Beta-blocker therapy substantially decreases mortality and re-infarction after acute myocardial infarction (AMI) (1). However, because beta-blockers can induce bronchospasm (2- 4), use of this medication has traditionally been contraindicated in patients with pulmonary conditions such as chronic obstructive pulmonary disease (COPD) or asthma. However, the American Medical Association, in collaboration with the American College of Cardiology (ACC) and other medical specialty societies, has stated through a recent Quality Care Alert that beta-blockers are effective in AMI and should be considered even in patients with COPD or asthma: “while relative contraindications may once have been thought to preclude the use of beta-blockers in some patients, new evidence suggests that the benefits of beta-blockers in reducing re-infarctions and mortality may actually outweigh their risks, even in patients with asthma … [and] chronic obstructive pulmonary disease” (5). In addition, the ACC and the American Heart Association (AHA) have recently updated their clinical guidelines for the treatment of AMI to emphasize that the survival benefit from beta-blockers is so strong that it may outweigh the risk of adverse events in patients with COPD or asthma (6).

Both recommendations caution that the decision to begin beta-blocker therapy should be considered on a “case-by-case basis” in these patients. However, there are no data available to assist the physician in differentiating in which types of patients with COPD or asthma beta-blockers should be considered, because these patients were largely excluded from the major randomized clinical trials. For example, the Metoprolol In Acute Myocardial Infarction (MIAMI) trial excluded patients with “severe COPD, e.g. requiring steroids or beta-agonists” (7). The Beta-Blocker Heart Attack Trial (BHAT) excluded patients with “asthma and COPD requiring therapy” (8). The Göteborg metoprolol trial and the Norwegian Timolol Study excluded patients with asthma and COPD, respectively (9- 10).

The aim of this study is to identify subgroups of patients with COPD or asthma in which beta-blockers appear to be effective in reducing mortality after AMI. We used data from the Cooperative Cardiovascular Project (CCP), a Health Care Financing Administration initiative designed to improve the care and outcomes of Medicare beneficiaries with AMI.

The CCP sample was identified from hospital bills in the Medicare National Claims History File (form UB-92), which included all claims submitted for patients treated under fee-for-service plans, but not Medicare-managed care contracts (11). Patients discharged from acute-care hospitals from all 50 states and Puerto Rico with a principal discharge diagnosis code of AMI (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] 410) were selected for the initial cohort, except those whose bills indicated a subsequent, nonacute treatment of AMI (fifth digit of ICD-9-CM code = 2). Cooperative Cardiovascular Project sampling was conducted for an eight-month period between February 1994 and July 1995, except for the CCP pilot study states (Alabama, Connecticut, Iowa and Wisconsin), which were sampled for a four-month period between August and November 1995. Predefined variables were abstracted from copies of hospital medical records, and included demographic characteristics, previous medical history, clinical presentation, electrocardiographic reports, laboratory test results, treatments and discharge status.

The study sample was restricted to patients ≥65 years of age with a clinically confirmed AMI, defined as chart documentation of either a creatine kinase (CK)-MB fraction >5%, lactate dehydrogenase (LDH) level more than 1.5 times normal and LDH₁ > LDH₂, or at least two of the following three criteria: chest pain, a twofold elevation of the CK level or a new AMI on the official electrocardiogram report. We defined a study sample of patients without chart-documented contraindications to beta-blockers other than COPD or asthma, based on the ACC/AHA clinical guidelines for the treatment of AMI (6)(Table le1).

We included only the patient’s first admission during the sample period to avoid double-counting patients. We excluded patients who were subsequently transferred to another acute-care institution because of an inability to determine their discharge medications. We omitted three patients for whom mortality could not be confirmed, and excluded those considered to have a terminal illness (chart-documented as unlikely to live past six months) or metastatic cancer, because the focus of their treatment may not have been targeted toward a survival benefit. We excluded 1,115 patients with chart-documented intolerance to beta-blockers.

We defined COPD or asthma based on the medical record, use of medications and prior admissions. The CCP definition included patients with the following chart-documented conditions: COPD, chronic obstructive lung disease, asthma, emphysema, chronic obstructive airway disease, bronchiectasis and chronic bronchitis. Patients with the following conditions were not considered to have COPD: findings of COPD on chest radiograph without a clinical history of lung disease, acute bronchitis, pneumonia and the common cold. We considered patients to have COPD or asthma if they had pre-admission use of or discharge prescription for the following medications: beta-agonist bronchodilators, inhaled anticholinergics, inhaled steroids, theophylline or cromolyn. We also included patients whose Medicare Part A files identified an admission in the year before the index AMI hospitalization for an ICD-9-CM-coded primary discharge diagnosis of COPD or asthma (490 to 494, 496).

We stratified these patients into three groups of relative severity according to the use of pharmacotherapy: patients with COPD or asthma not prescribed beta-agonists before admission or at discharge; patients with COPD or asthma prescribed beta-agonists before admission or at discharge; and patients prescribed oral steroids or admitted to the hospital at least once for COPD or asthma during the year before the AMI admission. Patients with COPD or asthma were compared with patients without these conditions.

The prescribed use of beta-blocker therapy was determined by identifying all patients with an oral beta-blocker as a discharge medication. Beta-blocker dosages were not available in the CCP database. We identified deaths within one year of discharge using the Medicare Enrollment Database, a valid source of vital status information (12). Hospital re-admissions with a primary discharge diagnosis of COPD or asthma were identified from Medicare Part A claims for all hospitalizations billed to Medicare using ICD-9-CM codes. Because of the time lag for the availability of the latest Part A data, this study was only able to consider hospital re-admission within six months of discharge (the longest follow-up available for analysis). Medicare Part A data were not available for three of the CCP pilot states (Alabama, Iowa and Wisconsin) and Minnesota. Overall, 93% of the patients in the study sample were included in the re-admission analysis.

Additional abstracted variables included patient demographics (age, gender, race), comorbidities (hypertension, current smoker, previous AMI, congestive heart failure, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, peripheral vascular disease, stroke, dementia, diabetes), clinical characteristics on admission (anterior infarction, left bundle branch block, atrial fibrillation/atrial flutter, respiratory rate >25 breaths/minute on admission, blood urea nitrogen >14.28 mmol/l or creatinine >221 μmol/l, albumin <30 g/l, prothrombin time >16 s, hematocrit <30%, stroke on admission), hospital treatment and course (thrombolytic therapy, recurrent chest pain, CK >4 times normal), functional status (urinary incontinence, ability to ambulate), discharge disposition (to home, skilled nursing facility, or other), discharge medications (aspirin, calcium channel-blockers, angiotensin-converting enzyme inhibitors, loop diuretics, digoxin), physician specialty, census region and length of stay. We also classified patients into the nine major regions defined by the U.S. Census based on the site of hospitalization (13). Length of stay was coded as >12 days (yes/no), approximately the 75th percentile for length of stay. For variables with >3% missing values (albumin and hematocrit), a dummy variable was created and included in the multivariate analyses.

We compared the likelihood of receiving a prescription for beta-blockers at discharge, one-year survival, and six-month re-admission for COPD or asthma across the four patient groups. Chi-square tests were used to test differences for categorical variables, and analysis of variance was used to test differences for continuous variables among patient categories.

We used multivariate logistic regression analysis to determine whether patients with COPD or asthma were less likely to be prescribed beta-blocker therapy at discharge compared with patients without COPD or asthma. Variables were considered in the multivariate models on the basis of backwards stepwise selection with the prescription of beta-blockers as the dependent variable, as in previous studies (14). The analysis was repeated after restricting the sample to patients who were not on beta-blocker therapy before the AMI admission.

For each of the patient categories, we used Cox proportional hazards models to estimate the association between one-year survival and the prescribed use of beta-blockers at discharge. The survival models adjusted for a set of covariates selected on the basis of clinical relevance and previous work. The assumption of proportionality was evaluated graphically and found to be satisfactory. We then evaluated whether the association between one-year mortality and prescribed use of beta-blockers differed among the COPD/asthma severity groups in a combined interaction model.

Lastly, we evaluated whether beta-blocker therapy was associated with increased rates of hospital admission for COPD or asthma. We used Poisson log-linear models to estimate the relative risk (RR) of hospital re-admission adjusting for prescribed beta-blocker use and other potential confounders. Patients were not considered at risk for re-admission while they were hospitalized or after death.

All calculations were performed using Stata 6.0 statistical software (StataCorp, College Station, Texas).

Of the 115,015 eligible patients (≥65 years of age, confirmed AMI, survived the hospitalization, no terminal illness and not transferred), 60,053 patients (52.2%) had one or more contraindications to beta-blocker therapy other than COPD or asthma (Table le1). Most exclusions were due to heart failure. After excluding patients with contraindications other than COPD or asthma, 54,962 elderly patients with AMI remained who were considered candidates for beta-blocker therapy at discharge.

Of the 54,962 patients in the study sample, 6,628 (12.1%) had COPD or asthma but were not prescribed beta-agonist therapy; 2,882 (5.2%) had COPD or asthma and were prescribed beta-agonist therapy but were not prescribed oral steroids, or were hospitalized for COPD or asthma in the previous year; and 1,478 (2.7%) had COPD or asthma and were on oral steroids or were hospitalized for COPD or asthma within the previous year. The remaining 43,974 (80%) patients did not have chart-documented disease or use of medications for COPD or asthma, or were not hospitalized for COPD or asthma in the year before the AMI admission. On average, patients with COPD or asthma were younger and had higher levels of smoking, history of AMI or congestive heart failure, and were less likely to receive thrombolytic therapy, percutaneous transluminal coronary angioplasty or coronary artery bypass surgery during the hospitalization (Table le2).

Overall 25,517 (46.4%) patients in the study sample were prescribed beta-blockers at discharge. The rate of beta-blocker use declined as COPD or asthma severity increased (p < 0.001). Beta-blockers were prescribed for 50.3% of patients without COPD or asthma, 37.4% of patients with COPD or asthma not prescribed beta-agonists, 25.2% of patients with COPD or asthma prescribed beta-agonists, and 12.5% of patients with severe COPD or asthma. Over 91% of patients discharged on beta-blockers were prescribed beta₁-selective agents. After adjusting for demographic and clinical factors, patients with COPD or asthma continued to be less likely to be prescribed beta-blocker therapy compared with patients without pulmonary disease (odds ratio [OR] 0.65) (95% confidence interval [CI] 0.62 to 0.69, for patients with COPD or asthma not prescribed beta-agonists, OR 0.38 [95% CI 0.34 to 0.41] for patients with COPD or asthma prescribed beta-agonists but not prescribed oral steroids or admitted in the prior year, and OR 0.17 [95% CI 0.14 to 0.20] for patients with severe COPD or asthma. The area under the receiver operator characteristic curve was 0.74, indicating good discriminant ability of the model (15).

Of the 45,322 patients not on beta-blocker therapy before admission, 18,071 (39.9%) were prescribed therapy at discharge. Again, there were significant differences in the prescription of beta-blocker therapy at discharge by COPD or asthma status. Beta-blocker therapy was prescribed to 31.1% of patients with COPD or asthma not prescribed beta-agonists, to 21.1% of patients with COPD or asthma prescribed beta-agonists, and to 9.3% of the patients with severe COPD or asthma (p < 0.001) compared with 43.8% of patients without COPD or asthma. In analyses adjusting for demographic and clinical factors, patients with COPD or asthma were less likely than other patients to be prescribed beta-blockers at discharge (OR 0.65 [95% CI 0.61 to 0.70] for patients with COPD or asthma not prescribed beta-agonist therapy, OR 0.39 [95% CI 0.35 to 0.43] for patients with COPD or asthma prescribed beta-agonist therapy, and OR 0.16 [95% CI 0.13 to 0.20] for patients with severe COPD or asthma).

There were marked differences in one-year mortality (p < 0.001) among the four patient categories (Table le3). Beta-blockers were significantly associated with decreased one-year mortality among patients without COPD or asthma (p < 0.001), patients with COPD or asthma not prescribed beta-agonists (p < 0.001), and among patients with COPD or asthma prescribed beta-agonists (p = 0.02). We did not find significant differences in one-year mortality associated with beta-blockers among patients with severe COPD or asthma (p = 0.72).

In the adjusted analyses, the prescribed use of beta-blockers was associated with a reduced risk of mortality in patients with COPD or asthma not prescribed beta-agonists (RR = 0.86, 95% CI 0.73 to 1.00, p = 0.048) that was similar to that of patients without COPD or asthma (RR = 0.86, 95% CI 0.81 to 0.92). Although not statistically significant in patients with COPD or asthma who were prescribed beta-agonists, the estimate for beta-blocker effectiveness was similar to that of patients in whom therapy was effective (RR = 0.88, 95% CI 0.69 to 1.14). We did not find a significant relationship between beta-blockers and mortality for patients with severe COPD or asthma (RR = 1.07, 95% CI 0.75 to 1.52).

Beta-blocker therapy was not significantly associated with different rates of six-month re-admission for COPD or asthma in unadjusted comparisons for patients without COPD or asthma (0.2% for patients prescribed beta-blockers vs. 0.2% for patients not prescribed beta-blockers, p = 0.85), for patients with COPD or asthma not prescribed beta-agonists (1.5% vs. 1.9%, p = 0.21), and for patients with COPD or asthma prescribed beta-agonists (3.9% vs. 5.1%, p = 0.53). Patients with severe COPD or asthma who received beta-blockers had lower re-admission rates (10.0% vs. 18.5%, p < 0.01), although this is most likely due to selection effects in the unadjusted model.

In models that adjusted for demographic and clinical severity, there was no significant increase in the risk of re-admission for patients without COPD or asthma (RR = 0.95, 95% CI 0.58 to 1.55), for patients with COPD or asthma not prescribed beta-blockers (RR = 0.74, 95% CI 0.49 to 1.13), for patients with COPD or asthma prescribed beta-agonists (RR = 0.75, 95% CI 0.49 to 1.16), and for patients with severe COPD or asthma (RR = 0.76, 95% CI 0.51 to 1.16).

A substantial number of patients with AMI (one-fifth of our study cohort) had evidence of COPD or asthma; for this group of patients there is a paucity of information about the benefits and risks of beta-blockers after AMI. The purpose of this analysis was to provide information about the benefits and risks of beta-blockers in patients with relative pulmonary contraindications to guide the clinician in making informed evidence-based decisions. We found beta-blockers to be significantly associated with lower one-year mortality in a subgroup of patients with COPD or asthma that was not active enough to warrant the current use of beta-agonists. The patients in this group appeared to benefit as much from beta-blocker therapy as did patients without pulmonary disease at no increased risk for subsequent hospitalizations for COPD or asthma. However, patients with COPD or asthma not using beta-agonist therapy had 35% lower odds of receiving a discharge prescription for the therapy. Because the majority of patients in our cohort with a history of COPD or asthma did not have chart-documented use of beta-agonists (61.8%), increasing the use of beta-blockers after AMI may represent an opportunity to improve their care and outcomes.

These findings support the ACC/AHA clinical guidelines and American Medical Association recommendations that beta-blockers may be beneficial after AMI for some patients with relative pulmonary contraindications. If a patient with COPD or asthma is also at high risk for adverse cardiac events (previous infarction, anterior AMI, advanced age, left ventricular systolic dysfunction and complex ventricular ectopy) (6), a physician may choose to initiate beta-blocker therapy in the belief that the benefits of lower mortality and re-infarction outweigh the risks associated with bronchospasm.

There are several ways to carefully initiate beta-blocker therapy in patients with COPD or asthma in order to reduce the risk of adverse pulmonary events. The clinician may choose to start patients on a short course of beta-blockers with frequent follow-up. Alternatively, physicians may wish to employ an “N of 1 trial,” where a single patient is randomized to either active drug or placebo. Symptoms or adverse events are recorded to assess tolerance to therapy, with crossover occurring after a predetermined period (16- 17). The use of a short-acting beta-blocker in a supervised setting may also be a helpful method to identify patients with COPD or asthma who are likely to tolerate chronic beta-blockade. In a study involving 114 patients with AMI with relative contraindications to beta-blockers (including 31 with COPD or asthma), patients who tolerated a maintenance dose of esmolol >100 μg/kg/min tolerated oral beta-blocker therapy without adverse effects (18). Regardless of the method of initiating beta-blockers, beta₁-selective agents should be used instead of nonselective agents for the treatment of AMI in patients with COPD or asthma (19). However, even beta₁-selective blockers should be used with caution in patients with pulmonary disease, as cardioselective beta-blockers are not without some beta₂ effect, and lung and other organs contain a mix of beta₁ and beta₂ adrenergic receptors (20).

Our study was unable to conclusively demonstrate a survival benefit from beta-blocker therapy in patients with COPD or asthma who were on beta-agonists. However, the point estimate of efficacy is similar to that of patients with COPD or asthma who were not taking beta-agonists, or patients without pulmonary disease, suggesting that our analysis may have been underpowered in this group. Alternatively, it is possible that the use of beta-agonists may diminish the efficacy of beta-blockers in reducing mortality after AMI. Although the extent of this phenomenon has not been well studied, drug manufacturers warn that albuterol and other beta₂ agonists may inhibit the effects of beta-blocker medications (21). With respect to lack of benefit in patients with more severe pulmonary disease, it is possible that these patients were less likely to tolerate beta-blocker therapy, and more prone to receive a lower dosage or to discontinue use after discharge. A higher rate of noncompliance or lower dosing practice would have biased the relationship between beta-blockers and lower mortality toward a finding of no benefit.

Our findings both confirm and contrast with the results from another study using the CCP database to examine beta-blocker effectiveness after AMI (22). Gottlieb et al. (22) found that beta-blockers were associated with reduced mortality after AMI in patients with COPD or asthma. However, because their study did not stratify by severity of disease, it suggested that beta-blockers were effective in all patients with COPD or asthma, a benefit we did not find in patients with more severe disease. The unstratified analysis may also explain why their estimate of beta-blocker effectiveness in patients with COPD (RR reduction of 40%) was greater than that found in the current study (RR reduction of 14%). If patients with less severe COPD were both intrinsically healthier and more likely to receive beta-blockers than those with more severe disease, an unstratified analysis would be biased toward finding a greater benefit for COPD patients treated with beta-blocker therapy, compared with an analysis stratified by severity of disease (23).

Our findings that rate of re-admission for COPD or asthma was similar between treatment and placebo groups are consistent with data from clinical trials that included some patients with COPD. In the MIAMI study, 18 out of 2,877 patients in the treatment arm experienced an “adverse respiratory event” compared with 19 out of 2,901 patients in the placebo arm (24). In the Göteborg trial, adverse pulmonary events were not specified, but 36 out of 686 patients receiving metoprolol withdrew for “side effects” or “other causes” compared with 33 out of 686 patients receiving placebo (9).

Our study has several limitations. First, nonrandomized retrospective studies are subject to the possibility of confounding. Patients with COPD or asthma who were best able to tolerate beta-blockers may have been those most likely to receive the therapy, associating beta-blocker therapy with patients with less severe pulmonary disease (and thus lower mortality) and no increased risk for hospital re-admission. Second, we do not have information regarding long-term compliance with therapy in the year after discharge, and we may have misclassified long-term patterns of use in some patients. However, the bias resulting from this misclassification would diminish any benefit associated with beta-blockers, and we did find a benefit of beta-blockers in patients with COPD or asthma who were not prescribed beta-agonists. Third, our stratification method of using pharmacotherapy and previous COPD and asthma admissions may not accurately reflect physiologic markers of severity of disease. However, our finding of significant differences in the likelihood of receiving beta-blockers, one-year mortality and re-admission for COPD or asthma across these categories suggests that these definitions reflect clinically meaningful categories of disease severity. Fourth, our ability to identify contraindications to beta-blocker therapy and adjust for confounding risk factors was limited by the information documented in the medical charts. However, our estimates of beta-blocker effectiveness are similar to those in randomized clinical trials (1). Lastly, we were unable to assess adverse effects from beta-blocker therapy that did not lead to hospitalization or admissions that occurred after six months of follow-up.

Our findings suggest that patients with COPD or asthma who are not using beta-agonists may be a group in whom the benefits of beta-blocker therapy outweigh the risks. Although there is no doubt that beta-blockers are contraindicated in many individual patients, these patients may represent a group with sufficiently mild disease for which a trial of beta-blocker therapy after AMI would be merited. Increasing the use of beta-blocker therapy among patients with relatively mild COPD or asthma would represent an opportunity to improve the care and outcomes of these patients after AMI.

We are indebted to all the health care professionals, hospitals and organizations that contributed to the development and implementation of the Cooperative Cardiovascular Project, and to Ms. Maria Johnson for her outstanding editorial assistance.