Influenza Vaccination and Risk of Ischemic Stroke: A Population-Based Case-Control Study

To assess the relationship between influenza vaccination in the general population and risk of a first ischemic stroke (IS) during pre-epidemic, epidemic, and postepidemic periods.

A nested case-control study was conducted in a Spanish primary care database over 2001-2015. Individuals aged 40-99 years with at least 1 year registry and no history of stroke or cancer were selected to conform the source cohort, from which incident IS cases were identified and classified as cardioembolic or noncardioembolic. Five controls per case were randomly selected, individually matched with cases for exact age, sex, and date of stroke diagnosis (index date). A patient was considered vaccinated when he/she had a recorded influenza vaccination at least 14 days before the index date within the same season. Adjusted odds ratios (aORs) and their respective 95% CIs were computed through a conditional logistic regression. Pneumococcal vaccination was used as a negative control.

From a cohort of 3,757,621 patients, we selected 14,322 incident IS cases (9,542 noncardioembolic and 4,780 cardioembolic) and 71,610 matched controls. Of them, 41.4% and 40.5%, respectively, were vaccinated yielding a crude OR of 1.05 (95% CI 1.01-1.10). Vaccinated patients presented a higher prevalence of vascular risk factors, diseases, and comedication than those nonvaccinated, and after full adjustment, the association of influenza vaccination with IS yielded an aOR of 0.88 (95% CI 0.84-0.92), appearing early (aOR_{15-30 days} 0.79; 95% CI 0.69-0.92) and slightly declining over time (aOR_{>150 days} 0.92; 95% CI 0.87-0.98). A reduced risk of similar magnitude was observed with both types of IS, in the 3 epidemic periods, and in all subgroups analyzed (men, women, individuals younger and older than 65 years of age, and those with intermediate and high vascular risk). By contrast, pneumococcal vaccination was not associated with a reduced risk of IS (aOR 1.08; 95% CI 1.04-1.13).

Results are compatible with a moderate protective effect of influenza vaccine on IS appearing early after vaccination. The finding that a reduced risk was also observed in pre-epidemic periods suggests that either the "protection" is not totally linked to prevention of influenza infection or it may be partly explained by unmeasured confounding factors.