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 < 90%, respiratory rate > 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.