Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis.

Abstract

BACKGROUND:

Andexanet alfa is approved (FDA "accelerated approval"; EMA "conditional approval") as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH).

METHODS:

This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression.

RESULTS:

The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16-6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13-0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC.

CONCLUSIONS:

In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

• Authors: Olivia S Costa, Stuart J Connolly, Mukul Sharma, Jan Beyer-Westendorf, Mary J Christoph, Belinda Lovelace, Craig I Coleman
• Journal: Critical care (London, England) (Crit Care) Vol. 26 Issue 1 Pg. 180 (06 16 2022) ISSN: 1466-609X [Electronic] England
• PMID: 35710578 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Anticoagulants
• Blood Coagulation Factors
• Factor Xa Inhibitors
• Hemostatics
• PRT064445
• Pyrazoles
• Pyridones
• Recombinant Proteins
• prothrombin complex concentrates
• apixaban
• Rivaroxaban
• Factor Xa

Topics

• Adult
• Aged
• Anticoagulants
• Blood Coagulation Factors (pharmacology, therapeutic use)
• Factor Xa (therapeutic use)
• Factor Xa Inhibitors (adverse effects)
• Hemorrhage
• Hemostatics
• Humans
• Intracranial Hemorrhages (chemically induced, drug therapy)
• Propensity Score
• Prospective Studies
• Pyrazoles
• Pyridones
• Recombinant Proteins (therapeutic use)
• Retrospective Studies
• Rivaroxaban (adverse effects)
• Thrombosis