Articles 744 www.thelancet.com Vol 368 August 26, 2006 Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study Klaus F Rabe, Tito Atienza, Pál Magyar, Per Larsson, Carin Jorup, Umesh G Lalloo 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. 1–5 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, 8–10 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, 12–14 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 re- mained symptomatic on regular budesonide-formoterol Lancet 2006; 368: 744–53 See Comment page 707 Department of Pulmonology, University of Leiden, Leiden, Netherlands (K F Rabe MD); Department of Pulmonary Medicine, Veterans Memorial Medical Center, Quezon City, Philippines (T Atienza MD); Department of Pulmonology, Semmelweis University, Budapest, Hungary (P Magyar MD); AstraZeneca Research and Development, Lund, Sweden (P Larsson PhD, C Jorup MD); and Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa (U G Lalloo MD) Correspondence to: Prof Klaus F Rabe, Department of Pulmonology, C3-P, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, Netherlands K.F.Rabe@lumc.nl