In patients with mild asthma, is as-needed use of an inhaled steroid plus a short-acting beta-agonist as effective as daily use of an inhaled steroid?
Increasingly, studies are showing that as-needed use of an inhaled steroid plus a short-acting beta-agonist (SABA) is as effective or very nearly as effective as the daily use of an inhaled steroid, with much lower cumulative steroid doses. The small benefit in terms of weeks with good symptom control with daily steroid use must be balanced against the cost and long-term effects. (LOE = 1b)(www.essentialevidenceplus.com)
O'Byrne PM, FitzGerald JM, Bateman ED, et al. Combined budesonide-formoterol as needed in mild asthma. N Engl J Med 2018;378(20):1865-1876.
Study design: Randomized controlled trial (double-blinded)
Funding source: Industry
Setting: Outpatient (any)
In this industry-sponsored trial, mild asthma was defined in a patient when it could be controlled by a daily low-dose steroid inhaler or leukotriene inhibitor, but not adequately controlled by intermittent SABAs. In this study, 3849 patients, 12 years and older, with mild asthma were randomized to receive 1 of 3 strategies: (1) placebo inhaler twice daily plus terbutaline 0.4 mg inhaler, as needed; (2) placebo inhaler twice daily plus budesonide 160 mcg/formoterol 4.5 mcg, as needed; and (3) budesonide 160 mcg twice daily plus terbutaline 0.4 mg inhaler, as needed. Patients were enrolled, given a 2- to 4-week run-in period of as-needed terbutaline only, and were followed up for one year. The mean age of patients was 40 years, 20% had a severe exacerbation in the year prior to enrollment, the mean pre-treatment FEV1 was 84%, and 87.4% completed the trial. Patients used a diary to record symptoms. Those in the budesonide maintenance group had a higher percentage of weeks with good control than the other 2 groups that used only as-needed inhalers (44% vs 34% for prn budesonide/formoterol vs 31% for prn terbutaline; P < .05). Over one year, this amounts to 5 additional weeks of good control for patients using a maintenance steroid inhaler compared with those using budesonide/formoterol as needed only. Both the budesonide maintenance and the budesonide/formoterol groups had significantly lower rates of severe exacerbations than the terbutaline only group (0.09 vs 0.07 vs 0.20, respectively). For moderate to severe exacerbations, the rates were also significantly lower for the regimens containing budesonide than for as-needed terbutaline only (0.14 vs 0.36). The overall steroid dose given to patients in the as-needed budesonide/formoterol group was approximately one-fifth that of those using maintenance steroid therapy.
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Is as-needed use of budesonide plus formoterol similarly effective to daily maintenance with budesonide plus as-needed terbutaline in patients with mild asthma?
As-needed use of budesonide plus formoterol is as effective as the daily use of maintenance budesonide plus as-needed terbutaline at preventing severe exacerbations, and results in a much lower cumulative steroid dose. (LOE = 1b-)(www.essentialevidenceplus.com)
Bateman ED, Reddel HK, O'Byrne PM, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med 2018;378(20):1877-1887.
Funding source: Industry
This industry-sponsored noninferiority trial included 4215 patients, of whom 4176 had data available for analysis. Their mean age was 41 years, and approximately 50% controlled their asthma by using a daily inhaled glucocorticoid during the previous year; the other half had uncontrolled asthma using a short-acting beta-agonist (SABA) alone. Fully 22% had a severe exacerbation during the previous year, defined as the need for at least 3 days of systemic steroids, hospitalization, or an emergency department visit, which seems high for "mild asthma." As in the similar SYGMA 1 trial published in the same issue of this journal, mild asthma was defined as asthma that is uncontrolled using only a SABA as needed, or well controlled using a low-dose steroid inhaler. After a run-in period during which patients used only an as-needed SABA (terbutaline 0.5 mg), the patients were randomized to receive: (1) placebo inhaler twice daily plus budesonide 200 mcg/formeterol 6 mcg, as needed; or (2) budesonide 200 mcg twice daily plus as-needed use of terbutaline 0.5 mg. This trial was initially designed as a superiority trial to show that one of the interventions was better than the other. However, a lower-than-expected rate of exacerbations and a higher-than-expected rate of adherence to the daily inhaled steroid hurt the power, so the authors moved the goalposts midgame and declared it a noninferiority trial. Noninferiority was defined as no more than a 20% increase in the number of severe exacerbations. Although it's not good research practice to change goals midstream, in some ways this is a more interesting research question, and the noninferiority margin the authors chose seems clinically reasonable. After one year, there was indeed no difference between the groups regarding the likelihood of a severe exacerbation (0.11 for as-needed use and 0.12 for daily steroid inhaler per patient per year). There was also no differences between groups regarding the time to a first severe exacerbation or regarding different types of severe exacerbations (ie, hospitalization or emergency department visit). Adverse events between groups were similar. Not surprisingly, patients in the as-needed inhaler group had only about one-fourth the total steroid dose during the study period.
Mark H. Ebell, MD, MS
University of Georgia
POEMs are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, please see http://www.essentialevidenceplus.com(www.essentialevidenceplus.com).
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