Long‐Term Stroke and Mortality Risk Reduction Associated With Acute‐Phase Paxlovid Use in Mild‐to‐Moderate COVID‐19

This retrospective cohort study investigated whether Paxlovid (nirmatrelvir/ritonavir) use during the acute phase of mild-to-moderate COVID-19 reduces the risk of ischemic or hemorrhagic stroke occurring more than 3 months post-diagnosis, a condition classified as long COVID. Utilizing TriNetX electronic health records comprising 118 million patients in the United States, adults aged 18 years or older with confirmed COVID-19 diagnoses from 2022 to 2023 were categorized into Paxlovid (administered within 5 days of diagnosis) and non-Paxlovid groups. Exclusion criteria included prior cerebrovascular disease, mortality within 3 months, use of specific antivirals, and severe clinical conditions such as ICU admission, intubation, mechanical support, SpO₂ 30/min, sepsis, systemic inflammatory response syndrome, and acute respiratory distress syndrome. The index date was the initial COVID-19 diagnosis. Propensity score matching in a 1:1 ratio controlled for confounding factors, and stroke (ischemic or hemorrhagic) and mortality were analyzed using Kaplan-Meier survival curves and Cox proportional hazards models. Among 181 992 matched pairs, Paxlovid use was associated with a significantly reduced risk of ischemic and hemorrhagic stroke (hazard ratio HR 0.85; 95% confidence interval CI: 0.80-0.89) and all-cause mortality (HR 0.68; 95% CI: 0.63-0.73) during the long COVID period, defined as more than 90 days post-diagnosis. Subgroup analyses demonstrated consistent protective effects across age, sex, BMI, comorbidities such as hypertension, diabetes, and hyperlipidemia, and vaccination status. Notably, older adults (HR 0.81; 95% CI: 0.76-0.86) and individuals with metabolic conditions, including obesity (HR 0.86; 95% CI: 0.78-0.96), exhibited pronounced benefits, and the protective effects were observed irrespective of vaccination status. These findings highlight that Paxlovid use during the acute phase of COVID-19 significantly reduces the risk of long-term cerebrovascular events and mortality, emphasizing its critical role in mitigating long-term complications associated with COVID-19.