We identified unrecognised recent influenza in almost 10% of participants, indicating that a clinical diagnosis of influenza may be missed in hospital patients with other presentations. A recent ARTI was more common in AMI cases, and increased the risk of AMI by twofold, highlighting the need for greater awareness of infection as an underlying or precipitating condition in hospital patients.
While influenza and ARTI significantly predicted AMI in unadjusted analysis, after adjustment for other factors, influenza and ARTI (data not shown) were no longer independent predictors of AMI. However, influenza vaccination in the study year was significantly protective against AMI, with unvaccinated subjects almost twice as likely as vaccinated subjects to have AMI. Our finding of vaccination being a protective factor is validated by the fact that other significant predictors of AMI in the model (age, gender, smoking, high cholesterol) are accepted risk factors for AMI. The estimated VE of influenza vaccine against AMI was 45% (95% CI 15% to 65%), suggesting potential population health benefits of vaccination in adults at risk of ischaemic heart disease. While other studies have looked at the association of influenza, influenza vaccination and AMI,15–20
none estimate influenza VE against AMI. A previous case-control study found influenza vaccination reduced the risk of recurrent AMI (OR 0.33, 95% CI 0.13 to 0.82).15
This equates to a VE of 67% (95% CI 18% to 87%) in the prevention of recurrent AMI, a finding which supports our own study.
While we showed a protective effect of influenza vaccination against AMI, we were unable to demonstrate a direct effect of influenza infection on AMI. This could reflect low statistical power, with laboratory-confirmed influenza being a much rarer event than vaccination, which showed significant association. Furthermore, the high vaccination rate in our participants likely reduced the risk of influenza and our ability to detect a difference between groups. However, other studies have shown an association among influenza, influenza vaccination and AMI. In a recent case-control study in China, serological evidence of influenza was found to significantly predict recent AMI.16
Other observational studies have found influenza vaccination to be protective against AMI, recurrent AMI and cardiac death.15
Three randomised controlled trials (RCTs) in which patients with coronary artery disease or admitted with acute coronary syndrome were randomised to receive the influenza vaccine have shown reductions in recurrent events at 6 22
and 12 months,17
and cardiovascular death (HR 0.34, 0.17 to 0.71)20
and any coronary ischaemic event at 12 months19
compared with placebo.
Clinical and animal studies have identified an association among inflammation and atherosclerotic disease development, destabilisation of advanced disease and healing delay.23
It is postulated that infection precipitates inflammation by induction of a prothrombotic state or autoimmune reactions in already-diseased coronary vessels, causing critical obstruction. Given the animal, observational and RCT data suggesting the precipitation of ischaemic events by infection, the prevention of influenza by vaccination may have an important role in reducing ischaemic events. Influenza vaccination is efficacious in preventing severe influenza, reducing the incidence of pneumonia and death in the elderly24
and is also a cost-effective intervention25
recommended by national expert committees. Australia funds immunisation for adults aged ≥65 years and those with pre-existing risk conditions with both influenza and pneumococcal vaccines.26
Although estimated influenza vaccination levels are high (>70%) for the age group ≥65 years, uptake in younger at-risk groups is low.27
This was reflected in our study, with controls who were on average older and eligible to receive free influenza vaccination had higher rates of vaccination, whereas the AMI cases, despite being at risk were on average younger and therefore not eligible for free vaccination had much lower vaccination uptake.
Extension of vaccination programmes to include those aged 50–64 years has been suggested. However, cost-effectiveness studies of a targeted programme for this age group28
do not include the prevention of AMI. Cardiovascular disease is the second largest contributor to disease burden in Australia, accounting for 18% of the total disability-adjusted life years lost.29
As such, even a small effect of influenza vaccination in preventing AMI may have significant population health gains. The influenza VE in protecting against AMI (45%, 95% CI 15% to 65%) in our study and other similar studies indicates a substantial potential population health impact on ischaemic heart disease by vaccinating younger adults. Approximately 3.4 million Australians are affected by cardiovascular disease.30
Although two-thirds of the burden is in older adults, 19% of 45–54-year-olds and 5% of those aged under 45 years are affected.30
Influenza vaccination of people with an index AMI could also have a significant impact, with high rates of subsequent acute coronary events in patients with AMI. Death or re-infarction occurred in six of 100 patients within 1 month, and 27 within 1 year in unvaccinated AMI patients on standard treatment.20
Clinicians should consider vaccination of AMI patients before hospital discharge.
Ours is an observational study and is subject to the limitations of its non-randomised and its unmatched study design. The sample size, although adequate to detect a difference in influenza positive results, was small considering the number of vaccinated participants, but the study was intensive and difficult to conduct, and achieving final sample size required 3 years of recruitment. Australia has a funded influenza vaccination programme for people aged 65 years and older, with uptake rates >85%. Our controls were older than AMI cases, and therefore more likely to be vaccinated and more likely to be living alone, which could affect exposure status. Given the strong relationship between age and vaccination uptake, and the older age of controls, the study would have benefited from being individually age-matched. However, we adjusted for age in our model, and influenza vaccination remained significant. Further, controls were recruited from outpatient clinics and representative of community-acquired influenza. While there is the possibility that controls may have not attended due to severe influenza infection, the majority of participants found to have laboratory evidence of influenza did not report acute respiratory symptoms. The modelling adjusted for the factors which were unequally distributed between cases and controls. It is reassuring that known risk factors of age, current smoking and high cholesterol were found to be significant predictors of AMI in our model, the last being the two largest predictors of AMI in the INTERHEART study.31
Our study did not find a self-reported history of diabetes or hypertension or alcohol consumption to be predictors of AMI.31
While we did not control for all possible confounders, residual confounding is a concern for all case-control studies if confounding variables are not measured or adjusted for. For example, influenza vaccination was excluded from the INTERHEART study.31
We believe we have included all major confounders in our model. The low national influenza season in 2010 limited our statistical power and may explain why influenza infection did not significantly predict AMI. The number of vaccinated subjects was far greater than the number with documented influenza infection, therefore affording greater statistical power for examining the association of AMI with vaccination. Our study is strengthened by collection over a number of influenza seasons and the use of laboratory-confirmed influenza as a primary variable of interest, rather than self-reported ARTI, which is subject to biases. With a strict definition of AMI, it is unlikely that misclassification of AMI has occurred, which would unduly bias VE calculations. An overestimation of vaccination status would bias VE estimates; however, we have classified vaccination status based on GP verified reports, in which more than 75% of participants were able to be verified.
There has been little international policy debate surrounding the use of influenza vaccination in the prevention of ischaemic cardiac disease morbidity in people less than 65 years of age. The current recommendations are for selective vaccination of people with known risk factors often at personal expense. However, this does not achieve adequate vaccination rates.27
Other studies which have looked at influenza and AMI in people aged <65 years have shown mixed results, but even a small reduction in AMI by prevention of influenza may have population health benefit.32
The role of an expanded vaccination programme for adults over 50 years of age, which would capture a significant proportion of people at risk of AMI, should be explored by further research. At the least, clinicians should be aware of influenza and infection as an underlying and poorly diagnosed precipitant or comorbidity in hospitalised patients and of the preventive benefit of influenza vaccine for patients at risk for AMI.