1 Center for Health Studies, Group Health Cooperative, Seattle, WA.
2 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA.
3 Department of Health Services, School of Public Health and Community Medicine, University of Washington, Seattle, WA.
4 Department of Medicine, School of Medicine, University of Washington, Seattle, WA.
5 Department of Biostatistics, School of Public Health and Community Medicine, University of Washington, Seattle, WA.
6 National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA.
Received for publication January 22, 2002; accepted for publication May 7, 2002.
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ABSTRACT |
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influenza; influenza vaccine; myocardial infarction
Abbreviations: Abbreviations: CI, confidence interval; HR, hazard ratio; OR, odds ratio.
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INTRODUCTION |
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If influenza infection is associated with ischemic cardiac events, receipt of an effective vaccine might decrease that risk. To date, two published case-control studies have reported a protective association of influenza vaccination with the risk of cardiac events. In the first (14), cases with out-of-hospital cardiac arrest were significantly less likely to have a history of influenza vaccination during the previous 12 months than were controls (adjusted odds ratio (OR) of vaccination = 0.51, 95 percent confidence interval (CI): 0.33, 0.79). In the second (15), cardiology clinic patients hospitalized with a recurrent myocardial infarction during one influenza season were less likely than other clinic patients to report receipt of that seasons influenza vaccine (adjusted OR of vaccination = 0.33, 95 percent CI: 0.13, 0.82).
To evaluate further the possible role of influenza vaccination in preventing recurrent coronary events, we conducted a population-based inception cohort study of 1,378 members of Group Health Cooperative who survived a first myocardial infarction in 1992 through 1996. Medical record and administrative data systems were used to collect information on recurrent coronary events, influenza and pneumococcal vaccinations, and other covariates. We evaluated the association of receipt of each seasons influenza vaccine with the risk of recurrent events during the corresponding time period of expected influenza circulation (November through April), the time period of relative influenza inactivity (May through October), and the entire 1-year period of November through October.
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MATERIALS AND METHODS |
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To ensure that study endpoints of recurrent coronary events were distinct from the incident myocardial infarction episode, the entry date into the cohort was defined as 90 days after the hospital discharge date for the incident myocardial infarction. Subjects were excluded if they 1) were less than age 30 or more than age 79 years at the first myocardial infarction; 2) had fewer than four Group Health Cooperative outpatient visits or were enrolled in Group Health Cooperative for less than 1 year before the first myocardial infarction; 3) had a first myocardial infarction that was a complication of surgery or a procedure; or 4) had a recurrent myocardial infarction, died, or disenrolled from Group Health Cooperative prior to the cohort entry date. Follow-up time for all subjects in the study cohort extended until the earliest of the following: death, recurrent myocardial infarction, disenrollment from Group Health Cooperative, or the end of the preassigned follow-up period.
Data collection
Data collection included review of the available inpatient records for the first hospitalization for myocardial infarction and review of the entire Group Health Cooperative ambulatory medical records for the period before the first myocardial infarction and the period after that infarction up to a prespecified study end date in 1997 or 1998. Trained research assistants reviewed these records to validate the incident myocardial infarction; identify complications that occurred during the hospitalization for the incident myocardial infarction; and collect information about factors such as smoking, hypertension, diabetes mellitus, and congestive heart failure. Hypertension and diabetes mellitus were defined as pharmacologically treated diseases. Chronic congestive heart failure was defined by a duration of at least 6 months. Information on the first recurrent myocardial infarction or death during postmyocardial infarction follow-up was obtained from the ambulatory medical record, available inpatient records, and the results of a match between the Washington State death records and the Group Health Cooperative enrollment records, as described previously (18). A separate chart abstraction was performed in 2000 to collect information on influenza vaccinations since 1992 and on any pneumococcal polysaccharide vaccinations recorded.
Prescriptions for specific classes of cardiac medications during the follow-up period were identified from the Group Health Cooperative computerized pharmacy database. These medications included calcium channel blockers, lipid-lowering agents (including 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors), beta-blockers, and angiotensin-converting enzyme inhibitors. Since 1976, the Group Health Cooperative pharmacy database has included a record for all prescriptions dispensed to Group Health enrollees from a Group Health pharmacy. Although several health care plans in Group Health Cooperative include copayments for drugs, interview data from this population indicate that 96 percent of Group Health members with a history of myocardial infarction fill all of their prescriptions at Group Health Cooperative pharmacies (16). Information on aspirin use was obtained by a combination of chart review and the computerized pharmacy database.
Statistical analysis
We defined the primary endpoint as a composite of nonfatal myocardial infarction and atherosclerotic cardiovascular disease death, which included death ascribed to myocardial infarction, ischemic heart disease, congestive heart failure, hypertensive heart disease, cardiac arrest, and atrial fibrillation. A more restricted secondary endpoint included only fatal and nonfatal myocardial infarctions. The association of influenza vaccination and risk of recurrent coronary events was evaluated by using a Cox proportional hazards model, adjusted for age, gender, the occurrence of shock or severe congestive heart failure (defined as requiring hemodynamic monitoring and/or vasopressor support) during hospitalization for the incident myocardial infarction, smoking status, diabetes mellitus, hypertension, chronic congestive heart failure, chronic obstructive pulmonary disease/asthma, and cardiac medication use. All adjustment covariates except gender, smoking status, and the occurrence of shock or severe congestive heart failure during hospitalization for the incident myocardial infarction were treated as time dependent in the models. Smoking status was a time-constant variable defined as status at the time of hospital admission for the first myocardial infarction. The values for the covariates of diabetes mellitus, hypertension, chronic congestive heart failure, and chronic obstructive pulmonary disease/asthma could change from absent at the time of the first myocardial infarction to present during the follow-up period if new onset during that period was noted by chart review. The status of use of specific classes of cardiac medications could change over the follow-up period as subjects started and stopped taking the medication. Only those medication classes that were significantly associated (p < 0.1) with the primary endpoint when added individually to the preliminary model were retained in the final models.
Receipt of each years influenza vaccine, typically administered from September through December, was evaluated in relation to risk of recurrent coronary events occurring between that November through the following October. For example, receipt of the 1993/1994 influenza vaccine was evaluated in relation to risk of events occurring from November 1993 through October 1994. To account for the lag between date of vaccination and attainment of protective antibody levels, we further defined the date of effective vaccine exposure as no less than 14 days after the date of administration. Therefore, a subject who was vaccinated on November 1, 1993, would be considered as exposed to the vaccine from November 15, 1993, through October 1994. The exposure status of this subject from November 1994 through October 1995 would then be based on receipt of the 1994/1995 influenza vaccine.
Additional analyses evaluated receipt of each years influenza vaccine in relation to events that occurred during the corresponding period of expected influenza circulation, defined as November through April, and noncirculation, defined as May through October. For evaluation of these two periods, the model included an interaction term for vaccination status and influenza circulation period.
For evaluations of the association of receipt of the 23-valent pneumococcal polysaccharide vaccine and risk of recurrent coronary events, the date of effective vaccine exposure was also defined as 14 days after the date of administration. The duration of effectiveness was assumed to persist for the remainder of the study period.
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RESULTS |
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Overall, 74 percent of the subjects received at least one influenza vaccine during their follow-up period. The proportion of subjects who received each seasons influenza vaccine increased progressively from a low of 43 percent for the 1992/1993 season to a high of 66 percent for the 1997/1998 season (chi-square test for trend, p < 0.001).
Characteristics of the 1,378 subjects by age group at entry into the cohort and influenza vaccination status are shown in table 1. Among subjects under age 65 years, some medical conditions that are an indication for influenza vaccination (diabetes and chronic obstructive pulmonary disease/asthma) were more common in those who received influenza vaccine in at least 1 year during the study period compared with those who did not. Among subjects age 65 years and over, the prevalence of those conditions did not vary according to the receipt of influenza vaccine. In both age groups, subjects who received influenza vaccine in at least 1 year during the study period were less likely to be current smokers than were those who were never vaccinated.
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Forty-eight percent of the study subjects had received pneumococcal vaccine before the end of their follow-up period. In a model adjusted only for age, pneumococcal vaccination was not associated with risk of recurrent myocardial infarction and atherosclerotic disease death over the period of November through October (HR = 1.39, 95 percent CI: 0.95, 2.02). Further adjustment for receipt of influenza vaccine and the other variables included in the previously reported influenza vaccine models did not substantially change this risk estimate (HR = 1.08, 95 percent CI: 0.73, 1.59).
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DISCUSSION |
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The strengths of this study include the use of a population-based inception cohort of persons with a first myocardial infarction, the validation of diagnoses for the first myocardial infarction and for recurrent coronary events, and the ascertainment of vaccination status by chart review. Limitations of the study are that, as with all observational studies of influenza vaccine, vaccination was self-selected by patients and their physicians and that this may have introduced bias. Detailed information was collected on the presence of many of the conditions that are indications for vaccination or are risk factors for coronary outcomes. Those variables, as well as the use of cardiac medications during the follow-up period, were incorporated into the models. Nevertheless, despite adjustment for those factors, there might have been unknown or unmeasured confounding factors associated with vaccination status and event risk. Since Group Health Cooperative has an aggressive influenza vaccination program targeting the elderly and adults with chronic diseases, we believe that few older adult enrollees receive influenza vaccination outside of Group Health Cooperative; however, some misclassification of vaccination status may have occurred, since vaccinations administered outside Group Health Cooperative would not have been captured by our data sources. The study population was restricted to survivors of a first myocardial infarction, and therefore, the results of this evaluation may not be generalizable to those without a previous myocardial infarction. Finally, the confidence intervals around the point estimates of the association of influenza vaccine and recurrent cardiovascular events were not narrow, and therefore, we cannot exclude a clinically important protective or adverse effect of vaccination.
Our results differ from those of two previous studies that found a protective association of vaccination with the risk of cardiac events and also differ from one study reporting a protective association between receipt of influenza vaccine and risk of stroke. Siscovick et al. (14) identified cases of out-of-hospital cardiac arrest in King County, Washington, from October 1988 through July 1994. Spouses of 342 cases and of their matched controls were asked whether the subject had received influenza vaccine in the 12 months before the event. In a conditional logistic regression analysis adjusting for known cardiac risk factors and other variables, influenza vaccination during the previous year was associated with a reduced risk of cardiac arrest (OR = 0.51, 95 percent CI: 0.33, 0.79).
Naghavi et al. (15) identified 109 outpatient cardiology clinic patients with a history of myocardial infarction who had a recurrent nonfatal myocardial infarction between November 1997 and March 1998 and compared them with an equal number of age- and sex-matched clinic patient controls. Receipt of influenza vaccine was assessed by telephone interview. In an unconditional logistic regression analysis incorporating hypertension, hypercholesterolemia, smoking, and history of influenza vaccination during previous years, influenza vaccination for the 1997/1998 season was associated with a reduced risk of myocardial infarction during the study period (OR = 0.33, 95 percent CI: 0.13, 0.82). Similarly, Lavallée et al. (19), in France, recently reported that patients aged 60 years or more who were hospitalized with stroke during the influenza epidemic period were less likely to report receipt of that seasons influenza vaccine than were age- and sex-matched controls (adjusted OR = 0.45, 95 percent CI: 0.24, 0.84).
Although all of these analyses included adjustment for covariates such as age, gender, and known cardiac risk factors, the possibility exists, as the authors of those studies acknowledged, that residual confounding may have influenced the results. On the basis of the magnitude of the risk reductions reported, the observed effects were unlikely to be attributable only to the benefits of influenza vaccination. The cardiac arrest study reported a point estimate of the odds ratio corresponding to an overall 49 percent reduction in risk associated with vaccination during the previous 12 months; the recurrent myocardial infarction study reported a 67 percent reduction in risk over the October through March study period. This raises the question of whether these reductions in risk are consistent with a biologic effect of influenza infection on cardiac outcomes. Given that influenza viral activity is largely confined to a limited number of weeks each year, that influenza attack rates for adults during a given season are typically on the order of 515 percent (2022), that the vaccine is not completely effective in preventing infection, especially among the elderly (20), and that other factors are known to influence the risk of cardiac events, it is not clear that an effect of vaccination on influenza infection could so substantially influence the overall risk of cardiovascular events among the populations evaluated. None of the studies evaluated whether the reduction in risk observed was restricted to periods of influenza viral activity or to influenza vaccine, specificities of the association that, if present, would tend to support a true effect of vaccination on disease risk.
Although our results do not suggest a benefit of influenza vaccine in the prevention of recurrent coronary events, the benefits of the vaccine in preventing serious complications of influenza infection are well documented. Vaccination has been consistently shown to reduce rates of mortality and hospitalizations for pneumonia and influenza during influenza epidemic periods, especially among the elderly (2327). Therefore, vaccination of high-risk groups as per current recommendations (28) is indicated.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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