Elsevier

The Lancet

Volume 365, Issue 9470, 30 April–6 May 2005, Pages 1552-1560
The Lancet

Articles
Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(05)66456-2Get rights and content

Summary

Background

Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes.

Methods

In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat.

Findings

The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI −25 to 10). The number of exacerbations per year did not differ between groups (1·25 [SD 1·35] vs 1·29 [SD 1·46]; hazard ratio 0·99 [95% CI 0·89–1·10, p=0·85]). Subgroup analysis suggested that the exacerbation rate might be reduced with N acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation.

Interpretation

N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD.

Introduction

Oxidative stress has major importance in the pathogenesis of chronic obstructive pulmonary disease (COPD),1, 2 as shown by: enhanced exhalation of hydrogen peroxide,3 nitric oxide,4 ethane,5 carbon monoxide,4 and isoprostane;6, 7 increased concentrations of 4-hydroxyl-2-nonenal in the lungs;8 or by increased urinary excretion of isoprostane.9 Oxidative stress leads to inactivation of antiproteases, activation of proteases, and expression of interleukin 8 and tumour necrosis factor α through expression of nuclear factor κB, further enhancing recruitment of neutrophils and formation of isoprostane from the oxidation of arachidonic acid.6, 7

Antioxidants such as N-acetylcysteine could well reduce oxidative stress in patients with COPD.10 However, the effects of antioxidants on outcomes in COPD have not been studied in detail. Results from meta-analyses11, 12, 13 of between six and 23 studies have shown that N-acetylcysteine reduces exacerbation by 22–29%. However, most of these studies assessed chronic bronchitis and not COPD. A retrospective study14 of the risk of readmission to hospital for 1291 patients with COPD associated N-acetylcysteine with a dose-dependent decrease in readmission rate. The effects of N-acetylcysteine on outcomes and progression of the disease have not been studied in a large-scale prospective trial lasting long enough to assess potential effects on disease progression.

The Bronchitis Randomized on NAC study (BRONCUS) was designed as a randomised controlled trial of the effects of N-acetylcysteine on the progression of disease and exacerbation rate in patients with COPD who had frequent exacerbations (ie, at least two per year for 2 years). Specifically, the study was designed to assess whether N acetylcysteine reduced the rate of decline in lung function, reduced exacerbation rate, and improved health status.

Section snippets

Patients

The design of the trial has been described in detail before.15 Briefly, the study was designed as a phase III, double-blind, randomised placebo-controlled parallel-group trial of 600 mg per day oral N-acetylcysteine versus placebo. This dose was chosen on the basis of efficacy in previous studies, which were later reviewed in meta-analyses.11, 12, 13 Patients were followed for 3 years and analysis was by intention-to-treat. Primary endpoints of the study were yearly reduction in lung function

Results

Table 1 shows baseline characteristics of patients. The number of patients enrolled exceeded that estimated and the true drop-out rate was less than assumed—70 (27%) of 256 in the N-acetylcysteine group and 99 (37%) of 267 in the placebo group (figure 1). Drop-out rate was significantly greater in the placebo group than in the N acetylcysteine group (p=0·018), and time to withdrawal was significantly shorter in patients assigned placebo than in those assigned N-acetylcysteine (p=0·014).

Discussion

This study found that treatment with 600 mg oral N acetylcysteine per day for patients with COPD did not affect the rate of decline in FEV1 or VC, yearly exacerbation, or deterioration in health status. Subgroup analysis suggested that N-acetylcysteine might reduce the risk of exacerbation in patients not taking inhaled steroids. Secondary analysis suggested that FRC was reduced with 0·374 L at the end of treatment. The results are negative in terms of the variables thought to be related to the

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