Skip to main content

Advertisement

SpringerLink
Log in

Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage

  • Original work
  • Published:
Neurocritical Care Aims and scope Submit manuscript

Abstract

Background/Objective

There are limited data on the risks and benefits of using andexanet alfa (AA) in comparison with four-factor prothrombin complex concentrate (4F-PCC) to reverse factor Xa inhibitors (FXi) associated intracranial hemorrhage (ICH). We sought to describe our experience with AA or 4F-PCC in patients with oral FXi-related traumatic and spontaneous ICH.

Methods

We conducted a retrospective review of consecutive adult patients with FXi-related ICH who received AA or 4F-PCC. FXi-related ICH cases included traumatic and spontaneous intracranial hemorrhages. Our primary analysis evaluated ICH stability on head computed tomography scan (CT), defined as a similar amount of blood from the initial scan at the onset of ICH to subsequent scans, at 6-h and 24-h post-administration of AA or 4F-PCC. For the subset of spontaneous intraparenchymal hemorrhages, volume was measured at 6-h and 24-h post-reversal. In secondary analyses, we evaluated good functional outcome at discharge, defined as a Modified Rankin Score of less than 3, and the incidence of thrombotic events after AA or 4F-PCC adminstration, during hospitalization.

Results

A total of 44 patients (16 traumatic and 28 spontaneous ICH) with median age of 79 years [72–86], 36% females, with a FXi-related ICH, were included in this study. The majority of spontaneous ICHs were intraparenchymal 19 (68%). Twenty-eight patients (64%) received AA and 16 patients (36%) received 4F-PCC. There was no difference between AA and 4F-PCC in terms of CT stability at 6 h (21 [78%] vs 10 [71%], p = 0.71) and 24 h (15 [88%] vs 6 [60%], p = 0.15). In a subgroup of patients with spontaneous intraparenchymal hemorrhage, there was no difference in the degree of achieved hemostasis based on hematoma volume between AA and 4F-PCC at 6 h (9.3 mL [6.9–26.4] vs 10 mL [9.4–22.1], adjusted p = 0. 997) and 24-h (9.2 mL [6.1–18.8] vs 9.9 [9.4–21.1], adjusted p = 1). The number of patients with good outcome based on mRS on discharge were 10 (36%) and 6 (38%) in the AA and 4F-PCC groups, respectively (adjusted p = 0.81). The incidence of thromboembolic events was similar in the AA and 4F-PCC groups (2 [7%] vs 0, p = 0.53).

Conclusion

In this limited sample of patients, we found no difference in neuroimaging stability, functional outcome and thrombotic events when comparing AA and 4F-PCC in patients with FXi-related ICH. Since our analysis is likely underpowered, a multi-center collaborative network devoted to this question is warranted.

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. Andexxa (coagulation factor Xa (recombinant), inactivated-zhzo) [package insert]. South San Francisco, CA: Portola Pharmaceuticals, Inc.; 2017.

  2. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: Chest guideline and expert panel report. Chest. 2018;154:1121–201.

    Article  Google Scholar 

  3. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2:3257–91.

    Article  Google Scholar 

  4. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American college of cardiology solution set oversight committee. J Am Coll Cardiol. 2020;76:594–622.

    Article  CAS  Google Scholar 

  5. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413–24.

    Article  CAS  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

  7. Panos NG, Cook AM, John S, Jones GM. Neurocritical care society pharmacy study G factor Xa inhibitor-related intracranial hemorrhage: results from a multicenter, observational cohort receiving prothrombin complex concentrates. Circulation. 2020;141:1681–9.

    Article  Google Scholar 

  8. Owusu KA, Effendi MK, DeFilippo NA, Reardon DP, Ian LA. Andexanet alfa: considerations and practical applications. Crit Pathw Cardiol. 2019;18:200–6.

    Article  Google Scholar 

  9. Dowlatshahi D, Demchuk AM, Flaherty ML, et al. Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes. Neurology. 2011;76:1238–44.

    Article  CAS  Google Scholar 

  10. Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032–60.

    Article  Google Scholar 

  11. Huttner HB, Steiner T, Hartmann M, et al. Comparison of ABC/2 estimation technique to computer-assisted planimetric analysis in warfarin-related intracerebral parenchymal hemorrhage. Stroke. 2006;37:404–8.

    Article  Google Scholar 

  12. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799–808.

    Article  CAS  Google Scholar 

  13. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.

    Article  CAS  Google Scholar 

  14. Investigators E, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–510.

    Article  Google Scholar 

  15. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.

    Article  CAS  Google Scholar 

  16. Christensen H, Cordonnier C, Korv J, et al. European stroke organisation guideline on reversal of oral anticoagulants in acute intracerebral haemorrhage. Eur Stroke J. 2019;4:294–306.

    Article  Google Scholar 

  17. Wilsey HA, Bailey AM, Schadler A, Davis GA, Nestor M, Pandya K. Comparison of low-versus high-dose four-factor prothrombin complex concentrate (4f-pcc) for factor Xa inhibitor-associated bleeding: a retrospective study. J Intensive Care Med 2020:885066620916706. https://doi.org/10.1177/0885066620916706.

  18. Smith MN, Deloney L, Carter C, Weant KA, Eriksson EA. Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study. J Thromb Thrombolysis. 2019;48:250–5.

    Article  CAS  Google Scholar 

  19. Barra ME, Das AS, Hayes BD, et al. Evaluation of andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC) for reversal of rivaroxaban- and apixaban-associated intracranial hemorrhages. J Thromb Haemost. 2020;18:1637–47.

    Article  CAS  Google Scholar 

  20. Kimpton M, Siegal DM. Evidence-Based Minireview: Mortality and thrombosis in patients receiving prothrombin complex concentrates or andexanet alfa for the management of direct oral factor Xa inhibitor-associated major bleeding. Hematol Am Soc Hematol Educ Progr. 2019;2019:204–8.

    Article  Google Scholar 

Download references

Acknowledgements

None.

Funding

GJF is supported by the National Institutes of Health (K76AG059992, R03NS112859 and P30AG021342), the American Heart Association (18IDDG34280056), the Yale Pepper Scholar Award (P30AG021342) and the Neurocritical Care Society Research Fellowship.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Yale New Haven Hospital, 55 Park Street, Lower Level, New Haven, CT, 06510, USA

    Abdalla A. Ammar, Mahmoud A. Ammar & Kent A. Owusu

  2. Clinical Redesign, Yale New Haven Health, New Haven, CT, USA

    Kent A. Owusu

  3. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale School of Medicine, 15 York Street, LLCI 1004D, Box 208018, New Haven, CT, 06520, USA

    Stacy C. Brown, Firas Kaddouh, Julián N. Acosta & Guido J. Falcone

  4. Departments of Neurosurgery, Yale School of Medicine, New Haven, CT, USA

    Aladine A. Elsamadicy MD

Authors
  1. Abdalla A. Ammar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahmoud A. Ammar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kent A. Owusu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stacy C. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Firas Kaddouh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aladine A. Elsamadicy MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julián N. Acosta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guido J. Falcone
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AAA, MAA, KAO, GJF conceived the study design and methodology. All authors had input on study design and execution. AAA, MAA, KAO, SCB, FK, AAE contributed to data collection. SCB, FK, AAE reviewed radiographic images. JNA performed data analysis. AAA, MAA, KAO, JNA, GJF contributed to preparing the manuscript. All authors critically revised the manuscript and approved the manuscript in its final form.

Corresponding author

Correspondence to Guido J. Falcone.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval/Informed Consent

All procedures performed in studies involving human participants were in accordance with the institutional and/or national research committee's ethical standards and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Yale New Haven Hospital Institutional Review Board and was exempted for minimal risk status.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 15 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ammar, A.A., Ammar, M.A., Owusu, K.A. et al. Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage. Neurocrit Care 35, 255–261 (2021). https://doi.org/10.1007/s12028-020-01161-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-020-01161-5

Keywords

Search

Navigation