Estimating cardiovascular effects of influenza vaccination in older adults: a target trial emulation using proximal causal inference.

Background: The substantial burden of cardiovascular diseases highlights the urgent need for cost-effective interventions to mitigate their impact. While existing evidence on the cardioprotective effect of the influenza vaccine comes primarily from populations with cardiovascular comorbidities, these studies remain susceptible to several sources of bias, including immortal time bias and unmeasured confounding. To attenuate these limitations, our study aimed to assess the effect of influenza vaccination on cardiovascular events in an older population in China, utilizing a target trial emulation framework in conjunction with a proximal causal inference (PCI) approach.

Methods: This is a sequentially designed, propensity score (PS) matched, vaccine effectiveness study under a target trial emulation framework. We used data from the Yinzhou Regional Health Care Database and included permanent residents of Yinzhou, China, aged 65 years or older. We employed a sequential trial approach in which participants were categorized as influenza vaccinees or non-vaccinees based on their vaccination regimen during the one-week enrollment period of each sequential trial from 2020 to 2022. The outcomes of interest were major adverse cardiovascular events (MACE) and acute coronary syndromes (ACS) within one year of follow-up. To address measured and unmeasured confounding, PS matching was performed in conjunction with PCI using a two-stage Poisson regression to estimate incidence rate ratios (IRRs).

Findings: A total of 8,181,638 older adults were included across the 50 emulated trials between 2020 and 2022. Of these, 170,011 received influenza vaccination, while 8,011,627 remained unvaccinated. Vaccinated participants were generally frailer (severely frail: 19.1% vs. 14.7%) and had a higher prevalence of hypertension (83.0% vs. 74.9%). After PS matching, all measured characteristics were well-balanced among 339,976 matched participants. In conjunction with the PCI approach, we found influenza vaccination was associated with a decrease in one-year risk of MACE (IRR: 0.86 [95% CI: 0.83-0.89]) and one-year risk of ACS (IRR: 0.87 [95% CI: 0.83-0.91]) compared to non-vaccination. Results were consistent across strata of enrollment year, age, sex, current smoking status, hypertension, hyperlipidemia, prior influenza vaccination status, and numerous sensitivity analyses.

Interpretation: Influenza vaccination may reduce the risk of MACE and ACS among older adults. Aligned with the World Health Organization guidelines, our findings further support influenza vaccination as an effective public health strategy for potentially reducing cardiovascular disease burden.

Funding: National Natural Science Foundation of China; Science and Technology Project of Science and Technology Bureau of Yinzhou District, Ningbo City; Zhejiang Provincial Centre for Disease Control and Prevention Science and Technology Program; Bill & Melinda Gates Foundation.