Long-acting beta2-agonists for people with COPD

We wanted to know whether twice-daily treatment with an inhaled long-acting beta2-agonist was better than treatment with a dummy inhaler for people with chronic obstructive pulmonary disease (COPD).

Background to the review
COPD is a disease of the lungs that causes airways to narrow. As a result, people with COPD experience symptoms of breathlessness, cough and mucus buildup, which worsen over time. Cigarette smoking is the most common cause of COPD, and it is the fourth or fifth most common cause of death worldwide.

Inhaled salmeterol and formoterol, known as long-acting beta2-agonists (LABAs), are widely used to manage the symptoms of COPD, so it is important to understand their benefits and side effects. They are often introduced when inhaled treatments for quick relief from symptoms (e.g. salbutamol) are no longer helpful. LABAs are designed to be taken twice a day to control symptoms and reduce the likelihood of flare-ups.

What did we find?
Twenty-six studies (including 14,939 people with moderate to severe symptoms of COPD) compared twice-daily salmeterol or formoterol with a dummy inhaler. The evidence gathered for this review is current up to June 2013. Results within studies were described most often after six months of treatment, but some were reported at three months and others after as long as three years. More men than women took part, and they had moderate to severe symptoms when they began treatment.

People who took LABA inhalers showed greater improvement on quality of life scales than those taking dummy inhalers, and they had fewer serious flare-ups that resulted in a hospital stay (18 fewer per 1000). They also had better lung function than people who had taken placebo. LABA inhalers did not reduce the number of people who died, and no significant difference was noted in the number who had serious adverse events while taking the medication.

These studies were most often sponsored by drug companies and were generally well designed. People in the studies did not know which treatment they were getting, and neither did the people doing the research. Several studies did not describe flare-ups, hospital stays or lung volume, so there is a chance that evidence obtained in future studies would change the strength of what has been concluded. Additionally, quite a lot of variation was noted between studies in the effects of LABA inhalers on quality of life, serious side effects and lung function. This may be explained in part by variation in study methods regarding what medications people could continue to take.

Authors' conclusions: 

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 events.

Read the full abstract...
Background: 

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.

Objectives: 

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.

Search strategy: 

We searched the Cochrane Airways Group trials register, ClinicalTrials.gov and manufacturers' websites in June 2013.

Selection criteria: 

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 placebo.

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.

Main results: 

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.

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