DALLAS — Single combination inhaler treatment with budesonide-formoterol on an as-needed basis, compared with albuterol, more than halved the risk for severe asthma attacks in patients with mild asthma, according to the results of the Novel START trial presented at the American Thoracic Society International Conference.
“We undertook a real-world study and the question we wanted to ask was that in adults with intermittent and mild asthma who were treated with reliever therapy alone — step 1 treatment — what is the efficacy of an inhaled corticosteroid combination fast-onset long-acting beta-agonist inhaler used as a reliever alone with two comparisons. The first was a continuation of step 1 therapy with reliever therapy alone and the other was a step up to step 2 therapy with maintenance inhaled corticosteroids and reliever therapy,” Richard Beasley, DSc, from the Medical Research Institute of New Zealand and the Capital and Coast District Health Board, said during his presentation of the data.
The 52-week, open-label, randomized, parallel-group, controlled trial included 668 patients with mild asthma who were randomly assigned one of three treatments: two inhalations of albuterol 100 µg (Ventolin, GlaxoSmithKline) from a pressurized metered-dose inhaler as needed for asthma symptoms; one inhalation of budesonide 200 g (Pulmicort Turbuhaler, AstraZeneca) taken twice daily plus as-needed albuterol; or one inhalation of budesonide 200 g/formoterol 6 g (Symbicort Turbuhaler, AstraZeneca) as needed.
Of 675 patients enrolled from 2016 to 2017 in New Zealand, Australia, United Kingdom and Italy, 668 were included in the analysis. To qualify for inclusion, patients had to be 18 to 75 years of age; a short-acting beta agonist (SABA) had to be the sole asthma therapy in the previous 3 months; and they had to report use of the SABA on at least two occasions, but on an average of two or fewer occasions per day, in the previous 4 weeks.
The primary outcome was annualized asthma exacerbation rates per patient. Exacerbations were characterized as worsening asthma that led to urgent medical care consultation, a prescription for systemic glucocorticoids or an
episode of high beta-2-agonist use, which was defined as use of albuterol more than 16 times or the use of budesonide-formoterol more than eight times during 24 hours.
The study was simultaneously published in The New England Journal of Medicine.
Reduced asthma exacerbations
The rate of asthma exacerbations was lower in the budesonide-formoterol group compared with the albuterol group (absolute rate per patient per year, 0.195 vs. 0.4; relative rate, 0.49; 95% CI, 0.33-0.72; P < .001), but not when compared with the budesonide-maintenance group (absolute rate per patient per year, 0.195 vs. 0.175; relative rate, 1.12; 95% CI, 0.70- 1.79; P = .65).
The researchers noted that the number of severe exacerbations was lower in the budesonide-formoterol group compared with the albuterol group (9 vs. 23; RR = 0.4; 95% CI, 0.18-0.86) and the budesonide-maintenance group (9 vs. 21; RR = 0.44; 95% CI, 0.2-0.96).
In a time-to-first-event analysis, patients in the budesonide-formoterol group had a lower risk for exacerbation than those in the albuterol-only group (HR = 0.46; 95% CI, 0.29-0.73). However, the risk in the combination group was not significantly different from the budesonide-maintenance group (HR = 0.93; 95% CI, 0.55-1.57).
At 52 weeks, there were no differences between groups in forced expiratory volume in 1 second. Asthma Control Questionnaire-5 scores were lower in the budesonide-formoterol group compared with the albuterol group, but higher when compared with budesonide-maintenance group.
In both the maintenance-budesonide and budesonide-formoterol groups, the median fraction of exhaled nitric oxide was lower than in the albuterol group.
Mean adherence to twice-daily doses of budesonide-maintenance therapy was 56%, which was higher than might be expected in normal clinical practice, Beasley noted, suggesting that adherence was perhaps greater in this clinical trial than in the real world.
The mean dose of budesonide was 107 g per day in the budesonide-formoterol group and 222 g per day in the budesonide-maintenance group, despite having greater efficacy, particularly in relation to severe exacerbations.
“This suggests that timing may be more important than dose itself in mild asthma and it may be likely that inhaled corticosteroids can be titrated to reduce the risk of exacerbation becoming severe exacerbation,” he said.
The results of this study highlight the need to reexamine current clinical practice, according to Beasley.
“These findings challenge both the appropriateness of SABA-only treatment and the necessity for regular, daily inhaled corticosteroid treatment in adults with intermittent and mild asthma,” he said.
In an accompanying editorial, Gary W.K. Wong, MD, from the department of pediatrics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China, also put these data into clinical context.
“The results of this trial, together with the findings of the SYGMA trials, provide convincing evidence that budesonide–formoterol used as needed is an acceptable alternative to maintenance budesonide maintenance therapy for patients with mild asthma,” he wrote. – by Melissa Foster
Beasley R. The New England Journal of Medicine and JAMA Discussion on the Edge: Reports of Recently Published Research. Presented at: American Thoracic Society International Conference; May 17-22, 2019; Dallas.