Influenza Vaccination and Reduction in Hospitalizations for Cardiac Disease and Stroke among the Elderly
Kristin L. Nichol, M.D., M.P.H., M.B.A., James Nordin, M.D., M.P.H., John Mullooly, Ph.D., Richard Lask, M.D., Kelly Fillbrandt, B.S., and Marika Iwane, Ph.D.
Background Upper respiratory tract illnesses have been associatedwith an increased risk of ischemic heart disease and stroke.During two influenza seasons, we assessed the influence of vaccinationagainst influenza on the risk of hospitalization for heart diseaseand stroke, hospitalization for pneumonia and influenza, anddeath from all causes.
Methods Cohorts of community-dwelling members of three largemanaged-care organizations who were at least 65 years old werestudied during the 19981999 and 19992000 influenzaseasons. Administrative and clinical data were used to evaluateoutcomes, with multivariable logistic regression to controlfor base-line demographic and health characteristics of thesubjects.
Results There were 140,055 subjects in the 19981999 cohortand 146,328 in the 19992000 cohort, of which 55.5 percentand 59.7 percent, respectively, were immunized. At base line,vaccinated subjects were on average sicker, having higher ratesof most coexisting conditions, outpatient care, and prior hospitalizationfor pneumonia than unvaccinated subjects. Unvaccinated subjects,however, were more likely to have been given a prior diagnosisof dementia or stroke. Vaccination against influenza was associatedwith a reduction in the risk of hospitalization for cardiacdisease (reduction of 19 percent during both seasons [P<0.001]),cerebrovascular disease (reduction of 16 percent during the19981999 season [P<0.018] and 23 percent during the19992000 season [P<0.001]), and pneumonia or influenza(reduction of 32 percent during the 19981999 season [P<0.001]and 29 percent during the 19992000 season [P<0.001])and a reduction in the risk of death from all causes (reductionof 48 percent during the 19981999 season [P<0.001]and 50 percent during the 19992000 season [P<0.001]).In analyses according to age, the presence or absence of majormedical conditions at base line, and study site, the findingswere consistent across all subgroups.
Conclusions In the elderly, vaccination against influenza isassociated with reductions in the risk of hospitalization forheart disease, cerebrovascular disease, and pneumonia or influenzaas well as the risk of death from all causes during influenzaseasons. These findings highlight the benefits of vaccinationand support efforts to increase the rates of vaccination amongthe elderly.
Serious complications of influenza among the elderly includepneumonia and exacerbations of coexisting conditions that canresult in hospitalization or death.1 Vaccination against influenzahas consistently been associated with reductions in hospitalizationsfor pneumonia and death from all causes in the elderly.2,3
During influenza epidemics, hospitalizations for cerebrovascularand cardiovascular causes increase,4,5,6,7,8 and acute infections,including upper respiratory tract infections, may increase therisk of acute cardiovascular9,10,11 and cerebrovascular12,13,14,15,16,17events. Several small observational studies have suggested thatinfluenza vaccination may be associated with a reduction inthe risk of cardiac arrest,18 myocardial infarction,19 and acutecerebrovascular events,20 although not all have found such abenefit.21 In a small, unblinded, controlled trial, vaccinationwas also associated with lower rates of death, myocardial infarction,or revascularization among persons with an acute coronary syndromeand those scheduled to undergo percutaneous coronary intervention.22We studied two large cohorts during the 19981999 and19992000 influenza seasons to assess whether influenzavaccination of community-dwelling elderly persons is associatedwith reduced rates of hospitalization for cardiac and cerebrovasculardisease.
Methods
Setting
This is one of several studies involving the pooling of computerizeddata from three large managed-care organizations. Previously,we reported on the ability of vaccination against influenzato reduce the rates of hospitalization for pneumonia and influenzaand death from all causes among the elderly members of theseorganizations23 and among elderly members with specific high-riskmedical conditions24 during the 19961997 and 19971998influenza seasons. The managed-care organizations are HealthPartners(650,000 members in Minnesota and Wisconsin), Oxford HealthPlan (1.8 million members in New York, New Jersey, Pennsylvania,and Connecticut), and Kaiser Permanente Northwest (420,000 membersin the Portland, OregonVancouver, Washington area). Thisproject was approved by the research-review boards of the healthplans.
Subjects
Plan members who were at least 65 years of age on October 1,1998 (for the 19981999 cohort), and October 1, 1999 (forthe 19992000 cohort), were included in the study if theywere not institutionalized and had been continuously enrolledduring the preceding 12 months and throughout the outcome period.These criteria were used to ensure adequate base-line and outcomedata on the subjects. In the case of the Oxford Health Plan,only members in the New York City area and adjacent countieswere included, since data for the rest of the areas coveredby the plan were incomplete. All elderly members of the otherhealth plans were included.
Data Collection and Outcomes
Using uniform definitions, we obtained from the administrativeand clinical data bases of each plan information on demographiccharacteristics (age, sex, and site); base-line coexisting conditions,defined by inpatient or outpatient diagnoses of heart disease(International Classification of Diseases, 9th Revision, ClinicalModification codes 093, 112.81, 130.3, 391, 393 through 398,402, 404, 410 through 429, 745, 746, 747.1, 747.49, 759.82,785.2, and 785.3), lung disease (codes 011, 460, 462, 465, 466,480 through 511, 512.8, 513 through 517, 518.3, 518.8, 519.9,and 714.81), diabetes (codes 250 and 251), renal disease (codes274.1, 408, 580 through 591, 593.71 through 593.73, and 593.9),cancer (codes 200 through 208, 140 through 198, and 199.1),vasculitis and rheumatologic disease (codes 446, 710, 714.0through 714.4, 714.8, 714.89, and 714.9), dementia and stroke(codes 290 through 294, 331, 340, 341, 348, and 438), hypertension(code 401), atrial fibrillation (code 427.3), and lipid disorders(code 272); the number of outpatient visits during the base-lineperiod; and the number of hospitalizations during the base-lineperiod. The study outcomes included hospitalization for pneumoniaor influenza (codes 480 through 487), acute cerebrovasculardisease (codes 431 through 437), cardiac disease ischemicheart disease (codes 410 through 414) and congestive heart failure(code 428) and death from any cause. Influenza-vaccinationstatus was also ascertained from the data bases, as definedby Current Procedural Terminology code 90657, and any site-specificflags in the clinical data bases.
Influenza Seasons
Influenza seasons were defined by the dates that the first andlast influenza isolates were obtained in a region accordingto surveillance data reported to the Centers for Disease Controland Prevention. Outcomes were included if they occurred duringan influenza season or within two weeks after its end in orderto include delayed complications of influenza.
Statistical Analysis
Bivariable comparisons of the base-line characteristics of vaccinatedand unvaccinated subjects were conducted using chi-square testsand Student's t-tests for categorical and continuous variables,respectively. Multivariable logistic regression (with SPSS 10.1for Windows, SPSS) was used to compare the study outcomes betweenvaccinated and unvaccinated subjects after adjustment for base-linedemographic characteristics, coexisting conditions, and previoususe of health care. The subject's age (65 to 74, 75 to 84, or85 years or older) and number of outpatient visits (12 or morevs. fewer than 12 [upper one third vs. lower two thirds]) wereincluded as categorical variables in the regression models.We estimated vaccine effectiveness by subtracting the adjustedodds ratio from 1, using the adjusted odds ratio as an approximationof relative risk. We calculated the numbers needed to treat(i.e., vaccinate) to prevent one outcome25 using the followingequation: 1 ÷ (vaccine effectiveness x the event ratein unvaccinated subjects). Analyses were conducted in subgroupsaccording to age, risk (high risk, defined by one of the followingcoexisting conditions: heart disease, lung disease, diabetesor endocrine disorders, renal disease, stroke or dementia, vasculitisor rheumatologic disease, or cancer; and low risk, defined bythe absence of any of these conditions), and site. Analysesinvolving a partial model (adjusted for demographic characteristics)and a complete model (adjusted for all the variables describedabove) were conducted to determine the effect of adjustmentfor covariates on the results.
To evaluate in more detail the adequacy of adjustment in theregression models, we assessed the effect of vaccination onthe risk of hospitalization during the summer months after eachinfluenza season (June through September 1999 and June throughSeptember 2000). This period was selected as a control period.We expected vaccination to provide minimal benefit then, becauseinfluenza was not circulating at those times. To account forlife-expectancy bias we estimated the ability of vaccinationto reduce the rate of hospitalization during the influenza seasonsafter excluding everyone who died during the outcome period.
Results
There were 140,055 subjects in the 19981999 cohort and146,328 in the 19992000 cohort. The respective ratesof vaccination against influenza were 55.5 percent and 59.7percent. At base line, vaccinated subjects were older and hada greater overall burden of illness and higher rates of healthcare use (Table 1). Unvaccinated subjects, however, were morelikely to have been given a diagnosis of dementia or stroke.These trends persisted after adjustment for demographic characteristics(age, sex, and site) (Table 1). Both influenza seasons werecharacterized by the circulation of type A (H3N2) influenzaviruses that were well matched to the corresponding strainsincluded in the vaccine.26,27
Table 1. Base-Line Characteristics of Subjects in the 19981999 and 19992000 Cohorts.
During the 19981999 influenza season, there were 1677and 1888 hospitalizations for study outcomes and 943 and 1361deaths among vaccinated and unvaccinated subjects, respectively,and during the 19992000 influenza season, there were1959 and 1574 hospitalizations for study outcomes and 1019 and1026 deaths among vaccinated and unvaccinated subjects, respectively(Table 2). The rates of all outcomes were higher among unvaccinatedsubjects than among vaccinated subjects.
Table 2. Outcomes during the Influenza Seasons among Vaccinated and Unvaccinated Subjects.
The partial logistic-regression models included demographiccharacteristics (site, sex, and age, categorized as 65 to 74,75 to 84, or 85 years or older) and vaccination status. Thecomplete models included these variables in addition to thepresence or absence at base line of various coexisting conditions(heart disease, lung disease, diabetes or endocrine disorders,cancer, renal disease, vasculitis or rheumatologic disease,dementia or stroke, hypertension, atrial fibrillation, and lipiddisorders), health care use during the base-line period (12or more outpatient visits vs. fewer than 12 outpatient visits),and the presence or absence of hospitalization for pneumoniaor influenza.
Analyses involving the complete models showed that influenzavaccination in both cohorts was associated with reductions inthe odds of all the study outcomes during the influenza seasons(Table 3), including hospitalization for cerebrovascular disease(reduction of 16 percent during the 19981999 season [P=0.018]and 23 percent during the 19992000 season [P<0.001]),cardiac disease (reduction of 19 percent during both seasons[P<0.001]), and pneumonia or influenza (reduction of 32 percentduring the 19981999 season [P<0.001] and 29 percentduring the 19992000 season [P<0.001]) and death fromall causes (reduction of 48 percent during the 19981999season [P<0.001] and 50 percent during the 19992000season [P<0.001]). When the odds of hospitalization for ischemicheart disease and congestive heart failure were analyzed separately,the reductions were also significant in every case except thatof ischemic heart disease during the 19992000 season(reduction, 10 percent; P=0.12). Estimates of vaccine effectivenesswere generally consistent among the age subgroups (Figure 1A),risk subgroups (Figure 1B), and site subgroups (Figure 1C) forboth influenza seasons. For the combined outcome of hospitalizationor death, the numbers needed to treat (i.e., vaccinate) to preventone outcome were 61 in the 19981999 cohort and 68 inthe 19992000 cohort (Table 3). Estimates of vaccine effectivenesswere lower in the partial models and in some instances were0 percent, highlighting the importance of the adjustment forcoexisting conditions and health care use in the complete models(Table 3).
Table 3. Effectiveness of Influenza Vaccination during the Influenza Seasons and Numbers Needed to Treat to Prevent One Outcome in the 19981999 and 19992000 Cohorts.
Figure 1. Effect of Vaccination against Influenza on the Odds Ratio for Hospitalization for Pneumonia or Influenza, Cardiac Causes, Cerebrovascular Causes, or Any Cause and the Odds Ratio for Death during the 19981999 Influenza Season, According to Age (Panel A), Risk (Panel B), and Study Site (Panel C).
The adjusted odds ratios and 95 percent confidence intervals (CIs) are for the comparison of vaccinated subjects with unvaccinated subjects and are from the complete regression models. High risk was defined by the presence of one of the following coexisting conditions: heart disease, lung disease, diabetes or endocrine disorders, renal disease, dementia or stroke, vasculitis or rheumatologic disease, and cancer. Low risk was defined by the absence of any of these conditions. All odds ratios have been adjusted for base-line demographic characteristics, coexisting conditions, and prior use of health care. The results of each of the subgroup analyses for the 19992000 season (data not shown) were similar to those for the 19981999 season.
In this observational study, influenza vaccination of elderlypersons was associated with substantial reductions in the riskof hospitalization for cardiac disease and cerebrovascular diseaseduring two influenza seasons. Several previous studies havesuggested similar findings. In a population-based casecontrolstudy of 342 married persons who had had an out-of-hospitalcardiac arrest but no other risk factors for cardiac disease,influenza vaccination during the previous 12 months was associatedwith a 49 percent reduction in the risk of cardiac arrest (oddsratio, 0.51; 95 percent confidence interval, 0.33 to 0.79).18In another casecontrol study of 109 patients in a cardiologyclinic who had a myocardial infarction during the 19971998influenza season, vaccination against influenza was associatedwith a 67 percent reduction in the risk of a myocardial infarctionas compared with control subjects, who had not had a myocardialinfarction (odds ratio, 0.33; 95 percent confidence interval,0.13 to 0.82).19 A casecontrol study of 90 patients whowere 60 years of age or older and living in France and who wereconsecutively admitted with a stroke during the 19981999and 19992000 influenza seasons and 180 controls foundthat influenza vaccination was associated with a 50 percentreduction in the risk of a stroke (odds ratio, 0.50; 95 percentconfidence interval, 0.26 to 0.94).20
In addition to the observational studies, an unblinded, controlledtrial of vaccination among 200 patients with acute myocardialinfarction and 101 patients who were undergoing angioplastyor stent placement in Argentina found that vaccination was associatedwith a lower risk of death from cardiovascular causes (relativerisk, 0.25; 95 percent confidence interval, 0.07 to 0.86) andof the combined end point of death, myocardial infarction, orrevascularization (relative risk, 0.50; 95 percent confidenceinterval, 0.29 to 0.85).22 Our study extends these observationsfrom previous studies by simultaneously assessing the risk ofhospitalization for cerebrovascular disease and cardiac diseaseas well as the more commonly evaluated influenza-associatedcomplications of hospitalization for pneumonia and death. Furthermore,we studied large cohorts that had many outcomes, thereby increasingthe power of the study. We also included data from two influenzaseasons and three geographically dispersed health care organizations,thus enhancing the generalizability of our findings to otherseasons and settings.
Not all reports have found that influenza vaccination protectsagainst cardiac disease. A cohort study of 1378 patients whosurvived a myocardial infarction between 1992 and 1996 foundno evidence that vaccination protected against recurrent coronaryevents after 3267 person-years of follow-up.21 That study alsoevaluated members of health maintenance organizations, but thesubjects differed from those in our study. About half were youngerthan 65 years of age, and all of them had survived a myocardialinfarction. Certain risk factors may have a stronger influenceon the risk of recurrent events among younger persons with cardiacdisease than among older persons, thus making it difficult todetect benefits attributable to vaccination. Although the analyticmodels were similar in the two studies, the covariates includedin the models were not identical, and this may also have contributedto the differences in results. In addition, the other studydefined the outcome period as the six-month period from Novemberthrough April. We used a more specific outcome period basedon influenza-surveillance data, and this may have enhanced ourability to detect the effectiveness of vaccination. Finally,we had a larger cohort and included a broader spectrum of outcomes.
Possible mechanisms of the increased risk of cerebrovascularand cardiovascular events after upper respiratory tract illnessessuch as influenza include alterations in circulating clottingfactors, platelet aggregation and lysis, concentrations of inflammatory-responseproteins, and alterations in cytokine concentrations.12,28 Thesechanges might enhance thrombotic tendencies, impair vasodilation,or cause endothelial injury.
We identified vaccination-associated reductions in the riskof hospitalizations for pneumonia and influenza and death fromall causes. Observational studies from various regions in theUnited States, Canada (Manitoba), the United Kingdom, Spain,Italy, and Argentina have also found that vaccination againstinfluenza is associated with reductions in the risk of hospitalizationfor pneumonia or influenza of about 20 to 40 percent.29,30,31,32,33,34,35,36,37,38In our study, vaccination was associated with a reduction inthe risk of hospitalization for pneumonia or influenza of 29to 32 percent.
Observational studies from the United States, Manitoba, andthe United Kingdom have reported that influenza vaccinationis associated with reductions in the risk of death from anycause of 30 to 50 percent.23,32,33,39 In our study, vaccinationwas associated with a reduction in the risk of death from allcauses of 48 to 50 percent. This reduction may be greater thanmight typically be expected. Hospitalization for pneumonia andexacerbations of underlying medical conditions are well-recognizedcomplications of influenza. Our finding that vaccination isassociated with reductions in the risk of hospitalization forcardiac and cerebrovascular disease suggests additional effectsof influenza that contribute to the overall disease burden andmay help to explain the reduction in the risk of death associatedwith vaccination.
The elderly, as well as persons younger than 65 years of agewho have high-risk medical conditions, are included in the high-prioritygroups targeted for vaccination.1 Influenza vaccination is similarlyeffective in reducing the risk of hospitalization for pneumoniaor death in healthy elderly persons and in those with coexistingconditions.24,32We found that vaccination reduced the riskof hospitalization for cardiac and cerebrovascular causes ina similar manner among both healthy and high-risk elderly persons.Many persons with high-risk medical conditions receive carefrom subspecialty physicians. Subspecialists, however, are lesslikely than generalists to recommend influenza vaccination totheir high-risk patients.40 Both generalists and medical subspecialistsshould recommend influenza vaccinations to their elderly andhigh-risk patients.
Our study has several potential limitations, and the resultsshould be interpreted with caution. Because this was an observationalstudy, we included important covariates in the analytic models.We also conducted subgroup analyses to identify possible interactionsor bias in the results. Nevertheless, residual confounding mayhave influenced our results. Misclassification of study data,including vaccination status, is another concern. However, atone of our health plan sites, more than 90 percent of high-riskmembers who were vaccinated received the vaccine at a healthplan site.41 Furthermore, agreement between medical recordsand computerized data bases has been excellent, with more than95 percent agreement at two of the study sites.23,24,25 Evenif substantial misclassification occurred, it would most likelybias the study toward negative results.
We did not collect information on pneumococcal vaccination statusfor the study. In contrast to influenza vaccinations, whichrequire annual administration, pneumococcal vaccinations areusually given only once and may be effective for 6 to 10 years.We were unable to obtain the data for the prior 6 to 10 yearsthat would be needed to characterize pneumococcal-vaccinationstatus accurately. Pneumococcal vaccination reduces the riskof bacteremic disease but has not consistently been shown toreduce the risk of hospitalization for pneumonia.42 In one studythat used analytic models similar to ours, the 12-month pneumococcal-vaccinationstatus was not a significant variable.43 In another study, pneumococcalvaccination was not associated with a reduction in the riskof recurrent coronary events.21 Nevertheless, if pneumococcalvaccination significantly reduces the risk of any of our studyoutcomes, then some of the benefits attributed to influenzavaccination may actually have been due to pneumococcal vaccination.
Supported by the National Vaccine Program Office and the Centersfor Disease Control and Prevention through an agreement withthe American Association of Health Plans.
Source Information
From the Veterans Affairs Medical Center and the University of Minnesota, Minneapolis (K.L.N.); HealthPartners Research Foundation, Minneapolis (J.N., K.F.); Kaiser Permanente Northwest, Portland, Oreg. (J.M.); Oxford Health Plan, New York (R.L.); and the Centers for Disease Control and Prevention, Atlanta (M.I.).
Address reprint requests to Dr. Nichol at the Veterans Affairs Medical Center (111), 1 Veterans Dr., Minneapolis, MN 55417, or at nicho014{at}umn.edu.
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