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Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial

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Summary

Background

Increased oxidative stress and inflammation has a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Drugs with antioxidant and anti-inflammatory properties, such as N-acetylcysteine, might provide a useful therapeutic approach for COPD. We aimed to assess whether N-acetylcysteine could reduce the rate of exacerbations in patients with COPD.

Methods

In our prospective, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 40–80 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <0·7 and FEV1 of 30–70% of predicted) at 34 hospitals in China. We stratified patients according to use of inhaled corticosteroids (regular use or not) at baseline and randomly allocated them to receive N-acetylcysteine (one 600 mg tablet, twice daily) or matched placebo for 1 year. The primary endpoint was the annual exacerbation rate in patients who received at least one dose of study drug and had at least one assessment visit after randomisation. This study is registered with the Chinese Clinical Trials Registry, ChiCTR-TRC-09000460.

Findings

Between June 25, 2009, and Dec 29, 2010, we screened 1297 patients, of whom 1006 were eligible for randomisation (504 to N-acetylcysteine and 502 to placebo). After 1 year, we noted 497 acute exacerbations in 482 patients in the N-acetylcysteine group who received at least one dose and had at least one assessment visit (1·16 exacerbations per patient-year) and 641 acute exacerbations in 482 patients in the placebo group (1·49 exacerbations per patient-year; risk ratio 0·78, 95% CI 0·67–0·90; p=0·0011). N-acetylcysteine was well tolerated: 146 (29%) of 495 patients who received at least one dose of N-acetylcysteine had adverse events (48 serious), as did 130 (26%) of 495 patients who received at least one dose of placebo (46 serious). The most common serious adverse event was acute exacerbation of COPD, occurring in 32 (6%) of 495 patients in the N-acetylcysteine group and 36 (7%) of 495 patients in the placebo group.

Interpretation

Our findings show that in Chinese patients with moderate-to-severe COPD, long-term use of N-acetylcysteine 600 mg twice daily can prevent exacerbations, especially in disease of moderate severity. Future studies are needed to explore efficacy in patients with mild COPD (GOLD I).

Funding

Hainan Zambon Pharmaceutical.

Introduction

COPD is characterised by persistent airflow limitation and frequent recurrent acute exacerbations that contribute to disease severity in individual patients.1 COPD with acute exacerbations results in a faster decline in lung function,2 impairment of health status,3 reduction in exercise tolerance, and high economic burden,4 leading to substantial rates of hospital admission, readmission and mortality. Therefore, effective prevention and treatment of exacerbations has been strongly recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD).1

Many factors are involved in the pathophysiology of COPD, such as mucus hypersecretion, oxidative stress, and inflammation of the airways and lungs.1 Thus, drugs that have antioxidative and anti-inflammatory properties, and mucolytic activity, might be effective for treatment of COPD.

N-acetylcysteine is a well-known, effective mucolytic drug that reduces sputum viscosity and elasticity, improves mucociliary clearance and modulates the inflammatory response.5, 6 Furthermore, N-acetylcysteine has both direct and indirect antioxidant properties, which have been extensively assessed in in-vitro and in-vivo studies,7, 8, 9 and might be important for the long-term management of patients with COPD.

Previous studies showed that treatment with N-acetylcysteine (400–1200 mg per day) reduced rates of acute COPD exacerbations10 and hospital readmissions.11 Nevertheless, these studies were not recognised as strong evidence because of limitations in their design, such as small sample sizes, absence of double-blinding and placebo controls, or a short study duration. Moreover, inconsistent results have been reported. In the BRONCUS study,12 523 patients with moderate-to-severe COPD were treated with N-acetylcysteine (600 mg per day) for 3 years; compared with placebo, active treatment did not significantly reduce the exacerbation rate, apart from in patients not concomitantly treated with inhaled corticosteroids.12 Schermer and colleagues13 reported that exacerbation rates did not reduce significantly in a trial of 286 patients with COPD or chronic bronchitis who were treated with twice daily inhaled fluticasone propionate 500 μg, once daily oral N-acetylcysteine 600 mg, or placebo for 3 years. For these reasons, N-acetylcysteine is not widely used in patients with COPD.

Because a dose-effect association of N-acetylcysteine has been shown,11, 14 we postulated that an increased dose of N-acetylcysteine might achieve improved outcomes. We aimed to assess whether long-term treatment with high-dose N-acetylcysteine could reduce COPD exacerbation rates, and whether the benefits of treatment would be apparent with and without concomitant treatment with inhaled corticosteroids.

Section snippets

Study design and participants

Details of our study's rationale, design, and analysis plan have been published elsewhere.15 In our multicentre, prospective, randomised, double-blind, placebo-controlled, parallel-group trial (the Placebo-controlled study on efficAcy and safety of N-acetylcysTeine High dose in Exacerbations of chronic Obstructive pulmoNary disease [PANTHEON] study), all participants were stratified by previous use of inhaled corticosteroid at baseline, which was defined as regular use of 500–2000 μg per day of

Results

Between June 25, 2009, and Dec 29, 2010, we screened 1297 patients, of whom 1006 were eligible for randomisation (figure 1). Reasons for screening failure were much the same between groups (appendix). Baseline characteristics and lung function parameters did not differ between completers and patients who did not complete treatment, apart from baseline FVC, which was slightly higher in completers (appendix).

Mean treatment duration was 319·0 days (SD 102·3) in the N-acetylcysteine group and 319·1

Discussion

In our study, treatment of Chinese patients with twice daily N-acetylcysteine 600 mg was associated with a reduction in acute exacerbations of COPD compared with placebo. This finding was in line with the long-term PEACE study (of carbocisteine 1500 mg per day)18 and the large TORCH19 and UPLIFT20 trials, which studied populations with much the same baseline characteristics as in our study (appendix). The exacerbation rate in the placebo group of this study was 1·49 per patient-year, which was

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