Andexanet alfa vs standard of care for factor Xa inhibitor-induced intracranial hemorrhage—a systematic review and meta-analysis

Background Direct oral anticoagulants (DOACs) are activated factor X (FXa) or thrombin inhibitors. Patients on FXa inhibitors are at increased risk for major bleeding events that require anticoagulation reversal. Andexanet alfa is a FXa inhibitor reversal agent, potentially offering better efficacy compared to standard of care options. Objectives To conduct a systematic review and meta-analysis comparing the efficacy and safety of Andexanet alfa versus standard of care for reversing FXa inhibitorinduced ICH. Methods Random-effects meta-analysis. Ovid Medline, EMBASE, and CINAHL were searched from inception until February 1 st , 2025. Primary outcomes included hemostatic efficacy, thrombotic events, and mortality. Subgroup analyses isolated studies using 4F-PCC as standard-of-care and ANNEXA-4 definitions of hemostatic efficacy. Results 3039 studies were identified, with 23 studies (1 RCT, 452 participants; 22 nonrandomized, 4085 participants) included in the final analysis. Thirteen studies assessed hemostatic efficacy, with a pooled odds ratio of 1.68 (95%CI 1.20-2.36, p=0.003, I 2 =0%) favoring Andexanet over standard of care. Thirteen studies reported thrombotic events, with a pooled odds ratio of 0.97 (95%CI 0.59-1.60, p=0.90, I 2 =0%). Thirteen studies assessed mortality, noted a pooled OR of 0.69 (95%CI 0.50-0.96, p=0.03, I 2 =27%) favoring the Andexanet group. Published RCTs showed similar hemostatic improvements but no mortality benefit and a higher rate of thrombotic events. Conclusions Our meta-analysis found low-certainty evidence supporting improved hemostatic efficacy with Andexanet alfa compared to standard-of-care, with a decrease in mortality and no effect on thrombotic complications. Further randomized data is required to establish a conclusive clinical benefit favoring Andexanet alfa.