P7. Mucolytic agents

Mucolytics may benefit certain patients with COPD [evidence level I, strong recommendation]

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 2015 Cochrane Review (Poole 2015) included 34 trials involving 6,233 participants with COPD OR chronic bronchitis.  The authors found treatment with mucolytics was associated with an increased likelihood of being exacerbation free during the period of study (OR 1.75, 95% CI 1.57 to 1.94) and calculated the number needed to treat with mucolytics for an additional beneficial outcome for an average of 10 months as eight (NNTB 8, 95% CI 7 to 10). Mucolytic use resulted in a reduction of 0.03 exacerbations per participant per month (mean difference (MD) -0.03, 95% CI -0.04 to -0.03) compared with placebo, that is, approximately one exacerbation every three years. These results however should be interpreted with care due to the very high heterogeneity (I2 = 85%) and the smaller effect in more recent trials. The authors concluded that the use of mucolytics in patients with chronic bronchitis or COPD may produce a small reduction in exacerbations and small improvements in quality of life.

A double blind randomised controlled trial of erdosteine found that erdosteine reduced exacerbations by 19.4% (0.9 versus 1.13 exacerbations /patient /year, p=0.01) largely due to an effect on mild events (Dal Negro 2017). Erdosteine also reduced exacerbation duration by 24.6% (9.55 versus 12.63 days, p=0.023) and decreased use of reliever (p <0.001); however it did not affect quality of life or time to first exacerbation.  In a subsequent meta-analysis of 10 RCTs involving 1,278 patients, that included the Dal Negro trial, Cazzola reported that compared to placebo, erdosteine improved the clinical condition of COPD, as measured by global overall clinical scores comprising a number of measures,  (SMD -0.56, 95% CI -0.94 to 0.17; p=0.001) (Cazzola 2018).  Erdosteine treatment also reduced the risk of COPD exacerbation and the risk of experiencing at least one exacerbation compared to control.

There is evidence to support the use of high dose oral N-acetylcysteine in the reduction of COPD exacerbations and improvements in lung function. This is supported by the results of a systematic review and meta-analysis by Cazzola et al (Cazzola 2015a).  In their meta-analysis of 13 studies involving 4155 COPD patients, both low (<600mg/day) and high doses (>1200mg/day) of N-acetylcysteine significantly reduced the frequency of exacerbations (relative risk 0.75, 95% CI 0.66–0.84; p<0.01).  The effectiveness of N-acetylcysteine in reducing exacerbations was also confirmed by seven RCTs performed in patients who were enrolled based on ATS/ERS or GOLD guidelines, spirometry confirmed COPD (relative risk 0.78, 95% CI 0.65–0.93; p<0.01) [evidence level I]. In patients with COPD, high dose (≥1200mg/day) N-acetylcysteine should be considered as an effective therapy for reducing exacerbations.  In patients with chronic bronchitis but without airflow limitation, a dose of 600mg/day leads to reduced exacerbations.