Skip to main content
SpringerLink
Log in

Andexanet Alfa: What We Have Learned from Clinical Trials and Real-World Data

  • Current Opinion
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Andexanet alfa is a specific reversal agent for factor Xa inhibitors with immediate reversal of their anticoagulant effect. Andexanet alfa is currently approved for use in patients treated with rivaroxaban and apixaban who have life-threatening or uncontrolled bleeding. New data from both controlled clinical trials and real-world experience are continuously being published, providing greater insight into the clinical characteristics of the drug, such as efficacy and safety. It is worth considering that andexanet alfa could be of benefit in a variety of different clinical scenarios where patients receiving treatment with apixaban and rivaroxaban (and endoxaban) have life-threatening conditions. These different clinical scenarios, which range from pre-treatment of urgent surgery, especially neurosurgical interventions, and concomitant use of andexanet alfa and prothrombin complex concentrate to onset of bleeding more than 6 h prior to admission, should be clarified as well as the issue of “low/high” dose of andexanet alfa and the need for baseline anti-Xa inhibitor levels measured by point-of-care testing. Finally, management of patients at high risk of thrombosis or recent arterial/venous thrombotic events needs to be further explored. In this current opinion, we address these urgent questions in the light of recent literature and clinical trial data.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Connolly SJ, Crowther M, Eikelboom JW, ANNEXA-4 Investigators, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380(14):1326–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Christensen H, Cordonnier C, Kõrv J, et al. European Stroke Organisation guideline on reversal of oral anticoagulants in acute intracerebral haemorrhage. Eur Stroke J. 2019;4(4):294–306.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Steffel J, Collins R, Antz M, External reviewers, et al. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace. 2021;23(10):1612–76.

    Article  PubMed  Google Scholar 

  4. Greenberg SM, Ziai WC, Cordonnier C, American Heart Association/American Stroke Association, et al. 2022 guideline for the management of patients with spontaneous intracerebral hemorrhage: a guideline from the American Heart Association/American Stroke Association. Stroke. 2022;53(7):e282-361. https://doi.org/10.1161/STR.0000000000000407.

    Article  CAS  PubMed  Google Scholar 

  5. Frol S, Oblak JP, Šabovič M, et al. Andexanet alfa to reverse the effect of factor Xa inhibitors in intracranial hemorrhage. CNS Drugs. 2023;37(6):477–87. https://doi.org/10.1007/s40263-023-01006-7.

    Article  CAS  PubMed  Google Scholar 

  6. Demchuk AM, Yue P, Zotova E, ANNEXA-4 Investigators, et al. Hemostatic efficacy and anti-FXa (factor Xa) reversal with andexanet alfa in intracranial hemorrhage: ANNEXA-4 substudy. Stroke. 2021;52(6):2096–105. https://doi.org/10.1161/STROKEAHA.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Strein M, May S, Brophy GM. Anticoagulation reversal for intracranial hemorrhage in the era of the direct oral anticoagulants. Curr Opin Crit Care. 2020;26(2):122–8. https://doi.org/10.1097/MCC.0000000000000706.

    Article  PubMed  Google Scholar 

  8. Milling TJ Jr, Middeldorp S, Xu L, ANNEXA-4 Investigators, et al. Final study report of andexanet alfa for major bleeding with Factor Xa inhibitors. Circulation. 2023;147(13):1026–38. https://doi.org/10.1161/CIRCULATIONAHA.121.057844.

    Article  CAS  PubMed  Google Scholar 

  9. Toyoda K, Arakawa S, Ezura M, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity: prespecified subgroup analysis of the ANNEXA-4 study in Japan. J Atheroscler Thromb. 2023. https://doi.org/10.5551/jat.64223.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Connolly SJ. Randomized trial of andexanet alfa versus usual care in patients with acute intracranial hemorrhage while on an oral factor Xa inhibitor: ANNEXa-I [presentation]. In: Presented at the World Stroke Congress (WSC); 10–12 October, 2023; Toronto (ON).

  11. Sutton SS, Magagnoli J, Cummings TH, et al. Real-world clinical outcomes among US veterans with oral factor xa inhibitor-related major bleeding treated with andexanet alfa or 4-factor prothrombin complex concentrate. J Thromb Thrombolysis. 2023;56(1):137–46. https://doi.org/10.1007/s11239-023-02820-y. (Epub 2023 May 23. Erratum in: J Thromb Thrombolysis. 2023 Jun 12).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Troyer C, Nguyen W, Xie A, et al. Retrospective review of andexanet alfa versus 4-factor prothrombin complex concentrate for reversal of DOAC-associated intracranial hemorrhage. J Thromb Thrombolysis. 2023;55(1):149–55. https://doi.org/10.1007/s11239-022-02715-4.

    Article  CAS  PubMed  Google Scholar 

  13. Ammar AA, Elsamadicy AA, Ammar MA, et al. Emergent external ventricular drain placement in patients with factor Xa inhibitor-associated intracerebral hemorrhage after reversal with andexanet alfa. Clin Neurol Neurosurg. 2023;226: 107621. https://doi.org/10.1016/j.clineuro.2023.107621.

    Article  PubMed  Google Scholar 

  14. Dobesh PP, Fermann GJ, Christoph MJ, et al. Lower mortality with andexanet alfa vs 4-factor prothrombin complex concentrate for factor Xa inhibitor-related major bleeding in a U.S. hospital-based observational study. Res Pract Thromb Haemost. 2023;7(6):102192. https://doi.org/10.1016/j.rpth.2023.102192.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Backus B, Beyer-Westendorf J, Body R, et al. Management of major bleeding for anticoagulated patients in the emergency department: an European experts consensus statement. Eur J Emerg Med. 2023;30(5):315–23. https://doi.org/10.1097/MEJ.0000000000001049.

    Article  PubMed  Google Scholar 

  16. Orban JE 3rd, Ruckel C, Harlan S. Concomitant andexanet alfa and 4 F-PCC for factor Xa inhibitor associated intracranial hemorrhage. Clin Neurol Neurosurg. 2023;20(233): 107908. https://doi.org/10.1016/j.clineuro.2023.107908.

    Article  Google Scholar 

  17. Wahbah Makhoul G, Mustafa A, Ling J, et al. Lactococcus endocarditis after Bentall procedure presenting with intracranial hemorrhage. IDCases. 2023;13(31): e01710. https://doi.org/10.1016/j.idcr.2023.e01710.

    Article  Google Scholar 

  18. Jenniches D, Kerns AF, DelBianco J, et al. Administration of andexanet alfa for traumatic intracranial hemorrhage in the setting of massive apixaban overdose: a case report. Am J Health Syst Pharm. 2023. https://doi.org/10.1093/ajhp/zxad215.

    Article  PubMed  Google Scholar 

  19. Coleman CI, Dobesh PP, Danese S, et al. 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. 2021;17(1):127–35. https://doi.org/10.2217/fca-2020-0073.

    Article  CAS  PubMed  Google Scholar 

  20. Giovino A, Shomo E, Busey KV, et al. An 18-month single-center observational study of real-world use of andexanet alfa in patients with factor Xa inhibitor associated intracranial hemorrhage. Clin Neurol Neurosurg. 2020;195: 106070. https://doi.org/10.1016/j.clineuro.2020.106070.

    Article  PubMed  Google Scholar 

  21. Culbreth SE, Rimsans J, Sylvester K, et al. Andexanet alfa: the first 150 days. Am J Hematol. 2019;94(1):E21–4. https://doi.org/10.1002/ajh.25326.

    Article  PubMed  Google Scholar 

  22. Ratcliff JJ, Hall AJ, Porto E, et al. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH): study protocol for a multi-centered two-arm randomized adaptive trial. Front Neurol. 2023;16(14):1126958. https://doi.org/10.3389/fneur.2023.1126958.

    Article  Google Scholar 

  23. Hall AJ, Ratcliff JJ, Porto E, et al. Very early minimally invasive removal of intracerebral hemorrhage: the ENIRCH trial [press release]. In: Presented at the European Stroke Organisation Conference; 25 May, 2023; Munich.

  24. Hall A, Ratcliff JJ. ENRICH trial: early surgical intervention in intracerebral hemorrhage [interview with VJNeurology]. May 2023.

  25. Alexion Pharmaceuticals. Trial of andexanet in patients receiving an oral FXa inhibitor who require urgent surgery (Annexa-S). Available from: https://clinicaltrials.gov/ct2/show/study/NCT04233073. Accessed 15 Feb 2024.

  26. Sobolewski KA, Brophy A, Choi SC, et al. Real-world observational review of andexanet alfa prescribing and utilization outcomes at a community teaching hospital. Crit Care Explor. 2021;3(4): e0356. https://doi.org/10.1097/CCE.0000000000000356.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Liu J, Elsamadisi P, Philips E, et al. Four-factor prothrombin complex concentrate plus andexanet alfa for reversal of factor Xa inhibitor-associated bleeding: case series. Am J Health Syst Pharm. 2022;79(16):1323–9. https://doi.org/10.1093/ajhp/zxac079.

    Article  PubMed  Google Scholar 

  28. Lu G, Lin J, Bui K, et al. Andexanet versus prothrombin complex concentrates: differences in reversal of factor Xa inhibitors in in vitro thrombin generation. Res Pract Thromb Haemost. 2020;4(8):1282–94. https://doi.org/10.1002/rth2.12418.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Dzik WH. Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal. J Thromb Haemost. 2015;13(Suppl. 1):S187–94. https://doi.org/10.1111/jth.12949.

    Article  MathSciNet  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Vascular Neurology, University Medical Center Ljubljana, Ljubljana, Slovenia

    Senta Frol & Janja Pretnar Oblak

  2. Department of Vascular Disorders, University Medical Center Ljubljana, Ljubljana, Slovenia

    Mišo Šabovič

  3. Faculty of Medicine, University of Ljubljana, Zaloška 2, 1000, Ljubljana, Slovenia

    Senta Frol, Janja Pretnar Oblak & Mišo Šabovič

  4. Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Friesland Kliniken GmbH, Sande, Germany

    Pawel Kermer

  5. University Medical Center, Göttingen, Germany

    Pawel Kermer

Authors
  1. Senta Frol
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Janja Pretnar Oblak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mišo Šabovič
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pawel Kermer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Senta Frol.

Ethics declarations

Funding

No external funding was used in the preparation of this article.

Conflict of Interest/Competing Interests

All authors received speaker’s honoraria from AstraZeneca. Other than that, the authors have no competing financial interests or personal relationships that could have influenced the work reported in this article.

Ethics Approval

The present research complies with the guidelines for human studies, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

Data sharing is not applicable to this article as no datasets were generated.

Code Availability

Not applicable.

Authors’ Contributions

SF and PK were responsible for the conception and design of the study. All authors were involved in the data acquisition, interpretation, drafting, and review of the article as well as its final approval.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frol, S., Oblak, J.P., Šabovič, M. et al. Andexanet Alfa: What We Have Learned from Clinical Trials and Real-World Data. CNS Drugs 38, 163–168 (2024). https://doi.org/10.1007/s40263-024-01071-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-024-01071-6

Search

Navigation