Effect of a single day of increased as-needed budesonide-formoterol use on short-term risk of severe exacerbations in patients with mild asthma: a post-hoc analysis of the SYGMA 1 study

Background In mild asthma, as-needed budesonide-formoterol reduces long-term exacerbation risk compared with as-needed short-acting beta(2)-agonist (SABA), with a similar or increased reduction versus maintenance with budesonide plus as-needed SABA, despite a lower budesonide dose. In this post-hoc analysis of the SYmbicort Given as needed in Mild Asthma (SYGMA) 1 study, we investigated the short-term risk of severe exacerbations after a single day with various levels of reliever use. Methods SYGMA 1 was a 52-week, double-blind, randomised, controlled, phase 3 trial, in which patients aged 12 years or older with mild asthma were randomly assigned (1:1:1) to placebo twice daily plus as-needed terbutaline 0.5 mg, placebo twice daily plus as-needed budesonide-formoterol 200-6 mu g, or budesonide 200 mu g twice daily plus as-needed terbutaline (ie, budesonide maintenance group). In this post-hoc analysis, we assessed the frequency of reliever use and the risk of a severe exacerbation in the 21 days after first use of more than two, four, six, or eight reliever inhalations in 24 h. SYGMA 1 is registered with ClinicalTrials.gov, NCT02149199, and is now complete. Findings Of 5721 patients enrolled in SYGMA 1, 3849 were randomly assigned to as-needed terbutaline (n=1280), asneeded budesonide-formoterol (n=1279), or budesonide maintenance (n=1290), of whom 3836 had evaluable data (n=1277 as-needed terbutaline, n=1277 as needed budesonide-formoterol, and n=1282 budesonide maintenance). Median reliever use was 0.32 (IQR 0.08-0.91) inhalations per day for the as-needed terbutaline group, 0.29 (0.07-0.72) for the as-needed budesonide-formoterol group, and 0.16 (0.04-0.52) for the budesonide maintenance group. Compared with as-needed terbutaline, after adjustment for age, sex, randomly assigned treatment, pre-study treatment group, baseline % predicted post-bronchodilator FEV 1, and severe exacerbation in the 12 months before enrolment in the study, the hazard ratio (HR) for severe exacerbation in the 21 days after a single day with more than two as-needed inhalations was 0.27 (95% CI 0.12-0.58; p=0.0008) with as-needed budesonide-formoterol and 0.39 (0.19-0.79; p=0.0091) with budesonide maintenance; after a single day of more than four as-needed inhalations the HR was 0.24 (0.10-0.62; p=0.0030) with as-needed budesonide-formoterol and 0.30 (0.13-0.72; p=0.0065) with budesonide maintenance; and after a single day of more than six as-needed inhalations the HR was 0.14 (0.02-1.06; p=0.057) with as-needed budesonide-formoterol and 0.43 (0.14-1.26; p=0.12) with budesonide maintenance. HRs were not calculated for more than eight as-needed inhalations due to the small number of events. Interpretation In mild asthma, as-needed budesonide-formoterol reduces the short-term risk of severe exacerbations after a single day of higher use (more than two as-needed inhalations), even when overall use is infrequent. Use of an anti-inflammatory reliever might reduce the risk of short-term severe exacerbations by the timely provision of increased doses of as-needed inhaled corticosteroids and formoterol when symptoms occur. These findings should be further assessed in prospective randomised clinical trials.