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.

Plain Language Summary Title

Nir/rit linked to better outcomes in unvaccinated COVID-19 patients treated in the emergency room.

Plain Language Summary

Aims and Purpose: This study looked at whether nir/rit, a pill used to treat COVID-19, improves outcomes of unvaccinated adults who test positive for COVID-19 in the emergency department. Nir/rit combines two drugs that help stop the virus from multiplying. Although this medicine has shown promise in some studies, others have found mixed results, especially in people who haven’t received a COVID-19 vaccine.

Methods and Research Design: We used a large U.S. health database containing medical records from over 100 million people. This study compared two groups of unvaccinated adults who had COVID-19 and went to the emergency room between 2022 and 2024. One group received nir/rit, while the other group did not. The study included only patients who were not admitted to the hospital right away. The researchers matched patients in both groups to make them similar in terms of age, health conditions, and other factors that could affect outcomes.

Result: We then looked at what happened to these patients over the next 28 days. We found that people who received nir/rit were less likely to die, be admitted to the intensive care unit (ICU), stay in the hospital, require monitoring, or experience dangerously low oxygen levels.

Importance: The results suggest that nir/rit may be strongly linked to reduced severity of outcomes in this group. These findings are important because unvaccinated people remain at a higher risk of serious illness from COVID-19. Also, some patients might not have access to the medication due to cost or other barriers. Still, these results support the use of nir/rit in unvaccinated adults seen in the emergency department for COVID-19.