Low-Dose Aspirin Linked to Lower Early Mortality in Sepsis Patients, but Causality Remains Uncertain

Adults with sepsis who received documented low-dose aspirin during their intensive care unit stay showed lower early mortality in a large retrospective analysis, but the researchers behind the study caution that the association cannot be interpreted as a causal benefit. The study, based on the MIMIC-IV database of critical care records, included 31,888 adults meeting the Sepsis-3 definition and examined whether enteral aspirin administration of 75 to 100 milligrams was associated with 28-day restricted in-hospital and ICU mortality.

The research team defined a time zero, or T0, as the later of ICU admission or suspected infection, with sepsis ascertainment allowed to occur after that point. Using piecewise time-dependent Cox models, they found that eligible aspirin administration was recorded at or after T0 for 4,771 patients, including 3,646 within the first 24 hours. Adjusted in-hospital mortality hazard ratios were 0.48 (95% confidence interval 0.31–0.75) during the first 0 to 24 hours and 0.63 (0.51–0.78) during 24 to 72 hours, with no clear associations in later intervals. ICU mortality estimates were similar.

A central methodological concern involved how baseline illness severity was measured. Qualifying sequential organ failure assessment, or SOFA, scores occurred after T0 in 24,916 of the patients, meaning their baseline severity was established after the reference time. When the analysis was restricted to the 6,972 patients whose qualifying SOFA scores were recorded by T0, the hazard ratios in the first two intervals were 0.54 (0.28–1.03) and 0.62 (0.44–0.88), broadly consistent with the primary findings though with wider uncertainty in the earliest window.

To address time-varying confounding, the investigators also fitted a continuous-time marginal structural model incorporating lagged clinical information. This model showed residual imbalance between groups, and its early estimates were sensitive to truncation. After multiple imputation of missing data, the first two in-hospital hazard ratios were 0.50 (0.32–0.79) and 0.66 (0.53–0.82), closely matching the primary estimates and suggesting the overall pattern was not driven solely by missing values.

The study also evaluated early safety outcomes using modified Poisson models. A hemoglobin decline of at least 2 grams per deciliter during the first 72 hours was associated with early aspirin administration, with an adjusted risk ratio of 1.10 (1.03–1.17). However, the temporality of this signal was questionable: 606 early aspirin recipients had a qualifying hemoglobin decline recorded before their first documented dose. When the analysis was restricted to the 24-to-72-hour window to respect temporality, no clear association remained, with a risk ratio of 1.05 (0.91–1.21).

Sensitivity analyses examined exposure history, eligibility timing, and a 24-hour matched landmark cohort, reflecting the authors’ concern that apparent benefits may reflect treatment timing and clinical selection rather than a drug effect. Patients who receive aspirin promptly after admission may differ systematically from those who do not, in ways that recorded variables cannot fully capture.

The authors conclude that documented aspirin administration was associated with lower early restricted mortality in this cohort, but they explicitly state that retrospective eligibility, residual confounding, and uncertain prior aspirin exposure prevent causal interpretation. Importantly, they note that these findings do not justify initiating aspirin solely for the treatment of sepsis.

For clinicians and researchers, the message is twofold. Until randomized evidence exists, aspirin should not be started in sepsis patients on the basis of this retrospective database study alone.

Subject of Research: Retrospective cohort analysis of low-dose aspirin administration and early mortality outcomes in adults with sepsis

Article Title: Time-dependent associations of documented low-dose aspirin administration with 28-day mortality and early safety outcomes in adults with sepsis: a MIMIC-IV cohort study

Article References: Hu, C., Cheng, D., & Hu, S. (2026). Time-dependent associations of documented low-dose aspirin administration with 28-day mortality and early safety outcomes in adults with sepsis: a MIMIC-IV cohort study. Frontiers in Medicine, 13, Article 1940916. https://doi.org/10.3389/fmed.2026.1940916

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.1940916

Keywords: aspirin, sepsis, MIMIC-IV, mortality, critical care, observational study, confounding, SOFA score, marginal structural model, hemoglobin, ICU, time-dependent analysis