Elsevier

The Lancet

Volume 361, Issue 9363, 29 March 2003, Pages 1071-1076
The Lancet

Articles
Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial*

https://doi.org/10.1016/S0140-6736(03)12891-7Get rights and content

Summary

Background

Although inhaled glucocorticosteroids are recommended for persistent asthma, their long-term effect on recent onset, mild, persistent asthma has yet to be established.

Methods

We did a randomised, double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids. Patients aged 5–66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications. The daily budesonide dose was 400 μg, or 200 μg for children younger than 11 years. The primary outcome was time to first severe asthma-related event, and analysis was by intention to treat.

Findings

198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation; hazard ratio 0·56 (95% CI 0·45–0·71, p<0·0001). Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo. Compared with placebo, budesonide increased postbronchodilator forced expiratory volume in 1 s (FEV1) from baseline by 1·48% (p<0·0001) after 1 year and by 0·88% (p=0·0005) after 3 years (expressed as percent of the predicted value). The corresponding increase in prebronchodilator FEV1 was 2·24% after 1 year and 1·71% after 3 years (p<0·0001 at both timepoints). The effect of treatment on all outcome variables was independent of the baseline lung function (prebronchodilator or postbronchodilator) or baseline medication. In children younger than 11 years, 3-year growth was reduced in the budesonide group by 1·34 cm. The reduction was greatest in the first year of treatment (0·58 cm) than years 2 and 3 (0·43 cm and 0·33 cm, respectively)

Interpretation

Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset.

Introduction

Chronic airway inflammation is a major cause of symptoms and abnormal airway physiology in asthma, even in mild disease.1, 2, 3 Such inflammation might lead to changes in airway structure, causing irreversible airflow limitation and persistent symptoms.4, 5, 6, 7, 8 Results from many studies have shown that inhaled glucocorticosteroids benefit patients with chronic persistent asthma by decreasing airway inflammation, improving lung function, lessening symptoms and airway hyper-responsiveness, and reducing mortality.9, 10, 11, 12, 13, 14 Results of some of these studies suggest that the greatest benefits are achieved if treatment is started within 2 years of symptom onset.9, 15, 16, 17 However, the effectiveness of early intervention has yet to be established in mild persistent disease of recent onset because previous large studies have included patients with moderate as well as mild asthma and those who had had the disease for several years.18, 19, 20 Therefore, we undertook a large, worldwide, long-term study to assess whether early intervention with a low dose of the inhaled glucocorticosteroid budesonide in patients with less than 2 years of mild persistent asthma would prevent severe asthma-related events and accelerated decline in lung function—START (inhaled steroid treatment as regular therapy in early asthma study).21 We report results after 3 years from the randomised, double-blind part of the study.

Section snippets

Patients

Between October, 1996, and January, 1998, we recruited patients aged 5–66 years from 499 sites in 32 countries who had had symptoms of mild asthma in the 3 months before trial entry. Mild asthma was defined by wheeze, cough, dyspnoea, or chest tightening at least once per week, but not as often as daily. All patients had reversible airway obstruction, defined as an increase in forced expiratory volume in 1 s (FEV1) of more than 12% after using a short-acting bronchodilator, a fall in FEV1 of

Results

We enrolled 7241 patients and randomly assigned them budesonide (n=3642) or placebo (n=3599) (figure 1). Data from four centres (56 patients) were discarded for administrative reasons, and 20 patients did not receive study treatment. 7165 patients were included in the analysis: 3597 on budesonide, and 3568 on placebo. 2010 patients dropped out before 3-year follow-up. Dropout rate (figure 1), mean time in the study (budesonide 2·47 years [SD 1·00], placebo 2·44 years [1·03]), and baseline

Discussion

The result of our long-term study in patients with mild persistent asthma of recent onset show that there is substantial morbidity associated with mild asthma. Our results also suggest that early once-daily treatment with low-dose budesonide reduces the risk of having a severe asthma exacerbation by almost half, and even more so for a life-threatening exacerbation. Budesonide treatment also resulted in more symptom-free days and a reduced need for courses of systemic glucocorticosteroids and

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