The Optimal Therapeutic Window for Nonbioartificial Liver Support in Acute‐On‐Chronic Liver Failure: A Meta‐Analysis and Meta‐Regression Based on Baseline MELD Score

ABSTRACT NBALS efficacy in ACLF remains controversial. We aimed to determine if a “therapeutic window” exists by stratifying clinical outcomes based on baseline Model for End‐Stage Liver Disease (MELD) scores. We searched PubMed, Embase, Cochrane Library, and Web of Science for RCTs and PSM‐cohorts comparing NBALS to standard medical therapy (SMT). Primary outcome was 28‐day mortality; MELD‐stratified subgroup analyses and random‐effects meta‐regression were performed. Eleven studies (comprising 12 datasets) involving 1958 patients (991 NBALS vs. 967 SMT) were included. Overall, NBALS significantly reduced 28‐day mortality compared with SMT (pooled RR 0.72, 95% CI [0.63–0.83], I 2  = 2.8%). Subgroup analysis suggested a clinical trend toward a distinct therapeutic window: the survival benefit was most significant in the Intermediate MELD group (25–30) (RR 0.65, 95% CI [0.52–0.81], I 2  = 0%) and the High MELD group (> 30) (RR 0.75, 95% CI [0.58–0.98], I 2  = 0%), while substantial uncertainty exists regarding the survival benefit in the Low MELD group (I 2  = 67.9%). Meta‐regression confirmed that the maximum survival benefit of NBALS is concentrated within a baseline MELD range of approximately 25 to 32. Furthermore, NBALS group achieved a significantly higher reduction in total bilirubin compared to SMT (pooled MD 98.15, 95% CI [66.50–129.79], I 2  = 99.2%). NBALS significantly improves short‐term survival in ACLF, suggesting a potential therapeutic window around a baseline MELD range of 25–32. Early stratification based on disease severity is crucial for optimizing NBALS application. Trial Registration: PROSPERO CRD420261334987.