Association of prophylactic heparin therapy and outcomes in critically ill patients with sepsis-induced coagulopathy: A marginal structural Cox model cohort study

Abstract BackgroundSepsis-induced coagulopathy (SIC) is defined as infection-induced organ dysfunction and coagulopathy. Although anticoagulation with heparin has been widely used in practice, its effectiveness for treating SIC remains controversial. This study aimed to investigate whether prophylactic heparin administration would provide a survival advantage for patients with SIC.Methods Patients with SIC were identified from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was ICU mortality, and the secondary outcomes were 7-day, 14-day, and 28-day mortality as well as hospital mortality. A Cox proportional hazards model and propensity score matching (PSM) were used to account for baseline differences in the probability of using prophylactic heparin. The marginal structural Cox model (MSCM) was employed to adjust for both baseline and time-varying confounding factors. E-value analysis was used for unmeasured confounding.Results A total of 6498 septic patients with SIC were enrolled in the study, with 1284 in the heparin group and 5124 in the nonheparin group. There was no significant effect on ICU mortality in the overall population (prematched, hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.77-1.14, P=0.517, postmatched, HR 0.89, 95% CI 0.70-1.12, P=0.323). Interestingly, the MSCM identified a significant effect on ICU mortality in the overall population (HR 0.77, 95% CI 0.60-0.98, P=0.032). Stratification analysis with the MSCM showed that prophylactic heparin administration was associated with decreased ICU mortality only among patients with a SIC score of 4 (HR 0.63, 95% CI 0.45-0.89, P=0.009). Similar results were replicated with PSM only for patients with a SIC score of 4 (ICU mortality HR 0.68, 95% CI 0.49-0.95, P=0.025; 7-day mortality HR 0.59, 95% CI 0.36-0.98, P=0.040; 14-day mortality HR 0.66, 95% CI 0.44-0.98, P=0.040; Hospital mortality HR 0.77, 95% CI 0.58-1.03, P=0.074; 28-day mortality HR 0.77, 95% CI 0.54-1.10, P=0.147). E-value analysis indicated robustness to unmeasured confounding.Conclusions: Prophylactic heparin administration to patients with a SIC score of 4 appears to be associated with improved survival outcomes, including ICU mortality and 7-day and 14-day mortality, but not with improvement in hospital or 28-day mortality. These results need to be verified in prospective randomized controlled trials.