Predictors of Hematoma Expansion and Response to Andexanet in Patients With Intracerebral Hemorrhage: Secondary Analyses of the ANNEXA-I Randomized Clinical Trial

BACKGROUND: – Andexanet improves hemostatic efficacy in FXa (factor Xa) inhibitor–associated intracranial hemorrhage but carries a risk of thrombotic events. These secondary analyses of the ANNEXA-I trial (A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor) examined determinants of hematoma expansion (HE) and the corresponding response to andexanet. METHODS: – ANNEXA-I enrolled patients aged ≥18 years with acute FXa inhibitor–associated intracranial hemorrhage within 6 hours of onset between June 6, 2019, and May 27, 2023, at 131 sites in 23 countries. Participants were randomized (1:1) to andexanet or usual care. Among 530 participants, 459 (87%) had a qualifying intracerebral hemorrhage and adequate brain imaging for these analyses. The primary outcome was HE (≥12.5-mL or ≥35% increase in baseline volume) at 12 hours. We report differences in the proportion of HE between treatment groups stratified by variables significantly associated with HE in regression models. RESULTS: – HE occurred in 149 of 459 participants (32.5%). Symptom onset-to-treatment time (adjusted odds ratio per hour, 0.73 [95% CI, 0.63–0.85]), baseline hematoma volume (adjusted odds ratio per 10 mL, 1.11 [95% CI, 1.01–1.23]), and diastolic blood pressure (adjusted odds ratio per 10 mm Hg, 1.15 [95% CI, 1.02–1.29]) were associated with HE but not thrombotic events. In a separate multivariable model replacing volume and onset-to-treatment time with prescan hematoma growth rate, growth rate was also associated with HE (adjusted odds ratio per mL/h, 1.02 [95% CI, 1.01–1.04]). Patients in the highest risk quartiles (baseline volume >22.4 mL, growth rate >11.4 mL/h, diastolic blood pressure >95.0 mm Hg, and onset-to-treatment time ≤3.3 hours) had ≈50% to 60% absolute risk of HE with usual care. Numerically greater absolute risk reductions with andexanet (≈25%; number needed to treat: 4) were observed in the highest quartiles of baseline volume and growth rate. CONCLUSIONS: – Shorter onset-to-treatment time, larger baseline hematoma volume, higher diastolic blood pressure, and higher prescan hematoma growth rate predict HE but not thrombotic events in FXa inhibitor–associated intracerebral hemorrhage. Andexanet benefit is observed across these ranges and may be amplified through patient selection using these metrics. REGISTRATION: – URL: https://www.clinicaltrials.gov; Unique identifier: NCT03661528.