Patients with moderate or severe chronic obstructive pulmonary disease (COPD) experience chronic progressive airflow obstruction and chronic progressive dyspnea that can be disabling. β-Agonist bronchodilators work by binding to and relaxing the airway smooth muscle. This relaxation results in dilation of the airway and allows more trapped air to escape with each exhalation. Reducing air trapping with β-agonists plays an important physiologic role in relieving dyspnea for patients with COPD.1 Because of the impressive clinical and physiologic effects, all published COPD guidelines advocate using short- or long-acting β-agonist bronchodilators to reduce dyspnea, improve exercise tolerance, and improve quality of life for patients with symptomatic COPD.2,3
There would be only 2 reasons to abandon β-agonist bronchodilators for therapy of COPD: if they were shown to be ineffective or if the risk of adverse events caused by the drugs eclipsed their benefits. In the following paragraphs I will summarize clinical trial evidence that proves β-agonist bronchodilators are effective and safe for treating COPD.
Effectiveness
Evidence supporting the effectiveness of short- and long-acting β-agonists for treatment of COPD is overwhelming. A Cochrane Collaboration systematic review of 13 clinical trials evaluated the clinical effectiveness of short-acting β-agonists. The meta-analysis of these 13 trials showed that regular use of short-acting β-agonists for patients with stable COPD was associated with improvements in lung function and a significant decrease in breathlessness compared with placebo. Trial patients were almost 10 times more likely to prefer treatment with β-agonists over placebo. The authors of the Cochrane review thus concluded that treatment with short-acting β-agonists is beneficial for patients with COPD.4
The newer long-acting β-agonists have a prolonged duration of action. These drugs have been shown in clinical trials to induce substantial lung deflation in COPD patients and to decrease dyspnea associated with exercise. Patients taking salmeterol (a long-acting β-agonist) improved their peak exercise endurance by 58% compared with placebo.5
A 2006 Cochrane Collaboration systematic review evaluated the clinical effectiveness of long-acting β-agonists.6 Twenty-three clinical trials that randomized 6061 patients were assessed. The meta-analysis of these 23 trials showed that there was a significant improvement in lung function in favour of salmeterol (50 μg twice daily) compared with placebo. There were also significant differences in health-related quality of life in favour of salmeterol (50 μg twice daily) compared with placebo. Regular use of salmeterol reduced the incidence of COPD exacerbations compared with placebo (number needed to treat = 21). Long-acting β-agonists clearly have been shown to be effective for treating COPD.
Safety
A recent meta-analysis by Salpeter et al questioned whether β-agonists might be associated with increased risk of respiratory death compared with placebo.7 A closer look at the data used in the Salpeter meta-analysis reveals several important flaws. Only 4 published trials were included. No attempts were made by the authors to obtain mortality data from large randomized trials of β-agonist therapy for COPD that might have contributed important information (such as the 2003 Calverley study,8 which randomized 1465 patients with COPD). Sixty percent of the weight of the Salpeter meta-analysis came from the results of only 1 study. Most importantly, the Salpeter meta-analysis contains data from duplicate publications. Data from the Donohue trial were duplicated in the Brusasco study. Duplicate publication of results from exactly the same patients inappropriately influenced the results of the Salpeter meta-analysis. In short, because of flawed methodology and inclusion of dubious studies, the results of the Salpeter meta-analysis are unreliable.
A more reliable assessment of the safety of long-term β-agonists for COPD can come from the largest clinical trial of COPD therapy performed to date, which assessed mortality as its primary outcome.9 The TORCH (Towards a Revolution in COPD Health) study randomized 6112 patients with moderate or severe COPD to 3 years of double-blinded therapy with salmeterol (n = 1521), fluticasone (n = 1534), fluticasone and salmeterol (n = 1533), or placebo (n = 1524). The primary outcome was all-cause mortality.9 Importantly, the risk of death in the group treated with salmeterol monotherapy was slightly lower than the risk in the group that received placebo (hazard ratio of death with salmeterol versus placebo = 0.88, 95% confidence interval 0.73–1.06). Clearly, in this very large, 3-year clinical trial there was no signal to suggest that therapy with salmeterol led to excess respiratory deaths compared with placebo; in fact, the odds ratio of 0.88 suggests that salmeterol might have had a small (but not statistically significant) protective effect on mortality. The TORCH trial contained more patients in its salmeterol and placebo arms than all the studies in the Salpeter meta-analysis taken together. Thus results of this trial would overwhelm the results of the Salpeter meta-analysis. The TORCH study has clearly established that long-term β-agonist therapy is safe and is not associated with excess mortality in patients with COPD.9
In summary, long-term therapy with β-agonist bronchodilators is effective and safe for treatment of dyspnea associated with COPD. There is no justification for avoiding β-agonists for patients with symptomatic COPD.
Notes
CLOSING ARGUMENTS
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Physiologic studies show that β-agonists dilate the airways and reduce air trapping in chronic obstructive pulmonary disease, and this leads to improved lung function and improved exercise tolerance for patients.
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Clinical trials clearly show that short- and long-acting β-agonists improve dyspnea and quality of life and reduce respiratory exacerbations in patients with chronic obstructive pulmonary disease.
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A very large new clinical trial has unequivocally demonstrated that long-term use of long-acting β-agonists over a period of 3 years is safe and is associated with a slightly lower risk of mortality compared with placebo.
Footnotes
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Competing interests
None declared
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