Research in context
Evidence before this study
Inhaled corticosteroids taken regularly reduce exacerbation risk in patients with mild asthma; however, in clinical practice adherence to inhaled corticosteroids is poor and the burden of disease from exacerbations is substantive. An alternative approach that potentially overcomes the problem of poor adherence is the use of an inhaled corticosteroid–formoterol combination as sole reliever therapy, thereby titrating use according to symptoms. We searched MEDLINE and Embase for studies published between Jan 1, 2000, and July 1, 2019, using the terms “inhaled corticosteroid-formoterol”, “budesonide-formoterol”, “as-required”, “asthma”, “adults”, and “randomised controlled trial”. Four studies of adults with mild or moderate asthma were identified which investigated the efficacy of budesonide–formoterol reliever monotherapy, all of which were published after this study was designed. In two studies, comparisons were made versus short-acting β-agonist (SABA) reliever monotherapy or with maintenance budesonide plus SABA reliever therapy; in one, versus maintenance budesonide plus SABA reliever therapy; and in one versus regular budesonide-formoterol plus SABA reliever therapy. Budesonide–formoterol reliever therapy was superior to SABA reliever therapy in patients with mild asthma, reducing the risk of severe exacerbations by at least 50% after a follow-up of 12 months. Of the three studies investigating budesonide–formoterol reliever therapy and maintenance budesonide plus SABA reliever therapy in patients with mild asthma, two were regulatory and one was a real-world study; there was non-inferiority in severe exacerbation risk in the two regulatory studies, whereas the real world study reported a significantly lower severe exacerbation risk with budesonide–formoterol reliever therapy compared with maintenance budesonide therapy plus SABA reliever. Budesonide-formoterol reliever monotherapy was inferior to regular budesonide-formoterol plus as-needed SABA for the outcome of treatment failure but not different for severe exacerbations in patients with moderate asthma. As a result, there is uncertainty about the relative efficacy and safety of inhaled corticosteroid–formoterol reliever monotherapy compared with maintenance inhaled corticosteroid plus SABA reliever therapy.
Added value of this study
This was the first independently funded open-label study comparing inhaled corticosteroid–formoterol reliever therapy with maintenance inhaled corticosteroid plus SABA reliever therapy in adults with mild to moderate asthma in a real-world setting. Budesonide–formoterol reliever therapy resulted in fewer severe exacerbations, and patients on this therapy had a longer time to first severe exacerbation, compared with patients on maintenance budesonide plus as-needed terbutaline. FENO was lower with budesonide maintenance. There was no significant between-group difference in asthma symptom control as measured by Asthma Control Questionnaire 5. The findings of sub-group analyses were consistent with the treatment effect being similar in all patient subgroups, suggesting that the findings are generalisable across the spectrum of mild and moderate asthma.
Implications of all the available evidence
Budesonide–formoterol reliever therapy is superior to maintenance budesonide plus SABA reliever therapy in adults with mild to moderate asthma in the real-world setting, reducing the risk of severe exacerbations without a clinically important worsening in asthma symptom control. Together the available evidence suggests that, for prevention of severe exacerbations, budesonide–formoterol reliever therapy is preferred to SABA reliever therapy for step 1 treatment, confirming the recommendation in the Global Initiative for Asthma (GINA) 2019 guidelines that adults and adolescents with asthma should not be treated with SABA alone. The evidence also supports the inclusion of budesonide–formoterol reliever therapy as an alternative to maintenance low-dose corticosteroids plus SABA reliever in GINA step 2. With the addition of this study, the evidence now also suggests that, of these two regimens, budesonide–formoterol reliever therapy might be the preferred option for prevention of severe exacerbations in mild to moderate asthma.