Document NeRmQxMa4bnEoyvnkEOL4gLRp

Article Cardioselective -Blockers in Patients with Reactive Airway Disease: A Meta-Analysis Shelley R. Salpeter, MD; Thomas M. Ormiston, MD; and Edwin E. Salpeter, PhD Objective: To assess the effect of cardioselective -blockers on respiratory function of patients with reactive airway disease. Data Sources: Comprehensive searches of the EMBASE, MED- LINE, and CINAHL databases from 1966 to May 2001 and scanning of references of the identified articles and related reviews. Study Selection: Randomized, blinded, placebo-controlled trials that studied the effects of cardioselective -blockers on FEV1, symptoms, and the use of inhaled 2-agonists in patients with reactive airway disease were selected. Interventions studied were the administration of a cardioselective -blocker and administration of 2-agonist after the study drug. Data Extraction: Outcomes measured were the change in FEV1 from baseline, the number of patients with respiratory symptoms, and the use of inhaled 2-agonists with active treatment compared with placebo. Data Synthesis: Nineteen studies on single-dose treatment and 10 studies on continued treatment were included. Administration of a single dose of a cardioselective -blocker was associated with a 7.46% (95% CI, 5.59% to 9.32%) decrease in FEV1 and a 4.63% (CI, 2.47% to 6.78%) increase in FEV1 response to -ag- onist compared with placebo, with no increase in symptoms. Trials lasting from 3 days to 4 weeks produced no significant change in FEV1 (0.42% [CI, 3.74% to 2.91%]), symptoms, or inhaler use compared with placebo but maintained an 8.74% (CI, 1.96% to 15.52%) increase in -agonist response. No significant treatment effect in terms of FEV1 was found in patients with concomitant chronic obstructive pulmonary disease, whether sin- gle doses (change in FEV1, 5.28% [CI, 10.03% to 0.54%]) or continued treatment (change in FEV1, 1.07% [CI, 3.3% to 5.44%]) was given. Conclusions: Cardioselective -blockers do not produce clini- cally significant adverse respiratory effects in patients with mild to moderate reactive airway disease. The results were similar for patients with concomitant chronic airways obstruction. Given their demonstrated benefit in such conditions as heart failure, cardiac arrhythmias, and hypertension, cardioselective -blockers should not be withheld from patients with mild to moderate reactive airway disease. Ann Intern Med. 2002;137:715-725. For author affiliations, see end of text. See editorial comment on pp 766-767. www.annals.org -Adrenergic blocking agents, or -blockers, are indicated in the management of angina pectoris, myocar- dial infarction, hypertension, congestive heart failure, car- diac arrhythmia, and thyrotoxicosis and are given to reduce perioperative complications (113). 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 concomi- tant conditions such as hypertension or cardiac arrhythmias, which necessitate the use of -blockers. However, review articles and practice guidelines usually list asthma and chronic obstructive pulmonary disease (COPD) as contraindications to -blocker use, citing cases of acute bronchospasm during administration of noncardioselective -blockers (6, 10, 18 22). Cardioselective -blockers, or 1-blockers, have greater than 20 times more affinity for 1 receptors than for 2 receptors and in theory should pose much less risk for bronchoconstriction (23). We used data from randomized, blinded, placebocontrolled trials to evaluate the effect of cardioselective 1blockers on respiratory function in patients with reactive airway disease (defined as asthma or COPD with a revers- ible obstructive component). We also sought to evaluate the respiratory response to 2-agonists administered after 1-blockers or after placebo in the same participants. This analysis has already been published as a review in the Cochrane Library (24). METHODS Patients 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 -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 -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 -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 1-blockers compared to placebo, even in patients with severe chronic airway obstruction. Search Strategy A search was performed to identify all relevant pub- lished clinical trials that addressed the effects of cardioselective -blockers on airway function in patients with reactive airway disease. Two investigators jointly developed strategies with the help of an information service librarian 2002 American College of PhysiciansAmerican Society of Internal Medicine 715 Article Cardioselective -Blockers in Reactive Airway Disease: A Meta-Analysis Context Although -blockers improve clinical outcomes in many patients with cardiovascular disease, clinicians sometimes avoid these agents in patients with concomitant lung disease because they fear precipitation of acute bronchospasm. Contribution This meta-analysis of 29 randomized trials shows that cardioselective -blockers (1-blockers), given for a few days to a few weeks, do not significantly worsen pulmonary function or respiratory symptoms and do not lead to increased use of inhalers in patients with mild to moderate reactive (reversible) airway disease. Cautions The studies in this meta-analysis were short, evaluated only cardioselective -blockers, and did not include patients with severe or irreversible airway disease. The Editors 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 -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. Study Selection 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 -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 -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) 2-agonists were withheld for at least 8 hours before initial FEV1 measurement; 3) patients were not selected on the basis of 716 5 November 2002 Annals of Internal Medicine Volume 137 Number 9 previous response to -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 2-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 2-agonist use and respiratory symptoms compared with placebo. Trials were also included if 2-agonists were not withheld during the trial. Assessment of Validity 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 -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 2-agonists for 8 hours before measurements. Study Characteristics The main intervention of interest was intravenous or oral cardioselective -blockers versus placebo, given as a single dose or as continued treatment. Administration of a 2-agonist, intravenously or by inhalation, after the study medication or after placebo was also studied. Each 1-blocker used was classified into one of two categories: 1-blockers without intrinsic sympathomimetic activity, and 1-blockers with intrinsic sympathomimetic activity. Data Extraction Two investigators independently extracted data on change in mean group FEV1 in response to placebo or study drug; response of FEV1 to 2-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 2-agonists. www.annals.org ArticleCardioselective -Blockers in Reactive Airway Disease: A Meta-Analysis Data Synthesis 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 2-agonists given after treatment or placebo, the new baseline value was the mean group FEV1 value obtained after study drug but before 2-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 placeboagonist response from the treatmentagonist 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 -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 (available at www.annals.org) 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 fixedeffects 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. www.annals.org A subgroup analysis was performed to compare the treatment effects of cardioselective -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. DATA SYNTHESIS Search Results The Appendix Figure (available at www.annals.org) 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 -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 (available at www.annals.org) shows the characteristics of the included studies. Clinical trials that did not meet inclusion criteria but gave data on FEV1 responses to cardioselective -blockers in patients with reactive airway disease were analyzed separately and used in a sensitivity analysis (69 78). Methodologic Quality of Included Studies 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. Quantitative Data Synthesis Single-Dose Treatment 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 -blockers without intrinsic sympathomimetic activity that were included in the study were atenolol, metoprolol, bisoprolol, and practolol. Cardioselective -blockers with intrinsic sympathomimetic 5 November 2002 Annals of Internal Medicine Volume 137 Number 9 717 Article Cardioselective -Blockers in Reactive Airway Disease: A Meta-Analysis Figure 1. Effects of treatment on FEV1 for single-dose studies. Diamonds represent the extent of the confidence intervals. For group 1, test for heterogeneity, P 0.2; test for overall effect, P 0.001. For group 2, test for heterogeneity, P 0.05; test for overall effect, P 0.15. For both groups, test for heterogeneity, P 0.09; test for overall effect, P 0.001. activity that were studied were celiprolol, acebutolol, and xamoterol. Compared with placebo, single doses of cardioselective -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 -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%]). Continued Treatment Data from 10 studies involving 141 participants (77% of whom were men) were evaluated for response to contin- 718 5 November 2002 Annals of Internal Medicine Volume 137 Number 9 ued 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 -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, www.annals.org ArticleCardioselective -Blockers in Reactive Airway Disease: A Meta-Analysis 0.02% to 0.04%]), or incidence of inhaler use (0.11% [CI, 6.75% to 6.54%]). Cardioselective -blockers produced an 8.74% increase (CI, 1.96% to 15.52%) in FEV1 compared with placebo after -agonist was given (Figures 3 and 4). Interstudy Variance 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 2-agonist use in both the single-dose and continued treatment studies. This heterogeneity was noted only for -blockers without intrinsic sympathomimetic activity. When the random-effects model was compared with the fixed-effects model for the 2-agonist response in patients who received -blockers without intrinsic sympathomi- metic 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%]). Subgroup Analysis For single-dose trials, 1-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 1-blockers without intrinsic sympathomimetic activity was associated with a 9.7% increase in FEV1 in response to -agonist (CI, 5.6 to 13.7%) compared to those with sympathomimetic activity. In the continued treatment trials, Figure 2. Effects of treatment after use of 2-agonists on FEV1 for single-dose studies. Diamonds represent the extent of the confidence intervals. For group 1, test for heterogeneity, P 0.001; test for overall effect, P 0.001. For group 2, test for heterogeneity, P 0.2; test for overall effect, P 0.2. For both groups, test for heterogeneity, P 0.001; test for overall effect, P 0.001. www.annals.org 5 November 2002 Annals of Internal Medicine Volume 137 Number 9 719 Article Cardioselective -Blockers in Reactive Airway Disease: A Meta-Analysis Figure 3. Effects of treatment on FEV1 for continued treatment studies. Diamonds represent the extent of the confidence intervals. For group 1, test for heterogeneity, P 0.2; test for overall effect, P 0.17. For group 2, test for overall effect, P 0.2. For both groups, test for heterogeneity, P 0.18; test for overall effect, P 0.2. no significant difference in FEV1 response was observed for 1-blockers without intrinsic sympathomimetic activity compared to those with sympathomimetic activity (5.94% [CI, 0.73% to 12.61%]). However, -blockers without intrinsic sympathomimetic activity produced a 12.6% increase in FEV1 (CI, 0.3% to 25.6%) after -agonist administration compared to -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 singledose 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%]). Sensitivity Analysis 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 720 5 November 2002 Annals of Internal Medicine Volume 137 Number 9 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 -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. DISCUSSION Our results indicate that the first dose of a cardioselective -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 -blockers, given as a single dose or as continued treatment, were associated with an increase in response to 2-agonists compared with placebo. Of the 80 trials on cardioselective -blockers that we identified, none demonstrated an increase in respiratory symptoms for 1-blockers compared with placebo or baseline values. Subgroup analyses were performed to evaluate the effect of cardioselective -blockers on patients with concom- www.annals.org ArticleCardioselective -Blockers in Reactive Airway Disease: A Meta-Analysis itant COPD or cardiovascular diseases, such as hypertension, because these patients are most often targeted for -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 -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 -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 -blockers (6, 10, 18 22). Because of the proven mortality benefit of -blockers, many of the other relative or absolute contraindications traditionally listed for -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 -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 2 receptors on bronchial smooth muscle (88 91). Pooled results of 16 trials that evaluated noncardioselective -blockers showed that regular use of nonselective -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 2-agonists were given (24, 32, 34, 43, 48, 52, 55 57, 59, 61, 68, 9296). No significant increase in symp- toms or inhaler use was found. However, the decrease in -agonist response seen with nonselective -blockers may increase the risk for a clinically significant adverse effect during an exacerbation of asthma. Cardioselective -blockers, such as atenolol, bisopro- lol, and metoprolol, are at least 20 times more effective at blocking 1-receptors than 2-receptors; thus, at therapeutic doses, their 2-blocking effect is negligible (23). The doses of 1-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 re- spiratory function. Linear regression analysis could not dif- ferentiate 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 -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 Figure 4. Effects of treatment after use of 2-agonists on FEV1 for continued treatment studies. Diamonds represent the extent of the confidence intervals. For group 1, test for heterogeneity, P 0.013; test for overall effect, P 0.003. For group 2, test for overall effect, P 0.2. For both groups, test for heterogeneity, P 0.01; test for overall effect, P 0.01. www.annals.org 5 November 2002 Annals of Internal Medicine Volume 137 Number 9 721 Article Cardioselective -Blockers in Reactive Airway Disease: A Meta-Analysis response to 2-agonist administration compared with placebo, and this increase is maintained with continued treatment. These results could be explained by upregulation or sensitization of 2 receptors that is accompanied by an increased effect of endogenous or exogenous 2-agonist stimulation (9799). Accumulating evidence indicates that continued use of inhaled 2-agonists in patients with reactive airway disease is associated with a tolerance to 2agonist stimulation and an increase in asthma attacks (100 105). There is also evidence that treatment with -blockers that have intrinsic 2 sympathomimetic activity is associated with downregulation of 2 receptors (106 109). This finding is consistent with data from our analysis showing that -blockers with intrinsic sympathomimetic activity did not produce the increase in 2-agonist response that was seen with -blockers without intrinsic sympathomimetic activity. Only a small proportion of patients with heart disease who would benefit from -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 -blockers compared with those who were not (14). Other studies of the use of -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 -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 -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 -blockers. However, the presenting features of COPD and reactive airway disease overlap substantially. Another recent meta-analysis evaluated the effect of cardioselective -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 -blockers should not be withheld in patients with reactive airway disease or COPD. 722 5 November 2002 Annals of Internal Medicine Volume 137 Number 9 From Stanford University School of Medicine, Palo Alto, California; Santa Clara Valley Medical Center, San Jose, California; and Cornell University, Ithaca, New York. Acknowledgments: The authors thank Steve Milan for guidance with the Cochrane review, Toby Lasserson for technical assistance, and Karen Blackhall for coordinating the trials search. Requests for Single Reprints: Shelley Salpeter, MD, Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128; e-mail, shelley.salpeter@hhs.co.santa-clara .ca.us. Current author addresses and author contributions are available at www .annals.org. References 1. Wadworth AN, Murdoch D, Brogden RN. Atenolol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders. Drugs. 1991;42:468-510. [PMID: 1720383] 2. Heidenreich PA, McDonald KM, Hastie T, Fadel B, Hagan V, Lee BK, et al. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA. 1999;281:1927-36. [PMID: 10349897] 3. Frishman WH, Furberg CD, Friedewald WT. Beta-adrenergic blockade for survivors of acute myocardial infarction. N Engl J Med. 1984;310:830-7. [PMID: 6142420] 4. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999; 318:1730-7. [PMID: 10381708] 5. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). The IPPPSH Collaborative Group. J Hypertens. 1985;3:379-92. [PMID: 2864374] 6. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157: 2413-46. [PMID: 9385294] 7. Lechat P, Packer M, Chalon S, Cucherat M, Arab T, Boissel JP. Clinical effects of beta-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation. 1998;98:118491. [PMID: 9743509] 8. Doughty RN, Rodgers A, Sharpe N, MacMahon S. Effects of beta-blocker therapy on mortality in patients with heart failure. A systematic overview of randomized controlled trials. Eur Heart J. 1997;18:560-5. [PMID: 9129883] 9. Steinbeck G, Andresen D, Bach P, Haberl R, Oeff M, Hoffmann E, et al. A comparison of electrophysiologically guided antiarrhythmic drug therapy with beta-blocker therapy in patients with symptomatic, sustained ventricular tachyarrhythmias. N Engl J Med. 1992;327:987-92. [PMID: 1355595] 10. Kendall MJ. Clinical relevance of pharmacokinetic differences between beta blockers. Am J Cardiol. 1997;80:15J-19J. [PMID: 9375944] 11. Klein I, Becker DV, Levey GS. Treatment of hyperthyroid disease. Ann Intern Med. 1994;121:281-8. [PMID: 7518659] 12. Jones MK, John R, Jones GR. The effect of oxprenolol, acebutolol and propranolol on thyroid hormones in hyperthyroid subjects. Clin Endocrinol (Oxf). 1980;13:343-7. [PMID: 7438476] 13. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med. 1996;335:1713-20. [PMID: 8929262] 14. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med. 1998;339:489-97. [PMID: 9709041] 15. Kennedy HL, Rosenson RS. Physician use of beta-adrenergic blocking therapy: a changing perspective [Editorial]. J Am Coll Cardiol. 1995;26:547-52. [PMID: 7608462] www.annals.org ArticleCardioselective -Blockers in Reactive Airway Disease: A Meta-Analysis 16. Viskin S, Barron HV. Beta blockers prevent cardiac death following a myocardial infarction: so why are so many infarct survivors discharged without beta blockers? [Editorial] Am J Cardiol. 1996;78:821-2. [PMID: 8857489] 17. Chafin CC, Soberman JE, Demirkan K, Self T. Beta-blockers after myocardial infarction: do benefits ever outweigh risks in asthma? Cardiology. 1999;92: 99-105. [PMID: 10702651] 18. Craig T, Richerson HB, Moeckli J. Problem drugs for the patient with asthma. Compr Ther. 1996;22:339-44. [PMID: 8814381] 19. Belli G, Topol EJ. Adjunctive pharmacologic strategies for acute MI. Contemp Intern Med. 1995;7:51-9. [PMID: 10150611] 20. O'Malley K, Cox JP, O'Brien E. Choice of drug treatment for elderly hypertensive patients. Am J Med. 1991;90:27S-33S. [PMID: 2006657] 21. Tattersfield AE. Beta adrenoceptor antagonists and respiratory disease. J Cardiovasc Pharmacol. 1986;8 Suppl 4:S35-9. [PMID: 2427850] 22. Tattersfield AE. Respiratory function in the elderly and the effects of beta blockade. Cardiovasc Drugs Ther. 1991;4 Suppl 6:1229-32. [PMID: 1672601] 23. Wellstein A, Palm D, Belz GG, Butzer R, Polsak R, Pett B. Reduction of exercise tachycardia in man after propranolol, atenolol and bisoprolol in comparison to beta-adrenoceptor occupancy. Eur Heart J. 1987;8 Suppl M:3-8. [PMID: 2897299] 24. Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blocker use in patients with reversible airway disease (Cochrane Review). The Cochrane Library. Oxford: Update Software; 2001:2. 25. Salpeter S, Ormiston T, Salpeter E, Poole P, Cates C. Cardioselective beta-blocker use in patients with COPD. (Cochrane Review). The Cochrane Library. Oxford: Update Software; 2002:2. 26. Lois M, Honig E. Beta-blockade post-MI: safe for patients with asthma or COPD? J Respir Dis. 1997;18:568-91. 27. Fitzgerald JD. The applied pharmacology of beta-adrenoceptor antagonists (beta blockers) in relation to clinical outcomes. Cardiovasc Drugs Ther. 1991;5: 561-76. [PMID: 1678960] 28. Nicolaescu V, Manicatide M, Stroescu V. -Adrenergic blockade with practolol in acetylcholine-sensitive asthma patients. Respiration. 1972;29:139-54. [PMID: 4401715] 29. Palmer KN, Hamilton WF, Lge JS, Diament ML. Effect of a selective beta-adrenergic blocker in preventing falls in arterial oxygen tension following isoprenaline in asthmatic subjects. Lancet. 1969;2:1092-4. [PMID: 4186991] 30. Lofdahl CG, Marlin GE, Svedmyr N. Pafenolol, a highly selective beta 1-adrenoceptor-antagonist, in asthmatic patients: interaction with terbutaline. Clin Pharmacol Ther. 1983;33:1-9. [PMID: 6129091] 31. Decalmer PB, Chatterjee SS, Cruickshank JM, Benson MK, Sterling GM. Beta-blockers and asthma. Br Heart J. 1978;40:184-9. [PMID: 25075] 32. Falliers CJ, Vrchota J, Blasucci DJ, Maloy JW, Medakovic M. The effects of treatments with labetalol and hydrochlorothiazide on ventilatory function of asthmatic hypertensive patients with demonstrated bronchosensitivity to propranolol. J Clin Hypertens. 1985;1:70-9. [PMID: 3836297] 33. Singh BN, Whitlock RM, Comber RH, Williams FH, Harris EA. Effects of cardioselective beta adrenoceptor blockade on specific airways resistance in normal subjects and in patients with bronchial asthma. Clin Pharmacol Ther. 1976; 19(5 Pt 1):493-501. [PMID: 6179] 34. Skinner C, Gaddie J, Palmer KN. Comparison of intravenous AH 5158 (ibidomide) and propranolol in asthma. Br Med J. 1975;2:59-61. [PMID: 236806] 35. Lois M, Roman J, Honig E. Using beta-blockers for CHF in patients with COPD. J Respir Dis. 1999;20:31-43. 36. Formgren H. Broncho-and cardioselective beta-receptor active drugs in the treatment of asthmatic patients. Clinical studies of effects and side effects of terbutaline, practolol and metoprolol. Scand J Respir Dis Suppl. 1977;97:1-37. [PMID: 266273] 37. Guidelines for the evaluation of impairment/disability in patients with asthma. American Thoracic Society. Medical Section of the American Lung Association. Am Rev Respir Dis. 1993;147:1056-61. [PMID: 8466106] 38. Mantel N, Haenszel WH. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719-48. 39. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335-71. [PMID: 2858114] www.annals.org 40. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-88. [PMID: 3802833] 41. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am J Respir Crit Care Med. 1995;152:S77-121. [PMID: 7582322] 42. Tantucci C, Bruni B, Dottorini ML, Peccini F, Motolese M, Lecaillon JB, et al. Comparative evaluation of cardioselectivity of metoprolol OROS and atenolol: a double-blind, placebo-controlled crossover study. Am Heart J. 1990; 120:467-72. [PMID: 2200257] 43. Chodosh S, Tuck J, Blasucci DJ. The effects of dilevalol, metoprolol, and placebo on ventilatory function in asthmatics. J Cardiovasc Pharmacol. 1988;11 Suppl 2:S18-24. [PMID: 2464094] 44. Lammers JW, Muller ME, Folgering HT, van Herwaarden CL. A comparative study on the ventilatory and haemodynamic effects of xamoterol and atenolol in asthmatic patients. Br J Clin Pharmacol. 1986;22:595-602. [PMID: 2878680] 45. Falliers CJ, Vincent ME, Medakovic M. Effect of single doses of labetalol, metoprolol, and placebo on ventilatory function in patients with bronchial asthma: interaction with isoproterenol. J Asthma. 1986;23:251-60. [PMID: 3771472] 46. Chatterjee SS. The cardioselective and hypotensive effects of bisoprolol in hypertensive asthmatics. J Cardiovasc Pharmacol. 1986;8 Suppl 11:S74-7. [PMID: 2439803] 47. Doshan HD, Brown R, Applin WJ, Kapoor M, Caruso FS. Effects of high doses of celiprolol in asthmatic patients. J Cardiovasc Pharmacol. 1986;8 Suppl 4:S109-11. [PMID: 2427837] 48. Doshan HD, Rosenthal RR, Brown R, Slutsky A, Applin WJ, Caruso FS. Celiprolol, atenolol and propranolol: a comparison of pulmonary effects in asthmatic patients. J Cardiovasc Pharmacol. 1986;8 Suppl 4:S105-8. [PMID: 2427836] 49. Lammers JW, Folgering HT, van Herwaarden CL. Ventilatory effects of beta 1-receptor-selective blockade with bisoprolol and metoprolol in asthmatic patients. Eur J Clin Pharmacol. 1984;27:141-5. [PMID: 6149939] 50. Greefhorst AP, van Herwaarden CL. Ventilatory and haemodynamic effects of beta 1-selective and beta 2-selective stimulation in asthmatic patients. Eur J Respir Dis Suppl. 1984;135:147-50. [PMID: 6329801] 51. Lawrence DS, Sahay JN, Chatterjee SS, Cruickshank JM. Asthma and beta-blockers. Eur J Clin Pharmacol. 1982;22:501-9. [PMID: 6127219] 52. Adam WR, Meagher EJ, Barter CE. Labetalol, beta blockers, and acute deterioration of chronic airway obstruction. Clin Exp Hypertens A. 1982;4:141928. [PMID: 6126285] 53. Lofdahl CG, Svedmyr N. Cardioselectivity of atenolol and metoprolol. A study in asthmatic patients. Eur J Respir Dis. 1981;62:396-404. [PMID: 6751838] 54. van den Bergh JH, van Herwaarden CL. Ventilatory effects of ordinary and slow-release tablets of metoprolol in asthmatic patients. Eur J Respir Dis. 1981; 62:168-72. [PMID: 7308331] 55. Ellis ME, Sahay JN, Chatterjee SS, Cruickshank JM, Ellis SH. Cardioselectivity of atenolol in asthmatic patients. Eur J Clin Pharmacol. 1981;21:173-6. [PMID: 7032947] 56. Ruffin RE, Frith PA, Anderton RC, Kumana CR, Newhouse MT, Hargreave FE. Selectivity of beta adrenoreceptor antagonist drugs assessed by histamine bronchial provocation. Clin Pharmacol Ther. 1979;25:536-40. [PMID: 35296] 57. Benson MK, Berrill WT, Cruickshank JM, Sterling GS. A comparison of four beta-adrenoceptor antagonists in patients with asthma. Br J Clin Pharmacol. 1978;5:415-9. [PMID: 26371] 58. Skinner C, Palmer KN. Comparison of the effects of acebutolol (Sectral) and practolol (Eraldin) on airways obstruction in asthmatics. Br J Clin Pharmacol. 1975;2:417-22. [PMID: 786353] 59. Johnsson G, Svedmyr N, Thiringer G. Effects of intravenous propranolol and metoprolol and their interaction with isoprenaline on pulmonary function, heart rate and blood pressure in asthmatics. Eur J Clin Pharmacol. 1975;8:17580. [PMID: 1233216] 60. Lammers JW, Muller ME, Folgering HT, van Herwaarden CL. Effects of terbutaline and atenolol on large and small airways in asthmatic patients. Eur Respir J. 1988;1:453-7. [PMID: 3169216] 5 November 2002 Annals of Internal Medicine Volume 137 Number 9 723 Article Cardioselective -Blockers in Reactive Airway Disease: A Meta-Analysis 61. Fogari R, Zoppi A, Tettamanti F, Poletti L, Rizzardi G, Fiocchi G. Comparative effects of celiprolol, propranolol, oxprenolol, and atenolol on respiratory function in hypertensive patients with chronic obstructive lung disease. Cardiovasc Drugs Ther. 1990;4:1145-9. [PMID: 1982059] 62. Nicolaescu V, Racoveanu C, Manicatide M. Effects of exercise on practololtreated asthmatic patients. Eur J Clin Pharmacol. 1973;6:3-8. [PMID: 4587515] 63. Dorow P, Clauzel AM, Capone P, Mayol R, Mathieu M. A comparison of celiprolol and chlorthalidone in hypertensive patients with reversible bronchial obstruction. J Cardiovasc Pharmacol. 1986;8 Suppl 4:S102-4. [PMID: 2427835] 64. Butland RJ, Pang JA, Geddes DM. Effect of beta-adrenergic blockade on hyperventilation and exercise tolerance in emphysema. J Appl Physiol. 1983;54: 1368-73. [PMID: 6863097] 65. Bauer K, Kaik G, Kaik B. Osmotic release oral drug delivery system of metoprolol in hypertensive asthmatic patients. Pharmacodynamic effects on beta 2-adrenergic receptors. Hypertension. 1994;24:339-46. [PMID: 7916004] 66. Fenster PE, Hasan FM, Abraham T, Woolfenden J. Effect of metoprolol on cardiac and pulmonary function in chronic obstructive pulmonary disease. Clin Cardiol. 1983;6:125-9. [PMID: 6851273] 67. van Zyl AI, Jennings AA, Bateman ED, Opie LH. Comparison of respiratory effects of two cardioselective beta-blockers, celiprolol and atenolol, in asthmatics with mild to moderate hypertension. Chest. 1989;95:209-13. [PMID: 2562825] 68. Lammers JW, Folgering HT, van Herwaarden CL. Ventilatory effects of long-term treatment with pindolol and metoprolol in hypertensive patients with chronic obstructive lung disease. Br J Clin Pharmacol. 1985;20:205-10. [PMID: 4041341] 69. Abraham TA, Hasan FM, Fenster PE, Marcus FI. Effect of intravenous metoprolol on reversible obstructive airways disease. Clin Pharmacol Ther. 1981; 29:582-7. [PMID: 7214788] 70. Boye NP, Vale JR. Effect in bronchial asthma of a new beta-adrenergic blocking drug atenolol (ICI 66, 082). Eur J Clin Pharmacol. 1977;11:11-4. [PMID: 319006] 71. Schindl R, Wurtz J, Hoffmann H. The effect of the cardioselective beta blocker celiprolol on pulmonary function in asthmatic patients. J Cardiovasc Pharmacol. 1986;8 Suppl 4:S99-101. [PMID: 2427862] 72. Larsson K. Influence of labetalol, propranolol and practolol in patients with asthma. Eur J Respir Dis. 1982;63:221-30. [PMID: 6124442] 73. Pujet JC, Dubreuil C, Fleury B, Provendier O, Abella ML. Effects of celiprolol, a cardioselective beta-blocker, on respiratory function in asthmatic patients. Eur Respir J. 1992;5:196-200. [PMID: 1348481] 74. Vilsvik JS, Schaanning J. Effect of atenolol on ventilatory and cardiac function in asthma. Br Med J. 1976;2:453-5. [PMID: 8188] 75. Beumer HM, Teirlinck C, Wiseman RA. Comparative investigation of the respiratory and cardiovascular effect of mepindolol, propranolol and pindolol in asthmatic patients. Int J Clin Pharmacol Biopharm. 1978;16:249-53. [PMID: 27463] 76. Mue S, Sasaki T, Shibahara S, Takahashi M, Ohmi T, Yamauchi K, et al. Influence of metoprolol on hemodynamics and respiratory function in asthmatic patients. Int J Clin Pharmacol Biopharm. 1979;17:346-50. [PMID: 489201] 77. Blaive B, Nahon F, Lemoigne F, Lewest G. [Long-term beta adrenergic antagonists in spastic bronchopathies]. Allerg Immunol (Paris). 1988;20:161-2, 164-5. [PMID: 2900013] 78. Cazzola M, Noschese P, D'Amato M, D'Amato G. Comparison of the effects of single oral doses of nebivolol and celiprolol on airways in patients with mild asthma. Chest. 2000;118:1322-6. [PMID: 11083681] 79. Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials. Arch Intern Med. 1991;151:1769-76. [PMID: 1679624] 80. Rosenson RS. The truth about beta-blocker adverse effects-- depression, claudication, and lipids. Journal of Ambulatory Monitoring. 1993;6:163-71. 81. Jonas M, Reicher-Reiss H, Boyko V, Shotan A, Mandelzweig L, Goldbourt U, et al. Usefulness of beta-blocker therapy in patients with non-insulin-dependent diabetes mellitus and coronary artery disease. Bezafibrate Infarction Prevention (BIP) Study Group. Am J Cardiol. 1996;77:1273-7. [PMID: 8677865] 82. Kjekshus J, Gilpin E, Cali G, Blackey AR, Henning H, Ross J Jr. Diabetic patients and beta-blockers after acute myocardial infarction. Eur Heart J. 1990; 724 5 November 2002 Annals of Internal Medicine Volume 137 Number 9 11:43-50. [PMID: 1968386] 83. Wicklmayr M, Rett K, Dietze G, Mehnert H. Effects of beta-blocking agents on insulin secretion and glucose disposal. Horm Metab Res Suppl. 1990; 22:29-33. [PMID: 1975244] 84. Bright RA, Everitt DE. Beta-blockers and depression. Evidence against an association. JAMA. 1992;267:1783-7. [PMID: 1347572] 85. Beto JA, Bansal VK. Quality of life in treatment of hypertension. A metaanalysis of clinical trials. Am J Hypertens. 1992;5:125-33. [PMID: 1349484] 86. Krumholz HM, Radford MJ, Wang Y, Chen J, Marciniak TA. Early betablocker therapy for acute myocardial infarction in elderly patients. Ann Intern Med. 1999;131:648-54. [PMID: 10577326] 87. Opie LH. Required beta blocker profile in the elderly. Cardiovasc Drugs Ther. 1991;4 Suppl 6:1273-80. [PMID: 1672603] 88. McNeill RS. Effect of a beta-adrenergic-blocking agent, propranolol, on asthmatics. Lancet. 1964;2:1101-2. 89. Zaid G, Beall GN. Bronchial response to beta-adrenergic blockade. N Engl J Med. 1966;275:580-4. [PMID: 5920412] 90. Anderson EG, Calcraft B, Jariwalla AG, Al-Zaibak M. Persistent asthma after treatment with beta-blocking agents. Br J Dis Chest. 1979;73:407-8. [PMID: 45308] 91. Raine JM, Palazzo MG, Kerr JH, Sleight P. Near-fatal bronchospasm after oral nadolol in a young asthmatic and response to ventilation with halothane. Br Med J (Clin Res Ed). 1981;282:548-9. [PMID: 6109556] 92. George RB, Manocha K, Burford JG, Conrad SA, Kinasewitz GT. Effects of labetalol in hypertensive patients with chronic obstructive pulmonary disease. Chest. 1983;83:457-60. [PMID: 6337786] 93. Light RW, Chetty KG, Stansbury DW. Comparison of the effects of labetalol and hydrochlorothiazide on the ventilatory function of hypertensive patients with mild chronic obstructive pulmonary disease. Am J Med. 1983;75:109-14. [PMID: 6356897] 94. Giulekas D, Georgopoulos D, Papakosta D, Antoniadou H, Sotiropoulou E, Vamvalis C. Influence of pindolol on asthmatics and effect of bronchodilators. Respiration. 1986;50:158-66. [PMID: 2948256] 95. Devereux G, Fishwick K, Aiken TC, Bourke SJ, Hendrick DJ. Adverse effects of a single dose of ()-sotalol in patients with mild stable asthma. Br J Clin Pharmacol. 1998;46:79-82. [PMID: 9690953] 96. Sue DY, Hansen JE, Wasserman K. Beta-adrenergic blockade with pindolol (LB-46) in mild to moderate asthma. Chest. 1981;80:537-42. [PMID: 7297143] 97. Motomura S, Deighton NM, Zerkowski HR, Doetsch N, Michel MC, Brodde OE. Chronic beta 1-adrenoceptor antagonist treatment sensitizes beta 2-adrenoceptors, but desensitizes M2-muscarinic receptors in the human right atrium. Br J Pharmacol. 1990;101:363-9. [PMID: 1979509] 98. Hall J, Kaumann A, Wells F, Brown M. Beta-2-adrenoceptor mediated inotropic responses of human atria: receptor subtype regulation by atenolol [Abstract]. Br J Pharmacol Proc 1983;Suppl 93:116P. 99. Hall J, Kaumann A, Brown M. Increased Beta-2 adrenoceptor coupling to inotropic effects in human atrial myocardium due to atenolol treatment [Abstract]. Br J Pharmacol Proc 1989;Suppl 87:391P. 100. Molinoff PB, Aarons RD. Effects of drugs on beta-adrenergic receptors on human lymphocytes. J Cardiovasc Pharmacol. 1983;5 Suppl 1:S63-7. [PMID: 6188922] 101. Kraan J, Koeter GH, vd Mark TW, Sluiter HJ, de Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J Allergy Clin Immunol. 1985;76:628-36. [PMID: 4056250] 102. Borst SE, Hui KK, Conolly ME. Beta-adrenergic receptors on human lymphocytes: comparison of down-regulation in vivo and in vitro. Pharmacology. 1990;40:325-9. [PMID: 1978356] 103. Cockcroft DW, McParland CP, Britto SA, Swystun VA, Rutherford BC. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet. 1993; 342:833-7. [PMID: 8104272] 104. Taylor DR, Sears MR, Herbison GP, Flannery EM, Print CG, Lake DC, et al. Regular inhaled beta agonist in asthma: effects on exacerbations and lung function. Thorax. 1993;48:134-8. [PMID: 8493626] 105. Wahedna I, Wong CS, Wisniewski AF, Pavord ID, Tattersfield AE. Asthma control during and after cessation of regular beta 2-agonist treatment. Am Rev Respir Dis. 1993;148:707-12. [PMID: 8103655] www.annals.org ArticleCardioselective -Blockers in Reactive Airway Disease: A Meta-Analysis 106. Sbirrazzuoli V, Drici M, Garraffo R, Candito M, Gibelin P, Morand P, et al. Changes in lymphocyte beta-adrenoceptor density after dilevalol oral treatment. Drugs Exp Clin Res. 1989;15:223-9. [PMID: 2551622] 107. Brodde OE, Daul A, Michel MC. Subtype-selective modulation of human beta 1- and beta 2-adrenoceptor function by beta-adrenoceptor agonists and antagonists. Clin Physiol Biochem. 1990;8 Suppl 2:11-7. [PMID: 1982757] 108. Basso A, Piantanelli L, Cognini G, Giunta S, Andreoni A, Paciaroni E. Acebutolol-induced decrease of mononuclear leukocyte beta-adrenoceptors in hypertension. Pharmacology. 1985;31:278-83. [PMID: 2999840] 109. Jakubetz J, Schmuck S, Poller U, Fuchs B, Gorf A, Radke J, et al. Cardiac effects of beta-adrenoceptor antagonists with intrinsic sympathomimetic activity in humans: beta1- and/or beta2-adrenoceptor mediated? J Cardiovasc Pharmacol. 1999;33:461-72. [PMID: 10069683] 110. Wang TJ, Stafford RS. National patterns and predictors of beta-blocker use in patients with coronary artery disease. Arch Intern Med. 1998;158:1901-6. [PMID: 9759686] 111. Krumholz HM, Radford MJ, Wang Y, Chen J, Heiat A, Marciniak TA. National use and effectiveness of beta-blockers for the treatment of elderly patients after acute myocardial infarction: National Cooperative Cardiovascular Project. JAMA. 1998;280:623-9. [PMID: 9718054] 112. Soumerai SB, McLaughlin TJ, Spiegelman D, Hertzmark E, Thibault G, Goldman L. Adverse outcomes of underuse of beta-blockers in elderly survivors of acute myocardial infarction. JAMA. 1997;277:115-21. [PMID: 8990335] 113. Sial SH, Malone M, Freeman JL, Battiola R, Nachodsky J, Goodwin JS. Beta blocker use in the treatment of community hospital patients discharged after myocardial infarction. J Gen Intern Med. 1994;9:599-605. [PMID: 7853068] 114. Mooss AN, Hilleman DE, Mohiuddin SM, Hunter CB. Safety of esmolol in patients with acute myocardial infarction treated with thrombolytic therapy who had relative contraindications to beta-blocker therapy. Ann Pharmacother. 1994;28:701-3. [PMID: 7919552] 115. Dorow P, Bethge H, Tonnesmann U. Effects of single oral doses of bisoprolol and atenolol on airway function in nonasthmatic chronic obstructive lung disease and angina pectoris. Eur J Clin Pharmacol. 1986;31:143-7. [PMID: 2879733] 116. Quan SF, Fenster PE, Hanson CD, Coaker LA, Basista MP. Suppression of atrial ectopy with intravenous metoprolol in chronic obstructive pulmonary disease patients. J Clin Pharmacol. 1983;23:341-7. [PMID: 6630583] 117. Formgren H. The effect of metoprolol and practolol on lung function and blood pressure in hypertensive asthmatics. Br J Clin Pharmacol 1976;3:1007-14. 118. Krauss S, Spitz E, Krauss A, Grizotzki B, Clement S. Treatment of hypertension in mild asthmatic patients with atenolol. Angiology. 1984;35:773-8. [PMID: 6507943] 119. Heller DA, Ahern FM, Kozak M. Changes in rates of beta-blocker use between 1994 and 1997 among elderly survivors of acute myocardial infarction. Am Heart J. 2000;140:663-71. [PMID: 11011343] www.annals.org 5 November 2002 Annals of Internal Medicine Volume 137 Number 9 725 Current Author Addresses: Dr. S. Salpeter: Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128. Dr. Ormiston: Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128. Dr. E. Salpeter: Center for Radiophysics and Space Research, Cornell University, 612 Space Sciences Building, Ithaca, NY 14853. Author Contributions: Conception and design: S.R. Salpeter, T.M. Ormiston. Analysis and interpretation of the data: S.R. Salpeter, T.M. Ormiston, E.E. Salpeter. Drafting of the article: S.R. Salpeter, T.M. Ormiston. Critical revision of the article for important intellectual content: S.R. Salpeter, T.M. Ormiston. Final approval of the article: S.R. Salpeter, T.M. Ormiston, E.E. Salpeter. Provision of study materials or patients: S.R. Salpeter, T.M. Ormiston. Statistical expertise: E.E. Salpeter. Collection and assembly of data: S.R. Salpeter, T.M. Ormiston. Appendix Figure. Results of search for and selection of trials. E-726 Annals of Internal Medicine Volume Number www.annals.org Appendix Table. Characteristics of Included Studies* Study, Year (Reference) Design Inclusion and Exclusion Criteria Adam et al., 1982 (52) Bauer et al., 1994 (65) Benson et al., 1978 (57) Single dose, double-blind, crossover Crossover (1 week treatment and 1 week placebo), double-blind Single dose, crossover, single-blind Butland et al., 1983 (64) Chatterjee, 1986 (46) Chodosh et al., 1988 (43) Crossover (4 weeks treatment and 4 weeks placebo), double-blind Single dose, crossover, double-blind Single dose, crossover, double-blind Dorow et al., 1986 (63) Doshan 1986a (47) Crossover (12 weeks treatment, 4 weeks placebo), double-blind Single dose, crossover, double-blind Inclusion: hypertension and reversible airway disease Inclusion: hypertension and stable asthma Exclusion: cardiac disease, renal disease, hepatic disease, diabetes, pregnancy, adverse reaction to -blocker Inclusion: reversible airway obstruction, stable Inclusion: COPD, FEV1 1 L with 20% reversal; inhalers, steroids allowed Exclusion: other lung disease or other serious disease Inclusion: asthma and hypertension, FEV1/vital capacity 30% Exclusion: pregnancy, heart or renal failure, antihypertensive or inhaler treatment Inclusion: normotensive patients with stable asthma, FEV1 60%90% predicted Exclusion: cromolyn use; change in steroid or inhaler use; recent asthma attack, upper respiratory tract infection, or status asthmaticus Inclusion: hypertension and reversible airway obstruction Exclusion: severe hypertension Inclusion: mild asthma Participants n 10 Dropout Rate % 0 18 0 Mean Age or Age Range y 65.1 48.6 12 14 before start 32.2 of study 12 0 61 12 0 60 16 11 before start 39 of study 34 0 15 6 Unclear 1955 Doshan et al., 1986 (48) Ellis et al., 1981 (55) Single dose, crossover, double-blind Single dose, crossover, double-blind Inclusion: normotensive and asthma, FEV1 50% predicted Exclusion: cromolyn or steroid use Inclusion: reversible airway disease 34 14 0 0 1857 Unclear Falliers et al., 1986 (45) Single dose, crossover, double-blind Fenster et al., 1983 (66) Fogari et al., 1990 (61) Greefhorst and van Herwaarden, 1984 (50) Johnsson et al., 1975 (59) Crossover (1 week treatment, 1 week placebo), single-blind Crossover (1 week treatment, 2 weeks placebo), double-blind Single dose, crossover, double-blind Single dose, crossover, single-blind Lammers et al., 1984 (49) Single dose, crossover, double-blind Lammers et al., 1985 (68) Crossover (4 weeks treatment and placebo), double-blind Lammers et al., 1986 (44) Lammers et al., 1988 (60) Single dose, crossover, single- and double-blind Single dose, crossover, single-blind Lawrence et al., 1982 (51) Crossover (single dose, then 3 weeks treatment and placebo), single-blind Inclusion: asthma, FEV1 80% predicted Exclusion: hypertension, hematologic or cardiovascular disease, recent asthma attack or respiratory infection, status asthmaticus, or cromolyn therapy Inclusion: reversible airway disease Inclusion: hypertension and reversible airway disease Exclusion: cardiovascular disease, renal insufficiency Inclusion: intrinsic atopic asthma, stable Exclusion: cardiovascular disease Inclusion: asthma for 2 years Exclusion: acute exacerbation, heart disease Inclusion: asthma, some with chronic bronchitis Exclusion: recent respiratory tract infection or increase in bronchoconstriction Inclusion: COPD and hypertension, with average FEV1 reversal 15%; all stable, with no recent respiratory tract infection or event Exclusion: none listed Inclusion: asthma Exclusion: heart disease Inclusion: asthma, FEV1 40%74% predicted, stable without steroids or theophylline Exclusion: none listed Inclusion: asthma and hypertension 18 6 10 8 7 8 8 11 11 14 0 0 0 0 0 0 0 0 0 0 2160 48.6 57 29 44 39 52.7 6.6 2260 55.7 Lofdahl et al., 1981 (53) Single dose, crossover, double-blind Nicolaescu et al., 1973 (62) Nicolescu et al., 1972 (28) Ruffin et al., 1979 (56) Skinner et al., 1975 (58) Crossover (3 days treatment and 3 days placebo), double-blind Crossover (3 days treatment and 3 days placebo) Single dose, crossover, double-blind Single dose, crossover, double-blind Inclusion: intrinsic asthma, stable Exclusion: none listed Inclusion: severe asthma for 5 years; steroids continued, inhalers held before measurements Exclusions: recent asthma attack Inclusion: mild asthma for 5 y Exclusion: none listed Inclusion: asthma with episodic dyspnea Exclusion: FEV1 70% predicted, or symptoms out of control Inclusion: asthma 8 10 10 12 10 0 0 0 0 0 52 46.6 43.7 30.8 36.8 Tantucci et al., 1990 (42) Single dose, crossover, double-blind van den Bergh and van Herwaarden, 1981 (54) Single dose, crossover, single- and double-blind Inclusion: reversible airway disease, stable Exclusion: history of atopy, recent respiratory tract infection, contraindications to -blocker, pregnancy Inclusion: asthma, mild to moderate, stable 12 8 0 0 van Zyl et al., 1989 (67) Crossover (4 weeks treatment, 2 weeks Inclusion: asthma and hypertension, FEV1 85% predicted 12 16 placebo), single- and double-blind 37.3 24 45.9 * COPD chronic obstructive pulmonary disease; OT ordinary tablets; SR sustained release. Some studies did not list exclusion criteria. www.annals.org Annals of Internal Medicine Volume Number E-727 Appendix Table--Continued Active Interventions Comparison Interventions Outcomes Measured Comments 1: metoprolol, 100 mg; atenolol, 100 mg 2: inhaled salbutamol after treatment Osmotic-release metoprolol, 204 mg/d, atenolol, 100 mg/d 1: acebutolol, 300 mg; atenolol, 100 mg 2: inhaled isoprenaline after treatment Atenolol, 100 mg/d; metoprolol, 100 mg/d 1: atenolol, 100 mg; bisoprolol, 10 mg; bisoprolol, 20 mg 2: inhaled salbutamol after treatment 1: metoprolol 200 mg 2: inhaled isoproterenol after treatment 1: placebo 2: inhaled salbutamol after placebo Placebo 1: placebo 2: inhaled isoprenaline after placebo Placebo 1: placebo 2: inhaled isoprenaline after placebo Atenolol, 100 mg/d; metoprolol, 100 mg/d 1: placebo 2: inhaled isoproterenol after placebo FEV1, symptoms Symptoms FEV1, symptoms Symptoms, exercise tolerance FEV1 symptoms FEV1 symptoms Celiprolol, 100600 mg/d 1: celiprolol, 400 mg; celiprolol, 600 mg; atenolol, 100 mg 2: inhaled albuterol after treatment Celiprolol, 200 mg; celiprolol, 400 mg; atenolol, 100 mg 1: atenolol, 50 mg; atenolol, 100 mg; atenolol, 200 mg 2: inhaled isoprenaline after treatment 1: metoprolol, 100 mg; metoprolol, 200 mg 2: inhaled isoproterenol after treatment Metoprolol, 200 mg/d 1: atenolol, 100 mg/d; celiprolol 200 mg/d 2: inhaled salbutamol after treatment 1: metoprolol, 100 mg; acebutolol, 400 mg 2: intravenous terbutaline after treatment Intravenous metoprolol, 0.12 mg/kg body weight 1: bisoprolol, 10 mg; bisoprolol, 20 mg; metoprolol, 100 mg 2: inhaled terbutaline after treatment Metoprolol, 100 mg twice daily Placebo 1: placebo 2: inhaled albuterol after placebo Placebo 1: placebo 2: inhaled isoprenaline after placebo 1: placebo 2: inhaled isoproterenol after placebo Placebo 1: placebo 2: inhaled salbutamol after placebo 1: placebo 2: intravenous terbutaline after placebo Intravenous placebo 1: placebo 2: inhaled terbutaline after placebo Placebo FEV1, symptoms, weekly inhaler use FEV1, symptoms FEV1, symptoms FEV1, symptoms FEV1, symptoms Increase in symptoms FEV1, symptoms FEV1, symptoms FEV1, symptoms FEV1, symptoms Symptoms 1: xamoterol, 200 mg; atenolol, 100 mg 2: inhaled terbutaline after treatment 1: atenolol, 50 mg 2: inhaled terbutaline after treatment 1: atenolol, 100 mg; metoprolol, 100 mg 2: inhaled salbutamol after treatment 3: atenolol, 100 mg/d; metoprolol, 100 mg twice daily 1: atenolol, 100 mg; metoprolol 100 mg 2: terbutaline, intravenous then inhaled, after treatment 1: practolol, 200 mg/d 2: inhaled orciprenaline after treatment 1: practolol, 50 mg four times daily 2: inhaled orciprenaline after treatment Metoprolol, 100 mg 1: acebutolol, 300 mg; practolol, 300 mg 2: inhaled isoprenaline after treatment Osmotic-release metoprolol, 204 mg; atenolol, 100 mg 1: metoprolol OT, 100 mg; metoprolol OT, 200 mg; metoprolol SR, 200 mg 2: intravenous terbutaline after treatment Atenolol, 100 mg/d; celiprolol, 400/d 1: placebo 2: inhaled terbutaline after placebo 1: placebo 2: inhaled terbutaline after placebo 1: placebo 2: inhaled salbutamol after placebo 3: placebo 1: placebo 2: terbutaline, intravenous then inhaled, after placebo 1: placebo 2: inhaled orciprenaline after placebo 1: placebo 2: inhaled orciprenaline after placebo Placebo 1: placebo 2: inhaled isoprenaline after placebo Placebo 1: placebo 2: intravenous terbutaline after placebo Placebo FEV1, symptoms FEV1, symptoms FEV1, symptoms, asthma attacks, weekly inhaler use FEV1, symptoms FEV1, symptoms FEV1, symptoms FEV1, symptoms FEV1, symptoms FEV1, symptoms FEV1, symptoms Symptoms, weekly inhaler use Nonselective agents studied were labetalol and propranolol; SDs derived from individual-patient data or P values Nonselective agents studied were propranolol and pindolol; SDs derived from individual-patient data or P values FEV1 reported as percentage of predicted normal value No SDs provided 2 Nonselective agent studied was dilevalol; SDs derived from individual patient data or P values SDs were reported for treatment effect and placebo effect separately SDs were reported for treatment effect and placebo effect separately Nonselective agent studied was propranolol; SDs were reported for treatment effect and placebo effect separately Nonselective agent studied was propranolol; no SD data provided Nonselective agent studied was labetalol; SDs were reported for treatment effect and placebo effect separately FEV1 reported as percentage of predicted value Nonselective agents studied were propranolol and oxprenolol; SDs were reported for treatment effect and placebo effect separately SDs were reported for treatment effect and placebo effect separately Isoprenaline given intravenously, but FEV1 not reported; nonselective agent studied was propranolol; SDs derived from individual-patient data or P values SDs were reported for treatment effect and placebo effect separately Nonselective agent studied was pindolol Placebo given single-blind, treatments given double-blind; SDs were reported for treatment effect and placebo effect separately No SDs provided SDs derived from individual-patient data or P values SDs derived from individual-patient data or P values SDs derived from individual-patient data or P values SDs derived from individual-patient data or P values Nonselective agents studied were propranolol and timolol; no SDs provided SDs were reported for treatment effect and placebo effect separately SDs derived from individual-patient data or P values Single-blind; metoprolol, 100 mg, and placebo; double-blind: metoprolol, 200 mg, 2 doses; SDs derived from individual-patient data or P values Placebo run-in, single-blind; treatment double-blind E-728 Annals of Internal Medicine Volume Number www.annals.org