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NIHR Signal Mucus-thinning drugs slightly reduce COPD symptom flare-ups

Published on 30 July 2019

doi: 10.3310/signal-000800

People with chronic obstructive pulmonary disease (COPD) have a slightly reduced risk of having a flare-up of symptoms if they take mucolytic drugs. The number of days on which they are too ill to perform their normal activities is also slightly reduced, from 1.57 days to 1.14 days per month.

A review of placebo-controlled trials, including 10,377 people taking a variety of mucolytic drugs, for between two months to three years, found improvements in exacerbations, days of disability, and hospital admissions. However, the improvements were small and more recent trials were likely to show less benefit than older trials. The results for hospitalisation suggested an improvement but were not consistent.

Mucolytics may be useful for some COPD patients, but their benefits are likely to be small. The review supports current guidance not to prescribe them routinely for patients with stable COPD.

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Why was this study needed?

Around 1.2 million people in the UK have COPD, making it the second most common respiratory disease after asthma. Exacerbation of symptoms such as breathlessness and sputum production can lead to emergency hospital treatment and account for much of the cost of managing COPD.

Reducing exacerbations is a major aim of COPD treatment. Inhaled bronchodilators and steroids are the main drug treatments which are used to keep the airways open and reduce inflammation. Mucolytic drugs, on the other hand, aim to thin mucus to make it easier to cough up.

So far, it has been unclear how well mucolytic drugs such as carbocysteine and N-acetylcysteine reduce exacerbations. Guidelines differ in their recommendations about the place of mucolytic drugs in COPD treatment. This review aimed to summarise the evidence to show whether mucolytics reduce exacerbations or days of disability for COPD patients.

What did this study do?

This was an updated Cochrane systematic review and meta-analysis of randomised controlled trials of oral mucolytic drugs compared to placebo in adults with chronic bronchitis or COPD.

Four new studies were added, giving a total of 38 trials with 10,377 participants. They did not include people with asthma or cystic fibrosis. Most studies were conducted in Europe, including four in the UK. There were four studies in China, two in India, two in the US, and one in Japan.

The average study length was 8.8 months (range two months to three years). Mucolytics tested included N-acetylcysteine, carbocysteine, and erdosteine. They were taken by mouth one to three times per day.

No data was provided on bronchodilator inhaler or other medication use, and there was a wide variation between the studies, which reduces the reliability of the results.

What did it find?

  • People receiving mucolytic drugs were more likely to remain free of exacerbation of symptoms (50.9%) than people receiving placebo (38.6%) during the study period (odds ratio [OR] for being exacerbation-free 1.73, 95% confidence interval [CI] 1.56 to 1.91; 28 trials, 6,723 participants).
  • People receiving mucolytic drugs had slightly fewer days of disability, where they were unable to do their usual activities, each month: 1.14 days, compared to 1.57 days for people taking a placebo (mean difference 0.43 days, 95% CI 0.30 to 0.56; 9 trials, 2,259 participants).
  • Fewer people were admitted to hospital (13.8%) on mucolytic drugs compared with placebo (18.7%) over 16.6 months of follow-up (OR 0.68, 95% CI 0.52 to 0.89; 5 trials, 1,833 participants).
  • There was no difference in the results when the use of inhaled corticosteroids was taken into account.
  • Researchers said the results were based on moderately certain evidence. However, the review found larger effects in earlier studies of mucolytics for chronic bronchitis and smaller effects in more recent studies of COPD.

What does current guidance say on this issue?

The NICE 2018 guideline only recommends considering mucolytic drug therapy for people with a chronic cough productive of sputum. Mucolytic drugs should be stopped if there is no improvement in symptoms such as cough frequency or sputum production. The guideline does not recommend their routine use to prevent exacerbations for all people with COPD.

What are the implications?

This updated Cochrane review suggests that the NICE guideline hits the right balance in its recommendation that mucolytics may be of help for some people with COPD, but should not be prescribed routinely.

It confirms that mucolytics may offer a small reduction in risk of an exacerbation of COPD symptoms, with few adverse effects, but authors add that the results may be driven by older studies that could have been subject to publication bias.

Citation and Funding

Poole P, Sathananthan K and Fortescue R. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;(5):CD001287.

Cochrane UK and the Cochrane Airways Review Group are supported by NIHR infrastructure funding.

Bibliography

NICE. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. NG115. London: National Institute of Health and Care Excellence; 2018.

British Lung Foundation. Chronic obstructive airways disease (COPD) statistics. London: British Lung Foundation; 2019.

Why was this study needed?

Around 1.2 million people in the UK have COPD, making it the second most common respiratory disease after asthma. Exacerbation of symptoms such as breathlessness and sputum production can lead to emergency hospital treatment and account for much of the cost of managing COPD.

Reducing exacerbations is a major aim of COPD treatment. Inhaled bronchodilators and steroids are the main drug treatments which are used to keep the airways open and reduce inflammation. Mucolytic drugs, on the other hand, aim to thin mucus to make it easier to cough up.

So far, it has been unclear how well mucolytic drugs such as carbocysteine and N-acetylcysteine reduce exacerbations. Guidelines differ in their recommendations about the place of mucolytic drugs in COPD treatment. This review aimed to summarise the evidence to show whether mucolytics reduce exacerbations or days of disability for COPD patients.

What did this study do?

This was an updated Cochrane systematic review and meta-analysis of randomised controlled trials of oral mucolytic drugs compared to placebo in adults with chronic bronchitis or COPD.

Four new studies were added, giving a total of 38 trials with 10,377 participants. They did not include people with asthma or cystic fibrosis. Most studies were conducted in Europe, including four in the UK. There were four studies in China, two in India, two in the US, and one in Japan.

The average study length was 8.8 months (range two months to three years). Mucolytics tested included N-acetylcysteine, carbocysteine, and erdosteine. They were taken by mouth one to three times per day.

No data was provided on bronchodilator inhaler or other medication use, and there was a wide variation between the studies, which reduces the reliability of the results.

What did it find?

  • People receiving mucolytic drugs were more likely to remain free of exacerbation of symptoms (50.9%) than people receiving placebo (38.6%) during the study period (odds ratio [OR] for being exacerbation-free 1.73, 95% confidence interval [CI] 1.56 to 1.91; 28 trials, 6,723 participants).
  • People receiving mucolytic drugs had slightly fewer days of disability, where they were unable to do their usual activities, each month: 1.14 days, compared to 1.57 days for people taking a placebo (mean difference 0.43 days, 95% CI 0.30 to 0.56; 9 trials, 2,259 participants).
  • Fewer people were admitted to hospital (13.8%) on mucolytic drugs compared with placebo (18.7%) over 16.6 months of follow-up (OR 0.68, 95% CI 0.52 to 0.89; 5 trials, 1,833 participants).
  • There was no difference in the results when the use of inhaled corticosteroids was taken into account.
  • Researchers said the results were based on moderately certain evidence. However, the review found larger effects in earlier studies of mucolytics for chronic bronchitis and smaller effects in more recent studies of COPD.

What does current guidance say on this issue?

The NICE 2018 guideline only recommends considering mucolytic drug therapy for people with a chronic cough productive of sputum. Mucolytic drugs should be stopped if there is no improvement in symptoms such as cough frequency or sputum production. The guideline does not recommend their routine use to prevent exacerbations for all people with COPD.

What are the implications?

This updated Cochrane review suggests that the NICE guideline hits the right balance in its recommendation that mucolytics may be of help for some people with COPD, but should not be prescribed routinely.

It confirms that mucolytics may offer a small reduction in risk of an exacerbation of COPD symptoms, with few adverse effects, but authors add that the results may be driven by older studies that could have been subject to publication bias.

Citation and Funding

Poole P, Sathananthan K and Fortescue R. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;(5):CD001287.

Cochrane UK and the Cochrane Airways Review Group are supported by NIHR infrastructure funding.

Bibliography

NICE. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. NG115. London: National Institute of Health and Care Excellence; 2018.

British Lung Foundation. Chronic obstructive airways disease (COPD) statistics. London: British Lung Foundation; 2019.

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

Published on 21 May 2019

Poole, P.,Sathananthan, K.,Fortescue, R.

Cochrane Database Syst Rev Volume 5 , 2019

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 (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 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.

Expert commentary

The place of mucolytic therapy in the management of COPD and chronic bronchitis is currently uncertain. The most recent Cochrane Review shows a small effect of various mucolytic agents in reducing acute exacerbations, but the heterogeneity of studies makes it difficult to recommend this therapy.

In the future, it will be important to select the patients most likely to benefit from mucolytics and to study their effect on mucus hypersecretion, chronic symptoms and quality of life in chronic bronchitis as well as COPD patients.

New approaches are required in the future for quantifying mucus hypersecretion as this is an important and common unmet medical need for which new therapies are needed.

Peter J Barnes, Margaret Turner-Warwick Professor of Medicine, Airway Disease Section, National Heart and Lung Institute, London

The commentator declares no conflicting interests