P7. Mucolytic agents

Mucolytics may reduce the frequency and duration of exacerbations (Poole 2010) [evidence level II]

Mucolytics, including N-acetylcysteine (NAC), ambroxol (3), sobrerol, carbocysteine, sobrerol, letosteine, cithiolone, iodinated glycerol, N-isobutyrylcysteine (NIC), myrtol and erdosteine have multiple possible actions in COPD including decreasing sputum viscosity, and antioxidant, anti-inflammatory or antibacterial activity. A 2010 Cochrane review (Poole 2010) included 9 studies in COPD and 19 studies in chronic bronchitis. The authors found treatment with mucolytics was associated with a small reduction in exacerbations, WMD -0.05 per month (95% CI -0.05 to -0.03) and a reduction in total number of days of disability WMD -0.56 (95% CI -0.77 to -0.35). This equated to a NNT of 6 to prevent one exacerbation over winter months, and they concluded mucolytics should be considered for use through the winter months at least, in patients with moderate or severe COPD in whom inhaled corticosteroids are not prescribed. The caveat on the use of inhaled corticosteroids was their belief that this was the cause of the decline in the observed effect of mucolytics over time. This is in keeping with a trial of 709 subjects with COPD randomised to carbocisteine or placebo (Zheng 2008), which found a significant decrease in exacerbations (risk ratio 0.75, 95% CI 0.62 to 0.92, p=0.004) in subjects where the use of inhaled corticosteroids was only 15% in the placebo and 18% in the carbocisteine arms (Zheng 2008) [evidence level II]. A placebo controlled trial of N-acetylcysteine in patients with stable COPD found significant improvement in small airway function and reduction in the frequency of exacerbations (Tse 2013) [evidence level II].

There is evidence to support the use of high dose oral N-acetylcysteine in the reduction of COPD exacerbations and improvements in lung function. A large RCT involving 1006 Chinese patients with moderate to severe COPD evaluated the effect of high dose (600mg bd) N-acetylcystine for a one year duration on exacerbations of COPD. They reported a significant reduction in exacerbations in the intervention group (1.16 exacerbations per patient-year ) compared to placebo ( 1·49 exacerbations per patient-year; risk ratio 0·78, 95% CI 0·67–0·90; p=0·0011) (Zheng 2014) [evidence level II]. In another RCT evaluating high dose N-acetylcysteine (600mg bd) compared to placebo in 120 Chinese patients, there were significant improvements in the primary outcomes of FEF25-75 and in forced oscillation technique parameters at one year. (Tse 2013) [evidence level II].

Shen and colleagues undertook a systematic review and a meta analysis to examine the difference of effect between high and low dose oral N-acetylcysteine on COPD exacerbations (Shen 2014). The results of the analysis support the use of high dose oral N-acetylcysteine (>600mg daily) in reducing exacerbations (RR 0.59, 95%CI 0.47-0.74) but not low dose.  In the meta analysis neither high or low dose N-acetylcysteine had any effect on FEV1.  The largest of the randomised controlled trials (Zheng 2014) recruited patients with moderate to severe COPD with at least two exacerbations in the previous two years.