Efficacy and Safety of Andexanet Alfa Versus Four Factor Prothrombin Complex Concentrate for Emergent Reversal of Factor Xa Inhibitor Associated Intracranial Hemorrhage: A Systematic Review and Meta-Analysis

Abstract

Factor Xa inhibitors (FXaI) are increasingly used for anticoagulation therapy, yet their association with intracranial hemorrhage poses a significant challenge. Although andexanet alfa (AA) and four-factor prothrombin complex concentrate (4F-PCC) have shown promise in reversing FXaI effects, their comparative efficacy and safety remain uncertain. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a literature search on electronic databases to obtain the relevant studies until May 16, 2024. Our primary outcomes were successful anticoagulation reversal, overall mortality (including 30-day and in-hospital mortality), and thromboembolic events. Secondary outcomes were length of hospital and intensive care unit stay and hematoma volume expansion. Data were pooled using a random-effects model. We included 16 eligible studies with a total of 2,977 patients. A statistically significant improvement in hemostatic efficacy rates was in favor of the AA group (risk ratio [RR] 1.10, 95% confidence interval [CI] 1.01-1.20, P = 0.02). Lower overall mortality rates were found in the AA group (RR 0.67, 95% CI 0.51-0.88, P = 0.004). However, no difference was found in 30-day mortality rates (RR 0.82, 95% CI 0.58-1.16, P = 0.26). In terms of thromboembolic events, more events were found in the AA group (RR 1.47, 95% CI 1.01-2.15, P = 0.046). AA was associated with a longer duration of hospital stay compared to 4F-PCC (mean difference [MD] 0.64, 95% CI 0.07-1.22, P = 0.03). Neither a significant difference in length of intensive care unit stay (MD 0.25, 95% CI - 0.36 to 0.86, P = 0.41) nor a significant difference in hematoma volume expansion was reported (MD - 0.89, 95% CI - 3.11 to 1.34, P = 0.435). Our results suggest that AA is superior to 4F-PCC in enhancing the hemostatic efficacy and reducing the overall and in-hospital mortality rates. More thromboembolic events are thought to be associated with the use of AA. However, more studies are required to validate whether the better results of AA in improving hemostatic efficacy are enough to make up for their higher cost and their possible risk of thromboembolic events.

Keywords: Andexanet alfa; Anticoagulants; Intracerebral hemorrhage; Prothrombin complex concentrates; Reversal agents.

Fig. 1

Prisma flow diagram of the included studies

Fig. 2

Forest plots of primary outcomes comparing andexanet alfa (AA) vs. four-factor prothrombin complex concentrate (4F-PCC). a Forest plot of successful anticoagulation reversal. b Forest plot of overall mortality, in-hospital mortality and 30-day mortality. c Forest plot of mortality after excluding study by Pham et al. (2022) [15] to resolve heterogeneity. d Forest plot of thromboembolic events

Fig. 2

Forest plots of primary outcomes comparing andexanet alfa (AA) vs. four-factor prothrombin complex concentrate (4F-PCC). a Forest plot of successful anticoagulation reversal. b Forest plot of overall mortality, in-hospital mortality and 30-day mortality. c Forest plot of mortality after excluding study by Pham et al. (2022) [15] to resolve heterogeneity. d Forest plot of thromboembolic events

Fig. 3

Forest plots of secondary outcomes comparing andexanet alfa (AA) vs. four-factor prothrombin complex concentrate (4F-PCC). a Forest plot of length of hospital stay. b Forest plot length of intensive care unit (ICU) admission. c Forest plot hematoma volume expansion. d Forest plot of good clinical outcome (modified Rankin scale [mRS] score ≤ 3 or Glasgow Outcome Scale [GOS] score > 3). e Forest plot of good clinical outcome (mRS score ≤ 3 or GOS score > 3) after exclusion of study by Barra et al. (2020) [29] to resolve heterogeneity