Elsevier

The Lancet

Volume 371, Issue 9629, 14–20 June 2008, Pages 2013-2018
The Lancet

Articles
Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study

https://doi.org/10.1016/S0140-6736(08)60869-7Get rights and content

Summary

Background

Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, and has many components including mucus hypersecretion, oxidative stress, and airway inflammation. We aimed to assess whether carbocisteine, a mucolytic agent with anti-inflammatory and antioxidation activities, could reduce the yearly exacerbation rate in patients with COPD.

Methods

We did a randomised, double-blind, placebo-controlled study of 709 patients from 22 centres in China. Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio (FEV1/FVC) of less than 0·7 and an FEV1 between 25% and 79% of the predicted value, were aged between 40 and 80 years, had a history of at least two COPD exacerbations within the previous 2 years, and had remained clinically stable for over 4 weeks before the study. Patients were randomly assigned to receive 1500 mg carbocisteine or placebo per day for a year. The primary endpoint was exacerbation rate over 1 year, and analysis was by intention to treat. This trial is registered with the Japan Clinical Trials Registry (http://umin.ac.jp/ctr/index/htm) number UMIN-CRT C000000233.

Findings

354 patients were assigned to the carbocisteine group and 355 to the placebo group. Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group (1·01 [SE 0·06] vs 1·35 [SE 0·06]), risk ratio 0·75 (95% CI 0·62–0·92, p=0·004). Non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Carbocisteine was well tolerated.

Interpretation

Mucolytics, such as carbocisteine, should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD.

Funding

Kyorin Pharmaceuticals.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, and pathophysiologically involves many components including mucus hypersecretion, oxidative stress, and inflammation in the airway and lungs.1 Therefore, agents active with mucolytic, anti-inflammatory, and antioxidative effects could offer promise for treatment.

In Europe and Asia, mucolytics such as carbocisteine have been widely used for treatment of respiratory diseases with phlegm production2 because of their capacity to facilitate sputum elimination.3, 4 Furthermore, carbocisteine seems likely to have a role in antioxidation5, 6 and anti-inflammation7, 8, 9 that might be more important than mucolysis itself for long-term management of COPD. Clinical studies have shown benefits in preventing exacerbation of COPD with carbocisteine.10, 11, 12 However, these results have been inconclusive because of certain pitfalls in study design, such as small sample size, not being double-blinded, lack of placebo control, or short period of study.13 Poole and Black14 did a systematic review of mucolytics in COPD, which has been updated15 with inclusion of the BRONCUS study16 using N-acetylcysteine. Their results showed that mucolytics including carbocisteine were effective in reducing the number of exacerbations in COPD and improving health status in all studies except BRONCUS.16 Since evidence on long-term efficacy remains insufficient, mucolytics are not recommended for regular treatment by guidelines such as that of the Global Initiative for Chronic Obstructive Lung Disease (GOLD).1 Clinical trials that closely follow reliable research study designs are therefore warranted to clarify whether COPD patients can benefit from protracted mucolytic therapy.

The aim of this study was to assess the effectiveness in preventing exacerbation, improving quality of life, as well as the safety profiles of long-term (1-year) carbocisteine administration in patients with COPD.

Section snippets

Patients

Participants were eligible for inclusion if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio (FEV1/FVC) of less than 0·70 and an FEV1 between 25% and 79% of predicted value. The severity of COPD was defined in accordance with GOLD criteria.1 Patients had to be aged between 40 and 80 years, have a history of at least two COPD exacerbations within the previous 2 years, yet have remained clinically stable for

Results

Recruitment ran from June 1 to Sept 30, 2005, and the study was completed by Oct 15, 2006. 709 patients underwent randomisation (figure 1). Of these, two patients (one in each group) were excluded because of ineligibility, but were included in the safety analysis. Non-significant difference was found in the withdrawal rate between these two groups (13·60% vs 12·15%, χ2=0·332; p=0·565).

The two groups were similar in patient demographics, including history of smoking, duration and severity of

Discussion

The results of our study support previous findings that long-term use of carbocisteine reduced the rate of exacerbations of COPD. The advantage of carbocisteine over placebo in prevention of an exacerbation was noteworthy, even after adjustment for COPD severity and concomitant therapy. We found no difference in exacerbation rate between the carbocisteine group and placebo group at early treatment (3 month), suggesting that longer use of carbocisteine was more effective for preventing

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