An intermittent high-dose budesonide regimen and a daily low-dose regimen resulted in similar reductions in asthma exacerbations in preschool children with recurrent wheezing, but the intermittent regimen was associated with significantly less drug exposure, according to a report in the Nov. 24 issue of the New England Journal of Medicine.
In the randomized double-blind MIST (Maintenance and Intermittent Inhaled Corticosteroids in Wheezing Toddlers) trial, the rates of exacerbations per patient-year were 0.97 and 0.95 in the 139 patients who received daily budesonide and the 139 patients who received intermittent budesonide, respectively (relative rate in the intermittent regimen group of 0.99), Dr. Robert S. Zeiger of Kaiser Permanente, San Diego, and his colleagues said.
No significant differences were seen between the groups with respect to time to the first exacerbation (hazard ratio, 0.97), time to second exacerbation (HR, 0.79), or frequency of treatment failure, nor were significant differences seen between the groups on a number of prespecified secondary outcomes, including the rates of respiratory tract illness per patient-year, respiratory tract illnesses in which prednisolone was administered, frequency of treatment for respiratory tract illnesses, and time to the first treatment for respiratory tract illness.
The rates of nonserious adverse events and serious adverse events were also similar in the two groups.
In addition, the mean cumulative exposure to budesonide was reduced significantly – by 104 mg – over the year-long treatment period in the intermittent regimen group vs. the daily regimen group (45.7 mg vs. 149.9 mg), the investigators said (N. Engl. J. Med. 2011;365:1990-2001).
This finding is of note because an association between daily use of inhaled glucocorticoids and significant reductions in height growth was previously shown, they said.
"Concern about growth retardation and parental resistance to a daily regimen of inhaled glucocorticoids for young children, who usually have only episodic but often severe symptoms, stimulated a search for alternative strategies – specifically intermittent therapy with inhaled glucocorticoids," they explained, adding that intermittent 7-day courses initiated during respiratory tract illnesses were subsequently shown to significantly reduce the severity of respiratory symptoms, compared with placebo, without affecting linear growth.
The benefits were greatest in children with positive values on the modified asthma predictive index (API), they said.
The current study was conducted to determine whether a daily low-dose regimen would be superior to an intermittent dose in young children with positive values on the modified API, as well as recurrent wheezing, at least one exacerbation in the previous year, and low impairment defined by infrequent use of albuterol and infrequent night awakenings between episodes, they said.
The multicenter parallel-group trial included children aged 12-53 months. Treatment included a 2-week run-in period with nightly placebo doses of budesonide inhalation suspension plus albuterol given as needed in all patients. The run-in period was followed by a 52-week treatment period during which those in the intermittent treatment group received budesonide inhalation suspension given as 1 mg twice daily for 7 days when a respiratory tract illness was identified, and those in the daily treatment group received budesonide inhalation suspension given at a 0.5-mg dose every night. Corresponding placebo doses were also provided in each group.
The findings indicate that daily budesonide dosing is not superior to intermittent dosing for preventing asthma exacerbations in young children at risk for asthma and future exacerbations. The results have implications for the preparation of future guidelines, particularly given that current U.S. guidelines and Global Initiative for Asthma (GINA) guidelines recommend daily therapy with inhaled glucocorticoids as the preferred option for young children with recurrent wheezing and risk factors for persistent asthma. GINA guidelines also caution against daily high-dose therapy with inhaled glucocorticoids for prolonged periods, and instead recommend use of the lowest effective dose.
The MIST investigators noted that their findings may not be applicable to young children with asthma that is more severe or otherwise different from that in the children in their study.
"Daily or intermittent use of inhaled glucocorticoids, or even short courses of oral glucocorticoids started at the onset of wheezing episodes, may not be as efficacious in preschool-age children with a first episode, with transient or infrequent wheezing, or without an asthma diagnosis or a high risk of asthma," they said.
This study was supported by grants from the National Heart, Lung, and Blood Institute; the Washington University, St. Louis, Clinical and Translational Science Awards (CTSA) Infrastructure for Pediatric Research; the Madison CTSA; and the Colorado CTSA (via a grant from the National Center for Research Resources of the National Institutes of Health); and by grants to the General Clinical Research Centers at Washington University, National Jewish Health, and the University of New Mexico, Albuquerque. Study drug and matching placebo were donated by AstraZeneca. Dr. Zeiger and several other authors had numerous disclosures, including various financial relationships with pharmaceutical companies. The complete list of disclosures is available with the full text of the article at NEJM.org.