Reference
Tse HN, Raiteri L, Wong KY, et al. High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest. 2013 Jul;144(1):106-118.
Design
Double-blind, randomized, placebo-controlled trial
Participants
This study included 120 participants (93.2% male, ages 50–80) with stable COPD. After a 4-week run-in period in which all mucolytic treatments were discontinued, participants were randomized to either N-acetylcysteine (NAC) 600 mg BID or placebo.
Study Parameters Assessed
This study looked at 3 types of parameters:
1. Measurements of small airway (<2 mm internal diameter without cartilage) function
These measurements included:
- Forced expiratory flow 25% to 75% (FEF 2, 5-75). Determined by spirometry, this is a measurement of average flow at the middle of lung volume. This is a more specific measurement for small airways than other spirometric values.
- Forced oscillation technique (FOT). This technique can differentiate function in large and small airways by applying different external oscillations to the lungs, with lower frequencies correlating to small airways. The FOT parameters evaluated in this study are reactance, frequency resonance (FRes), and frequency dependence (FDep). Reactance is a measurement of the elastic properties of the lungs outside of the pattern of breathing. This decreases in COPD. FRes, the frequency at which reactance equals zero, is expressed as the point at which capacitative reactance (more prominent at low resonance) and inertive reactance (more prominent at high resonance) are equal. FRes increases with increased severity of both obstructive and restrictive disease. FDep is the slope of resistance vs oscillation frequency, resistance at 6 Hz, and reactance at 6 Hz. This will decrease with increased severity of disease.
2. Measurements of large airway function
Inspiratory capacity (IC), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC) were all measured.
3. Clinical outcomes
The study assessed COPD exacerbation rate, hospitalization rate due to exacerbation, dyspnea, 6-minute walking distance (6MWD), and quality of life based on the results of the St. George’s Respiratory Questionnaire (SGRQ).
Primary Outcome Measures
Measurements of small and large airway function, listed above, were the primary outcome measures. Clinical outcomes were secondary.
Key Findings
Measurements of small airway function were shown to have significant improvement vs placebo over a 1-year period:
- FEF 25%–75% increased (0.72 +/- 0.07 L/s to 0.80 +/- 0.07 L/s) with NAC, whereas it remained static with placebo (0.679 +/- 0.07 L/s to 0.677 +/- 0.07 L/s).
- Reactance improved 22.3% with NAC and decreased 10.7% with placebo.
- FRes improved by decreasing 21.7% vs a decrease of only 3.7% with placebo.
- FDep improved by increasing 25.3% vs a 58.3% decrease with placebo.
Clinical Findings
Frequency of COPD exacerbations was decreased with NAC relative to placebo, with 50 in the NAC group and 96 in the placebo group (some participants had multiple exacerbations). Hospital admissions in the NAC group were also lower (26 vs 45 with placebo), and average number of days in hospital was also lower (1.8 d/y vs 4.2 d/y with placebo). There was no difference found in other clinical parameters such as respiratory symptoms, quality of life, and exercise capacity.
Practice Implications
This study is the latest in a growing body of research assessing the utility of NAC as a therapy for COPD. In theory, NAC is a perfect substance to prevent exacerbations and lung damage of progressive COPD. It is a mucolytic, it lessens oxidative damage (via glutathione), and it has low toxicity. However, the data thus far have been mixed on whether it can produce the expected clinical results of these actions. This latest study helps to clarify that NAC can be a beneficial treatment for COPD when administered in sufficient dosage and duration. This benefit is most clearly shown when the assessment parameters look specifically at small airway function.
NAC is well-known as a mucolytic agent. This is important in COPD because muco-inflammatory exudate obstruction in small airways is an independent factor in airway limitation.1 Treatment with mucolytic drugs has generally been shown to decrease the symptoms and frequency of exacerbations in COPD, so it would logically follow that NAC would be useful for this application and has been found to increase ease of expectoration.2,3
Additionally, NAC’s antioxidant capacity could potentially decrease inflammation and damage to the airways over time. Oral NAC is deacetylated into cysteine, 1 of 3 amino acids that form glutathione, part of a potent antioxidative enzyme system in cells. Glutathione levels do increase in alveolar lavage fluid after administration with NAC.4 In the lungs, reduced glutathione (GSH) plays an important role in “immune modulation, remodeling of the extracellular matrix, apoptosis, and mitochondrial respiration.” Decreased levels of reduced glutathione (GSH) have been found to be a primary feature of inflammatory lung disease.5 NAC can also play its own role as an antioxidant by decreasing H202 in the lungs and protecting alveolar cells and bronchial fibroblasts against damage.6,7
As more data is collected, a trend is emerging that is starting to show a few key components that are essential to NAC's efficacy as a treatment in COPD: higher dosage and longer duration improve results. Also, looking at the right parameters gives us a better idea of whether treatments are efficacious.
Studies that have failed to show NAC as a useful therapy in COPD have generally either used low doses of 600 mg per day8–10 or have been of short duration, lasting 7 days or less.11,12 NAC tends to have poor bioavailability, but it is hypothesized that higher doses will improve bioavailability and consolidate its effects.13 Studies using higher doses of 1,200–1,800 mg per day and duration of 6 months or more showed positive results in COPD.14,15
Another important difference between this study and others is assessment parameters. Other experiments such as the BRONCHUS study have primarily used spirometry to evaluate airflow in the lungs, with varying results.16,17 Similarly, traditional spirometric parameters in this study also showed no significant change. However, measurements that were more specific to small airway function, such as FEF 25-75 and data from forced oscillation technique (FOT), showed significant improvement. 25%–75% is the one value from spirometry that is considered an indicator of small airway obstruction. With FOT, using higher frequencies will produce data that corresponds to the function of the large airways, while lower frequencies are more specific to small airways.18,19 Specifically looking at small airways makes sense given the current view that this is the predominant site of airflow limitation due to increased wall thickness and obstruction by mucus.20
Although they were secondary in this study, clinical outcomes and improvement were also significant. Interestingly, clinical parameters such as reported symptoms, quality of life, and exercise capacity did not change with NAC, but the need for medical intervention decreased. Patients taking 600 mg BID of NAC were found to have fewer exacerbations of their symptoms, hospital admissions, and days spent in the hospital vs placebo. Other studies have found similar outcomes in decreased exacerbations23 and a 30% decrease in hospital admissions with longer-term use at higher dosage.24
NAC is a safe and well tolerated option for improving the longer-term function of the small airways in COPD, and decreasing the frequency of exacerbations and hospitalization. This study helps to solidify the need for higher doses (1,200–1,800 mg/day) and longer duration of treatment (6 months or more). By decreasing mucus and preventing oxidative damage, NAC can be a useful adjunct to any treatment regimen for patients with COPD.
