Influenza vaccination within the past year was associated with a 19% reduction in the rate of acute myocardial infarction among patients aged 40 years and over. Influenza vaccination administered within influenza season was also associated with a significant reduction (20%) in the rate of acute myocardial infarction. We found that early vaccination within the influenza season (i.e., September to mid-November) was associated with greater benefit than vaccination later in the season (21% v. 12% reduction in the rate of acute myocardial infarction compared with no vaccination). Pneumococcal vaccination or combined vaccination had no additional benefit compared with influenza vaccination alone.
Unsurprisingly, cases and controls were different in their disease and treatment characteristics, with cases more likely to have comorbidities or be receiving treatment than controls. Cases were more likely to have been vaccinated than controls, particularly those between age 40 and 64 years, a finding that accords with current UK guidelines to vaccinate all those in a target group. Importantly, we found that multivariate adjustment for confounding factors led to a protective association for influenza vaccination.
Convincing evidence of a protective role for influenza infection is emerging. Our findings lend support to previous evidence from observational studies of primary prevention10
and randomized studies of secondary prevention11
suggesting a beneficial effect of influenza vaccination for prevention of acute myocardial infarction or its complications. Previous observational studies have been limited by methodologic problems, including recall bias in self-reported vaccination status.10,18
Studies with no evidence of benefit had low power, poor case ascertainment, misclassification of vaccination status and lack of investigator blinding.19–21
The additional benefit of early within-season influenza vaccination (i.e., during the period from September to mid-November) compared with late vaccination (i.e., after mid-November) has been suggested by findings of previous research,22
but is not part of current recommendations for influenza vaccination.23
Given that influenza vaccination is likely to be effective only against circulating strains of influenza virus, our findings are strengthened by the biological plausibility of a within-season or within-year effect of influenza vaccination in preventing influenza-related acute myocardial infarction. The finding that influenza vaccination was associated with a reduction in the risk of acute myocardial infarction, whereas no effect was found for pneumococcal vaccination, is evidence against the explanation that unknown confounders constituted a “healthy user” effect. If the 12-month protective effect of influenza vaccination was a result of confounding by indication, then we would also expect to find a protective effect for influenza vaccination beyond 12 months and for pneumococcal vaccination by the same token. But we did not. We believe that this discrepancy also supports the plausibility of our findings, and that the difference between the effect of early versus late vaccination on the risk of acute myocardial infarction cannot be explained by confounding by indication. Influenza vaccination was beneficial regardless of the month of acute myocardial infarction. This finding could be an indication of longer-term benefits for prevention of influenza infection, given that vaccinations considered in this instance had been given in the preceding 12 months. Following biological explanations for the association between acute myocardial infarction and influenza, the flu virus would have had a lesser effect on the vaccinated patients’ circulatory systems.
Although previous studies have shown an additive effect of pneumococcal vaccination for prevention of respiratory disease,24
we did not find a reduction in the rate of acute myocardial infarction for pneumococcal vaccination after adjusting for influenza vaccination, even among people aged 65 years and over. Our findings contrast with those of a recent study suggesting that pneumococcal vaccination was associated with a 50% reduction in the rate of acute myocardial infarction.25
Investigators in that study did not account for differences in cardiovascular risk factors, nor, crucially, for the confounding effect of influenza vaccination.
Strengths and limitations
Despite their known problems of bias and confounding, case–control designs are efficient in examining the association between outcomes and exposures. The large General Practice Research Database sample provided good power to investigate associations in a representative population with precision. We minimized selection bias by including all cases of acute myocardial infarction within the selected time period and matched controls, free of the outcome of interest and independent of the exposure of interest.26
Matching for age, sex, practice and calendar time (month corresponding to index date of acute myocardial infarction) increased the precision of our results compared with those of previous, unmatched case–control studies. Information on exposures was recorded before the index date, eliminating recall bias.
To minimize bias due to misclassification and missing data, patients were selected only if they had at least five years of up-to-standard data on the General Practice Research Database. To reduce confounding from “healthy user,” “indication” or “treatment” biases, we adjusted for many known confounders, including vaccination target groups and cardiovascular risk groups, treatments and general practitioner consultation rate, of which the latter is thought to be related to functional and economic status.27
Potential confounders such as functional status were not fully accounted for because of unavailability of data, and we did not have data for other triggers, such as stressful life events. Although we observed missing values for variables such as smoking status, systolic blood pressure, BMI and total cholesterol, we used standard imputation procedures to account for these and obtained results similar to those of our complete case analysis.
Our findings reinforce current recommendations for annual influenza vaccination of target groups,23,28
with a potential added benefit for prevention of acute myocardial infarction in those without established cardiovascular disease.29
This benefit may lead to an increase in suboptimal rates of vaccination, particularly among younger patients.15
Further research is needed to confirm our finding that early vaccination, in particular, confers additional reduction in risk for acute myocardial infarction. If substantiated, this finding has implications for timely supply and administration of influenza vaccine and could lead to changes in recommendations for timing of vaccination.