Effects of Annual Influenza Vaccination on Winter Mortality in Elderly People With Chronic Heart Disease

Cinta de Diego; Angel Vila-Córcoles; Olga Ochoa; Teresa Rodriguez-Blanco; Elisabeth Salsench; Imma Hospital; Ferran Bejarano; M. del Puy Muniain; Mercé Fortin; Montserrat Canals and EPIVAC Study Group

Disclosures

Eur Heart J. 2009;30(2):209-216. 

In This Article

Discussion

Nowadays, there is a general agreement for the recommendation of the influenza vaccine to elderly and high-risk adults.[2,3] However, the magnitude of clinical effectiveness and benefit from the annual vaccination campaigns is controversial.[14,18]

In this study, we have assessed the effects of the annual influenza vaccination on winter mortality in older adults with chronic heart disease (basically congestive heart failure and/or coronary artery disease). Although it was not randomized, the relatively large size of the study population together with the adjustment for important covariates in the multivariable analysis, provides an adequate basis for assessing the effects of the influenza vaccine status on winter mortality throughout a time-period with different severity of influenza seasons.

In the present study, annual influenza vaccine coverages varied from 64 to 74%, which is consistent with data reported for elderly people with chronic heart diseases in Spain and other developed countries, which have reported that approximately 30% of these subjects are not annually immunized against influenza.[2,19,20]

In this study, the influenza vaccination was associated with a nearly significant reduction of 25% in the unadjusted rate of all-cause winter mortality in vaccinated subjects, whereas the multivariable analysis showed a significant effectiveness of 37% (9–56%) in decreasing the risk of winter mortality throughout the overall study period among those patients who had received influenza vaccine in the prior autumn. Our result fits with those recently reported by Voordouw et al.[13] in a retrospective cohort study focussed on people over 65 in the Netherlands, who found that the annual influenza vaccination was associated with an all-cause mortality risk reduction of approximately 24% during the overall study period and 28% during the epidemic periods.

Although a benefit of the influenza vaccination to prevent hospitalization and death has been largely reported, the effectiveness of the vaccine is not well understood for major cause-specific mortality, except pneumonia. Recently, Wang et al.[7] have analysed 10 months mortality data of 102 692 individuals aged 65 years or older in Southern Taiwan, reporting that the influenza vaccination was significantly associated with a 44% lower risk of all-cause mortality and they have also reported a significant 22% reduction in the risk of death from heart diseases among vaccinated subjects.

In our study, cause specific mortality was not available in 39% of cohort members who died during the study period and furthermore, in some patients the cause of death was not specific enough to classify as influenza-related mortality or not. Thus, we have chosen all cause mortality as the main outcome measure, taking into consideration a possible misclassification bias and a lack of statistical power from an analysis of specific mortality. Given the difficulty for laboratory confirmed diagnosis of influenza infections, all-cause death has been considered an acceptable outcome to evaluate influenza vaccine effectiveness in many observational studies and meta-analyses.[21,22] In favour of choosing all-cause mortality as the outcome to assess the effect of influenza vaccination on mortality is the difficulty to classify a death as influenza-related mortality and, consequently, the possibility of misclassification bias when cause-specific mortality is considered. In general, when the event of interest is death, all-cause mortality is considered a more robust event than cause specific mortality. Nevertheless, we emphasize that, given that specific mortality was not evaluated, a residual confounding in the estimates of vaccine effectiveness cannot be completely excluded.

The effectiveness of the influenza vaccine to decrease all-cause mortality is controversial, and nowadays there is disagreement about the magnitude of the protective effects from the vaccination. In a classical meta-analysis, Gross et al.[21] estimated that influenza vaccine effectiveness against all-cause mortality varied from 27 to 30% in case–control studies to 56–76% in cohort studies. In a meta-analysis focused on elderly people living in the community, Vu et al.[22] estimated vaccine effectiveness against all-cause mortality as 45–56%. Simonsen et al.[18] have analysed influenza vaccine coverages and the estimates of influenza-related mortality and all-cause deaths for 33 influenza seasons from 1968 to 2001 in the USA elderly population. They reported that there was no correlation between increasing vaccination coverage after 1980 with declining mortality rates in any age group and concluded that many studies substantially overestimated the benefits of vaccination.[18]

In the present study, the difference between all-cause mortality in non-vaccinated and vaccinated subjects (attributable risk) was 47.7 deaths per 100 000 person-weeks during the overall January–April period, and we estimated that in the total population one winter death was prevented for every 122 annual influenza vaccinations, although this estimation does not exclude the possibility of a greater number since the value of the upper limits in the confidence interval reached infinite.

Important aspects that determine vaccine effectiveness are the intensity of viruses circulating during the study periods and the similarity between vaccine strains and circulating strains.[23] During our study period (2002–2005), influenza activity in northern hemisphere countries was mild-to-moderate in most countries, and was associated with a mixed circulation of Virus A and Virus B. In this period, vaccine strains and the predominant circulating strain (mainly A[H3N2]) generally were well matched.[24–27] In the study area, during the study period, the mean incidence rates of influenza-like illness reported between January and April among the overall population in the eight participating PHCCs were 63.4 cases per 100 000 person-weeks in 2002, 14.0 in 2003, 13.6 in 2004, and 84.3 in 2005.[15] Our findings are epidemiologically plausible considering that, as it can be expected, in the present study the greatest level of vaccine effectiveness was observed in the winters with the highest influenza epidemic activity (2002 and 2005) where unadjusted vaccine effectiveness was 40 and 38% (with NNVs ranging from 49 to 99), whereas the lowest vaccine effectiveness occurred in those winters with lower epidemic activity (2003 and 2004) where unadjusted vaccine effectiveness reached only –8 and 22% (with NNVs ranging between 162 and 455).

Our study has several strengths. Vaccination was evaluated by survival analysis methods to estimate vaccine effectiveness adjusted for age and co-morbidity. The study was population-based and study population was large enough to evaluate the relationship between annual influenza vaccine status and winter mortality throughout the overall study period. On the other hand, the sample size was small in assessing vaccine effectiveness separately for each influenza season. The study also has some intrinsic limitations and to interpret our findings, some characteristics of the study need to be addressed. In this study, influenza vaccination was considered as a simple dichotomous variable ('vaccinated' or 'non-vaccinated') in each year, but other categories of influenza vaccine status (such as 'first vaccination', 'revaccination', 'vaccination interruption', or 'vaccination restart') which can influence vaccine effects were not evaluated.[13]

The main limitation of observational designs is a possible selection bias. In our study, vaccinated subjects were older and had more co-morbidity than non-vaccinated subjects (Table 1). Moreover those patients who had a higher number of underlying conditions had more visits than those patients who did have not, and this meant a higher probability of vaccination. However, in Spain all individuals are assigned to a PHCC and a free influenza vaccine is offered each autumn for all individuals over 65 years. We account for differences between vaccinated and non-vaccinated subjects in the analysis, by adjusting for these variables in the multivariable Cox proportional hazard model. However, as with all observational studies, the possible influence of residual confounding due to unknown confounding factors on the estimates of vaccine effectiveness cannot be completely excluded (Szklo M., Nieto J., 2000). Information bias may have occurred if some co-morbidity or vaccination was not recorded, but such misclassification would likely be random because vaccination and covariates were recorded before occurrence of death.

The efficacy of influenza vaccination and the estimated impact of annual influenza epidemics on morbid-mortality have been the basis for implementing influenza vaccination programmes for elderly and high-risk individuals.[2,3,21,22] However, the effectiveness of vaccination has been reported to decrease in older age-groups and high-risk persons, and the magnitude of clinical effectiveness of annual vaccination campaigns is unclear. Nowadays, in this field, the gold standard of a large randomized controlled trial would be unethical and non-experimental studies evaluating influenza vaccination effectiveness must be applied.[23,28] Our results show that the reception of the annual conventional inactivated influenza vaccine was associated with a significant low risk of all-cause winter mortality among community-dwelling elderly patients with chronic heart disease followed throughout a consecutive 4 year series that included four influenza seasons.

Our data confirms the benefit of the influenza vaccination, even considering mild-or-moderate severity of influenza seasons, and it supports an annual vaccination strategy for these patients. It must not be forgotten that approximately one-third of elderly patients with chronic heart diseases remain annually non-vaccinated, and the increase in vaccination uptakes should be a major goal in the care of these patients.

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