http://orcid.org/0000-0003-0713-8312
ABSTRACT
Purpose: To evaluate the hypothesis that receipt of anthrax vaccine adsorbed (AVA) increases the risk of atrial fibrillation in the absence of identifiable underlying risk factors or structural heart disease (lone atrial fibrillation).
Methods: We conducted a retrospective population-based cohort study among U.S. military personnel who were on active duty during the period from January 1, 1998 through December 31, 2006. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were used to identify individuals diagnosed with atrial fibrillation in the Defense Medical Surveillance System, and electronic records were screened to include only individuals without evidence of predisposing medical conditions. We used multivariable Poisson regression to estimate the risk of lone atrial fibrillation after exposure to AVA. We also evaluated possible associations with influenza and smallpox vaccines.
Results: Our study population consisted of 2,957,091individuals followed for 11,329,746 person-years of service. Of these, 2,435 met our case definition for lone atrial fibrillation, contributing approximately 8,383 person-years of service. 1,062,176 (36%) individuals received at least one dose of AVA; the median person time observed post-exposure was 3.6 years. We found no elevated risk of diagnosed lone atrial fibrillation associated with AVA (adjusted risk ratio = 0.99; 95% confidence interval = 0.90, 1.09; p = 0.84). No elevated risk was observed for lone atrial fibrillation associated with influenza or smallpox vaccines given during military service.
Conclusions: We did not find an increased risk of lone atrial fibrillation after AVA, influenza or smallpox vaccine. These findings may be helpful in planning future vaccine safety research.
Introduction
In December 1997, the U.S. Department of Defense (DoD) launched a mandatory Anthrax Vaccination Immunization Program (AVIP).Citation1 In 2002, the Centers for Disease Control and Prevention established the Vaccine Analytic Unit (VAU) in collaboration with the DoD with the participation of the Food and Drug Administration (FDA) for the purpose of monitoring the safety of the anthrax vaccine adsorbed (AVA) and investigating rare, unusual, or longer term adverse events potentially associated with this vaccine. Atrial fibrillation was one of eleven priority topics included in the VAU research agenda by the VAU Internal Steering Committee. The process for selection of this and other priority topics has been described elsewhere.Citation2
Atrial fibrillation is the most common sustained cardiac arrhythmia, with an estimated prevalence from 3.0 to 6.0 million cases among adults in the United States, and a lifetime risk of approximately one in four for men and women aged 40 years and older.Citation3-Citation5 Substantial morbidity and mortality is associated with atrial fibrillation primarily as the result of ischemic stroke, thromboembolism, heart failure, dementia and impaired quality of life. Not only is cardioembolic stroke attributable to atrial fibrillation estimated to account for up to 30% of all ischemic strokes, but also hemorrhagic stroke is a well-recognized serious complication of warfarin anticoagulant therapy if used prophylactically in these patients.Citation5,Citation6 Older age and several different medical conditions predispose to atrial fibrillation, including hypertension, congestive heart failure, coronary artery disease, valvular heart disease and diabetes mellitus.Citation5,Citation7 Atrial fibrillation may also occur in the absence of identifiable underlying risk factors or comorbidities (“lone atrial fibrillation”).Citation8
Reports of atrial fibrillation following vaccination are uncommon. A 1956 Hungarian case report describes a 40-year-old male who developed onset of high fever (40°C), palpitations and dyspnea upon exertion in the few days following receipt of a combination polysaccharide vaccine directed against enteric bacterial infections (typhoid, shigella, cholera).Citation9 Upon admission he was diagnosed with Jarisch-Herxheimer reaction complicating latent syphilitic aortitis and following specific anti-luetic therapy his atrial fibrillation resolved spontaneously and further recovery was uneventful. In 1962, McAdam et al., described a case of atrial fibrillation following smallpox vaccine.Citation10 In 1973, Gavrilesco et al. described a patient who developed atrial fibrillation and ventricular tachycardia after cholera vaccine.Citation11 In 2002, the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) listed atrial fibrillation as one of many adverse events reported following influenza vaccine.Citation12 However, to date no population-based epidemiologic studies evaluating atrial fibrillation after vaccination have been published.
We evaluated the hypothesis that there is an association between receipt of AVA, influenza, or smallpox vaccines and atrial fibrillation.
Results
We studied 2,957,091 individuals followed for 11,329,746 person-years of active duty military service. We identified 4,390 individuals with at least one ICD-9-CM code for atrial fibrillation (427.31) within the study period who were on active duty military service. After electronic screening, we excluded 1,955 (45%) because of medical conditions that could have predisposed them to atrial fibrillation (). After completing this screening, 2,435 cases (who contributed 8,383 person years of follow-up) remained and were included in the analysis. Demographic information on the study population is shown in and illustrating that the AVA exposed and unexposed groups had different distributions of sex, race, ethnicity, age, and military service characteristics.
Table 1. Risk factors for atrial fibrillation among participants with a diagnosis of atrial fibrillation.
Table 2. Demographics of lone atrial fibrillation cases and non-cases service members exposed to anthrax vaccine adsorbed (AVA) during 1998–2006.
Table 3. Demographics of lone atrial fibrillation cases and non-cases based on person-time exposed and unexposed to anthrax vaccine (AVA) during 1998–2006.
Approximately 36% (n = 1,062,176) of all study participants received at least one dose of AVA, and approximately 33% (PY = 3,850,536) of the total follow-up time was after the initial AVA vaccination, an average of approximately 3.6 years of post-exposure person time per person. The most common vaccine, given to approximately 71% of the study population, was influenza with 3.6 years of post-exposure person time per person (7,564,290 PY/2,112,914 individuals). presents the person-time and proportion of person years for subjects, exposed and non-exposed, for each vaccine.
Table 4. Distribution of vaccine recipients and observation time for cases and non-cases by vaccine.
We did not find an increased risk of lone atrial fibrillation after administration of any of the studied vaccines in either our univariate or our multivariable Poisson regressions (). In the univariate analysis, the risk ratios for exposure to each vaccine were less than one. The multivariable model controlled for potential confounding factors, among which all but ethnicity and service branch were independently associated with lone atrial fibrillation after adjustment. The adjusted risk ratio was 0.99 (95% CI: 0.90, 1.09; p = 0.84) for AVA, 0.94 (95% CI: 0.84, 1.04; p = 0.25) for influenza vaccine, and 1.05 (95% CI: 0.91, 1.22; p = 0.51) for smallpox vaccine. The covariate demonstrating the strongest confounding effect on the relationships between AVA and smallpox vaccine exposures and lone atrial fibrillation was deployment status, whereas for influenza vaccine, calendar year vaccinated and age were the strongest confounders. Though not shown here, we examined risk of lone atrial fibrillation after exposure to vaccine combinations using an interaction Poisson model, and none of these interactions were statistically significant.
Table 5. Results of Poisson regression analysis of lone atrial fibrillation.
The secondary analysis using the same statistical model with all potential cases of atrial fibrillation, including those previously excluded based on medical criteria, yielded similar results: 0.95 (95% CI: 0.89, 1.03; p = 0.21) for AVA, 0.93 (95% CI: 0.86, 1.01; p = 0.07) for influenza vaccine, and 1.00 (95% CI: 0.90, 1.12; p = 0.98) for smallpox vaccine. The secondary analysis including only subjects who had two or more inpatient and/or outpatient codes for atrial fibrillation found an adjusted risk ratio of 1.01 (95% CI: 0.89, 1.15; p = 0.85) for AVA; influenza and smallpox vaccine exposure similarly showed either no increased risk or no statistical significance. The secondary analysis combining individuals with atrial fibrillation and flutter found no increased risk after AVA, influenza, or smallpox vaccines (data not shown).
In order to address the hypothesis that post-vaccination atrial fibrillation would, like myopericarditis, be an acute event, we identified those individuals who were diagnosed with atrial fibrillation within 30 days of vaccination. Very few of the atrial fibrillation cases were diagnosed during this time interval, including 11 after AVA (1.4%), 12 after influenza vaccine (0.8%), and 8 after smallpox vaccine (2.5%). The majority of individuals developed atrial fibrillation more than 30 days following vaccination with AVA (median 614 days: range 0–2,906 days), influenza vaccine (median 2,044 days; range 0–6,159 days), and smallpox vaccine (median 588 days; range 0–7,135 days).
Discussion
We found no evidence of an association between receipt of AVA and diagnosed lone atrial fibrillation in the U.S. military population. In addition, we observed no significant associations between lone atrial fibrillation and influenza or smallpox vaccines given during military service. The crude incidence rate of lone atrial fibrillation was lower in the vaccine exposed groups, however, the vaccine exposed and unexposed groups differed on several potentially important confounding factors. Previous studies have identified older age, male sex, and European ancestry as risk factors for atrial fibrillation.Citation4 In our study of a military population, we identified deployment status as an important confounding factor. Deployment status might be a proxy for overall health status, with healthy individuals who are at a lower risk of developing a condition such as atrial fibrillation being more likely to deploy. AVA and smallpox vaccines were required for certain deployments during the study period. Therefore, individuals who deployed would be both more likely to be healthy and more likely to be vaccinated. After adjusting for these confounding factors in our multivariate analysis, the risk ratios were closer to 1 and non-significant, indicating neither a protective effect nor an increased risk of lone atrial fibrillation associated with vaccination.
The strengths of this investigation include the availability of the large DMSS database, which contains more than 11 million person-years of data, for studying this uncommon diagnostic endpoint. Analysis of large linked databases, such as the DMSS, provides an efficient method for timely assessments of rare adverse events, as well as chronic conditions with onset several years after vaccination.Citation13-Citation15 Evaluation of such conditions is often not possible without access to very large numbers of individuals and high vaccination rates. The quality of DMSS vaccine data, has been previously demonstrated to be suitable for post-marketing vaccine safety studies.Citation16,Citation17 Similar methodology has been used in prior studies using large linked data bases with identification of new-onset atrial fibrillation and exclusion of comorbidities using ICD-9 codes without medical record review or with medical record review of a small sample.Citation18-Citation21
Even though the accuracy of using the ICD-9 code for the identification of atrial fibrillation cases has been evaluated previously and used in other large linked database studies,Citation22–Citation26 the lack of medical record and/or electrocardiogram review to confirm cases might have resulted in the inclusion of individuals who did not have atrial fibrillation in the case group. We performed a secondary analysis to assess whether this might be a potential limitation of our study. A study by Go et al. evaluated the prevalence of atrial fibrillation in adults age 20 years and older in a California HMO using both ICD-9-CM code diagnoses and information from an electrocardiogram databaseCitation22 In that study, a medical record review on a subset of patients to assess code validity found that 56% identified with a single outpatient atrial fibrillation diagnosis had a corresponding electrocardiogram with atrial fibrillation in the medical records. In patients with two or more codes for atrial fibrillation, 78% of patients had at least one confirmatory electrocardiogram in their record. Based on these published data, we performed a secondary analysis including only subjects who had two or more codes for atrial fibrillation and the results were similar to our primary analysis.
As noted above, service members were considered to be “disease free” at entrance into the military. However, it is possible that some individuals had undiagnosed risk factors for atrial fibrillation. Echocardiograms and electrocardiograms are not a routine part of the entrance physical examination; some cases of asymptomatic structural heart disease may not have been detected. Non-cardiac conditions of slow onset (e.g. thyroid disease, connective tissue disease, etc.) may also have been missed if in the early stages. Furthermore, behavioral risk factors, such as smoking, alcohol and high caffeine intake, may not have been documented in the ICD-9-CM codes.
Although atrial fibrillation and atrial flutter are usually readily distinguished from each other, misdiagnosis occasionally occurs which could impact code validity.Citation26 Individuals may also alternate between these two conditions, and some cases of atrial fibrillation in our study population may not have been detected if the patient was in atrial flutter at the time of physical examination. The secondary analysis we did to address these concerns by grouping atrial fibrillation and flutter together into a single outcome also found no increased risk.
The term “lone” atrial fibrillation was first introduced in 1953 for atrial fibrillation occurring in the absence of other known risk factors such as structural heart disease, thyrotoxicosis, and hypertension.Citation8 A more recent definition specified the condition as having no clinical or echocardiographic evidence of concomitant cardiovascular, or pulmonary conditions in younger adults.Citation26-Citation28 However, advances in the understanding of complex atrial fibrillation pathophysiology suggest that even young apparently healthy patients with atrial fibrillation may often have subtle alterations in cardiac function and structure which may have prognostic significance; thus the relevance of distinguishing this class of disease has been recently questioned in clinical reports and the current American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) patient management guidelines recommend against use of the term for making treatment decisions.Citation29-Citation32 Nevertheless, the term has proven useful for epidemiologic research studies; a recent report from the Framingham Heart Study on the epidemiology of atrial fibrillation without comorbidities (“lone” atrial fibrillation) found the risk of cardiovascular outcomes and mortality was lower than typical atrial fibrillation, but is significantly elevated compared to matched individuals without atrial fibrillationCitation33
In our study, we evaluated calf-lymph Dryvax (Wyeth) smallpox vaccine which was the parental precursor to the currently licensed cell culture derived ACAM2000® (Sanofi Pasteur) smallpox vaccine.Citation34 ACAM2000 was licensed by the FDA on August 31, 2007 and the DoD began administering the vaccine on February 1, 2008 (by which date all remaining Dryvax stock were required to be destroyed). Both ACAM2000 and Dryvax use live vaccinia virus, a close relative of smallpox, and clinical studies found these two vaccines to have comparable safety profiles. However, retrospective epidemiologic studies and pre-licensure trial data for ACAM2000 have causally linked both vaccines to myopericarditis at a similar approximately 7.5 fold higher incidence rate of this outcome than the expected background rate among comparable unvaccinated service members.Citation35-Citation37 Whether our study’s similar negative findings for atrial fibrillation would apply to the ACAM2000 smallpox vaccine is unknown.
The pathophysiology of atrial fibrillation is not well understood, although it may involve an inflammatory process.Citation38-Citation41 Frustaci et al. found previously un-identified localized myocarditis (active in 25%) in the endomyocardial biopsies of 9 of 12 patients with paroxysmal lone atrial fibrillation refractory to antiarrhythmic treatment, suggesting that a substantial number of patients with lone atrial fibrillation could have undetected underlying heart disease.Citation42 Kim et al, in a large automated population–based cohort study found gout was associated with modestly increased risk of incident atrial fibrillation compared with osteoarthritis and non-gout.Citation43 As above, an association between smallpox vaccine and myopericarditis has also been reported.Citation35-Citation37 The time from vaccination to symptom onset has ranged from 1–42 days, with a median of approximately two weeks, and it has been recommended that post-vaccinial myopericarditis be considered in the differential diagnosis of patients who develop chest pain within 30 days after smallpox vaccination. However, this cardiac association appears unique to the smallpox vaccine as Kuntz and colleagues recently found the occurrence of myopericarditis following other live viral vaccines is rare with an estimated incidence of 0.24 per 100,000 vaccinated which is not higher than the background rate and is much lower than the incidence rates reported following smallpox vaccination.Citation44 Interestingly, a recent report of an automated study conducted using data on 11,374 insured patients in Taiwan aged 20 years and older found influenza infection was significantly associated with the development of atrial fibrillation, with an 18% increase in the risk, which could be reduced through influenza vaccination.Citation23 A follow up study from the same research group has also suggested influenza vaccination may be effective in reducing the risk of ischemic stroke in patients aged greater than 65 years with atrial fibrillation.Citation45
Our study has some limitations. This study was conducted using the DMSS administrative database and we were unable to access medical records to validate the diagnosis of atrial fibrillation (e.g., using EKG) and to determine more accurately its onset in relation to specific vaccinations. We also used an electronic screening approach to exclude individuals with identifiable underlying risk factors and it is possible additional important risk factors and it is possible conditions were not excluded. We used a traditional cohort study design and in our multivariable model controlled for potential confounding factors available in our analytic database; however, we may have missed controlling in the analysis for other unmeasured confounding factors. We also conducted three post-hoc secondary analyses for each of the vaccines under investigation in an attempt to correct for any misclassification of case status but additional refinements to the analysis may also have been revealing.
Conclusions
In this study, we observed no detectable association between atrial fibrillation and AVA, influenza or smallpox vaccination. Evidence from other studies suggests that some cases of lone atrial fibrillation are secondary to undiagnosed cardiac pathology, including unrecognized myopericarditis. Consequently, future studies should evaluate atrial fibrillation in the context of these other conditions.
Methods
Data source
The Defense Medical Surveillance System (DMSS) is an active surveillance system administered by DoD that integrates data from military treatment facilities (MTF), vaccination centers, and military personnel offices worldwide.Citation13 Inpatient and outpatient diagnosis data were coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
The study protocol was reviewed by the Army Medical Surveillance Activity (AMSA) and submitted to the Centers for Disease Control and Prevention Institutional Review Board, which exempted it from review.
Study design
We conducted a retrospective population-based cohort study using DMSS data. The study population included military personnel in the Army, Air Force, Marines, and Navy who were on active duty at any time during the period from January 1, 1998 through December 31, 2006. We excluded records from individuals not on active duty or in the Coast Guard because much of the medical encounter data from these individuals resides in civilian medical facilities, and are outside the scope of DMSS. Follow-up time for each individual continued until the end of their active duty or the end of the study period, whichever was sooner.
Our study cohort comprised two exposure groups; exposed and unexposed. The unexposed group included individuals who did not receive AVA prior to the end date and person time for vaccinated individuals during the period prior to their first AVA vaccination. Individuals in the AVA exposed group contributed person time following their first AVA vaccination up until their end date. Individuals with evidence of vaccination prior to the study start date were considered to be in the exposed group at study entry and contributed person-time to the exposed group until their study end date. All individuals exposed to AVA prior to January 1, 1998, were entered into the exposed group on January 1, 1998. Individuals who received their first AVA vaccination after January 1, 1998 were entered into the exposed group on the date of their first AVA vaccination.
We defined the starting date for follow up as the date of an individual’s entry into the study: January 1, 1998, or the date of his/her beginning active duty, whichever was later. The end date for follow-up for non-cases was December 31, 2006 or the date active duty ended from the military, whichever came first. For cases, the end date was the date of the first atrial fibrillation diagnosis. In addition to AVA, we assessed possible associations between lone atrial fibrillation and exposure to influenza or smallpox vaccines using the same methods. These vaccines were selected because they are among the most frequently reported by military sources to the U.S. Vaccine Adverse Event Reporting System (VAERS) in association with atrial fibrillation (unpublished data).
Outcome ascertainment
We searched the DMSS for individuals with the five-digit ICD-9-CM code for atrial fibrillation (427.31) given in either the inpatient or the outpatient setting. We used an electronic screening process to ensure that subjects had no documented history of atrial fibrillation prior to the start of the study and applied this to all active-duty individuals who entered the military prior to January 1, 1998. Subjects who entered active-duty service after January 1, 1998 were assumed to be disease free, given the strict health and fitness standards required for entry into the military.Citation46
We classified individuals as having “lone atrial fibrillation” if they had ICD-9-CM code 427.31 on at least one occasion, and no ICD-9-CM codes for identifiable underlying risk factors, such as pre-existing cardiac disease, hypertension, certain chronic medical conditions or acute conditions occurring in close temporal proximity to the first diagnosis of atrial fibrillation. We compiled a list of ICD-9-CM codes mapped to these known risk factors and then used the list to electronically screen potential cases of lone atrial fibrillation for evidence of disqualifying conditions (). These conditions were also identified among persons without atrial fibrillation.
We determined the time from vaccine exposure to development of atrial fibrillation and described the median and range; we also determined what proportion of atrial fibrillation cases might be considered relatively acute adverse events based on their occurrence within 30 days of vaccination.
Statistical analysis
We used Poisson regression to estimate adjusted risk of lone atrial fibrillation related to AVA using SAS and considered p-values less than 0.05 statistically significant. Univariate models for each of the vaccines under investigation provided unadjusted measurements of risk ratio to assist in building the final model.
The multivariable model included exposure to AVA, influenza, and smallpox vaccines and controlled for the following factors: race, ethnicity, age, sex, military service branch, military grade, occupational category, deployment status, and calendar year. Using an interaction Poisson model we tested for risk of lone atrial fibrillation after exposure to vaccine combinations.
Using the same statistical model we conducted three post-hoc secondary analyses for each of the vaccines under investigation 1) using all potential atrial fibrillation cases, including those previously excluded based on medical criteria 2) limiting to only subjects who had two or more atrial fibrillation codes and 3) using the umbrella 4-digit ICD-9-CM code 427.3 (atrial fibrillation and flutter).
Disclosure of potential conflicts of interest
No potential conflict of interest was reported by the authors.
Disclaimer
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. Use of trade names and commercial sources is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention, or the U.S. Department of Health and Human Services.
Acknowledgments
The authors would like to thank the following individuals for their valuable contribution to this investigation: LTC Steven K. Tobler, LTC Patrick M. Garman, Dr. Dale Burwen, Dr. Robert Ball and Dr. Linda Neff for their review of the manuscript and Dr. Judit Jassó for technical assistance.
Additional information
Funding
References
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