Elsevier

The Lancet

Volume 353, Issue 9167, 29 May 1999, Pages 1819-1823
The Lancet

Articles
Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(98)10019-3Get rights and content

Summary

Background

Little is known about the long-term efficacy inhaled corticosteroids in chronic obstructive pulmonary disease (COPD). We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD.

Methods

We used a parallel-group, randomised, double-blind, placebo-controlled design in a single-centre study, nested in a continuing epidemiological survey (the Copenhagen City Heart Study). Inclusion criteria were as follows: no asthma; a ratio of forced expiratory volume in 1 s (FEV1) and vital capacity of 0·7 or less; FEV1 which showed no response (<15% change) to 1 mg inhaled terbutaline or prednisolone 37·5 mg orally once daily for 10 days. 290 patients were randomly assigned budesonide, 800 μg plus 400 μg daily for 6 months followed by 400 μg twice daily for 30 months, or placebo for 36 months. The mean age of the participants was 59 years and the mean FEV1 2·37 L or 86% of predicted. The main outcome measure was rate of FEV1 decline. Analyses were by intention to treat.

Findings

The crude rates of FEV1 decline were slightly smaller than expected (placebo group 41·8 mL per year, budesonide group 45·1 mL per year). The estimated rates of decline from the regression model did not differ significantly (49·1 mL vs 46·0 mL per year; difference 3·1 mL per year [95% CI −12·8 to 19·0]; p=0·7). Before the study, the minimum relevant difference was defined as 20 mL per year; this difference was outside the 95% CI. No effect of inhaled budesonide was seen on respiratory symptoms. 316 exacerbations occurred during the study period, 155 in the budesonide group and 161 in the placebo group. Treatment was well tolerated.

Interpretation

Inhaled budesonide was of no clinical benefit in COPD patients recruited from the general population by screening. We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD.

Introduction

Although the use of inhaled corticosteroids in asthma is regarded as first-line therapy, treatment with inhaled corticosteroids in chronic obstructive pulmonary disease (COPD) is not based on evidence. Nevertheless, inhaled corticosteroids are used extensively in COPD; for example, in a Canadian survey 43% of patients who used inhaled corticosteroids had COPD.1 Although inhaled cortico-steroids can reduce cough and mucus secretion by suppressing acute inflammatory changes in the airways, the long-term aim is directed towards decreasing the excess decline in forced expiratory volume in 1 s (FEV1), which is characteristic of COPD.

Data on the effect of inhaled corticosteroids on rate of FEV1 decline are limited and leave much room for different interpretations owing to below optimum methods. An early indication of a beneficial effect of corticosteroids has come from uncontrolled studies of long-term treatment with low to moderate doses of systemic corticosteroids.2, 3 However, there have been no placebo-controlled long-term studies of oral corticosteroids and few controlled long-term studies of inhaled corticosteroids in COPD. Kerstjens and colleagues4 showed an effect on both FEV1 and number of exacerbations, but their study had limited value because no distinction was made between asthma and COPD at inclusion. This distinction was more obvious in a smaller study,5 which also showed an effect of inhaled corticosteroids of FEV1. Two studies6, 7 have reported substantial effects on the rate of FEV1 decline, although the statistical power was poorly described. A meta-analysis of substrata including patients without asthmatic features from three of these studies4, 5, 6 showed an estimated 2-year difference in prebronchodilator FEV1 between patients treated with inhaled corticosteroids and placebo (34 mL per year).8 This difference was significant even though a third of the patients originally included were excluded from the meta-analysis. Paggiaro and colleagues9 showed an effect of inhaled fluticasone on FEV1, respiratory symptoms, and disease severity in patients with well-defined COPD; the study, however, only lasted 6 months.

The aim of this study was to assess the long-term efficacy of inhaled budesonide on change in FEV1 in individuals with airway obstruction in whom FEV1 was not substantially improved in response to inhaled β2-agonists and oral steroids. Respiratory symptoms and frequency of exacerbations were secondary outcome measures.

Section snippets

Study population

The study was a 3-year double-blind, parallel-group, randomised clinical trial nested in a continuing epidemiological study, the Copenhagen City Heart Study (CCHS). The CCHS was started in the mid-1970s and the study population was a random, age-stratified sample of 19 327 individuals of 87 172 aged at least 20 years, who were living in a defined area around Rigshospitalet in Copenhagen in 1976. In 1976–78, CCHS examined 14223 individuals (response rate 73·6%); a detailed description of the

Results

290 individuals were included as a result of the initial screening; all individuals were assigned treatment as shown in figure 1. 87 patients withdrew from the study, 36 from the budesonide group and 51 from the placebo group. 16 patients in the budesonide group and 17 patients in the placebo group were withdrawn because of adverse events with no particular difference in pattern. Ten patients were withdrawn because of rapid deterioration of disease. 14 patients had been wrongly included, and 30

Discussion

This long-term single-centre study did not show an effect of budesonide on rate of decline in lung function in patients with irreversible COPD sampled from a large population survey. The small difference in rate of FEV1 decline of 3·1 mL per year was not statistically or clinically significant.

Much controversy exists in the area of inhaled steroids in COPD, mainly because there have been no long-term controlled trials in patients with irreversible airflow obstruction and no features of asthma.

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