Single maintenance and reliever therapy (SMART) of asthma: a critical appraisal

Abstract

The use of a combination inhaler containing budesonide and formoterol as both maintenance and quick relief therapy (SMART) has been recommended as an improved method of using inhaled corticosteroid/long-acting beta agonist (ICS/LABA) therapy. Published double-blind trials show that budesonide/formoterol therapy delivered in SMART fashion achieves better asthma outcomes than budesonide monotherapy or lower doses of budesonide/formoterol therapy delivered in constant dosage. Attempts to compare budesonide/formoterol SMART therapy with regular combination ICS/LABA dosing using other compounds have been confounded by a lack of blinding and unspecified dose adjustment strategies. The asthma control outcomes in SMART-treated patients are poor; it has been reported that only 17.1% of SMART-treated patients are controlled. In seven trials of 6-12 months duration, patients using SMART have used quick reliever daily (weighted average 0.92 inhalations/day), have awakened with asthma symptoms once every 7-10 days (weighted average 11.5% of nights), have suffered asthma symptoms more than half of days (weighted average 54.0% of days) and have had a severe exacerbation rate of one in five patients per year (weighted average 0.22 severe exacerbations/patient/year). These poor outcomes may reflect the recruitment of a skewed patient population. Although improvement from baseline has been attributed to these patients receiving additional ICS therapy at pivotal times, electronic monitoring has not been used to test this hypothesis nor the equally plausible hypothesis that patients who are non-compliant with maintenance medication have used budesonide/formoterol as needed for self-treatment of exacerbations. Although the long-term consequences of SMART therapy have not been studied, its use over 1 year has been associated with significant increases in sputum and biopsy eosinophilia. At present, there is no evidence that better asthma treatment outcomes can be obtained by moment-to-moment symptom-driven use of ICS/LABA therapy than conventional physician-monitored and adjusted ICS/LABA therapy.

Figure 1

Study designs for double-blind single maintenance and reliever therapy (SMART) studies. (A) Comparison of inhaled corticosteroid (ICS) monotherapy with ICS/long-acting β agonist (LABA). (B) Comparison of ICS monotherapy with ICS/LABA. (C) Comparison of ICS monotherapy with two doses of ICS/LABA, SMART being the higher dosage ICS/LABA treatment arm. (D) Comparison of three ICS/LABA treatment arms: with short-acting β₂ agonist, with additional LABA or with additional ICS and additional LABA. BUD, budesonide; FORM, formoterol.

Figure 2

Changes from baseline in (A) sputum cellularity and (B) endobronchial biopsy cellularity following 1 year of single maintenance and reliever therapy (SMART) (budesonide/formoterol 200/6 twice daily plus as needed) or fixed dose therapy (budesonide/formoterol 800/12 twice daily). Sputum and biopsy eosinophils decreased significantly with fixed dose combination therapy while with SMART there was a non-significant trend towards increased sputum eosinophils and a significant increase in biopsy eosinophils. p Values are between-treatment comparisons.