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 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.