Association of Biomarkers With Intracerebral Hematoma Expansion and Arterial Thromboembolic Events in Patients With Acute Intracranial Hemorrhage: The ANNEXA-I Biomarker Substudy

BACKGROUND: ANNEXA-I (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors) was a randomized trial that demonstrated that andexanet compared with usual care in patients with intracranial hemorrhage associated with FXa (factor Xa) inhibitor treatment reduces the risk of hematoma expansion and increases the risk of arterial thromboembolic events. METHODS: In a secondary analysis of the ANNEXA-I trial, we compared the effects of andexanet with usual care on change in anti-FXa activity and endogenous thrombin potential (ETP) using Wilcoxon rank-sum test. We examined the associations between 1-hour reduction in anti-FXa and 1-hour increase in ETP and hematoma expansion at 12 hours (≥12.5 mL or percentage volume change ≥35%) using logistic regression, both unadjusted and adjusted for time from symptom onset to baseline scan, baseline diastolic blood pressure, hematoma volume, baseline biomarker level and time from baseline scan to treatment, and association with arterial thromboembolic events (ischemic stroke, myocardial infarction, and systemic embolism) during 30 days of follow-up using Cox regression, both unadjusted and adjusted for age, baseline biomarker level, prior MI, and eligibility for treatment with high-dose andexanet. RESULTS: ANNEXA-I enrolled 530 patients. Among 438 patients with baseline anti-FXa results, andexanet compared with usual care reduced anti-FXa activity at 1 hour (median, 8.6 versus 97.5 ng/mL; median reduction from baseline, 98.3 versus 10.9 ng/mL; P <0.001). Among 328 patients with baseline ETP data, andexanet compared with usual care increased ETP at 1 hour (median, 1573.5 versus 874.5 nmol/L-min; median increase, 753.1 versus 126.6 nmol/L-min; P <0.001). In adjusted analyses, reduction in anti-FXa at 1 hour was associated with reduced hematoma expansion (per 100 ng/mL: odds ratio, 0.69 [95% CI, 0.53–0.92]; P =0.010), and increase in ETP at 1 hour was associated with reduced hematoma expansion (per 100 nmol/L-min: odds ratio, 0.94 [95% CI, 0.90–0.99]; P =0.019) and risk of thromboembolic events (per 100 nmol/L-min: odds ratio, 1.08 [95% CI, 1.00–1.16]; P =0.047). CONCLUSIONS: In patients with apixaban- or rivaroxaban-associated intracranial hemorrhage, andexanet compared with usual care produces greater reduction in anti-FXa and greater increase in ETP at 1 hour. Reduction in anti-FXa from baseline to 1 hour is independently associated with reduced hematoma expansion, and increase in ETP from baseline to 1 hour is independently associated with both reduced hematoma expansion and increase of thromboembolic events. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03661528.