Pre‐Infection COVID‐19 Vaccination and Long‐Term Cardiovascular Outcomes in Adults Without Preexisting Cardiovascular Disease: A Retrospective Cohort Study

Background Long‐term cardiovascular complications after COVID‐19 are increasingly recognized, yet the protective effect of pre‐infection vaccination in individuals without prior cardiovascular disease (CVD) remains unclear. This study examined the association between COVID‐19 vaccination and major cardiovascular and related outcomes up to 3 years post‐infection in adults without preexisting CVD. Methods In this retrospective cohort analysis using the TriNetX US Collaborative Network, adults (≥ 18 years) diagnosed with COVID‐19 from March 1, 2020, to December 31, 2023, without prior CVD were identified. Patients who received ≥ 1 vaccine dose before diagnosis were 1:1 propensity score–matched (caliper 0.1) to unvaccinated patients on 90 covariates, including demographics, comorbidities, medications, and laboratory values. Outcomes were assessed at one and 3 years. Risk ratios (RRs) with 95% confidence intervals (CIs) and p ‐values were calculated. Results After 1:1 propensity score matching, 55,752 patients were included in each cohort for the 1‐year analysis and 55,622 patients per cohort for the 3‐year analysis. Vaccination was associated with lower risk of the primary composite outcome at 1 year (RR, 0.21; 95% CI, 0.17–0.27; p < 0.001). Significant reductions were observed at 1 year for cerebrovascular disease (RR, 0.35; 95% CI, 0.27–0.46; p < 0.001), circulatory system diseases (RR, 0.52; 95% CI, 0.50–0.55; p < 0.001), and all‐cause mortality (RR, 0.20; 95% CI, 0.15–0.26; p < 0.001). Protective effects persisted at 3 years for cerebrovascular disease (RR, 0.71; 95% CI, 0.61–0.82; p < 0.001) and circulatory system diseases (RR, 0.82; 95% CI, 0.80–0.85; p < 0.001). Conclusions Pre‐infection COVID‐19 vaccination was associated with sustained reductions in major cardiovascular events, mortality, and healthcare utilization up to 3 years post‐infection in adults without prior CVD.