Cardioselective β-Blockers in Patients with Reactive Airway Disease: A Meta-Analysis FREE

–The Editors

β-Adrenergic blocking agents, or β-blockers, are indicated in the management of angina pectoris, myocardial infarction, hypertension, congestive heart failure, cardiac arrhythmia, and thyrotoxicosis and are given to reduce perioperative complications (1 - 13). Despite clear evidence of the effectiveness and mortality benefit of these drugs, clinicians are often hesitant to administer them in patients with some common conditions for fear of adverse reactions (14 - 17).

Many patients with reactive airway disease, with or without a chronic obstructive component, have concomitant conditions such as hypertension or cardiac arrhythmias, which necessitate the use of β-blockers. However, review articles and practice guidelines usually list asthma and chronic obstructive pulmonary disease (COPD) as contraindications to β-blocker use, citing cases of acute bronchospasm during administration of noncardioselective β-blockers (6,10,18 - 22). Cardioselective β-blockers, or β₁-blockers, have greater than 20 times more affinity for β₁ receptors than for β₂ receptors and in theory should pose much less risk for bronchoconstriction (23).

We used data from randomized, blinded, placebo-controlled trials to evaluate the effect of cardioselective β₁-blockers on respiratory function in patients with reactive airway disease (defined as asthma or COPD with a reversible obstructive component). We also sought to evaluate the respiratory response to β₂-agonists administered after β₁-blockers or after placebo in the same participants. This analysis has already been published as a review in the Cochrane Library (24).

We chose to evaluate only patients with documented reactive airway disease because these patients are thought to be particularly susceptible to the adverse respiratory effects of β-blockers. Patients with COPD are generally at greater risk for ischemic heart disease than are patients with asthma and thus may benefit more from the use of β-blockers. This study evaluates a subgroup of patients with a documented chronic obstructive component of disease but was not designed to make recommendations about patients with COPD. A recent meta-analysis evaluated the use of cardioselective β-blockers in patients with COPD, given as a single dose or as continued treatment (25). Pooled data from 19 trials demonstrated no adverse effect on FEV₁ or respiratory symptoms for β₁-blockers compared to placebo, even in patients with severe chronic airway obstruction.

A search was performed to identify all relevant published clinical trials that addressed the effects of cardioselective β-blockers on airway function in patients with reactive airway disease. Two investigators jointly developed strategies with the help of an information service librarian and the Cochrane Airways Group Trial Search Coordinator. The EMBASE, MEDLINE, and CINAHL databases were searched comprehensively to identify all relevant clinical trials in humans published between 1966 and May 2001. The search was performed by using the Cochrane Airways Group registry to identify randomized, blinded, placebo-controlled trials of reactive airways disease. Terms used in the search were asthma *, bronchial hyperreactivity *, respiratory sounds *, wheez *, obstructive lung disease * and obstructive airway disease *. Trials of β-blockers were sought by using the terms adrenergic antagonist *, sympatholytic * and adrenergic receptor block *. Trials were not excluded on the basis of language. The search was further augmented by scanning references of identified articles, reviews, and abstracts at clinical symposia.

Two investigators independently evaluated studies for inclusion. In choosing articles, investigators were blinded to results but not to journal, author, or institution of studies. The observed interrater agreement for the assessment of inclusion was calculated as a percentage. For all clinical trials identified from the search, investigators determined whether the β-blocker used was cardioselective and whether it was considered to have intrinsic sympathomimetic activity (1,26 - 36). Studies were evaluated if intravenous or oral cardioselective β-blockers were administered as a single dose or as continued treatment lasting 3 days or longer.

Single-dose trials were included if 1) FEV₁ at rest was reported, either as liters or as a percentage of the normal predicted value at baseline and at follow-up; 2) β₂-agonists were withheld for at least 8 hours before initial FEV₁ measurement; 3) patients were not selected on the basis of previous response to β-blockers; 4) the study was randomized, placebo-controlled, and single- or double-blinded; and 5) only patients with documented reactive airway disease were included. Reactive airway disease was demonstrated by a mean increase of at least 15% in FEV₁ in response to β₂-agonist, response to methacholine challenge, or presence of asthma as defined by the American Thoracic Society (37). Crossover trials were included if different interventions were administered in random order.

We decided a priori that inclusion criteria 3, 4, and 5 would be applied to trials of continued treatment. Studies of continued treatment were included if they did not report FEV₁ but instead evaluated the amount of β₂-agonist use and respiratory symptoms compared with placebo. Trials were also included if β₂-agonists were not withheld during the trial.

The methodologic quality of each trial was assessed according to the following factors: 1) Was the study randomized? If so, was the randomization procedure adequate, and was allocation concealed? 2) Were the patients and people administering the treatment blinded to the intervention? 3) Were withdrawals and dropouts described, and was the analysis performed on an intention-to-treat basis? On the basis of these criteria, studies were broadly subdivided as all quality criteria met (A), one or more quality criteria only partially met (B), or one or more criteria not met (C).

Clinical trials that did not meet criteria for inclusion but gave information on FEV₁ response to cardioselective β-blockers in patients with reactive airway disease were analyzed separately and used in a sensitivity analysis. These included studies that were not placebo-controlled; did not document asthma criteria; did not give baseline FEV₁ data; or, for single-dose studies, did not withhold β₂-agonists for 8 hours before measurements.

The main intervention of interest was intravenous or oral cardioselective β-blockers versus placebo, given as a single dose or as continued treatment. Administration of a β₂-agonist, intravenously or by inhalation, after the study medication or after placebo was also studied.

Each β₁-blocker used was classified into one of two categories: β₁-blockers without intrinsic sympathomimetic activity, and β₁-blockers with intrinsic sympathomimetic activity.

Two investigators independently extracted data on change in mean group FEV₁ in response to placebo or study drug; response of FEV₁ to β₂-agonist administered after placebo or study drug; symptoms reported during the trial, such as wheezing, dyspnea, or exacerbation of asthma; and, for trials of continued treatment, weekly use of inhaled short-acting β₂-agonists.

The ratio of the lowest group FEV₁ value after administration of study drug to baseline FEV₁ was measured for placebo and active treatment and was recorded as the percentage change from baseline. The placebo response was then subtracted from the treatment response to obtain the net treatment effect, reported as a percentage of the baseline FEV₁ value. For response to β₂-agonists given after treatment or placebo, the new baseline value was the mean group FEV₁ value obtained after study drug but before β₂-agonist administration. The net treatment effect was estimated by calculating the ratio of FEV₁ measured after agonist administration to the new baseline value for both placebo and active treatment and then subtracting the placebo–agonist response from the treatment–agonist response.

Whenever possible, the SD for the net treatment effect was calculated from individual-patient data or P values and was then used to derive the SDs for the analysis. Some trials provided SDs for treatment response and placebo response separately. For trials that reported no information on SDs, the average SD was obtained from trials that provided such data, calculated separately for placebo, treatment, and β-agonist responses. Sensitivity analyses were performed to evaluate the effect of including these trials by using the lowest and highest available SD in place of the pooled SD and also by excluding these trials from the analysis. The Appendix Table shows the method used to obtain SDs for each trial.

The mean treatment effects were pooled to obtain a weighted average of the study means using the fixed-effects model for continuous outcomes (38 - 39). Confidence intervals with 95% significance were obtained for the pooled study means. The analysis was performed by using Meta View 4.1 (Cochrane Library software [Update Software, Oxford, United Kingdom]).

Results for respiratory symptoms were measured as a risk difference by subtracting the percentage of patients with respiratory events during treatment from the percentage of patients with respiratory events during placebo use. The risk differences were then pooled by using the fixed-effects model for dichotomous outcomes. The results for inhaler use during continued treatment trials were measured as the incidence of use during placebo minus the incidence of use during treatment. The weighted mean treatment effects were pooled by using the fixed-effects model for continuous outcomes.

To test for interstudy heterogeneity, the chi-square value was calculated for the assumption of homogeneity. In addition, the confidence intervals from the fixed-effects model were compared with those from the random-effects model (40). The fixed-effects model was chosen to report the results because minimal heterogeneity was seen in most of the analyses. When heterogeneity was noted, the results from both the random-effects model and fixed-effects model were reported.

A subgroup analysis was performed to compare the treatment effects of cardioselective β-blockers with and without intrinsic sympathomimetic activity. Another analysis was done to evaluate the response of patients with concomitant chronic airways obstruction, defined as a baseline FEV₁ of less than 80% of the normal predicted value or less than 1.8 L, or defined by using American Thoracic Society criteria (41). A third subgroup analysis evaluated the treatment response in participants known to have comorbid cardiovascular conditions, such as hypertension.

The Appendix Figure shows the results of the search for articles. The database search identified 200 potentially relevant articles. After review of articles and bibliographies, 104 trials of β-blockers in patients with reactive airway disease were found. Of these trials, 29 met inclusion criteria: Nineteen gave information on singe-dose studies (42 - 60) and 10 provided data on continued treatment of longer duration (28,51,61 - 68). One of the articles (51) gave data for both types of administration. Interrater agreement for study eligibility was 94%. Consensus was reached on the remaining trials. The Appendix Table shows the characteristics of the included studies.

Clinical trials that did not meet inclusion criteria but gave data on FEV₁ responses to cardioselective β-blockers in patients with reactive airway disease were analyzed separately and used in a sensitivity analysis (69 - 78).

All studies were small crossover trials that received a quality score of B because the randomization process was not described in detail or the trial was single-blind instead of double-blind. Many of the trials were performed 20 or 30 years ago and did not provide adequate information with which to calculate SDs for the net treatment effect. Sensitivity analyses were performed to evaluate the effect of including trials that provided no information on SDs.

Nineteen studies of single-dose treatment included 240 patients, 79% of whom were men. Each study included an average of 12.6 patients, and the total dropout rate was 2.0%. From the available information, the age range of participants was 19.5 to 65.1 years (mean, 40.1 years). These baseline characteristics were the same for the placebo and treatment groups. The baseline FEV₁ was 2.41 ± 0.15 L in the treatment group and 2.42 ± 0.2 L in the placebo group. Cardioselective β-blockers without intrinsic sympathomimetic activity that were included in the study were atenolol, metoprolol, bisoprolol, and practolol. Cardioselective β-blockers with intrinsic sympathomimetic activity that were studied were celiprolol, acebutolol, and xamoterol.

Compared with placebo, single doses of cardioselective β-blockers as a group were associated with a 7.46% (CI, 5.59% to 9.32%) reduction in FEV₁ but with a 4.63% (CI, 2.47% to 6.78%) increase in FEV₁ after β-agonist was given (Figures 1 and 2). The number of patients with respiratory symptoms did not increase significantly in any of the 19 studies (0.01% [CI, −0.02% to 0.03%]).

Data from 10 studies involving 141 participants (77% of whom were men) were evaluated for response to continued treatment ranging from 3 days to 4 weeks. Each study contained an average of 15.4 patients, and the dropout rate was 1.3%. From the available information, the average age of the participants was 51.3 years. The average baseline FEV₁ was 1.81 ± 0.13 L for the treatment group and 1.81 ± 0.15 L for the placebo group. Five of the studies (54 participants) did not provide data on FEV₁; these studies were included in analyses of symptoms and inhaler use.

In the continued treatment trials, cardioselective β-blockers as a group did not significantly differ from placebo in terms of FEV₁ response (−0.42% [CI, −3.74% to 2.91%]), number of patients with symptoms (0.01% [CI, −0.02% to 0.04%]), or incidence of inhaler use (−0.11% [CI, −6.75% to 6.54%]). Cardioselective β-blockers produced an 8.74% increase (CI, 1.96% to 15.52%) in FEV₁ compared with placebo after β-agonist was given (Figures 3 and 4).

No significant interstudy variance was found in FEV₁ treatment effect, symptoms, and long-term use of an inhaler. Heterogeneity was detected between studies in FEV₁ after β₂-agonist use in both the single-dose and continued treatment studies. This heterogeneity was noted only for β-blockers without intrinsic sympathomimetic activity. When the random-effects model was compared with the fixed-effects model for the β₂-agonist response in patients who received β-blockers without intrinsic sympathomimetic activity, a difference of less than 1 percentage point was found for single-dose studies (5.66% [CI, 1.81% to 9.51%] vs. 6.59% [CI, 4.18% to 9.01%]) and a difference of 1.7 percentage points was found for continued treatment studies (10.32% [CI, −6.38% to 27.01%] vs. 12.0% [CI, 4.12% to 19.89%]).

For single-dose trials, β₁-blockers without intrinsic sympathomimetic activity were associated with a 6.5% reduction in FEV₁ (CI, 2.2% to 10.7%) compared to those with sympathomimetic activity. However, treatment with β₁-blockers without intrinsic sympathomimetic activity was associated with a 9.7% increase in FEV₁ in response to β-agonist (CI, 5.6 to 13.7%) compared to those with sympathomimetic activity. In the continued treatment trials, no significant difference in FEV₁ response was observed for β₁-blockers without intrinsic sympathomimetic activity compared to those with sympathomimetic activity (5.94% [CI, −0.73% to 12.61%]). However, β-blockers without intrinsic sympathomimetic activity produced a 12.6% increase in FEV₁ (CI, 0.3% to 25.6%) after β-agonist administration compared to β-blockers with sympathomimetic activity.

To evaluate the treatment effect in patients with concomitant COPD, 10 trials that included only patients with documented chronic airway obstruction were analyzed separately (46,52 - 53,59,61,63 - 66,68). No significant difference in FEV₁ treatment effect was observed in single-dose trials (−5.28% [CI, −10.03% to −0.54%]) or continued treatment (1.07% [CI, −3.3% to 5.44%]), and no increase in symptoms occurred in any of the trials.

In eight of the trials, all participants had a comorbid condition, such as hypertension (46,51 - 52,61,63,65,67 - 68). When only these trials were included in the analysis, the treatment effect for FEV₁ did not change significantly in single-dose trials (−6.83% [CI, −11.46% to −2.20%]) or with continued treatment (1.31% [CI, −2.62% to 5.24%]).

A sensitivity analysis was performed to evaluate the effect of including studies that did not provide SDs (46,55 - 56,60). When these trials were excluded from the analysis, the difference in all variables measured was less than 0.5 percentage point. When the analysis was performed by replacing the pooled SD with the lowest and highest available SD, the difference in results between the highest and lowest SD was 2 percentage points or less.

A sensitivity analysis was also performed to evaluate the effect of excluding trials that did not meet the inclusion criteria set by the study but that provided information on FEV₁ and symptoms for cardioselective β-blocker use in patients with reactive airway disease (69 - 78). Data analysis of 10 excluded studies with 141 participants showed no significant difference in any variables compared with studies that met inclusion criteria.

Our results indicate that the first dose of a cardioselective β-blocker produces a small decrease in FEV₁ that is not associated with adverse respiratory effects compared to placebo. After continued treatment for a few days to weeks, FEV₁, symptoms, and inhaler use did not differ. Cardioselective β-blockers, given as a single dose or as continued treatment, were associated with an increase in response to β₂-agonists compared with placebo. Of the 80 trials on cardioselective β-blockers that we identified, none demonstrated an increase in respiratory symptoms for β₁-blockers compared with placebo or baseline values.

Subgroup analyses were performed to evaluate the effect of cardioselective β-blockers on patients with concomitant COPD or cardiovascular diseases, such as hypertension, because these patients are most often targeted for β-blocker treatment. No significant difference in the FEV₁ treatment effect or incidence of symptoms or inhaler use was observed.

Our meta-analysis has several limitations. Most of the participants were relatively young and had mild to moderate airway obstruction; persons with recent exacerbation of asthma were often excluded from study. In addition, because many of the studies were of short duration, we cannot comment on the effect of cardioselective β-blockers on the frequency or severity of acute asthma exacerbations after several months of treatment. Furthermore, this analysis was based only on published literature and therefore is subject to publication bias. However, funnel plots of effect size versus standard error for the trials in this analysis showed no evidence of bias. We believe that these pooled results provide valuable information on the safety of cardioselective β-blockers in patients with reactive airway disease, with or without concomitant COPD or cardiovascular disease.

The current standard of care is to consider reactive airway disease to be a contraindication to the use of all β-blockers (6,10,18 - 22). Because of the proven mortality benefit of β-blockers, many of the other relative or absolute contraindications traditionally listed for β-blockers, including impaired left ventricular function, peripheral vascular disease, diabetes mellitus, depression, and advanced age (7,14,79 - 87), have been questioned and disproved.

The original evidence of a potential adverse effect of β-blockers in reactive airway disease was based on case reports of acute bronchospasm precipitated by high doses of noncardioselective blockers, presumably due to their blockade of β₂ receptors on bronchial smooth muscle (88 - 91). Pooled results of 16 trials that evaluated noncardioselective β-blockers showed that regular use of nonselective β-blockers compared with placebo caused a 13.5% decrease (CI, − 23.0% to −4.0%) in FEV₁ and a 22.5% decrease (CI, −32.5% to −12.5%) in the FEV₁ response after β₂-agonists were given (24,32,34,43,48,52,55 - 57,59,61,68,92 - 96). No significant increase in symptoms or inhaler use was found. However, the decrease in β-agonist response seen with nonselective β-blockers may increase the risk for a clinically significant adverse effect during an exacerbation of asthma.

Cardioselective β-blockers, such as atenolol, bisoprolol, and metoprolol, are at least 20 times more effective at blocking β₁-receptors than β₂-receptors; thus, at therapeutic doses, their β₂-blocking effect is negligible (23). The doses of β₁-blockers that we evaluated ranged from therapeutic to mildly supratherapeutic. For example, single-dose studies using atenolol or metoprolol in doses ranging from 50 to 200 mg showed no clinically apparent effect on respiratory function. Linear regression analysis could not differentiate a treatment effect between low and high doses because there were few low-dose trials and no trials used doses high enough to diminish cardioselectivity.

Our results indicate that for cardioselective β-blockers without intrinsic sympathomimetic activity, the minimal decrease in FEV₁ noted with a single dose is attenuated over a few days to weeks. In addition, FEV₁ increases in response to β₂-agonist administration compared with placebo, and this increase is maintained with continued treatment. These results could be explained by upregulation or sensitization of β₂ receptors that is accompanied by an increased effect of endogenous or exogenous β₂-agonist stimulation (97 - 99). Accumulating evidence indicates that continued use of inhaled β₂-agonists in patients with reactive airway disease is associated with a tolerance to β₂-agonist stimulation and an increase in asthma attacks (100 - 105). There is also evidence that treatment with β-blockers that have intrinsic β₂ sympathomimetic activity is associated with downregulation of β₂ receptors (106 - 109). This finding is consistent with data from our analysis showing that β-blockers with intrinsic sympathomimetic activity did not produce the increase in β₂-agonist response that was seen with β-blockers without intrinsic sympathomimetic activity.

Only a small proportion of patients with heart disease who would benefit from β-blockers currently receive this treatment, mainly owing to unfounded fears about their adverse effects (110 - 113). A study of survivors of myocardial infarction included 46 000 patients with asthma and chronic obstructive lung disease and showed a significant reduction in total mortality rate among those treated with β-blockers compared with those who were not (14). Other studies of the use of β-blockers in patients with cardiac disease and concomitant chronic obstructive lung disease or asthma found that these medicines were well tolerated (114 - 116). Other trials evaluating the use of β-blockers in hypertensive patients, many of whom had reactive airway disease, did not demonstrate worsening of respiratory symptoms or FEV₁ in these patients (32,92,117 - 118). A recent study showed that COPD and asthma were the comorbid conditions most commonly associated with β-blockers' being withheld in elderly patients after a myocardial infarction (119).

Patients with COPD are thought to be at greater risk than those with reactive airway disease for developing ischemic heart disease and other cardiovascular conditions requiring the use of β-blockers. However, the presenting features of COPD and reactive airway disease overlap substantially.

Another recent meta-analysis evaluated the effect of cardioselective β-blockers in patients with COPD and found no change in FEV₁ or respiratory symptoms for single doses or continued use of these agents compared with placebo (25). Subgroup analyses revealed no difference in results for patients with concomitant reactive airway disease and those with severe chronic airways obstruction, as demonstrated by a baseline FEV₁ less than 1.4 L or less than 50% the normal predicted value. Three of the trials from that meta-analysis are also included in our analysis (52,61,66). The cumulative evidence from these two meta-analyses indicates that cardioselective β-blockers should not be withheld in patients with reactive airway disease or COPD.