Volume 64, February 2023, Pages 74-77Author links open overlay panelAbstractObjective

to describe the clinical and safety outcomes between andexanet alfa (AA) and 4-factor prothrombin complex concentrate (4F-PCC) for the reversal of apixaban or rivaroxaban in the setting of an intracranial hemorrhage (ICH).

Methods

A retrospective, multicentered descriptive study was conducted in hospitalized patients 18 years of age or older from June 2018 to October 2019 who received AA or 4F-PCC for the reversal of apixaban or rivaroxaban in the setting of ICH. Patients were excluded if they had received 4F-PCC prior to AA after its addition to the institution wide formulary. Other exclusion criteria were history or presence of heparin-induced thrombocytopenia or disseminated intravascular coagulation, estimated hematoma volume of >60 mL, Glasgow Coma Scores <7, or no repeat CT head scan. Information was collected from the electronic medical records. The primary outcome was the achievement of excellent or good hemostatic efficacy upon the repeat computer tomography (CT) scan performed after the infusion of study drugs. Secondary outcomes included disposition, survival to hospital discharge, 30-day readmission, length of hospital stay, length of ICU stay, incidence of thromboembolic events.

Results

A total of 24 patients were included in the study, of which 9 received AA and 15 received 4F-PCC. The achievement of excellent or good hemostatic efficacy upon repeat CT scan occurred in 7 (77.8%) patients in the AA group and in 14 (93.3%) patients in the 4-F PCC group. All patients in the AA group survived to hospital discharge with no 30-day morality and 86.7% patients in the 4F-PCC group.

Conclusion

This study suggests that real-world clinical and safety outcomes between andexanet alfa and 4F-PCC for the reversal of factor Xa inhibitors in the setting of ICH are similar to ones reported in clinical trials.

Introduction

Andexanet alfa (AA) is a modified recombinant coagulation factor Xa approved for the reversal of apixaban and rivaroxaban in life-threatening or uncontrolled bleeds. It binds to and sequesters factor Xa inhibitors to reverse their anticoagulant effect [1]. Before its introduction into the market, Neurocritical Care Society recommended the administration of 4-factor prothrombin complex concentrate (4F-PCC) or activated prothrombin complex concentrate (PCC) for the reversal of factor Xa inhibitors in the setting of an intracranial hemorrhage [2]. Since its approval, the American Heart Association/ American College of Cardiology/ the Heart Rhythm Society have stated AA is a useful agent for the reversal of rivaroxaban and apixaban in the event of a life-threatening or uncontrolled bleed [3]. The updated American Heart Association/American Stroke Association have similar recommendations in which AA is reasonable to reverse for direct factor Xa inhibitor-associated spontaneous intracranial hemorrhage (ICH) with 4F-PCC or activated PCC as an agent that may be considered [4]. Despite the shift in recommendation, there have not been prospective clinical trials comparing therapies.

ANNEXA-4, an open-label, single group phase 3 trial, found 80% of patients with ICH achieved excellent or good hemostatic efficacy at 12 h. Clinical trials comparing AA with other therapies are lacking [5]. A phase 4 study comparing AA to usual care in acute ICH in patients receiving factor Xa inhibitors is underway but expected to be completed by 2024 [6]. There is limited evidence for AA usefulness in the community setting. The objective of this study is to describe clinical and safety outcomes of AA and 4F-PCC for the reversal of apixaban or rivaroxaban in the setting of an ICH.

Section snippetsStudy design

A multi-centered, retrospective descriptive study was conducted at a hospital system located in New Jersey from June 2018 to October 2019. Both arms were for separate 6-month periods from June 2018 to November 2018 for the 4F-PCC group and May 2019 to October 2019 for the AA group. These time periods were chosen due to the introduction of AA to the hospital-wide formulary on May 2019 and to match a similar timeframe the year prior for the 4F-PCC group. The hospital system consisted of five

Patient characteristics

A total of 34 patients received either AA or 4-F PCC for the reversal of apixaban or rivaroxaban in the setting of an ICH within the study timeframe. Of these, a total of 24 patients were included of which 9 received AA, and 15 received 4F-PCC. Three patients were excluded as they were transitioned to comfort care thus a repeat CT scan was not performed after the administration of the study drug. Two patients were excluded for receiving 4F-PCC prior to AA. Additional excluded patients are

Discussion

Currently, the comparison between AA and PCC are limited to retrospective studies or case series [[8], [9], [10], [11], [12]]. Semon et al., reported no significant difference between treatments when comparing the achievement of hemostatic efficacy or mortality [8]. Ammar et al., also found no difference in mortality when comparing both groups [9]. An ongoing Phase IV prospective trial comparing AA and usual care is projected to be completed in 2024 and will provide further insight in the

Conclusion

This multicentered descriptive study suggests real-world clinical and safety outcomes between AA and 4F-PCCs for the reversal of factor Xa inhibitors in the setting of ICH are similar to ones reported in clinical trials.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors contributions

ESO, FD, KS, and MES conceived and designed the study. SC acted as an advisor to the study. ESO, PS, FD, KS, JR, and MES supervised the conduct of the study and data collection. ESO and PS managed the data. ESO, FD, KS, and MES provided the statistical advice on study design and analyzed the data. ESO drafted the manuscript, and all authors contributed to its revision. ESO takes responsibility for the paper as a whole.

CRediT authorship contribution statement

Elly S. Oh: Writing – original draft, Methodology, Investigation, Formal analysis, Conceptualization. Paul Schulze: Writing – review & editing, Methodology, Investigation. Frank Diaz: Writing – review & editing, Supervision, Project administration, Methodology, Formal analysis, Conceptualization. Kunal Shah: Writing – review & editing, Supervision, Project administration, Methodology, Formal analysis, Conceptualization. Jose Rios: Writing – review & editing, Supervision, Methodology. Michael E.

Declaration of Competing Interest

The authors received no financial support for the research, authorship, and/or publication of this article.

Acknowledgements

We thank Stephanie Chiu, MS and Teodoro Jerves Serrano, MD for statistical advice on this study.

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