De Ritis Ratio and Heparin Therapy in Sepsis-Associated Liver Injury: A Multicenter Cohort Study

Sepsis-associated liver injury (SALI) is a highly heterogeneous thromboinflammatory disorder with no specific treatment. The De Ritis ratio (DRR, aspartate aminotransferase/alanine aminotransferase) stratifies mortality risk, and unfractionated heparin (UFH) possesses pleiotropic effects that may attenuate thromboinflammation. We investigated whether DRR identifies a SALI subphenotype that derives differential benefit from UFH therapy.

This retrospective multicenter cohort study included 9,561 SALI patients from the Medical Information Mart for Intensive Care IV (MIMIC-IV; n = 6,133) and eICU-CRD (n = 3,428) databases. The primary outcome was intensive care unit (ICU) mortality. We employed propensity score matching (PSM) and marginal structural Cox models (MSCM) to adjust for baseline and time-varying confounders. Subgroup analyses evaluated the association between UFH and mortality across DRR strata, with formal testing for UFH × DRR interaction.

UFH therapy was associated with significantly reduced ICU mortality after PSM in both cohorts MIMIC-IV (hazard ratio [HR]: 0.34, 95% confidence interval [CI]: 0.28-0.42) and eICU (HR: 0.43, 95% CI: 0.29-0.65), with consistent results in MSCM analyses (HR: 0.22, 95% CI: 0.17-0.30). Subgroup analysis suggested numerical benefit in patients with DRR > 1, but formal tests for interaction were not significant in either cohort (MIMIC-IV: p = 0.111; eICU: p = 0.775).

UFH therapy is associated with reduced mortality in SALI patients. Although DRR identifies a high-risk subgroup, the lack of significant interaction precludes its use as a predictive biomarker for UFH response. A prospective randomized trial is warranted to validate these findings and DRR-stratified UFH benefits.