Background: We applied a target trial emulation framework to estimate the association between early and delayed initiation of remdesivir (RDV) with mortality in hospitalized adults between May 1, 2020, and July 31, 2024, with varying coronavirus disease 2019 (COVID-19) clinical severity.

Methods: Using electronic health records in the National COVID Cohort Collaborative (N3C) database, we emulated a sequence of randomized target trials initiated on each of the first 7 days of hospitalization. We identified 373 226 eligible person-trial hospitalizations, of which 53 959 were initiators and 319 267 were noninitiators of RDV treatment. Patients were divided into clinical severity subgroups based on baseline oxygenation, which included no supplemental oxygen (NSO), noninvasive supplemental oxygen (NISO), or invasive ventilation (IV). In each trial, initiators were matched with replacement to noninitiators receiving the same oxygenation type. Trials beginning on days 1-3 and days 4-7 of hospitalization were pooled separately to evaluate the effects of early and delayed initiation of RDV, respectively. Cox proportional hazards regression was used to estimate the marginal hazard ratio for mortality between initiators and noninitiators within each treatment delay.

Results: Across trials, 53 449 initiators were matched to 26 600 unique noninitiators. Early, but not delayed, RDV treatment was associated with a reduction in 60-day mortality in the NSO (hazard ratio [HR], 0.89; 95% CI, 0.84-0.95) and NISO subgroups (HR, 0.91; 95% CI, 0.84-0.99), but not in those receiving IV. Results were consistent across sensitivity analyses.

Conclusions: Early treatment with RDV is associated with reduced mortality risk in hospitalized COVID-19 patients either not on supplemental oxygen or receiving noninvasive supplemental oxygen.