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

Background 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 therapies that reduce the occurrence of exacerbations are likely to be useful. Mucolytics are oralmedicines that are believed to increase expectoration of sputum by reducing its viscosity, thus making it easier to cough it up. Improved expectoration of sputum may lead to a reduction in exacerbations of COPD. Objectives Primary objective To determine whether treatment with mucolytics reduces exacerbations and/or days of disability in patients with chronic bronchitis or COPD 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 Search methods We searched the Cochrane Airways Group Specialised Register and reference lists of articles on 12 separate occasions, most recently on 23 April 2019. Selection criteria 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. Data collection and analysis 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 5.3 for analysis. Main results We added four studies for the 2019 update. The review now includes 38 trials, recruiting a total of 10,377 participants. Studies lasted between two months and three years and investigated a range of mucolytics, including N-acetylcysteine, carbocysteine, erdosteine, and ambroxol, given at least once daily. Many studies did not clearly describe allocation concealment, and we had concerns about blinding and high levels of attrition in some studies. The primary outcomes were exacerbations and number of days of disability. Results of 28 studies including 6723 participants show that receiving mucolytics may be more likely to be exacerbation-free during the study period compared to those given placebo (Peto odds ratio (OR) 1.73, 95% confidence interval (CI) 1.56 to 1.91; moderatecertainty evidence). 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 average of nine months to keep an additional participant free from exacerbations was eight (NNTB 8, 95% CI 7 to 10). High heterogeneity was noted for this outcome (I-2 = 62%), 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 use of placebo (95% CI -0.56 to -0.30; studies = 9; I-2 = 61%; moderate-certainty evidence). 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%; moderate-certainty evidence). Investigators reported improved quality of life with mucolytics (mean difference (MD) 1.37, 95% CI -2.85 to 0.11; participants = 2721; studies = 7; I-2 = 64%; moderate-certainty evidence). However, the mean difference did not reach the minimal clinically important difference of -4 units, and the confidence interval includes no difference. Mucolytic treatment was associated with a possible reduction in adverse events (OR 0.84, 95% CI 0.74 to 0.94; participants = 7264; studies = 24; I-2 = 46%; moderate-certainty evidence), but the pooled effect includes no difference if a random-effects model is used. Several studies that could not be included in the meta-analysis reported high numbers of adverse events, up to a mean of five events per person during follow-up. There was no clear difference between mucolytics and placebo for mortality, but the confidence interval is too wide to confirm that treatment has no effect on mortality (Peto OR 0.98, 95% CI 0.51 to 1.87; participants = 3527; studies = 11; I-2 = 0%; moderate-certainty evidence). Authors 'conclusions In participants with chronic bronchitis or COPD, we aremoderately confident that treatment withmucolytics leads to a small reduction in the likelihood of having an acute exacerbation, in days of disability per month and possibly hospitalisations, but is not associated with an increase in adverse events. There appears to be limited impact on lung function or health-related quality of life. Results are too imprecise to be certain whether or not there is an effect on mortality. Our confidence in the results is reduced by high levels of heterogeneity in many of the outcomes and the fact that effects on exacerbations shown in early trials were larger than those reported by more recent studies. This may be a result of greater risk of selection or publication bias in earlier trials, thus benefits of treatment may not be as great as was suggested by previous evidence.