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

      1 , 2 , 3

      Cochrane Airways Group

      Cochrane Database of Systematic Reviews

      Wiley

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          Abstract

          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. 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 We searched the Cochrane Airways Group Specialised Register and reference lists of articles on 12 separate occasions, most recently on 23 April 2019. 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 5.3 for analysis. 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). 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. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease Background to the question Chronic obstructive pulmonary disease (COPD) and chronic bronchitis are long‐term breathing conditions. They cause symptoms such as shortness of breath, cough, and excess sputum. People with COPD and chronic bronchitis may have flare‐ups (exacerbations) when their symptoms become worse. Mucolytics are medicines taken orally that may loosen sputum, making it easier to cough it up. Mucolytics may have other beneficial effects on lung infection and inflammation and may reduce the number of flare‐ups that people with COPD and chronic bronchitis have. Mucolytics can also be inhaled, but we did not look at inhaled mucolytics in this review. Study characteristics We looked for studies lasting at least two months, in which it was decided at random whether a person received a mucolytic drug or a placebo. We did not include studies involving children or people with other breathing conditions such as asthma and cystic fibrosis. We found 38 studies to include in our review. These studies included a total of 10,377 adults with COPD or chronic bronchitis. The studies used a variety of mucolytic drugs, including N‐acetylcysteine, carbocysteine, and erdosteine and lasted from two months to three years. Mucolytics were taken by mouth between one and three times per day. These studies measured several different outcomes to find out if the drug was useful, including flare‐ups, hospital admissions, quality of life, lung function, and side effects. Key results We found that people taking mucolytic drugs were less likely to experience a flare‐up compared to those taking placebo. Approximately eight people would need to take the drug for nine months for one extra person to avoid having a flare‐up. This result was based on 28 studies involving 6723 people. However, the studies carried out a longer time ago (1970s to 1990s) show greater benefit than those carried out more recently. Shorter studies also seemed to show more benefit than longer studies. This could be because the newer trials were larger and may be showing that mucolytics are less beneficial than the earlier studies showed. Or it could be that only studies that showed mucolytics as beneficial were published before the 2000s, when there was a push to report all trial results regardless of whether or not they showed benefit. People taking mucolytics had fewer days of disability (i.e. days when they could not do their normal activities) every month, but this was quite a small difference ‐ less than half a day per person per month. They were also approximately one‐third less likely to be admitted to hospital, although this result is based on only five studies that provided this information. Study results suggest that mucolytics do not have an important impact on quality of life or lung function. People taking mucolytics did not experience more unwanted side effects than those taking placebo. But we could not be sure about their impact on death during the study period because only 37 deaths occurred amongst the 3527 participants in studies where deaths were measured and reported. Quality of the evidence We are moderately confident about the results we have presented. Our confidence is reduced by the results from individual studies looking quite different from one another and the mix of older and newer studies that we found. Also, in some cases there were not enough data to be sure whether mucolytics were better or worse than, or the same as, placebo. Conclusions Mucolytics appear to be useful for reducing flare‐ups, days of disability, and hospital admissions in people with COPD or chronic bronchitis, and they do not appear to cause more side effects. However, they do not appear to have much impact on quality of life or lung function, and we could not be sure about their impact on death. This plain language summary is current to April 2019.

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          Most cited references 50

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          Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society.

          This guideline is an official statement of the American College of Physicians (ACP), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), and European Respiratory Society (ERS). It represents an update of the 2007 ACP clinical practice guideline on diagnosis and management of stable chronic obstructive pulmonary disease (COPD) and is intended for clinicians who manage patients with COPD. This guideline addresses the value of history and physical examination for predicting airflow obstruction; the value of spirometry for screening or diagnosis of COPD; and COPD management strategies, specifically evaluation of various inhaled therapies (anticholinergics, long-acting β-agonists, and corticosteroids), pulmonary rehabilitation programs, and supplemental oxygen therapy. This guideline is based on a targeted literature update from March 2007 to December 2009 to evaluate the evidence and update the 2007 ACP clinical practice guideline on diagnosis and management of stable COPD. RECOMMENDATION 1: ACP, ACCP, ATS, and ERS recommend that spirometry should be obtained to diagnose airflow obstruction in patients with respiratory symptoms (Grade: strong recommendation, moderate-quality evidence). Spirometry should not be used to screen for airflow obstruction in individuals without respiratory symptoms (Grade: strong recommendation, moderate-quality evidence). RECOMMENDATION 2: For stable COPD patients with respiratory symptoms and FEV(1) between 60% and 80% predicted, ACP, ACCP, ATS, and ERS suggest that treatment with inhaled bronchodilators may be used (Grade: weak recommendation, low-quality evidence). RECOMMENDATION 3: For stable COPD patients with respiratory symptoms and FEV(1) 50% predicted. (Grade: weak recommendation, moderate-quality evidence). RECOMMENDATION 7: ACP, ACCP, ATS, and ERS recommend that clinicians should prescribe continuous oxygen therapy in patients with COPD who have severe resting hypoxemia (Pao(2) ≤55 mm Hg or Spo(2) ≤88%) (Grade: strong recommendation, moderate-quality evidence).
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            Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study.

            Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, and has many components including mucus hypersecretion, oxidative stress, and airway inflammation. We aimed to assess whether carbocisteine, a mucolytic agent with anti-inflammatory and antioxidation activities, could reduce the yearly exacerbation rate in patients with COPD. We did a randomised, double-blind, placebo-controlled study of 709 patients from 22 centres in China. Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s (FEV(1)) to forced vital capacity (FVC) ratio (FEV(1)/FVC) of less than 0.7 and an FEV(1) between 25% and 79% of the predicted value, were aged between 40 and 80 years, had a history of at least two COPD exacerbations within the previous 2 years, and had remained clinically stable for over 4 weeks before the study. Patients were randomly assigned to receive 1500 mg carbocisteine or placebo per day for a year. The primary endpoint was exacerbation rate over 1 year, and analysis was by intention to treat. This trial is registered with the Japan Clinical Trials Registry (http://umin.ac.jp/ctr/index/htm) number UMIN-CRT C000000233. 354 patients were assigned to the carbocisteine group and 355 to the placebo group. Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group (1.01 [SE 0.06] vs 1.35 [SE 0.06]), risk ratio 0.75 (95% CI 0.62-0.92, p=0.004). Non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Carbocisteine was well tolerated. Mucolytics, such as carbocisteine, should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD.
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              High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study.

              The mucolytic and antioxidant effects of N-acetylcysteine (NAC) may have great value in COPD treatment. However, beneficial effects have not been confirmed in clinical studies, possibly due to insufficient NAC doses and/or inadequate outcome parameters used. The objective of this study was to investigate high-dose NAC plus usual therapy in Chinese patients with stable COPD. The 1-year HIACE (The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of Chronic Obstructive Pulmonary Disease-a Double-blinded, Randomized, Placebo-controlled Trial) double-blind trial conducted in Kwong Wah Hospital, Hong Kong, randomized eligible patients aged 50 to 80 years with stable COPD to NAC 600 mg bid or placebo after 4-week run-in. Lung function parameters, symptoms, modified Medical Research Council (mMRC) dyspnea and St. George's Respiratory Questionnaire (SGRQ) scores, 6-min walking distance (6MWD), and exacerbation and admission rates were measured at baseline and every 16 weeks for 1 year. Of 133 patients screened, 120 were eligible (93.2% men; mean age, 70.8±0.74 years; %FEV1 53.9±2.0%). Baseline characteristics were similar in the two groups. At 1 year, there was a significant improvement in forced expiratory flow 25% to 75% (P=.037) and forced oscillation technique, a significant reduction in exacerbation frequency (0.96 times/y vs 1.71 times/y, P=.019), and a tendency toward reduction in admission rate (0.5 times/y vs 0.8 times/y, P=.196) with NAC vs placebo. There were no significant between-group differences in mMRC dypsnea score, SGRQ score, and 6MWD. No major adverse effects were reported. In this study, 1-year treatment with high-dose NAC resulted in significantly improved small airways function and decreased exacerbation frequency in patients with stable COPD. ClinicalTrials.gov; No.: NCT01136239; URL: www.clinicaltrials.gov.
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                Author and article information

                Journal
                Cochrane Database of Systematic Reviews
                Wiley
                14651858
                May 20 2019
                Affiliations
                [1 ]University of Auckland; Department of Medicine; Private Bag 92019 Auckland New Zealand
                [2 ]St George's, University of London; Population Health Research Institute; London UK
                [3 ]St George's, University of London; Cochrane Airways, Population Health Research Institute; London UK SW17 0RE
                Article
                10.1002/14651858.CD001287.pub6
                6527426
                31107966
                © 2019
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