixaban by andexanet alfa while on VA-ECMO immediately after emergent surgery for acute type A aortic dissection. J Cardiothorac Vasc Anesth. 2021;35:262-4.
      • 6
        Beller JP, Mangunta VR, Kern JA. Nonvitamin K oral anticoagulants in cardiac surgery: Continuing education continues to evolve. J Thorac Cardiovasc Surg. 2022:S0022-5223(22)01153-9.
        European Medicines Agency. Direct healthcare professional communication: ondexxya (andexanet alfa): avoid use of andexanet prior to heparinization; 2020. Accessed February 19, 2023.
      • 7
        Hassan K, Kannmacher J, Wohlmuth P, et al. CytoSorb adsorption during emergency cardiac operations in patients at high risk of bleeding. Annals of Thoracic Surgery. 2019;108:45–51.

      Linked Article

      • Andexanet Alfa-Induced Heparin Resistance Missing From SCA Blood Management in Cardiac Surgery Guidelines
        Journal of Cardiothoracic and Vascular AnesthesiaVol. 36Issue 12
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          Current 2021 Society of Cardiovascular Anesthesiologists (SCA) guidelines recommend giving novel oral anticoagulant-reversal agent to patients who recently ingested them and require emergent cardiac surgery.1,2 These guidelines specifically recommend giving andexanet alfa to patients who have taken rivaroxaban or apixaban. Andexanet alfa has a structure that mimics endogenous factor Xa and acts as a decoy that sequesters rivaroxaban and apixaban. This prevents factor Xa inhibitors from interacting with endogenous factor Xa, thus reversing anticoagulation.
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