Safety of Andexanet Alfa Use in Cardiac Surgery.

We read with great interest the letter by Pauls et al.1Pauls 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: 4557-4558Abstract Full Text Full Text PDF Google Scholar 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.2Tibi 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: 2569-2591Abstract Full Text Full Text PDF PubMed Google Scholar,3Huang 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: 3493-3495Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar In the recent guideline,2Tibi 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: 2569-2591Abstract Full Text Full Text PDF PubMed Google Scholar a recommendation is proposed for the administration of a specific reversal antidote (ie, 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 the anticoagulation of Xa inhibitors. Andexanet alfa is approved in the United States, Europe, and Japan for adult patients treated with direct factor Xa inhibitors when a reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.4Connolly 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: 1326-1335Crossref PubMed Scopus (479) Google Scholar,5Matejic-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: 3030-3044Crossref Scopus (3) Google Scholar However, andexanet alfa also binds to antithrombin III, reduces the circulating antithrombin III-heparin complexes, and may render heparin ineffective.6Lu 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: 446-451Crossref PubMed Scopus (578) Google Scholar Several reports suggested that the competition between andexanet alfa and heparin or antithrombin III and/or heparin complex could manifest as heparin resistance.7Eche 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: 861-865Crossref PubMed Scopus (16) Google Scholar, 8Apostel HJCL Winckers K Bidar E et al.Successful antithrombin administration in andexanet alfa-associated heparin resistance.J Cardiothorac Vasc Anesth. 2021; 35: 904-907Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 9Flaherty 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: 271-273Crossref PubMed Google Scholar, 10Kainz 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: 262-264Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar An unpublished case series suggested that andexanet alfa was associated with heparin resistance and thrombus formation during bypass and could preclude adequate anticoagulation if administered before cardiac surgery.11Beller JP, Mangunta VR, Kern JA. Nonvitamin K oral anticoagulants in cardiac surgery: Continuing education continues to evolve [e-pub ahead of print]. J Thorac Cardiovasc Surg. https://doi.org/10.1016/j.jtcvs.2022.10.032. Accessed February 19, 2023.Google Scholar 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, the use of andexanet alfa before planned heparinization should be avoided.12European Medicines Agency. Direct healthcare professional communication: Ondexxya (andexanet alfa): Avoid use of andexanet prior to heparinization; 2020. Available at: https://www.ema.europa.eu/en/medicines/dhpc/ondexxya-andexanet-alfa-avoid-use-andexanet-prior-heparinization. Accessed February 19, 2023.Google Scholar 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 natural drug clearance. In emergent cardiac surgery, the administration of andexanet alfa should be postponed until after bypass so that heparin anticoagulation can be used safely. If a reversal of anticoagulation must be achieved before bypass, prothrombin complex concentrates may be considered, as guided with viscoelastic testing (Fig 1). For the patient who has received andexanet alfa and demonstrates heparin resistance, administration of antithrombin III may be an alternative approach.8Apostel HJCL Winckers K Bidar E et al.Successful antithrombin administration in andexanet alfa-associated heparin resistance.J Cardiothorac Vasc Anesth. 2021; 35: 904-907Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Bivalirudin anticoagulation also may 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 United States (Fig 1).13Hassan K Kannmacher J Wohlmuth P et al.CytoSorb adsorption during emergency cardiac operations in patients at high risk of bleeding.Ann Thorac Surg. 2019; 108: 45-51Abstract Full Text Full Text PDF PubMed Google Scholar 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 consider this new evidence for the next guideline update. None Andexanet Alfa-Induced Heparin Resistance Missing From SCA Blood Management in Cardiac Surgery GuidelinesJournal of Cardiothoracic and Vascular AnesthesiaVol. 36Issue 12PreviewCurrent 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. Full-Text PDF