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 2019 Cochrane Review (Poole 2019) [evidence level I] included 38 trials involving 10,377 participants with COPD or chronic bronchitis, who were randomised to receive at least daily oral N-acetylcysteine, carbocysteine, erdosteine, ambroxol, or placebo.  The authors found treatment with mucolytics was associated with an increased likelihood of being exacerbation free during the period of study (OR 1.73, 95% CI 1.56 to 1.91) and calculated the number needed to treat with mucolytics for an average of nine months to keep an additional participant exacerbation free was eight (NNTB 8, 95% CI 7 to 10). For this outcome there was high heterogeneity I2 = 62%), and the authors recommend caution with the interpretation of the results. Overall the effect size of the more recent trials was smaller. Further the number of people with one or more hospitalisation was reduced, but study results were not consistent (Peto OR 0.68, 95% CI 0.52 to 0.89; I2 = 58%). Mucolytic use resulted in a reduction of 0.43 days of disability per participant per month compared to placebo (95% CI -0.56 to -0.30; I2 = 61%). The authors concluded that the use of mucolytics in patients with chronic bronchitis or COPD may produce a small reduction in the likelihood of an exacerbation, in days of disability per month, and possibly hospitalisation.  There was no clinically or statistically significant effect on quality of life.

In another meta-analysis of 10 RCTs involving 1,278 patients, 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.