Oral N-acetylcysteine (NAC) reduces COPD exacerbations in RCT
N-acetylcysteine (NAC) Improves COPD Outcomes
Oxidative stress (imbalance between oxidants and antioxidants) is part of the story of how COPD causes symptoms of cough and shortness of breath. Cigarette smoke is the main source of oxidation damage in the lungs leading to COPD, but even after they quit smoking, people with COPD still have a so-called "redox imbalance" that contributes to their daily COPD symptoms.
N-acetylcysteine (NAC) is an antioxidant, anti-inflammatory, anti-mucus medicine that has already been tested in people with COPD as an oral drug. Also called Mucomyst, N-acetylcysteine was no blockbuster at preventing COPD exacerbations or improving symptoms -- most trials did not show a benefit -- but reviews and analyses have produced some optimism:
A 2010 Cochrane review suggested Mucomyst/NAC might reduce COPD exacerbations and their severity, but it was unclear whether there was any additive benefit to inhaled corticosteroids.
A 2000 meta-analysis also suggested N-acetylcysteine might prevent COPD exacerbations.
However, the single largest multicenter randomized trial (BRONCUS 2005, n=523) found no benefit of oral Mucomyst (600 mg daily) in reducing rate of lung function decline or COPD exacerbations over a 3 year follow up period.
Most of these trials used doses of oral N-acetylcysteine of 600 mg a day or less; the drug can be dosed higher. So Hoi Nam Tse et al doubled the dose to 600 mg b.i.d. and gave it for a year, to ask yet again if oral N-acetylcysteine can prevent COPD exacerbations.
What They Did
Authors randomized 120 people with stable COPD (almost all men aged ~70, most with mild or moderate COPD) at one hospital in Hong Kong to receive 600 mg N-acetylcysteine orally twice daily or placebo for 1 year. Patients with recent COPD exacerbations were allowed into the trial 8 weeks after their COPD exacerbations resolved. Those on long-term oxygen therapy were excluded.
Patients were seen every 4 months, checking for COPD exacerbation symptoms (2 out of 3: increased dyspnea, purulence, or volume of sputum) and assorted other outcomes (dyspnea, quality of life, etc). Spirometry was checked at 4 months and one year.
What They Found
After a year, patients receiving NAC had better respiratory function: a significantly higher forced expiratory flow 25% to 75% (FEF 25-75) and improvement in reactance as measured by forced oscillation technique. They had fewer COPD exacerbations: about 1 per year per patient with NAC, compared to 1.7 with placebo. Fewer people taking N-acetylcysteine were hospitalized with COPD exacerbations (26 vs. 45), although this did not reach statistical significance. Six minute walk distance, quality of life and dyspnea scores were not different between groups. They noted no major adverse effects.
What It Means
This is a weak study with a tantalizing result, that a cheap and relatively safe therapy could prevent COPD exacerbations. Authors suggest that the higher dose of N-acetylcysteine they used was responsible for their positive findings (as opposed to previous negative studies using 600 mg/day), noting that NAC's antioxidant effects really only kick in at 1200 mg / day. Since people with emphysema (the more common phenotype of COPD) usually also have mucus impaction of their small airways, the mechanistic story that NAC's anti-inflammatory and mucolytic properties open up these airways (improving FEF 25-75) has face plausibility.
Combined with the abundant supportive basic science data and enough clinical study data to be interesting, you'd have to be a medical Grinch to dismiss N-acetylcysteine out-of-hand as having no conceivable benefit in the treatment of COPD.
Until larger, more rigorous randomized trials are done (none of which are listed as upcoming on clinicaltrials.gov), N-acetylcysteine's main role may be as an empiric, almost-placebo treatment for people living with COPD and burdened with frequent exacerbations or excessive sputum production. There's no solid proof that it will help, but it just might do something, and trying it won't cost much or create much risk. And no physician should ever underestimate the power of the placebo effect, which not infrequently exceeds the benefits in intervention arms in clinical trials. Many (even the AMA) have argued we physicians should harness the psychological power of placebos and unproven therapies for patient benefit, while being honest about their lack of known benefit. N-acetylcysteine may prove definitively efficacious someday at improving COPD outcomes, and for now there's no reason for people with COPD not to try NAC in the hope it might help.
Hoi Nam Tse et al. High-Dose N-Acetylcysteine in Stable COPD:The 1-Year, Double-Blind, Randomized, Placebo-Controlled HIACE Study. Chest 2013;144(1):106-118.