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Andexanet Alfa-Induced Heparin Resistance Missing From SCA Blood Management in Cardiac Surgery Guidelines

      To the Editor:
      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.
      • Tibi P
      • McClure RS
      • Huang J
      • et al.
      STS/SCA/AmSECT/SABM update to the clinical practice guidelines on patient blood management.
      ,
      • Huang J
      • Firestone S
      • Moffatt-Bruce S
      • et al.
      2021 clinical practice guidelines for anesthesiologists on patient blood management in cardiac surgery.
      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. However, andexanet alfa may be associated with heparin resistance in cardiac surgery patients.
      • Watson CJ
      • Zettervall SL
      • Hall MM
      • et al.
      Difficult intraoperative heparinization following andexanet alfa administration.
      • 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.
      • Apostel HJCL
      • Winckers K
      • Bidar E
      • et al.
      Successful antithrombin administration in andexanet alfa-associated heparin resistance.
      Emergent cardiac surgeries usually require heparinization for cardiopulmonary bypass, and, currently, the manufacturer of andexanet alfa recommends against heparin use for systemic anticoagulation because of the concern for heparin resistance. The current 2021 SCA guidelines do not address this phenomenon, how to best achieve systemic anticoagulation, or how to best monitor coagulation status in patients who have received andexanet alfa.
      The mechanism of action for heparin resistance due to andexanet alfa is unclear. Some studies suggested it is related to antithrombin III deficiency.
      • Kalathottukaren MT
      • Creagh AL
      • Abbina S
      • et al.
      Comparison of reversal activity and mechanism of action of UHRA, andexanet, and PER977 on heparin and oral FXa inhibitors.
      • Thalji N
      • Chabata C
      • Patel P
      • et al.
      Characterization of andexanet alfa-associated heparin resistance: Implications for management.
      • Siddiqui F
      • Tafur A
      • Bontekoe E
      • et al.
      Assay-based differentiation in the neutralization profile of unfractionated heparin, enoxaparin, and fondaparinux by andexanet alfa.
      A few case reports described successful treatment of heparin resistance resulting from andexanet alfa with antithrombin III administration.
      • Apostel HJCL
      • Winckers K
      • Bidar E
      • et al.
      Successful antithrombin administration in andexanet alfa-associated heparin resistance.
      Monitoring anticoagulation status is challenging because of the different effects of andexanet alfa on unfractionated heparin depending on the coagulation test and assays used. In activated partial thrombin time and thrombin time tests, the effect of unfractionated heparin was reversed nearly completely by andexanet alfa. In contrast, andexanet alfa demonstrated only a modest reversal of unfractionated heparin action in the chromogenic anti-Xa and anti-IIa assays.
      • Siddiqui F
      • Tafur A
      • Bontekoe E
      • et al.
      Assay-based differentiation in the neutralization profile of unfractionated heparin, enoxaparin, and fondaparinux by andexanet alfa.
      Novel oral anticoagulants are becoming more popular for stroke prevention, nonvalvular atrial fibrillation, and deep vein thrombosis therapy. The likelihood that cardiac anesthesiologists will encounter patients treated with novel oral anticoagulants requiring emergent cardiac surgery is increasing.
      There is a conflict between SCA guidelines and drug manufacturer recommendations regarding andexanet alfa-induced heparin resistance. The most recent SCA guidelines recommend administration of antithrombin III, but manufacturer prescribing information recommends use of an alternate anticoagulant.

      Andexxa. Full prescribing information. Available at: https://www.andexxa.com/prescribing-information.html. Accessed February 2, 2022.

      In addition to the risk of heparin resistance, andexanet alfa also has a high risk of thrombosis. In the ANNEXA-4 trial, 18% of patients had thrombotic events during the 30-day follow-up period.
      • Connolly SJ
      • Milling Jr, TJ
      • Eikelboom JW
      • et al.
      Andexanet alfa for acute major bleeding associated with factor Xa inhibitors.
      As such, the risks and benefits of andexanet alfa warrant a thorough discussion among the anesthesiologist, cardiac surgeon, and perfusionist. Management algorithms have been proposed that recommend against reversal of andexanet alfa before bypass and to administer the drug only after bypass after full protamine dose is given.
      • Neira VM
      • Baghaffar A
      • Doggett N
      • et al.
      Coagulopathy management of an acute type A aortic dissection in a patient taking apixaban.
      In our opinion, andexanet alfa should not be given to reverse novel oral anticoagulants for patients presenting for emergent cardiac surgery requiring cardiopulmonary bypass. The risk of andexanet alfa-related heparin resistance is potentially dangerous, especially when emergent bypass initiation may be necessary. During the next revision of SCA Clinical Practice Guidelines for Patient Blood Management, andexanet alfa-related heparin resistance should be discussed and addressed as a separate etiology from antithrombin III deficiency-related heparin resistance.

      Conflict of Interest

      None

      References

        • Tibi P
        • McClure RS
        • Huang J
        • et al.
        STS/SCA/AmSECT/SABM update to the clinical practice guidelines on patient blood management.
        Ann Thorac Surg. 2021; 112: 981-1004
        • 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
        • Watson CJ
        • Zettervall SL
        • Hall MM
        • et al.
        Difficult intraoperative heparinization following andexanet alfa administration.
        Clin Pract Cases Emerg Med. 2019; 3: 390-394
        • 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: 861-865
        • Apostel HJCL
        • Winckers K
        • Bidar E
        • et al.
        Successful antithrombin administration in andexanet alfa-associated heparin resistance.
        J Cardiothorac Vasc Anesth. 2021; 35: 904-907
        • Kalathottukaren MT
        • Creagh AL
        • Abbina S
        • et al.
        Comparison of reversal activity and mechanism of action of UHRA, andexanet, and PER977 on heparin and oral FXa inhibitors.
        Blood Adv. 2018; 2: 2104-2114
        • Thalji N
        • Chabata C
        • Patel P
        • et al.
        Characterization of andexanet alfa-associated heparin resistance: Implications for management.
        Res Pract Thromb Haemost. 2021; 5: LPB0052
        • Siddiqui F
        • Tafur A
        • Bontekoe E
        • et al.
        Assay-based differentiation in the neutralization profile of unfractionated heparin, enoxaparin, and fondaparinux by andexanet alfa.
        Clin Appl Thromb Hemost. 2020; 261076029619895120
      1. Andexxa. Full prescribing information. Available at: https://www.andexxa.com/prescribing-information.html. Accessed February 2, 2022.

        • Connolly SJ
        • Milling Jr, TJ
        • Eikelboom JW
        • et al.
        Andexanet alfa for acute major bleeding associated with factor Xa inhibitors.
        N Engl J Med. 2016; 375: 1131-1141
        • Neira VM
        • Baghaffar A
        • Doggett N
        • et al.
        Coagulopathy management of an acute type A aortic dissection in a patient taking apixaban.
        J Cardiothorac Vasc Anesth. 2022; 36: 1720-1725