Long-acting beta2-agonists for chronic obstructive pulmonary disease
Kew, KM and Mavergames, C and Walters, JAE, Long-acting beta2-agonists for chronic obstructive pulmonary disease, Cochrane Database of Systematic Reviews Article CD010177. ISSN 1469-493X (2013) [Contribution to Refereed Journal]
Chronic obstructive pulmonary disease (COPD) is a respiratory disease that causes progressive symptoms of breathlessness, cough and
mucus build-up. It is the fourth or fifth most common cause of death worldwide and is associated with significant healthcare costs.
Inhaled long-acting beta2-agonists (LABAs) are widely prescribed to manage the symptoms of COPD when short-acting agents alone
are no longer sufficient. Twice-daily treatment with an inhaled LABA is aimed at relieving symptoms, improving exercise tolerance and
quality of life, slowing decline and even improving lung function and preventing and treating exacerbations.
To assess the effects of twice-daily long-acting beta2-agonists compared with placebo for patients with COPD on the basis of clinically
important endpoints, primarily quality of life and COPD exacerbations.
We searched the Cochrane Airways Group trials register, ClinicalTrials.gov and manufacturers’ websites in June 2013.
Parallel, randomised controlled trials (RCTs) recruiting populations of patients with chronic obstructive pulmonary disease. Studies
were required to be at least 12 weeks in duration and designed to assess the safety and efficacy of a long-acting beta2-agonist against
Data collection and analysis
Data and characteristics were extracted independently by two review authors, and each study was assessed for potential sources of bias.
Data for all outcomes were pooled and subgrouped by LABA agent (formoterol 12 μg, formoterol 24 μg and salmeterol 50 μg) and
then were separately analysed by LABA agent and subgrouped by trial duration. Sensitivity analyses were conducted for the proportion
of participants taking inhaled corticosteroids and for studies with high or uneven rates of attrition.
Twenty-six RCTs met the inclusion criteria, randomly assigning 14,939 people with COPD to receive twice-daily LABA or placebo.
Study duration ranged from three months to three years; the median duration was six months. Participants were more often male
with moderate to severe symptoms at randomisation; mean forced expiratory volume in 1 second (FEV1) was between 33% and 55%
predicted normal in the studies, and mean St George’s Respiratory Questionnaire score (SGRQ) ranged from 44 to 55 when reported.
Moderate-quality evidence showed that LABA treatment improved quality of life on the SGRQ (mean difference (MD) -2.32, 95%
confidence interval (CI) -3.09 to -1.54; I2 = 50%; 17 trials including 11,397 people) and reduced the number of exacerbations requiring
hospitalisation (odds ratio (OR) 0.73, 95% CI 0.56 to 0.95; I2 = 10%; seven trials including 3804 people). In absolute terms, 18
fewer people per 1000 were hospitalised as the result of an exacerbation while receiving LABA therapy over a weighted mean of 7
months (95% CI 3 to 31 fewer). Scores were also improved on the Chronic Respiratory Disease Questionnaire (CRQ), and more
people receiving LABA treatment showed clinically important improvement of at least four points on the SGRQ.
The number of people who had exacerbations requiring a course of oral steroids or antibiotics was also lower among those taking LABA
(52 fewer per 1000 treated over 8 months; 95% CI 24 to 78 fewer, moderate quality evidence).
Mortality was low, and combined findings of all studies showed that LABA therapy did not significantly affect mortality (OR 0.90,
95% CI 0.75 to 1.08; I2 = 21%; 23 trials including 14,079 people, moderate quality evidence). LABA therapy did not affect the
rate of serious adverse events (OR 0.97, 95% CI 0.83 to 1.14; I2 = 34%, moderate quality evidence), although there was significant
unexplained heterogeneity, especially between the two formoterol doses.
LABA therapy improved predose FEV1 by 73 mL more than placebo (95% CI 48 to 98; I2 = 71%, low quality evidence), and people
were more likely to withdraw from placebo than from LABA therapy (OR 0.74, 95% CI 0.69 to 0.80; I2 = 0%). Higher rates of
withdrawal in the placebo arm may reduce our confidence in some results, but the disparity is more likely to reduce the magnitude
of difference between LABA and placebo than inflate the true effect; removing studies at highest risk of bias on the basis of high and
unbalanced attrition did not change conclusions for the primary outcomes.
Moderate-quality evidence from 26 studies showed that inhaled long-acting beta2-agonists are effective over the medium and long term
for patients with moderate to severe COPD. Their use is associated with improved quality of life and reduced exacerbations, including
those requiring hospitalisation. Overall, findings showed that inhaled LABAs did not significantly reduce mortality or serious adverse