Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease

Phillippa Poole, Jimmy Chong, Christopher J Cates

Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume or purulence of sputum, or both. Personal and healthcare costs associated with exacerbations indicate that any therapy that reduces the occurrence of exacerbations is useful. A marked difference among countries in terms of prescribing of mucolytics reflects variation in perceptions of their effectiveness. Primary objective• To determine whether treatment with mucolytics reduces frequency of exacerbations and/or days of disability in patients with chronic bronchitis or chronic obstructive pulmonary disease. Secondary objectives• To assess whether mucolytics lead to improvement in lung function or quality of life.• To determine frequency of adverse effects associated with use of mucolytics. We searched the Cochrane Airways Group Specialised Register and reference lists of articles on 10 separate occasions, most recently in July 2014. We included randomised studies that compared oral mucolytic therapy versus placebo for at least two months in adults with chronic bronchitis or COPD. We excluded studies of people with asthma and cystic fibrosis. This review analysed summary data only, most derived from published studies. For earlier versions, one review author extracted data, which were rechecked in subsequent updates. In later versions, review authors double-checked extracted data and then entered data into RevMan for analysis. We added four studies for the 2014 update. The review now includes 34 trials, recruiting a total of 9367 participants. Many studies did not clearly describe allocation concealment; hence selection bias may have inflated the results, which reduces our confidence in the findings.Results of 26 studies with 6233 participants show that the likelihood that a patient could be exacerbation-free during the study period was greater among mucolytic groups (Peto odds ratio (OR) 1.75, 95% confidence interval (CI) 1.57 to 1.94). However, more recent studies show less benefit of treatment than was reported in earlier studies in this review. The overall number needed to treat with mucolytics for an additional beneficial outcome for an average of 10 months - to keep an additional participant free from exacerbations - was eight (NNTB 8, 95% CI 7 to 10). Use of mucolytics was associated with a reduction of 0.03 exacerbations per participant per month (mean difference (MD) -0.03, 95% CI -0.04 to -0.03; participants = 7164; studies = 28; I(2) = 85%) compared with placebo, that is, about 0.36 per year, or one exacerbation every three years. Very high heterogeneity was noted for this outcome, so results need to be interpreted with caution. The type or dose of mucolytic did not seem to alter the effect size, nor did the severity of COPD, including exacerbation history. Longer studies showed smaller effects of mucolytics than were reported in shorter studies.Mucolytic use was associated with a reduction of 0.43 days of disability per participant per month compared with placebo (95% CI -0.56 to -0.30; studies = 13; I(2) = 61%). With mucolytics, the number of people with one or more hospitalisations was reduced, but study results were not consistent (Peto OR 0.68, 95% CI 0.52 to 0.89; participants = 1788; studies = 4; I(2) = 58%). Investigators reported improved quality of life with mucolytics (MD -2.64, 95% CI -5.21 to -0.08; participants = 2231; studies = 5; I(2) = 51%). Although this mean difference did not reach the minimal clinically important difference of -4 units, we cannot assess the population impact, as we do not have the data needed to carry out a responder analysis. Mucolytic treatment was not associated with any significant increase in the total number of adverse effects, including mortality (Peto OR 1.03, 95% CI 0.52 to 2.03; participants = 2931; studies = 8; I(2) = 0%), but the confidence interval is too wide to confirm that the treatment has no effect on mortality. In participants with chronic bronchitis or COPD, we are moderately confident that treatment with mucolytics may produce a small reduction in acute exacerbations and a small effect on overall quality of life. Our confidence in the results is reduced by the fact that effects on exacerbations shown in early trials were larger than those reported by more recent studies, possibly because the earlier smaller trials were at greater risk of selection or publication bias, thus benefits of treatment may not be as great as was suggested by previous evidence.