Predictors of Thrombotic Events and Mortality in Patients Treated With Andexanet: A Pooled Analysis

BACKGROUND: Andexanet reduces hematoma expansion compared with usual care for acute FXa (factor Xa) inhibitor-associated intracerebral hemorrhage but is associated with a risk of thrombotic events (TE). We pooled data from andexanet-treated trial participants to determine baseline predictors of TE. METHODS: Secondary analyses of andexanet-treated participants in ANNEXA-I (Andexanet Alfa, a Novel Antidote to the Anticoagulant Effects of Factor Xa Inhibitors in ICH) and ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors), which included adults with acute life-threatening hemorrhage on FXa inhibitors. Stratified Cox proportional hazards models were used to examine associations between baseline variables and arterial or all TE and mortality. A stratified Cox regression model with arterial events as time-dependent covariates was used to examine associations of arterial events with mortality, adjusted for clinical covariates. RESULTS: Of 741 participants (mean age, 78.5 years; 54.5% male), 593 (80.0%) had intracranial hemorrhage and 109 (14.7%) had gastrointestinal hemorrhage. Seventy-seven (10.4%) participants had ≥1 TE, and 147 (19.8%) died. Arterial and venous thromboembolism events occurred a median of 3.5 days (interquartile range, 2.0-12.0) and 14.0 days (interquartile range, 10.0-20.0), respectively, after randomization. No baseline factors were associated with all TE. Arterial TE were associated with prior myocardial infarction (hazard ratio [HR], 2.64 [95% CI, 1.33-5.26]), high-dose eligibility (HR, 2.44 [95% CI, 1.33-4.48]), female sex (HR, 1.78 [95% CI, 1.00-3.16]), and age (HR per year, 1.04 [95% CI, 1.00-1.08]). Mortality was associated with arterial TE (HR, 2.68 [95% CI, 1.64-4.36]), prior congestive heart failure (HR, 2.53 [95% CI, 1.76-3.63]), intracerebral hemorrhage or intraventricular hemorrhage (HR, 1.90 [95% CI, 1.20-3.01]), and age (HR per year, 1.06 [95% CI, 1.03-1.08]). The initiation of anticoagulation after randomization was associated with a reduction in TE. CONCLUSIONS: In FXa inhibitor-associated hemorrhage treated with andexanet, baseline factors are associated with arterial TE and can be used to inform treatment decisions. Initiation of anticoagulation reduces the occurrence of TE. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02313909. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.