Alexander J. Preiss Xuya Xiao M. Daniel Brannock G. Caleb Alexander Robert F. Chew Megan Fitzgerald Elaine Hill Elizabeth P. Kelly Hemalkumar B. Mehta Charisse Madlock-Brown Kenneth J. Wilkins Christopher G. Chute Melissa Haendel Richard Moffitt Emily R. Pfaff
Nirmatrelvir with ritonavir (Paxlovid) is indicated for patients with Coronavirus Disease 2019 (COVID-19) who are at risk for progression to severe disease due to the presence of one or more risk factors. Millions of treatment courses have been prescribed in the United States alone. Paxlovid was highly effective at preventing hospitalization and death in clinical trials. Several studies have found a protective association in real-world data, but they variously used less recent study periods, correlational methods, and small, local cohorts. Their estimates also varied widely. The real-world effectiveness of Paxlovid remains uncertain, and it is unknown whether its effect is homogeneous across demographic strata. This study leverages electronic health record data in the National COVID Cohort Collaborative’s (N3C) repository to investigate disparities in Paxlovid treatment and to emulate a target trial assessing its effectiveness in reducing severe COVID-19 outcomes. Using a cohort of 703,647 patients with COVID-19 seen at 34 clinical sites across the United States between April 1, 2022 and August 28, 2023, we used the clone-censor-weight technique with inverse probability of censoring weights to balance covariates including demographics, comorbidities, and healthcare factors. We estimated that Paxlovid reduced hospitalization risk by 39% (95% confidence interval [CI] [36%, 41%]) and death risk by 61% (95% CI [55%, 67%]). Absolute risk reductions were similar between vaccinated and unvaccinated patients but greater among those aged 65+ years. We observed treatment disparities, with lower rates among black and Hispanic or Latino patients and within socially vulnerable communities. While this study’s main limitation is potential unmeasured confounding in observational data, our findings demonstrate Paxlovid’s real-world effectiveness at preventing severe outcomes, particularly in older patients, even in the Omicron era. However, disparities in treatment rates suggest its benefits are not equitably distributed.