Importance Prior observational studies suggest that aspirin use may be associated with reduced mortality in high-risk hospitalized patients with COVID-19, but aspirin’s efficacy in patients with moderate COVID-19 is not well studied.

Objective To assess whether early aspirin use is associated with lower odds of in-hospital mortality in patients with moderate COVID-19.

Design, Setting, and Participants  Observational cohort study of 112 269 hospitalized patients with moderate COVID-19, enrolled from January 1, 2020, through September 10, 2021, at 64 health systems in the United States participating in the National Institute of Health’s National COVID Cohort Collaborative (N3C).

Exposure Aspirin use within the first day of hospitalization.

Main Outcome and Measures The primary outcome was 28-day in-hospital mortality, and secondary outcomes were pulmonary embolism and deep vein thrombosis. Odds of in-hospital mortality were calculated using marginal structural Cox and logistic regression models. Inverse probability of treatment weighting was used to reduce bias from confounding and balance characteristics between groups.

Results Among the 2 446 650 COVID-19–positive patients who were screened, 189 287 were hospitalized and 112 269 met study inclusion. For the full cohort, Median age was 63 years (IQR, 47-74 years); 16.1% of patients were African American, 3.8% were Asian, 52.7% were White, 5.0% were of other races and ethnicities, 22.4% were of unknown race and ethnicity. In-hospital mortality occurred in 10.9% of patients. After inverse probability treatment weighting, 28-day in-hospital mortality was significantly lower in those who received aspirin (10.2% vs 11.8 %). The rate of pulmonary embolism, but not deep vein thrombosis, was also significantly lower in patients who received aspirin (1.0% vs 1.4 %). Patients who received early aspirin did not have higher rates of gastrointestinal hemorrhage (0.8% aspirin vs 0.7% no aspirin), cerebral hemorrhage (0.6% aspirin vs 0.4% no aspirin), or blood transfusion (2.7% aspirin vs 2.3% no aspirin). The composite of hemorrhagic complications did not occur more often in those receiving aspirin (3.7% aspirin vs 3.2% no aspiri). Subgroups who appeared to benefit the most included patients older than 60 years and patients with comorbidities.

Conclusions and Relevance In this cohort study of US adults hospitalized with moderate COVID-19, early aspirin use was associated with lower odds of 28-day in-hospital mortality. A randomized clinical trial that includes diverse patients with moderate COVID-19 is warranted to adequately evaluate aspirin’s efficacy in patients with high-risk conditions.