Using budesonide/formoterol as needed was as effective as budesonide maintenance therapy in preventing exacerbations but with a lower exposure to ICS among patients with mild asthma, including adolescent patients and regardless of prior treatment used, according to two subgroup analyses of the SYGMA* 1 and 2 studies presented at the ATS 2019 Congress.

Although the use of inhaled corticosteroid (ICS)-containing medication is supported by the Global Initiative for Asthma (GINA) to reduce the risk of severe exacerbations in asthma, poor adherence to such medication remains a prime concern across all asthma severities.

This is often the case in mild asthma, when symptoms are intermittent and patients become reluctant to take ICS-containing medication daily after they feel better, according to lead investigator Professor Helen Reddel from Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia.

Not only have previous primary analyses from the SYGMA 1 and 2 studies shown that using the ICS/LABA** combination of budesonide/formoterol as needed or maintenance budesonide (plus terbutaline as needed) significantly reduced the rates of severe exacerbations in mild asthma compared with as-needed terbutaline alone, both studies revealed that exposure to ICS was lower with as-needed budesonide/formoterol than maintenance budesonide. [N Engl J Med 2018;378:1865-1876; N Engl J Med 2018;378:1877-1887]

This finding of a lower exposure to ICS is particularly relevant to adolescent patients, in whom adherence to maintenance treatment was found to be lower than the adult population in a pooled subgroup analysis of the SYGMA 1 and 2 trials (mean adherence rate, 67–70 percent vs 80–81 percent in SYGMA 1 and 52–53 percent vs 64–65 percent in SYGMA 2). [ATS 2019, abstract A7191/P816]

Subjects included in the subgroup analysis were 889 adolescent patients (mean age ~14 years) with mild asthma from SYGMA 1, which randomized patients 1:1:1 to as-needed budesonide/formoterol (200/6 µg), budesonide 200 µg twice daily as maintenance plus terbutaline 0.5 mg as needed, or as-needed terbutaline 0.5 mg alone; and SYGMA 2, which randomized patients 1:1 to either as-needed budesonide/formoterol or maintenance budesonide. Both studies enrolled patients who met the criteria for GINA 2012 step 2 treatment.  

Consistent with the results from the overall population, annual rate of serious exacerbations among adolescents was significantly lower with as-needed budesonide/formoterol than as-needed terbutaline alone (p=0.014) and was comparable to maintenance budesonide (p=0.658).     

The adverse event (AE) profile in the adolescent subgroup was also consistent with the overall population, with similar incidence of any AE between the as-needed budesonide/formoterol and the maintenance budesonide arms (33.9 percent and 33.2 percent), while AE was more frequent in the as-needed terbutaline arm (41.0 percent).

“Anti-inflammatory reliever therapy with as-needed budesonide/formoterol therefore provides an alternative treatment option for adolescents with mild asthma, and may be particularly suitable given the well-recognized challenges of adherence in the adolescent population,” said Reddel.

Similar results were seen in a separate subanalysis investigating the influence of prior medication on treatment efficacy. As-needed budesonide/formoterol significantly reduced the annual rates of severe exacerbations compared with as-needed terbutaline, regardless of whether patients were previously treated with as-needed inhaled short-acting bronchodilators (subgroup 1; rate ratio [RR], 0.34; p<0.001) or with ICS or LTRA*** (subgroup 2; RR, 0.37; p<0.001). There was no significant difference between as-needed budesonide/formoterol and maintenance budesonide regardless of prior treatment. [ATS 2019, abstract A7082/P504]        

However, pooled analysis of both the SYGMA 1 and 2 studies suggested that patients in subgroup 1 benefited more from as-needed budesonide/formoterol vs maintenance budesonide (estimated RR, 0.738; p=0.032), while there is no significant difference between treatments among patients in subgroup 2 (p=0.436).

In addition, exposure to ICS was also lower with as-needed budesonide/formoterol than maintenance budesonide regardless of prior treatment, consistent with findings from the overall population.

“[The results] challenged the idea of inhaled glucocorticoid maintenance therapy for persistent asthma by showing that as-needed use of a budesonide-formoterol combination was as effective as budesonide maintenance therapy in the prevention of exacerbations, at a fraction of the overall exposure to inhaled glucocorticoids,” wrote Dr Gary Wong of the Chinese University of Hong Kong, Hong Kong in an editorial. [N Engl J Med 2019;380:2064-2066]