A meta-analysis of high-dose versus low-dose 4-factor prothrombin complex concentrate for reversal of factor Xa inhibitor-associated intracerebral hemorrhage

Abstract

Abstract Background Four-factor prothrombin complex concentrate (4FPCC) are often used off-label for treating factor Xa inhibitor-associated major bleeding, including intracerebral hemorrhage (ICH). In addition to debate over 4FPCC’s effectiveness and safety compared with specific reversal agents, questions regarding the optimal 4FPCC dose remain. Purpose To evaluate the comparative effectiveness of high-dose versus low-dose 4FPCC for management of factor Xa inhibitor-associated ICH. Methods A systematic literature search of electronic databases (PubMed, Embase, and Cochrane) was conducted through January 31, 2023, to identify studies comparing high-dose versus low-dose 4FPCC for reversal of factor Xa inhibitors in individuals with an ICH. The outcomes of interest were hemostatic effectiveness (as defined by the individual study) and thromboembolism. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) individual study comparisons of high- and low-dose 4FPCC were pooled using a random-effects model. Studies were stratified according to whether multivariable adjusted analyses were performed. Results Six studies with a total of 447 individuals (high-dose = 254, low-dose = 193) were included. Definition of high-dose 4FPCC included ≥ 30 IU/kg (n=1), ≥ 35 IU/kg (n=3), and 50 IU/kg (n=2). Definition of low-dose 4FPCC 25 IU/kg (n=2), < 30 IU/kg (n=1), and <35 IU/kg (n=3). The overall pooled proportion of hemostatic effectiveness for 4FPCC was 81.4% (95% CI 77.6 to 84.8%) with no evidence of a difference between those receiving high-dose versus low-dose 4FPCC (OR 1.36, 95% CI 0.57-3.28; Figure). In five studies, the pooled proportion of individuals who developed a thrombosis after receiving 4FPCC was 3.1% (95% CI 0 to 15.7%) with no evidence of a difference in odds between high-dose and low-dose (OR 1.23, 95% CI 0.56 to 2.72). Conclusion Evidence from mostly small single-center retrospective cohort studies suggests that using high-dose 4FPCC for reversal of factor Xa inhibitor-associated ICH is not associated with differences in the odds of hemostatic effectiveness or thrombosis when compared to the low-dose.Figure.Results of Meta-Analysis