Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage

Abstract

Background/Objective: There are limited data on the risks and benefits of using andexanet alfa (AA) in comparison with four-factor prothrombin complex concentrate (4F-PCC) to reverse factor Xa inhibitors (FXi) associated intracranial hemorrhage (ICH). We sought to describe our experience with AA or 4F-PCC in patients with oral FXi-related traumatic and spontaneous ICH. Methods:We conducted a retrospective review of consecutive adult patients with FXi-related ICH who received AA or 4F-PCC. FXi-related ICH cases included traumatic and spontaneous intracranial hemorrhages. Our primary analysis evaluated ICH stability on head computed tomography scan (CT), defined as a similar amount of blood from the initial scan at the onset of ICH to subsequent scans, at 6-h and 24-h post-administration of AA or 4F-PCC. For the subset of spontaneous intraparenchymal hemorrhages, volume was measured at 6-h and 24-h post-reversal. In secondary analyses, we evaluated good functional outcome at discharge, defined as a Modified Rankin Score of less than 3, and the incidence of thrombotic events after AA or 4F-PCC adminstration, during hospitalization.Results: A total of 44 patients (16 traumatic and 28 spontaneous ICH) with median age of 79 years [72-86], 36% females, with a FXi-related ICH, were included in this study. The majority of spontaneous ICHs were intraparenchymal 19 (68%). Twenty-eight patients (64%) received AA and 16 patients (36%) received 4F-PCC. There was no difference between AA and 4F-PCC in terms of CT stability at 6 h (21 [78%] vs 10 [71%], p = 0.71) and 24 h (15 [88%] vs 6 [60%], p = 0.15). In a subgroup of patients with spontaneous intraparenchymal hemorrhage, there was no difference in the degree of achieved hemostasis based on hematoma volume between AA and 4F-PCC at 6 h (9.3 mL [6.9-26.4] vs 10 mL [9.4-22.1], adjusted p = 0. 997) and 24-h (9.2 mL [6.1-18.8] vs 9.9 [9.4-21.1], adjusted p = 1). The number of patients with good outcome based on mRS on discharge were 10 (36%) and 6 (38%) in the AA and 4F-PCC groups, respectively (adjusted p = 0.81). The incidence of thromboembolic events was similar in the AA and 4F-PCC groups (2 [7%] vs 0, p = 0.53). Conclusion:In this limited sample of patients, we found no difference in neuroimaging stability, functional outcome and thrombotic events when comparing AA and 4F-PCC in patients with FXi-related ICH. Since our analysis is likely underpowered, a multi-center collaborative network devoted to this question is warranted.

Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding

“…5,29,30 Irrespective of these recommendations there is currently limited evidence comparing the 2 agents. 15,[31][32][33] Therefore, the aim of this retrospective cohort is to compare hemostatic efficacy and safety outcomes between andexanet alfa and 4F-PCC for reversal of FXa-inhibitor-related bleeding.…”

Efficacy and Safety of Andexanet Alfa for Bleeding Caused by Factor Xa Inhibitors: A Systematic Review and Meta-Analysis

“…In contrast, the overall mortality rate in a recent 4F-PCC meta-analysis in FXa inhibitor bleeding was 18% compared to 12.13% in our analysis and 14% in the ANNEXA-4 trial [ 27 ]. The studies done by Ammar et al and Barra et al showed a higher mortality rate of 39% and 22% respectively which is higher than that of other studies as these studies included only ICH patients [ 17 , 18 ]. Mortality was also significant in a study done by Culbreth (40%) as 14 out of 15 patients had ICH.…”

“…Only the Connolly et al study had more incidence of stroke (14) than DVT (13) [ 21 ]. Ammar et al reported no thrombotic event in the 4F-PCC group, while one event was reported in the Barra et al study, which is fewer than that reported in the AA group [ 17 , 18 ]. Restarting anticoagulation showed a significant decrease of thrombotic events in studies by Connolly et al and Stevens et al [ 21 , 26 ].…”

“…Mortality was also significant in a study done by Culbreth (40%) as 14 out of 15 patients had ICH. The Ammar et al study showed a similar mortality rate in the andexanet group and 4F-PCC group (39% and 38% respectively) while the Barra et al study showed higher mortality in the 4F-PCC group (63.6%) than in andexanet receiving patients (22.2%) [ 17 , 18 ]. Patients in the 4F-PCC group in the Barra et al study had lower baseline GCS and higher baseline hematoma volume which might have contributed to the higher mortality [ 18 ].…”

Management of Coagulopathy in Bleeding Patients

“…Low-dose 4F-PCC was successfully used to manage DOAC-associated ICH in 94.7% of treated patients [ 66 ]. A retrospective analysis of adult patients with FXa inhibitor-related ICH receiving andexanet alfa or 4F-PCC reported no difference in functional outcome or thrombotic events between the two groups [ 67 ]. In another retrospective study of FXa-associated ICH, excellent or good haemostatic efficacy was observed in 16/18 (89%) patients treated with andexanet alfa, compared with 6/10 (60%) patients treated with 4F-PCC [ 68 ].…”