Elsevier

The Lancet

Volume 368, Issue 9537, 26 August–1 September 2006, Pages 744-753
The Lancet

Articles
Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study

https://doi.org/10.1016/S0140-6736(06)69284-2Get rights and content

Summary

Background

The contributions of as-needed inhaled corticosteroids and long-acting β2 agonists (LABA) to asthma control have not been fully established. We compared the efficacy and safety of three reliever strategies: a traditional short-acting β2 agonist; a rapid-onset LABA (formoterol); and a combination of LABA and an inhaled corticosteroid (budesonide-formoterol) in symptomatic patients receiving budesonide-formoterol maintenance therapy.

Methods

We did a 12-month, double-blind, parallel-group study in 3394 patients (aged 12 years or older), in 289 centres in 20 countries, who were using inhaled corticosteroids at study entry and symptomatic on budesonide-formoterol (160 μg and 4·5 μg, respectively), one inhalation twice daily, during a 2-week run-in. After run-in, patients were randomly assigned budesonide-formoterol maintenance therapy plus one of three alternative as-needed medications—terbutaline (0·4 mg), formoterol (4·5 μg), or budesonide-formoterol (160 μg and 4·5 μg). The primary outcome was time to first severe exacerbation, defined as an event resulting in hospitalisation, emergency room treatment, or both, or the need for oral steroids for 3 days or more.

Findings

Time to first severe exacerbation was longer with as-needed budesonide-formoterol versus formoterol (p=0·0048; log-rank test) and with as-needed formoterol versus terbutaline (p=0·0051). The rate of severe exacerbations was 37, 29, and 19 per 100 patients per year with as-needed terbutaline, formoterol, and budesonide-formoterol, respectively (rate ratios budesonide-formoterol versus formoterol 0·67 [95% CI 0·56–0·80; p<0·0001]; budesonide-formoterol versus terbutaline 0·52 [0·44–0·62; p<0·0001]; formoterol versus terbutaline 0·78 [0·67–0·91; p=0·0012]). Asthma control days increased to a similar extent in all treatment groups. As-needed formoterol did not significantly improve symptoms compared with as-needed terbutaline. All treatments were well tolerated.

Interpretation

Both monocomponents of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance.

Introduction

Over the past decade, maintenance treatment in patients with persistent asthma has evolved from inhaled corticosteroids alone to combination therapy with long-acting β2 agonists (LABA). This move has led to improved symptom control and a reduced need for higher doses of inhaled corticosteroids.1, 2, 3, 4, 5 However, despite evidence that add-on LABA therapy can reduce exacerbations by 3–14% compared with higher doses of inhaled corticosteroids,3, 6 the dose of inhaled steroid at which the addition of LABA is most beneficial has not been clearly established.7

This dilemma could be overcome if a pragmatic way of delivering increased anti-inflammatory therapy at the first sign of increased symptoms were found, rather than relying on as-needed short-acting β2 agonists. In clinical studies, the use of a combination of inhaled corticosteroids and LABA (budesonide-formoterol) in one inhaler for both maintenance and as-needed therapy reduced the risk of experiencing severe exacerbations by 39–54% compared with a higher maintenance dose of budesonide,8, 9, 10 by 45% compared with fixed-dose budesonide-formoterol,9 and by 25% compared with a higher dose of salmeterol-fluticasone.11 Moreover, this novel treatment approach reduced both inhaled corticosteroids and oral corticosteroid exposure, with a similar or reduced effect on morning plasma cortisol and adrenal function, compared with budesonide 800 μg per day.9, 10

This simplified approach is possible because formoterol provides rapid symptom relief,12, 13, 14 with the result that a separate short-acting β2 agonist is not needed. However, the mechanism underlying the reduction in exacerbations seen with budesonide-formoterol maintenance and reliever therapy is not fully understood. As-needed formoterol was shown to reduce asthma exacerbations compared with terbutaline in a large, double-blind study in asthma patients with a persistent high use of reliever therapy despite using regular inhaled corticosteroids.14 However, whether patients on combination therapy would experience such a benefit was not clear. Additionally, the specific contribution of the as-needed budesonide component of budesonide-formoterol for maintenance and relief has not been assessed. The present 12-month, double-blind study was therefore done in patients with moderate to severe persistent asthma who remained symptomatic on regular budesonide-formoterol combination maintenance therapy, to assess the add-on efficacy of three alternative reliever medications—budesonide-formoterol, formoterol, and terbutaline.

Section snippets

Patients

Outpatients aged 12 years or older with a clinical diagnosis of asthma15 for at least 6 months were enrolled if they had had more than one severe asthma exacerbation in the 12 months before entry. All patients had used inhaled corticosteroids for at least 3 months and at a constant dose for 4 weeks or more immediately before entry. Inclusion criteria also included a forced expiratory volume in 1 s (FEV1) 50–100% of predicted normal (prebronchodilator) with 12% reversibility or more (and an

Results

The first patient was enrolled into the study on April 10, 2003, and the last patient completed the study on Dec 21, 2004. Of the 3829 patients enrolled in the study, 3394 were randomised. Of the 435 patients (11%) who were not randomised, 355 did not satisfy eligibility criteria, 32 had an adverse event, 12 were lost to follow-up, and 36 discontinued for other reasons. The full analysis set included all randomised patients who provided any data after randomisation. Data were not obtained for

Discussion

In this large, 12-month, double-blind study, we have shown that maintenance plus as-needed budesonide-formoterol reduced the risk of severe exacerbations and events resulting in emergency room visits or hospitalisations compared with maintenance budesonide-formoterol plus either formoterol or terbutaline as needed. Our study shows that the budesonide component of the budesonide-formoterol combination used when needed has a beneficial role in patients who remain symptomatic despite treatment

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