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Association Between Inhaled ß-Agonists and the Risk of Unstable Angina and Myocardial Infarction^*

^* From Northwest Health Services Research and Development Center of Excellence (Ms. McDonell), Veterans Administration Puget Sound Health Care System, Seattle Division, Seattle; and Department of Medicine (Drs. Au, Curtis, Every, and Fihn), University of Washington, Seattle, WA.

Correspondence to: David H Au, MD, MS, Health Services Research and Development (152), Division of Pulmonary and Critical Care Medicine, University of Washington, Veterans Administration Puget Sound Health Care System, Seattle Division, 1660 South Columbian Way, Seattle, WA 98108; e-mail: dau{at}u.washington.edu

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: ß-Adrenoceptor agonists (ß-agonists) are commonly used to treat obstructive lung diseases, and preliminary studies have suggested they are associated with an increased risk of adverse cardiovascular outcomes. We further examined the association between acute coronary syndromes and inhaled ß-agonist therapy.

Methods: We performed a nested, case-control study using data that were collected as part of a larger, ongoing, prospective study of quality improvement in the primary care clinics of seven Veterans Administration Medical Centers. We identified 630 patients with unstable angina or acute myocardial infarction hospitalized between 1996 and 1999. We frequency matched these case patients to 10,486 control subjects according to clinic location, and randomly assigned each an "index date." The computerized pharmacy database at each center was used to ascertain ß-agonist use. Cardiovascular risk factors were assessed from mailed questionnaires and electronic medical records, which included inpatient and outpatient diagnoses, medications, and laboratory results.

Results: In comparison with patients who had not filled a ß-agonist prescription during the 90 days prior to their index date, patients who had filled a ß-agonist prescription had an increased risk of experiencing an acute coronary syndrome. The increased risk of an acute coronary syndrome persisted after adjusting for age and cardiovascular risk factors, including hypertension, diabetes, and smoking history. Moreover, there was a dose-response relationship with an adjusted odds ratio (OR) of 1.38 for one to two metered-dose inhaler (MDI) canisters (95% confidence interval [CI], 0.86 to 2.23), an OR of 1.57 for three to five MDI canisters (95% CI, 1.01 to 2.46), and an OR of 1.93 for six or more MDI canisters (95% CI, 1.23 to 3.03). After stratifying for receipt of a ß-blocker prescription, the adjusted OR in subjects who did not receive a ß-blocker was 1.55 for one to two MDI canisters (95% CI, 0.60 to 3.99), an OR of 4.07 for three to five canisters (95% CI, 2.17 to 7.64), and an OR of 3.83 for six or more canisters (95% CI, 2.02 to 7.29). Subjects who had received both ß-blockers and ß-agonists had no increase in risk in acute coronary syndromes unless they had filled six or more ß-agonist MDI canisters.

Conclusions: A prescription for inhaled ß-agonists may increase the risk of myocardial infarction and unstable angina in patients with COPD.

Key Words: angina pectoris • asthma • ß-adrenoceptor • ß-agonists • cardiovascular disease • COPD • drug • myocardial ischemia • obstructive pulmonary disease

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The use of ß-blockers in subjects with previous myocardial infarctions decreases the risk of recurrent myocardial ischemic events and all-cause mortality.^{1 2} The long-term use of ß-blockers leads to upregulation in ß-receptors,³ and their withdrawal in the susceptible individual leads to a transient fourfold increase in the risk of myocardial infarction.⁴ ßAgonists that are used in the treatment of obstructive lung disease exert a physiologic opposite effect to that of ß-blockers. ß₂-Adrenoceptors are present throughout the heart⁵ and increase myocardial chronotropic⁶ and inotropic responses.⁷ Oral and nebulized ß₂-agonists, which are in widespread use for patients with COPD and asthma, have been associated with an increase risk of cardiovascular mortality.⁸ In patients with cardiovascular disease, an initial prescription of an inhaled ß-agonist has been associated with a sevenfold increase in the risk of myocardial infarction.⁹ To further explore this relationship, we used data collected as part of a large ongoing study of quality improvement in Department of Veterans Affairs Medical Centers, to examine the relationship between inhaled ß-agonists delivered by metered-dose inhalers (MDIs) and the risk of hospital admission for a subsequent acute coronary event.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The data for this study were collected as part of the Ambulatory Care Quality Improvement Project (ACQUIP). ACQUIP was a multicenter, randomized, clinical trial designed to test whether monitoring patients’ self-reported health and provision of regular reports to primary-care clinicians improves clinical outcomes and patients’ satisfaction. This study included those subjects who were enrolled in ACQUIP from December 1996 through May 1999. The study was clinic based and sought to enroll all patients who were actively enrolled in the general internal medicine clinics of seven Veterans Administration Medical Centers (VAMCs). These sites include the Seattle division of the Veterans Administration Puget Sound Health Care System, Seattle, WA; the West Los Angeles VAMC, Los Angeles, CA; the Birmingham VAMC, Birmingham, AL; the Little Rock VAMC, Little Rock, AR; the San Francisco VAMC, San Francisco, CA; the Richmond VAMC, Richmond, VA; and the White River Junction VAMC, White River Junction, VT. The parent study, ACQUIP, as well as this specific protocol were both approved by the Human Subjects Committee of the University of Washington.

Study Subjects
To be eligible to participate in ACQUIP, subjects must have made at least one visit to a participating general internal medicine clinic within 12 calendar months, must have been assigned a primary-care provider, and must have had a valid mailing address. These subjects were considered active unless they no longer fulfilled entry criteria or expressly declined participation in ACQUIP. For this study, from the seven sites, a total of 56,342 subjects were eligible for participation in ACQUIP.

For the present analysis, cases of acute coronary syndromes were defined as patients discharged from a Veterans Administration (VA) facility with a primary diagnosis of unstable angina (International Classification of Diseases [ICD]-9 code 411) or acute myocardial infarction (ICD-9 code 410) between October 1996 and May 1999. If a subject had multiple hospital admissions for myocardial ischemia, only the first admission was considered. As part of a large, ongoing VA study that had approximately 3,000 subjects with an ICD-9 code of 410 or 411, a primary ICD-9 diagnosis of acute myocardial infarction or unstable angina was found to be 90% accurate. Control subjects were randomly sampled from all eligible ACQUIP members and frequency matched to the case distribution by site at a ratio of 18–1.

Data Collection
As part of ACQUIP, baseline assessment of comorbid illnesses was obtained by mailed survey at entry into the cohort. A baseline health checklist questionnaire was sent to all subjects on study entry into the cohort, which inquired about several chronic health conditions, including chronic lung disease, congestive heart failure (CHF), ischemic heart disease, and tobacco use. Complete outpatient pharmacy records were obtained from each site and were used to ascertain exposure to MDI ß-agonists, including albuterol, metaproterenol, isoetharine, and pirbuterol. Primary and secondary inpatient discharge diagnoses, coded in ICD-9, were obtained from the VA computerized records system.

Definitions of Variables and Statistical Analysis
All subjects were assigned an index date. For each case, the index date was the date of hospital admission for either acute myocardial infarction or unstable angina. Since no control subjects had a myocardial ischemic event, each control subject was assigned an index date that was randomly selected from the distribution of index dates in the case group. The exposure of interest was the number of ß-agonist MDI canisters received from the VA pharmacy during the 90 days prior to the subject’s index date.

Additional information, such as the presence of potentially confounding, comorbid conditions, was also obtained from data collected in the mailed survey conducted on entry into the ACQUIP and from the computerized database of the VA, and enabled us to establish their presence or absence prior to a patient’s index date. Patients were considered to have COPD if they checked affirmatively on the self-administered questionnaire or if they had filled more than two prescriptions for ipratropium bromide prior to their index date.

We defined the presence of cardiovascular disease as a self-reported history or a disease diagnosis (ICD-9 code) of one or more of the following conditions: angina, previous myocardial infarction, CHF, peripheral vascular disease, atherosclerosis, and cerebral vascular disease. In addition to self-reported diagnoses and those recorded in the electronic medical record, we used the computerized pharmacy records to identify subjects who had filled medications that had specific indications, such as CHF, anytime during the study (prior to the index date). We considered subjects who had filled a prescription for carvedilol or the combination of a loop diuretic, digoxin, and an angiotensin-converting enzyme inhibitor to have CHF. In an ancillary study, we determined that the combination of a loop diuretic, digoxin, and an angiotensin-converting enzyme inhibitor had a specificity of 0.91 for echocardiographically confirmed left ventricular systolic dysfunction.

Subjects were defined as having diabetes if they had a self-reported or computerized diagnosis of diabetes, filled a prescription for insulin or an oral hypoglycemic medication, or had a glycosylated hemoglobin test level of 7% prior to their index date. Subjects completed the Short Form-36 as part of the baseline health status assessment. We used the Short Form-36 physical function scale to control for physical function as a measure of severity of disease.

We used logistic regression and stratification to adjust for potential confounding factors and to estimate odds ratios (ORs). The dependent variable was a primary discharge diagnosis of either unstable angina or myocardial infarction. Age, smoking, diabetes, hypertension, and history of cardiovascular disease were entered into all regression models. All statistical tests were two tailed, and a p value of 0.05 was used to define statistical significance.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
We identified a total of 10,569 case patients and control subjects who had been sent a baseline health checklist questionnaire. Of these, 6,463 individuals (61%) had returned the health checklist questionnaire and had provided complete information. As expected, case patients and control subjects differed in a number of cardiovascular risk factors, including age, hypertension, number of pack-years smoked, and diabetes (Table 1 ). In addition, the prevalence of cardiovascular disease was significantly higher in case patients than control subjects, as were the number of clinic visits to the patient’s primary-care provider (Table 1) . Current smoking status was not statistically different between case patients and control subjects.

We used the VA computerized medical and pharmacy records as a comparable and unbiased source to assess the potential of nonresponse bias to the baseline health screening questionnaire. Responders had a slightly higher prevalence of hypertension (14.5% vs 15.9%), cardiovascular disease (21.2% vs 25.5%), previous myocardial infarction (2.1% vs 2.4%), CHF (8.5% vs 10%), COPD (10.1% vs 12.1%), and diabetes (19.1% vs 22.1%) than nonresponders. Responders were also, on average, older than nonresponders (64.9 years vs 59.4 years).

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
We found that patients hospitalized for myocardial infarction or unstable angina were significantly more likely than control subjects to have received a ß-agonist MDI during the 3 months immediately prior to their index date. We observed a dose-response relationship that did not appear to be confounded by tobacco use, COPD history, cardiovascular disease, or cardiovascular risk factors. Furthermore, the increased risk of an acute coronary syndrome was highest in those subjects who had not been prescribed ß-blockers.

This study had several strengths. First, we studied patients from multiple centers, which minimized the chance that the patterns of diagnosis and or treatment by any single physician or any particular clinic exerted undue influence on our results. Moreover, the use of data from several geographically dispersed institutions enhances the generalizability of our results. Second, case patients and control subjects were drawn from complete clinic populations, reducing the likelihood of selection bias. Third, we employed a computerized pharmacy database to ascertain dispensed ß-agonist MDI canisters among case patients and control subjects in a comparable and unbiased fashion. The VA provides medications free of charge or with a minimal co-payment; as a consequence, 98 to 99% of veterans enrolled in primary clinics obtain all of their prescription medications from VA pharmacies.^{10 11} Fourth, we were able to access data from both computerized medical records and self-administered questionnaires, which provided more complete ascertainment of potential confounding variables, such as comorbid conditions. In addition, comparisons of different data sources permitted us to estimate the likely degree of inaccuracy of these sources. Fifth, we observed a strong dose-response relationship that makes a spurious association improbable. Finally, because of the high prevalence of current and ex-smokers in our population, the vast majority of subjects were likely to have had chronic obstructive lung disease and not asthma.

Furthermore, there is a reasonable biological basis for postulating that treatment with inhaled ß-agonists might induce or worsen myocardial ischemia. These agents are systemically absorbed through the lungs and reach the heart without undergoing first-pass metabolism. Even "selective" ß₂-agonists have been described to increase chronotropic⁶ and inotropic responses⁷ and increase atrial and ventricular ectopy.^{12 13}

However, other potential explanations exist, and it is possible that the association we describe in this study is not causal. For example, patients may have presented to their physicians for dyspnea or nonspecific chest discomfort that were, in fact, symptoms of angina for which physicians may have mistakenly prescribed ß-agonists. Patients on their own may also have increased their use of ß-agonists during episodes of unstable angina. If present, these effects would have created bias by indication. However, were this the case, one would not expect that exposure to ß-blockers would eliminate the positive association observed (except in the highest dose of ß-agonists) because, in the absence of overt cardiovascular disease, it is unlikely that ß-blockers would be prescribed. The purpose of stratification by ß-blocker use was to assess for effect modification by ß-blocker use. The elimination of the positive association between ß-agonists and cardiovascular events in the lower dosage stratum does not, however, preclude bias by indication. A less likely alternative is that ß-agonists were prescribed in the setting of acute upper respiratory illnesses, which have been associated with myocardial infarction.¹⁴ Finally, ß-agonists might be noncausally related because the airflow limitation for which they were prescribed might have caused hypoxemia and resultant myocardial ischemia.⁵

The findings of this study are generally in agreement with our earlier study⁹ that was conducted in an entirely different patient population. In that study, we observed sevenfold increase in the odds of incident myocardial infarction in patients receiving short-acting inhaled ß-agonists. The current study had a much larger patient sample, and we were able to detect a strong dose-response relationship. In addition, in this study we were able to assess the risk of both myocardial infarction and unstable angina. Despite its strengths, this study did have a number of limitations. First, because of the observational nature of this study, no cause-and-effect relationship can be extrapolated. Despite the fact that the association persisted after the addition of COPD or the physical function domain of the Short Form-36 to the model, the possibility remains that the described association is confounded by the indication for ß-agonists or the severity of lung disease. Regardless of the mechanism operating, the association we describe is important because it suggests that clinicians who have patients that receive relatively large amounts of ß-agonists may need to explore the reason for such use to ensure that it is not secondary to worsening pulmonary disease or other potential medical conditions, such as angina. Second, the measure of exposure was assessed solely through our pharmacy database, and we have no way of assessing when and if the subject actually used a ß-agonist inhaler. This type of misclassification of exposures would not, however, invalidate our results unless it occurred differentially in the case patients vs the control subjects. There is no reason to expect such systematic misclassification. Third, as in our previous study, we were unable to assess the type or severity of lung disease and could not control for severity of airflow obstruction. However, as noted previously, the vast majority of patients in this study were elderly male smokers, making significantly reversible airflow limitation uncommon. We did use the Short Form-36 physical function domain to adjust for severity of disease, but while this is an accurate measure of the physical capabilities of patients with COPD,^{15 16} its correlation with the degree of airflow limitation is admittedly limited.^{15 17} Fourth, although there is no evidence to suggest that men and women react differently to treatment with ß-agonists, the reader should use caution in extrapolating these results to women until further studies are done. Finally, we had no way to assess the myocardial ischemic events in patients admitted to a hospital outside the VA setting. Again, there is no reason to hypothesize systematic misclassification of outcomes, as it is unlikely that individuals not receiving ß-agonists would preferentially receive care for myocardial ischemia at a non-VA hospital.

This study found that filling a prescription for a MDI ß-agonist is associated with an increase in the risk of acute coronary syndromes. While it is not possible to conclude that ß-agonists cause acute coronary syndromes, the implication of this study is that clinicians should exercise caution when prescribing ß-agonists to subjects at risk of myocardial ischemia, and that myocardial ischemia should be considered as a potential cause of dyspnea in patients with obstructive lung disease. Given the dose- response relationship in this study, clinicians may consider limiting ß-agonist use to doses with demonstrated efficacy and encourage patients to not overuse this medication. In addition, clinicians may consider limiting the oral absorption of ß-agonists by recommending that patients use spacer devices when possible. Inhaled ß-agonists are an important and effective medication for treating obstructive lung disease. Therefore, additional studies are needed to confirm this association and determine potential mechanisms and interventions to decrease the risk of myocardial ischemia in users of ß-agonist inhalers.

	Footnotes

 
Abbreviations: ACQUIP = Ambulatory Care Quality Improvement Project; CHF = congestive heart failure; CI = confidence interval; ICD = International Classification of Diseases; MDI = metered-dose inhaler; OR = odds ratio; VA = Veterans Administration; VAMC = Veterans Administration Medical Center

Funding for this project was provided through the Department of Veterans Affairs and Health Services Research and Development, SDR96-002, Ambulatory Care Quality Improvement Project.

Dr. Au is supported by a Health Services Research and Development Fellowship from the Department of Veteran Affairs. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veteran Affairs.

Received for publication January 10, 2001. Accepted for publication July 11, 2001.

	References

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