Effectiveness of Nirmatrelvir/Ritonavir in Unvaccinated COVID-19 Patients Treated in the Emergency Department: A Retrospective Propensity-Matched Cohort Analysis

Background: Nirmatrelvir/Ritonavir (nir/rit) is an antiviral combination, often sold under the brand name Paxlovid, used to treat COVID-19, particularly in high-risk individuals. Numerous COVID-19 treatments exist, but clinical studies have reported conflicting data on their efficacy, particularly in unvaccinated patients. Objectives: This study aims to compare 28-day mortality, hospitalization, intensive care unit (ICU) admission, observation status, and hypoxia rates among unvaccinated COVID-19 patients treated with nir/rit in the emergency department (ED) versus those who did not receive nir/rit. Design: This retrospective, propensity-matched cohort study utilized the TriNetX database, which included records of 112 million patients from 64 academic medical centers and healthcare organizations across the U.S. The study period was 2022–2024. Methods: The treatment cohort consisted of COVID-19-unvaccinated ED patients aged 18 and above who tested positive for COVID-19 via RNA test and were administered nir/rit on the same day. Patients admitted for observation or inpatient care on the same day were excluded. Outcomes assessed within 28 days post-ED diagnosis included mortality, ICU admission, inpatient hospitalization, observation status, and hypoxia (O₂ saturation ≤90%). Propensity score matching adjusted for demographics and 21 pre-existing conditions associated with COVID-19 severity and mortality. Results: A total of 194 181 unvaccinated COVID-19 patients were identified, with 14 799 receiving nir/rit and 179 382 not receiving it. After propensity matching, 14 799 patients were included in each cohort. Paxlovid treatment was associated with lower mortality (risk ratios [RR] = 0.28, P < .001), fewer ICU admissions (RR = 0.53, P = .01), decreased inpatient visits (RR = 0.40, P < .001), reduced observation status (RR = 0.36, P = .004), and less hypoxia (RR = 0.49, P < .001). Trends were similar before propensity matching. Conclusions: Nir/rit treatment in unvaccinated adults diagnosed with COVID-19 in the ED is associated with significantly lower mortality, ICU admissions, hospitalizations, observation status, and hypoxia, supporting its use in this patient population.