Budesonide/Formoterol for the Prevention of Serious Asthma Exacerbations

The SYGMA trials assessed the use of an as-needed combined corticosteroid/beta-agonist inhaler in patients with mild asthma.

Regularly administered low-dose inhaled corticosteroids are recommended as maintenance therapy for mild persistent asthma. However, patient adherence to maintenance therapy is low and using only an as-needed combined corticosteroid/beta-agonist inhaler may be attractive to many patients.

In the SYGMA 2 noninferiority trial (ClinicalTrials.gov Identifier:  NCT02224157), 4215 patients with mild persistent asthma were randomly assigned to either as-needed combination budesonide 200 mcg/formoterol 6 mcg inhaler or maintenance budesonide 200 mcg inhaler twice daily for 1 year.1 The as-needed budesonide/formoterol regimen also included twice-daily placebo doses, and the maintenance budesonide regimen also included an as-needed terbutaline 0.5 mg inhaler. Exacerbations were considered severe if they required systemic corticosteroids for ≥3 days, an emergency department visit leading to systemic corticosteroids, or hospitalization. Overall symptom severity was assessed with the Asthma Control Questionnaire-5 score (total score range 0-6), with symptom improvement defined as a ≥0.5-point decrease from baseline. Treatment completion was accomplished by 91% of patients, and 99% were included in the analyses. 

Noninferiority for as-needed budesonide/formoterol was met: the annualized rate of severe asthma exacerbations was 0.11 with as-needed budesonide/formoterol vs 0.12 with maintenance budesonide, rate ratio 0.97. The 2 groups had similar risks of experiencing at least 1 severe exacerbation during the year (8.5% vs 8.8%), proportion of patient-days without using as-needed inhalers (69% vs 76%), and adherence to maintenance doses (64% vs 63%). Daily inhaled corticosteroid use was numerically less with as-needed budesonide/formoterol (median 66 vs 268 mcg), but a statistical comparison was not reported. However, as-needed budesonide/formoterol was associated with a slightly lower likelihood of symptom improvement (40.3% vs 44.3%, P <.05). Rates of adverse events were similar between the 2 groups (42.5% vs 44% of patients), the most common of which was viral upper respiratory tract infection (7.4% vs 8%); however, statistical comparisons were not reported.

The results from the SYGMA 2 trial demonstrated that, in adolescents and adults with mild persistent asthma, an as-needed budesonide/formoterol inhaler may be an alternative to daily maintenance corticosteroids. In secondary analyses, the as-needed regimen also may have reduced inhaled corticosteroid exposure, but it was slightly inferior regarding symptom improvement. Whether or not these differences are clinically relevant may depend on the individual patient. Also, the long-term effects of these differences, particularly with regard to a potential role of corticosteroids in preventing airway remodeling, remain to be seen. On the other hand, an as-needed regimen may be more attractive than a maintenance regimen for many patients.

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The companion SYGMA 1 trial (ClinicalTrials.gov Identifier:  NCT02149199) reported consistent results and also reported that as-needed budesonide/formoterol was superior to as-needed terbutaline monotherapy.2

Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Massachusetts, and assistant clinical professor in family medicine, University of Massachusetts Medical School, Worcester.

DynaMed is a database that provides evidence-based information on more than 3000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.


  1. Bateman ED, Reddel HK, O’Byrne PM, et al. As-needed budesonide/formoterol versus maintenance budesonide in mild asthmaN Engl J Med. 2018;378:1877-1887.
  2. O’Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide/fomoterol as needed in mild asthma. N Engl J Med. 2018;378:1865-1876.

This article originally appeared on Clinical Advisor