Andexanet Alfa for the Management of Acute Major Bleeding Associated with FXa Inhibitors (P5.059)

Objective: This is an interim report of the Effects of FXA Inhibitors (ANNEXA-4) study designed to evaluate the use of andexanet in patients with acute major bleeding. Background: Factor Xa (FXa) inhibitors are effective, but the risk of major bleeding is a concern and no specific antidotes are available for reversal. Andexanet alfa has been developed as a specific reversal agent for FXa inhibitors. It has been shown to reverse the inhibition of FXa in healthy volunteers. Design/Methods: The interim report of this multicenter, prospective, open-label, single-group study included patients (safety population, n=67; efficacy population, n=47) who had acute major bleeding within 18 hours after taking FXa inhibitor (rivaroxaban or apixaban). Patients received andexanet bolus followed by a 2-hour infusion. Efficacy assessments included anti-FXa activity and clinical hemostatic efficacy (adjudicated by an independent committee) during a 12-hour period. All patients were followed for 30 days. Results: The mean age was 77 years; most patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. After andexanet bolus, the median anti-FXa activity decreased by 89% (95% confidence interval [CI], 58 to 94) among rivaroxaban patients, and by 93% (95% CI, 87 to 94) among apixaban patients; these levels were sustained during the 2-hour infusion. Twelve hours after andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 79% (37/47) patients (95% CI, 64 to 89). Thrombotic events occurred in 18% (12/67) patients during the 30-day follow-up. Anticoagulation was re-started in 18 patients (27%) by 30 days; therapeutic anticoagulation was re-started in 1 patient before a thrombotic event occurred. Conclusions: This descriptive preliminary analysis showed that andexanet substantially reduced anti-FXa activity in patients with acute major bleeding associated with FXa inhibitors, with effective hemostasis occurring in 79%. Thrombotic events occurred at rates consistent with the high risk profile of the patients. Study Supported by: Funded by Portola Pharmaceuticals; ANNEXA-4 Clinical Trials gov number, NCT02329327. Disclosure: Dr. Connolly has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals as a consultant. Dr. Milling has received personal compensation for activities with CSI Behring, Janssen, BI, and Portola. Dr. Eikelboom has nothing to disclose. Dr. Gibson has received personal compensation for activities with Portola Pharmaceuticals as a consultant and has been an investigator on clinical trials funded by Portola Pharmaceuticals. Dr. Curnutte has received personal compensation for activities with Portola as an employee. Dr. Gold has received personal compensation for activities with Portola as an employee. Dr. Lu has received personal compensation for activities with Portola as an employee. Dr. Conley has received personal compensation for activities with Portola as an employee. Dr. Verhamme has nothing to disclose. Dr. Schmidt has nothing to disclose. Dr. Middeldorp has nothing to disclose. Dr. Cohen has received personal compensation for activities with Portola as a consultant and investigator. Dr. Beyer-Westendorf has nothing to disclose. Dr. Albaladejo has nothing to disclose. Dr. Lopez-Sendon has nothing to disclose. Dr. Goodman has received personal compensation for activities with Portola as an employee. Dr. Leeds has received personal compensation for activities with Portola as an employee. Dr. Siegal has received personal compensation for activities with Portola as a consultant. Dr. Zotova has nothing to disclose. Dr. Nakamya has nothing to disclose. Dr. Lim has nothing to disclose. Dr. Crowther has received personal compensation for activities with Portola as a consultant.