Abstract Body: Background: Andexanet reverses the anticoagulant effect of factor Xa (FXa) inhibitors and thereby also enhances thrombin generation. Prothrombin complex concentrates (PCC) are clotting factor concentrates that enhance thrombin generation. Andexanet prevented hematoma expansion (HE) but increased the rate of arterial thromboembolic events (ATE) compared to usual care in the ANNEXa-I trial. We examined the association between change from baseline to 1 hour in anti-FXa level and endogenous thrombin potential (ETP) and outcome in patients with apixaban- or rivaroxaban-associated intracerebral hemorrhage (ICH).
Methods: We compared the effects of andexanet with usual care on change in biomarker levels between baseline and 1 hour using Wilcoxon rank sum test. In separate analyses, we examined the association between 1-hour reduction in anti-FXa and 1-hour increase in ETP and HE at 12 hours using logistic regression, and the association with ATE during 30 days of follow-up using Cox regression. Analyses were adjusted for previously reported baseline predictors of HE and ATE, respectively.
Results: Among 438 patients with acute FXa inhibitor-associated ICH who had available baseline anti-FXa results, andexanet compared with usual care (89.1% received PCC, median dose 41 units/kg) reduced anti-FXa levels at 1 hour (median levels at 1 hour: 8.6 vs 97.5 ng/mL; absolute reduction 98.3 vs 10.9 ng/mL, p<0.001). Among the 328 patients who had available baseline ETP results, andexanet compared with usual care increased ETP at 1 hour (median levels at 1 hour: 1573.5 vs 874.5 nM-min, absolute increase 753.1 vs 126.6 nM-min, p<0.001). After adjusting for time from symptom onset to baseline scan; baseline diastolic blood pressure, hematoma volume, and biomarker level; and time from baseline scan to treatment, reduction in anti-FXa and increase in ETP at 1 hour were independently associated with reduced odds of HE (per 100 ng/mL: OR 0.69, 95% CI 0.53-0.92, p=0.010 and per 100 nM-min: OR 0.94, 95% CI 0.90-0.99, p=0.019, respectively). Twenty-seven patients experienced ATE during 30 days of follow up. Neither reduction in anti-FXa nor increase in ETP was associated with ATE.
Conclusion: In patients with factor Xa inhibitor-associated ICH, andexanet compared with usual care produces greater reduction in anti-FXa and greater increase in ETP at 1 hour. Both reduction in anti-FXa and increase in ETP between baseline and 1 hour are independent predictors of HE but do not predict ATE.