Target trial emulation of early acetaminophen use and mortality in critically ill stroke patients.

The role of acetaminophen in managing critically ill patients with acute ischemic stroke (AIS) is debated. While it is commonly used for fever and pain, its direct impact on mortality in the intensive care unit (ICU) setting is unclear. This study aims to estimate the causal effect of early acetaminophen administration on mortality in critically ill adults with AIS. This study employed a target trial using retrospective data from the MIMIC-IV database (2008–2019, 1779 patients) and an external validation cohort in the eICU database (1182 patients). We compared acetaminophen (ACE) use within 48 h of ICU admission with non-ACE use within 48 h and used clone-censor-weight methods for the main analysis. The primary outcomes were 30-day and 90-day all-cause mortality. Furthermore, the findings were substantiated by sensitivity analyses, competing risk models, and subgroup analyses. In the primary CCW-weighted analysis, early acetaminophen administration was associated with a statistically significant reduction in 90-day all-cause mortality (HR, 0.70; 95% CI 0.58–0.84; P < 0.001). Similarly, the 30-day mortality risk was significantly lower in the ACE group (HR, 0.66; 95% CI 0.54–0.81). Early acetaminophen administration was associated with reduced mortality in critically ill AIS patients, particularly those without diabetes. Despite the variability in external validation, these findings suggest a phenotype-specific survival benefit warranting confirmation in precision-based randomized trials.