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. 2019 May 20;5(5):CD001287.
doi: 10.1002/14651858.CD001287.pub6.

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

Phillippa Poole  1 , Kavin Sathananthan, Rebecca Fortescue
Affiliations

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

Phillippa Poole et al. Cochrane Database Syst Rev. .

Abstract

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 oral medicines 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 COPDSecondary 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; moderate-certainty 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 (I² = 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; I² = 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; I² = 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; I² = 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; I² = 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; I² = 0%; moderate-certainty evidence).

Authors' conclusions: In participants with chronic bronchitis or COPD, we are moderately confident that treatment with mucolytics 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.

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Conflict of interest statement

PP: none known. I am an editor with Cochrane Airways.

KS: none known.

RF: none known. I am Joint Co‐ordinating Editor of Cochrane Airways, employed by an NIHR grant, and a qualified general practitioner.

Figures

1
1
Funnel plot of comparison: 1 Mucolytic versus placebo, outcome: 1.11 Days of disability per participant per month.
2
2
Funnel plot of comparison: 1 Mucolytic versus placebo, outcome: 1.13 FEV₁ at end of study.
3
3
Study flow diagram: review update.
4
4
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
5
5
Forest plot of comparison: 1 Mucolytic versus placebo, outcome: 1.1 Participants with no exacerbations in study period.
6
6
In the control group, 39 of 100 people were free from exacerbations over 9 months (represented by green faces) compared with 52 (95% CI 49 to 55) of 100 for the mucolytic group (represented by green plus yellow faces).
7
7
Forest plot of comparison: 1 Mucolytic versus placebo, outcome: 1.2 Participants with no exacerbation by decade; double‐blind trials only.
8
8
Funnel plot of comparison: 1 Mucolytic versus placebo, outcome: 1.1 Participants with no exacerbations in study period.
1.1
1.1. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 1 Participants with no exacerbations in study period.
1.2
1.2. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 2 Participants with no exacerbation by decade, double‐blind trials only.
1.3
1.3. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 3 Participants with no exacerbations in the study period ‐ winter treatment only.
1.4
1.4. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 4 Participants with no exacerbations in study period ‐ by dose or type of mucolytic.
1.5
1.5. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 5 Participants with no exacerbations in study period ‐ by FEV₁.
1.6
1.6. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 6 Participants with no exacerbations in study period ‐ by study duration.
1.7
1.7. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 7 Participants with no exacerbations in study period ‐ by country.
1.8
1.8. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 8 Participants with no exacerbations in study period ‐ by history of exacerbation.
1.9
1.9. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 9 Participants with no exacerbations in study period ‐ by ICS use.
1.11
1.11. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 11 Days of disability per participant per month.
1.12
1.12. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 12 Days on antibiotics per participant per month.
1.13
1.13. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 13 FEV₁ at end of study.
1.14
1.14. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 14 Percent predicted FEV₁.
1.15
1.15. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 15 PEFR at end of study.
1.16
1.16. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 16 FVC at end of study.
1.17
1.17. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 17 Adverse effects.
1.18
1.18. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 18 Hospitalisation during study period.
1.19
1.19. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 19 Death during study period.
1.20
1.20. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 20 Health‐related quality of life (total score St. George's Respiratory Questionnaire).
1.21
1.21. Analysis
Comparison 1 Mucolytic versus placebo, Outcome 21 Health‐related quality of life (total score COPD Assessment Test).
2.1
2.1. Analysis
Comparison 2 Systemic thiol donor versus placebo, Outcome 1 Participants with no exacerbations in the study period.
2.3
2.3. Analysis
Comparison 2 Systemic thiol donor versus placebo, Outcome 3 Days of disability per participant per month.
2.4
2.4. Analysis
Comparison 2 Systemic thiol donor versus placebo, Outcome 4 Adverse effects.
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References to studies excluded from this review

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References to studies awaiting assessment

CTRI/2015/01/005432 {published data only}
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References to ongoing studies

ChiCTR1800016712 {published data only}
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