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Carbocisteine reduces the mean frequency of exacerbations by a modest amount, from 1.35/patient-year to 1.01/patient-year, compared with placebo, in Chinese patients with chronic obstructive pulmonary disease (COPD).
Action
Although, this study may not apply to typical patients in the UK, it adds to the growing body of evidence supporting the use of mucolytics in COPD. It would seem sensible to continue to follow NICE guidance and only consider mucolytics in COPD patients with a chronic cough, productive of sputum. Treatment should be stopped after four weeks if no benefit is seen, but continued if there is symptomatic improvement.
What is the background to this?
NICE guidance states that mucolytic drug therapy should be considered in COPD patients with a chronic cough productive of sputum. This should be continued if there is symptomatic improvement (for example, reduction in frequency of cough and sputum production) with the British National Formulary adding that mucolytic therapy should be stopped if there is no benefit after a four week trial. NICE considered the evidence from three systematic reviews as well as two further studies and concluded that mucolytic therapy was associated with a significant reduction in the number of exacerbations of COPD compared with placebo. Since NICE guidance was published, the Cochrane review has been updated (26 randomised controlled trials [RCTs] n=7,335) and found that oral mucolytic treatment for at least two months significantly reduced the number of exacerbations by 0.05/month in patients with stable chronic bronchitis (21 RCTs) or COPD (5 RCTs) (weighted mean difference [WMD] –0.05, 95% confidence interval [CI] –0.05 to –0.04) compared with placebo. The odds of remaining exacerbation-free were doubled in the mucolytic group (odds ratio [OR] 2.13, 95% CI 1.86 to 2.42).
What does this study claim?
The PEACE study showed that long-term (one year) use of carbocisteine reduced the mean number of exacerbations of COPD per patient per year compared with placebo (relative risk [RR] 0.75, 95% CI 0.62 to 0.92; P=0.004). This result was independent of smoking status, COPD severity, or concomitant use of inhaled corticosteroids or xanthines (e.g. aminophylline, theophylline). There was no significant difference in lung function between the groups, as shown by post-bronchodilator FEV1 measurements. Adverse effects with carbocisteine occurred with a similar frequency to that in the placebo group and study withdrawal rates were also similar.
The study was a large (n=709), Chinese multi-centre RCT in patients with moderately severe COPD (mean FEV1 after taking a bronchodilator 44% of predicted at baseline). Participants were randomised to receive carbocisteine 500mg three times daily or placebo and were followed up every three months for one year.
So what?
In the discussion section of the PEACE study and also in an accompanying editorial, some of the limitations of the study are discussed. Use of concomitant inhaled bronchodilators and corticosteroids was much lower than in other large COPD studies. Only 16.7% of study participants received inhaled corticosteroids. Also, xanthines have been shown to reduce exacerbations in Chinese patients, which has not been reported in white patients. In addition, causes of exacerbations of COPD may differ in the Chinese population. For example, in rural areas of developing countries like China, pollution is problematic and may be a cause of exacerbations. The Chinese differ from Europeans in terms of dietary patterns, nutritional status and lifestyle. It remains unclear whether mucolytics will prevent exacerbations in patients in the UK, whose COPD has generally been caused by smoking.
Clinicians should continue to follow NICE guidance and only consider mucolytic therapy in patients with a chronic cough, productive of sputum. Treatment should be stopped after four weeks if no benefit is seen, but continued if there is symptomatic improvement.
Study details
Design: Randomised, double-blind, placebo-controlled, parallel group study in 709 patients recruited from 22 medical centres in China. Allocation was concealed.
Patients: Eligible patients were aged between 40 and 80 years and had a previous history of at least two exacerbations of COPD within the previous two years, but were clinically stable for at least four weeks before the study. COPD was defined as FEV1/FVC ratio < 0.70 and an FEV1 between 25–79% of predicted.
Intervention and comparison: After a two-week run in period, patients were randomised to receive carbocisteine 500mg three times daily or placebo for one year. They were followed up every three months via interview.
Outcomes: The primary endpoint was exacerbation rate over one year. Exacerbation rate was defined as at least two-day persistence of at least two major symptoms (worsening dyspnoea and an increase in sputum purulence, volume, or both) or of any single major symptom plus more than one minor symptom (upper airway infection, unexplained fever, and increased wheezing). Secondary endpoints included quality of life, lung function and arterial oxygen saturation.
Results: Carbocisteine reduced the mean frequency of exacerbations from 1.35/patient-year to 1.01/patient-year (a 24.5% reduction), compared with placebo (RR 0.75, 95% CI 0.62 to 0.92, P=0.004). COPD staging and concomitant treatment (theophyllines and inhaled corticosteroids) were also found to affect the risk of COPD exacerbations but after adjusting for these carbocisteine was still significantly more effective than placebo (COPD stage – RR 0.74, 95% CI 0.61 to 0.89, P=0.002; inhaled corticosteroid use – RR 0.75, 95% CI 0.63 to 0.91, P=0.004; xanthine use – RR 0.74, 95% CI 0.61 to 0.89, P=0.002). Smoking status also had no effect on the results (RR 0.74, 95% CI 0.64–0.86, P<0.0001). There was no significant difference between the groups in total, activity or impact quality of life scores, although symptom scores were significantly better in the carbocisteine group, albeit by a clinically insignificant amount (change from baseline –11.34 vs. –3.54, P=0.004). Lung function, as shown by post-bronchodilator FEV1 measurements, was not significantly different between the groups. The nature and incidence of adverse effects were similar across the groups (57 in the carbocisteine group compared with 56 in the placebo group). Study withdrawal rates were also similar (13.60% vs 12.15%; P=0.565)
Sponsorship: Funded by Kyorin Pharmaceuticals, Japan.
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