Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding: A Systematic Review and Meta-Analysis

Abstract

OBJECTIVES: To combine evidence on andexanet alfa and prothrombin complex concentrates for factor Xa inhibitor-associated bleeding to guide clinicians on reversal strategies. DATA SOURCES: Embase, Pubmed, Web of Science, and the Cochrane Library. STUDY SELECTION: Observational studies and randomized clinical trials studying hemostatic effectiveness of andexanet alfa or prothrombin complex concentrate for acute reversal of factor Xa inhibitor-associated hemorrhage. DATA EXTRACTION: Two independent reviewers extracted the data from the studies. Visualization and comparison of hemostatic effectiveness using Sarode et al or International Society of Thrombosis and Hemostasis Scientific and Standardization Committee criteria at 12 and 24 hours, (venous) thrombotic event rates, and inhospital mortality were performed by constructing Forest plots. Exploratory analysis using a logistic mixed model analysis was performed to identify factors associated with effectiveness and venous thromboembolic event. DATA SYNTHESIS: A total of 21 studies were included (andexanet: 438 patients; prothrombin complex concentrate: 1,278 patients). The (weighted) mean effectiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours. The (weighted) mean effectiveness for prothrombin complex concentrate was 88% at 12 hours and 76% at 24 hours. The mean 30-day symptomatic venous thromboembolic event rates were 5.0% for andexanet alfa and 1.9% for prothrombin complex concentrate. The mean 30-day total thrombotic event rates for andexanet alfa and prothrombin complex concentrate were 10.7% and 3.1%, respectively. Mean inhospital mortality was 23.3% for andexanet versus 15.8% for prothrombin complex concentrate. Exploratory analysis controlling for potential confounders did not demonstrate significant differences between both reversal agents. CONCLUSIONS: Currently, available evidence does not unequivocally support the clinical effectiveness of andexanet alfa or prothrombin complex concentrate to reverse factor Xa inhibitor-associated acute major bleeding, nor does it permit conventional meta-analysis of potential superiority. Neither reversal agent was significantly associated with increased effectiveness or a higher rate of venous thromboembolic event. These results underscore the importance of randomized controlled trials comparing the two reversal agents and may provide guidance in designing institutional guidelines.

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

“…In this retrospective cohort study, there was no statistically significant difference in the achievement of effective hemostasis at 12 h between andexanet alfa and 4F-PCC for FXa-inhibitor-related bleeding. Though some study definitions differ, in general, these rates are within the ranges of effective hemostasis seen in previously published reports, which range from 47.6% to 90.9% for andexanet alfa, 8,[10][11][12]15,38 and 60% to 94.7% for 4F-PCC. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]38 A recent meta-analysis of realworld use estimated weighted mean effectiveness of 82% and 88% at 12 h for andexanet alfa and 4F-PCC, respectively.…”

“…Though some study definitions differ, in general, these rates are within the ranges of effective hemostasis seen in previously published reports, which range from 47.6% to 90.9% for andexanet alfa, 8,[10][11][12]15,38 and 60% to 94.7% for 4F-PCC. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]38 A recent meta-analysis of realworld use estimated weighted mean effectiveness of 82% and 88% at 12 h for andexanet alfa and 4F-PCC, respectively. 38 When looking exclusively at patients with an ICH, andexanet alfa, although lower, was not statically different in achievement of effective hemostasis compared to 4F-PCC in our cohort.…”

“…[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]38 A recent meta-analysis of realworld use estimated weighted mean effectiveness of 82% and 88% at 12 h for andexanet alfa and 4F-PCC, respectively. 38 When looking exclusively at patients with an ICH, andexanet alfa, although lower, was not statically different in achievement of effective hemostasis compared to 4F-PCC in our cohort. This contrasts with estimates from a retrospective study by Barra et al who reported a numerically higher incidence of excellent or good hemostasis with andexanet alfa compared to 4F-PCC for ICH (88.9% vs 60%, respectively).…”

“…The aforementioned metaanalysis evaluated patients with ICH at 12 and 24 h. The estimated mean hemostatic effectiveness was 57% and 89% with andexanet alfa and 88% and 73% for 4F-PCC, respectively. 38 In ICH, a low GCS is a poor prognostic factor. 39,40 Barra et al reported median GCS scores of 15 and 10 for andexanet alfa and 4F-PCC, respectively.…”

“…Previously reported rates of thrombotic events range 0% to 19% for andexanet alfa 8,[10][11][12]15,38,43,44 and 0 to 12.9% for 4F-PCC. [14][15][16][17][18][20][21][22][23][24][25][26][27][28]38,[45][46][47] Numerically more patients in the andexanet alfa cohort had venous thromboembolism (VTE) indication for FXa inhibitor use compared to 4F-PCC in our cohort. Those who received andexanet alfa with a baseline VTE indication had a 40% (2 of 5) incidence of new thrombosis development.…”