Clinical & Experimental Cardiology
Open Access

Challenges and Strategies in Anticoagulation Management for DOAC-Treated Patients Undergoing Emergency Cardiac and Aortic Surgeries

Kohei Nagashima^{* *}Correspondence: Kohei Nagashima, Department of Clinical Engineering, Toranomon Hospital, Tokyo, Japan, Email:

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Description

Direct Oral Anticoagulants (DOACs) are widely used for cardiovascular diseases due to their predictable effects and ease of management [1]. Andexanet alfa , functions as a factor Xa analog, which reverses the effects of Xa inhibitors [2]. However, Andexanet alfa also binds to Unfractionated Heparin (UFH)-antithrombin complexes, leading to instances of heparin resistance, consequently complicating anticoagulation management during emergency surgeries [3-5].

UFH resistance occurs when normal heparin doses fail to achieve the expected anticoagulant effect. This phenomenon is particularly concerning in patients receiving DOACs when Andexanet alfa is administered. as studies suggest that Andexanet alfa nay partially inhibit heparin [6]. Furthermore, overcoming this resistance might necessitate higher heparin doses, which increases bleeding risk.

To prevent UFH resistance, avoiding Andexanet alfa during emergency surgeries involving Cardiopulmonary Bypass (CPB) is recommended. However, if Andexanet alfa has been administered preoperatively, alternative anticoagulation strategies may be necessary [4,5]. Research is ongoing to optimize the management of Andexanet alfa-induced UFH resistance, but a definitive solution has yet to be established.

Replenishing Antithrombin (AT) has shown promise as a viable solution by enhancing the effect of heparin, partially recovering the desired anticoagulant effect [3]. Nevertheless, this method may not be effective in all cases, requiring comprehensive individual patient assessments [4,5]. Additionally, Andexanet alfa risk of thrombotic complications [7,8]. Thus, close monitoring for thrombus formation is essential when using these drugs after CPB.

Four-Factor Prothrombin Complex Concentrate (4F-PCC), which is used in managing warfarin side effects and DOACassociated bleeding, has been reported to be an effective alternative to Andexanet alfa. Furthermore, 4F-PPC does not induce UFH resistance after CPB, potentially allowing safe heparin use for subsequent procedures [9-14].

Another viable alternative is the use of CytoSorb® (CytoSorbents Corporation, Monmouth Junction, USA). This blood adsorber device reduces inflammatory mediator levels, mitigates excessive immune responses and cytotoxic effects, and enhances recovery potential. Additionally, it is CE-marked and capable of removing ticagrelor and rivaroxaban during CPB surgery. CytoSorb® is also effective for the in vitro removal of multiple DOACs and rapid reduction in plasma levels. In fact, patients undergoing cardiac surgery with CytoSorb following apixaban administration were reported to exhibit significantly reduced anti-factor Xa activity [15].

Conclusion

Andexanet alfa-induced UFH resistance poses a significant challenge in anticoagulation management during cardiovascular surgery. potentially complicating anticoagulation management during emergency surgeries. While strategies such as AT supplementation or alternative anticoagulation methods are being considered, a definitive solution has yet to be established. Novel treatment options, such as 4F-PCC and CytoSorb®, show promise in managing DOAC-associated bleeding, especially in surgeries involving CPB.

References

1. Yeh CH, Fredenburgh JC, Weitz JI. The real decoy: An antidote for factor Xa-directed anticoagulants. Circ Res. 2013;113(8):954-957.

   [Crossref] [Google Scholar] [PubMed]

2. Connolly SJ, Milling Jr TJ, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-1141.

   [Crossref] [Google Scholar] [PubMed]

3. Apostel HJ, Winckers K, Bidar E, Schreiber JU. Successful antithrombin administration in andexanet alfa-associated heparin resistance. J Cardiothorac Vasc Anesth. 2021;35(3):904-907.

   [Crossref] [Google Scholar] [PubMed]

4. Honda J, Itakura Y, Tanaka S, Inoue S. Successful use of an antithrombin for heparin resistance with andexanet alfa. JA Clin Rep. 2023;9(1):26.

   [Crossref] [Google Scholar] [PubMed]

5. Kitaura A, Iwamoto T, Hamasaki S, Tsukimoto S, Nakajima Y. Successful nafamostat mesilate administration for andexanet alfa-induced heparin resistance. Cureus. 2023;15(8):44003.

   [Crossref] [Google Scholar] [PubMed]

6. Müther M, Schwindt W, Mesters RM, Minnerup J, Stracke P, Holling M, et al. Andexanet-alfa-associated heparin resistance in the context of hemorrhagic stroke. Neurocrit Care. 2022;37(2):372-376.

   [Crossref] [Google Scholar] [PubMed]

7. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380(14):1326-1335.

   [Crossref] [Google Scholar] [PubMed]

8. Milling Jr TJ, Middeldorp S, Xu L, Koch B, Demchuk A, Eikelboom JW, et al. Final study report of andexanet alfa for major bleeding with factor Xa inhibitors. Circulation. 2023;147(13):1026-1038.

   [Crossref] [Google Scholar] [PubMed]

9. Pham H, Medford WG, Horst S, Levesque M, Ragoonanan D, Price C, et al. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban-or rivaroxaban-associated intracranial hemorrhages. Am J Emerg Med. 2022;55:38-44.

   [Crossref] [Google Scholar] [PubMed]

10. Coleman CI, Dobesh PP, Danese S, Ulloa J, Lovelace B. Real-world management of oral factor Xa inhibitor-related bleeds with reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: A multicenter study. Future Cardiol. 2020;17(1):127-135.

    [Crossref] [Google Scholar] [PubMed]

11. Ammar AA, Ammar MA, Owusu KA, Brown SC, Kaddouh F, Elsamadicy AA, et al. Andexanet alfa versus 4-factor prothrombin complex concentrate for reversal of factor Xa inhibitors in intracranial hemorrhage. Neurocrit Care. 2021;35:255-261.

    [Crossref] [Google Scholar] [PubMed]

12. Lipski M, Pasciolla S, Wojcik K, Jankowitz B, Igneri LA. Comparison of 4-factor prothrombin complex concentrate and andexanet alfa for reversal of apixaban and rivaroxaban in the setting of intracranial hemorrhage. J Thromb Thrombolysis. 2023;55(3):519-526.

    [Crossref] [Google Scholar] [PubMed]

13. Koo SJ, Hussain Y, Booth DY, Desai P, Oh ES, Rios J, et al. Four-factor prothrombin complex concentrate versus andexanet alfa for direct oral anticoagulant reversal. J Am Pharm Assoc. 2024;64(2):395-401.

    [Crossref] [Google Scholar] [PubMed]

14. Pasciolla S, Wojcik K, Kavi T, Green D, Shaikh H, Jankowitz B, et al. Comparison of 4-factor PCC reversal of apixaban and rivaroxaban versus warfarin for intracranial hemorrhage. J Thromb Thrombolysis. 2022:1-8.

    [Crossref] [Google Scholar] [PubMed]

15. Matejic-Spasic M, Hassan K, Thielmann M, Geidel S, Storey RF, Schmoeckel M, et al. Management of perioperative bleeding risk in patients on antithrombotic medications undergoing cardiac surgery-A systematic review. J Thorac Dis. 2022;14(8):3030-3044.

    [Crossref] [Google Scholar] [PubMed]