COVID-19 vaccination confers long-term cardioprotection against post-COVID cardiovascular disease: >5-year evidence from causal mediation and target trial emulation

Background COVID-19 vaccination has been shown to reduce the risk of long COVID, but its role in preventing major post-COVID cardiovascular disease (CVD), particularly when administered before or after SARS-CoV-2 infection, remains unclear. Purpose To evaluate whether pre- and post-infection COVID-19 vaccination reduces the risk of post-COVID CVD and whether protection varies according to vaccine dose. Methods We included 496,338 COVID-19 positive and 1,537,275 COVID-19 negative individuals. Using a causal mediation framework, we evaluated the effects of pre-infection COVID-19 vaccination on post-COVID CVD, considering SARS-CoV-2 infection and reinfection as mediators. The effect of post-infection vaccination was examined using a target trial emulation framework, and dose-dependent associations were assessed using Cox proportional hazards models. Modes were adjusted for age, sex, Charlson Comorbidity Index, and the Index of Relative Socioeconomic Disadvantage (IRSD). Outcomes included total CVD, stroke, heart failure (HF), acute myocardial infarction (AMI), and acute coronary syndrome (ACS). Result Vaccination before infection reduced the absolute risk (ARR) of post-COVID CVD by 2.00% (95% CI: 1.92–2.04%), with most of this effect due to direct protection (ARR 1.73% [1.64–1.80%]) and a smaller portion mediated through prevention of SARS-CoV-2 infection (ARR 0.27% [0.23–0.29%]). Significant reductions were observed for stroke (ARR 0.26%), HF (ARR 0.38%), AMI (ARR 0.23%), and ACS (ARR 0.33%). Vaccination administered after infection was also protective, with total CVD ARR 1.40% (number needed to treat 71), and consistent reductions in stroke (ARR 0.26%), HF (ARR 0.25%), AMI (ARR 0.18%), and ACS (ARR 0.06%). Dose-response analyses showed increasing protection with additional vaccine doses, and influenza vaccination alone or combined with COVID-19 vaccination provided further cardiovascular benefit. Conclusion COVID-19 vaccination, administered either before or after SARS-CoV-2 infection, is associated with notable reductions in post-COVID CVD. Vaccination prevented approximately 1-2 post-COVID CVD events per 100 individuals at the population level. The protective effect increases with the number of vaccine doses, is driven primarily by direct effects, and is further enhanced through prevention of infection and reinfection.