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

Background: Direct oral anticoagulants are activated factor (F)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 vs standard of care for reversing FXa inhibitor-induced intracranial hemorrhage. Methods: Random-effects meta-analysis. Ovid Medline, EMBASE, and CINAHL were searched from inception until February 1, 2025. Primary outcomes included hemostatic efficacy, thrombotic events, and mortality. Subgroup analyses isolated studies using 4-factor prothrombin complex concentrate as standard of care and the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) trial's definitions of hemostatic efficacy. Results: A total of 3039 studies were identified, with 23 studies (1 randomized controlled trial, 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, 1.2, 2.36; P = .003; I ² = 0%) favoring andexanet alfa over standard of care. Thirteen studies reported thrombotic events, with a pooled odds ratio of 0.97 (95% CI, 0.59, 1.60; P = .90; I ² = 0%). Thirteen studies assessed mortality, noting a pooled odds ratio of 0.69 (95% CI, 0.50, 0.96; P = .03; I ² = 27%) favoring the andexanet alfa group. Published randomized controlled trials showed similar hemostatic improvements but no mortality benefit and a higher rate of thrombotic events. Conclusion: Our meta-analysis found low-certainty evidence supporting improved hemostatic efficacy with andexanet alfa compared with 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.