Patel, Mitesh Dilipkumar Kantilal
(2013)
Efficacy and safety of maintenance and reliever combination budesonide/formoterol therapy in asthma patients at risk of severe exacerbations: a randomised controlled trial.
PhD thesis, University of Nottingham.
Abstract
The Single combination budesonide/formoterol inhaler as Maintenance And Reliever Therapy (SMART) regimen reduces severe asthma exacerbations, but it is uncertain whether it increases the risk of adverse effects due to high corticosteroid and beta-agonist doses with both short-term and cumulative exposure in patients at risk of severe exacerbations. The primary hypothesis was that the SMART regimen would reduce the risk of beta-agonist overuse. Secondary aims were to investigate whether patients treated with the SMART regimen were less likely to seek medical review in the setting of beta-agonist overuse and to determine whether any reduction in severe asthma exacerbations would be at a cost of a higher systemic corticosteroid burden.
This 24-week, open-label, parallel-group, multicentre randomised controlled trial randomised 303 asthma patients with a recent exacerbation to combination 200/6µg budesonide/formoterol metered dose inhaler (MDI) according to the SMART regimen (two actuations twice daily as maintenance with one extra actuation as-needed for relief of symptoms) or a fixed-dose regimen (two actuations twice daily as maintenance) with one to two actuations of 100µg salbutamol MDI as-needed for relief of symptoms (the ‘Standard’ regimen), with electronic monitoring to measure actual medication use. The use of electronic monitoring allowed beta-agonist overuse to be applied as a marker of the risk of life-threatening asthma. The primary outcome was the proportion of participants with at least one high beta-agonist use episode (more than eight actuations per day of budesonide/formoterol in addition to the four maintenance doses in the SMART group or more than 16 actuations per day of salbutamol in the Standard group).
There was no significant difference between groups in the proportion of participants with at least one high use episode: SMART 84/151 (55.6%) versus Standard 68/152 (44.7%), relative risk (95% CI) 1.24 (0.99 to 1.56), p=0.058. There were fewer days of high use in the SMART group [mean (SD) 5.1 days (14.3) versus 8.9 days (20.9), relative rate (95% CI) 0.58 (0.39 to 0.88), p=0.01]. Of the participants who had at least one high use episode, those in the SMART group had fewer days of high use without medical review [mean (SD) 8.5 days (17.8) versus 18.3 days (24.8), relative rate (95% CI) 0.49 (0.31 to 0.75), p=0.001]. The SMART regimen resulted in higher inhaled corticosteroid exposure [mean (SD) 943.5µg budesonide per day (1502.5) versus 684.3µg budesonide per day (390.5), ratio of means (95% CI) 1.22 (1.06 to 1.41), p=0.006], but reduced oral corticosteroid exposure [mean (SD) 77.5mg prednisone (240.5) versus 126.6mg prednisone (382.1), p=0.011], with no significant difference in composite systemic corticosteroid exposure [mean (SD) 793.7mg prednisone equivalent per year (893.1) versus 772.1mg prednisone equivalent per year (1062.7), ratio of means (95% CI) 1.03 (0.86 to 1.22), p=0.76]. Participants in the SMART group had fewer severe asthma exacerbations [35 (weighted mean rate per year 0.53) versus 66 (0.97), relative rate (95% CI) 0.54 (0.36 to 0.82), p=0.004].
The SMART regimen has a favourable risk/benefit profile in patients at risk of severe asthma exacerbations.
Funding
This study was funded by the Health Research Council of New Zealand, a government funding organisation.
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