Introduction
The Global Initiative for Asthma (GINA) and the National Asthma Education and Prevention Program (NAEPP) of the US National Heart, Lung, and Blood Institute (NHLBI) recently recommended the use of a s ingle inhaler that contains both an inhaled corticosteroid (ICS) and formoterol, a long-acting beta 2 -agonist with a rapid onset, for both m aintenance a nd r eliever t herapy of asthma. The acronym for this mode of therapy is S.M.A.R.T. In addition, GINA specifically recommends using an ICS with formoterol, as needed (PRN) for symptom relief as the only therapy in patients with intermittent or mild persistent asthma . We argue against these proposals. While that combination may have merit for some adult patients, the data does not support the routine use of an ICS with each dose of a PRN beta 2 -agonist in children.
Pharmacologic management of asthma has traditionally focused on maintenance medication to prevent symptoms of asthma with separate measures to treat acute symptoms when they occur. Since the introduction of inhaled beclomethasone in the 1970s, various inhaled corticosteroids with minimal systemic effects have become the primary maintenance medication for asthma. Various short-acting β 2 -agonist bronchodilators (SABA) such as terbutaline and albuterol (salbutamol) have been used for relief of acute symptoms, as well as formoterol.
Should an ICS now accompany each dose of beta 2 agonist bronchodilator used for symptom relief? What is the merit of that strategy for children, and what are the concerns? Should we abandon separate medications for maintenance and acute therapy and utilize a product that provides S.M.A.R.T. assuring an ICS is always administered whenever a β 2 agonist bronchodilator is taken?
What are the data?
The NAEPP commissioned a systematic review with meta-analysis of randomized controlled trials of S.M.A.R.T. . There were 16 trials analyzed (N = 22,524 subjects; mean age 42 yr.). Children ≥12 yr. were included, but data for this age group was not analyzed separately. Fifteen of the studies included a combination of budesonide and formoterol delivered by dry powder inhaler (DPI) (Symbicort® Turbuhaler, AstraZeneca), and one included beclomethasone and formoterol delivered by metered-dose inhaler (MDI) . While S.M.A.R.T. was associated with fewer exacerbations compared with controls, it was not associated with increased asthma symptom control, better quality of life, higher FEV 1, or reduction in use of rescue medications .
There was only one published study on the use of S.M.A.R.T. that included patients in the 4–11-year age group . It was a 12-month, double-blind, parallel study of 341 children with asthma uncontrolled on ICS alone. Patients were randomized to one of three regimens. These included S.M.A.R.T. (budesonide/formoterol DPI, 80/4.5 mcg), once daily as maintenance with up to 7 additional actuations per day PRN acute symptoms (a maximum total of 8 actuations/day), the same combination as maintenance but with terbutaline PRN for acute symptoms, or maintenance of a higher dose of budesonide, 320 mcg once daily, with terbutaline PRN for acute symptoms. While the time to first exacerbation (defined as a peak flow <70% for 2 days, need for oral corticosteroids, an emergency department visit or hospitalization) was significantly longer with S.M.A.R.T. than the higher dose budesonide maintenance regimen, there were few hospitalizations and emergency visits in all three arms of the study with no significant difference between them. Asthma control days, a day without asthma symptoms or use of relief medication, were low in all three treatment arms (51–60%) and not significantly better in the S.M.A.R.T. group. While on average growth was one centimeter less in the higher dose budesonide group, there were no differences in response to adrenocorticotropic hormone between the groups. The relevance of this study is limited because of the once daily administration of maintenance medication, that is less effective than twice daily administration . Thus, the extra PRN doses of budesonide-formoterol apparently compensated for the suboptimal maintenance medication which essentially biased the outcome.
Five studies of PRN use of budesonide-formoterol as the only asthma therapy to relieve symptoms in patients with mild asthma were analyzed in a Cochrane Systematic Review . Only two of the studies recruited children in the 12 to 17-year age group, and they represented 16 and 20%, of the subjects in this age group, respectively. All five studies (9657 subjects, (mean age 40 years) compared as needed budesonide-formoterol, delivered by DPI, with either PRN SABA, regular-maintenance ICS and PRN SABA or both. When compared to PRN SABA alone, the need for systemic corticosteroids was reduced but judged to be non-inferior to maintenance budesonide . All the data are derived from studies of DPI formulations and may not necessarily apply to pressurized metered-dose inhalers, that deliver much less drug to the airways . A further conclusion was that research was needed in children under 12 years of age.
Comparison of PRN budesonide-formoterol with maintenance budesonide twice daily and PRN SABA demonstrated consistently better control of asthma than with the PRN combination ( Fig. 1 ).
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