Clinical Question

Is as-needed use of budesonide/formoterol (Symbicort) similarly effective to daily maintenance with budesonide (Rhinocort) plus as-needed terbutaline in patients with mild asthma?

Bottom Line

As-needed use of budesonide/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. (Level of Evidence = 1b–)

Synopsis

This industry-sponsored noninferiority trial included 4,215 patients, of whom 4,176 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 three 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/formoterol, 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 is 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 were also no differences between groups regarding the time to a first severe exacerbation or regarding different types of severe exacerbations (i.e., 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.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Allocation: Concealed

Setting: Outpatient (any)

Reference:BatemanEDReddelHKO'ByrnePMet alAs-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med2018;378(20):1877–1887.