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Efficacy and safety of maintenance and reliever combination budesonide–formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial

Patel, Mitesh; Pilcher, Janine; Pritchard, Alison; Perrin, Kyle; Travers, Justin; Shaw, Dominick; Holt, Shaun; Harwood, Matire; Black, Peter; Weatherall, Mark; Beasley, Richard

Authors

Mitesh Patel

Janine Pilcher

Alison Pritchard

Kyle Perrin

Justin Travers

Dominick Shaw

Shaun Holt

Matire Harwood

Peter Black

Mark Weatherall

Richard Beasley



Abstract

Background
The Single combination budesonide–formoterol inhaler Maintenance And Reliever Therapy (SMART) regimen reduces severe asthma exacerbations in patients, but whether the high doses of corticosteroid and β agonist increase the risk of adverse effects with both short-term and cumulative exposure is not certain. Our aim was to investigate whether the SMART regimen would reduce the risk of overuse of β agonist, reduce the likelihood of patients to seek medical review when such episodes occurred, and if any reduction in severe asthma exacerbations would be at the cost of a higher burden of systemic corticosteroid.

Methods
In this 24-week trial undertaken at four primary health-care practices and one hospital in New Zealand, patients (aged 16–65 years) with a recent asthma exacerbation were randomly assigned in a 1:1 ratio to the SMART or standard fixed-dose regimen. Treatment in the SMART group consisted of two actuations of budesonide–formoterol (200 μg and 6 μg, respectively, per actuation) twice daily, delivered through a combination metered dose inhaler (MDI), with one extra actuation as needed for relief of symptoms; treatment in the standard group consisted of two actuations of budesonide–formoterol (200 μg and 6 μg, respectively, per actuation) twice daily through a combination MDI with one to two actuations of salbutamol (100 μg per actuation) by MDI as needed for relief of symptoms. MDIs were monitored electronically to measure actual use of medication. The allocation sequence for randomisation was computer generated, with a block size of eight per site. Participants, investigators, and the statistician were not masked to group assignment. The primary outcome was the proportion of participants with at least one high-use episode of β agonist (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). Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000515099.

Findings
303 patients were randomly assigned to the SMART (n=151) or standard group (n=152). No significant difference was noted between the SMART and standard groups in the proportion of participants with at least one high-use episode of β agonist (84 [56%] vs 68 [45%], respectively, relative risk 1·24 [95% CI 0·99–1·56]; p=0·058). There were fewer days of high use in the SMART group (mean 5·1 days [SD 14·3] vs 8·9 days [20·9], relative rate 0·58 [0·39–0·88]; p=0·01). Of the patients who had at least one high-use episode, those in the SMART group had fewer days of high use without medical review (8·5 days [17·8] vs 18·3 days [24·8], 0·49 [0·31–0·75]; p=0·001). The SMART regimen resulted in higher inhaled corticosteroid exposure (943·5 μg budesonide per day [1502·5] vs 684·3 μg budesonide per day [390·5], respectively; ratio of means 1·22 [1·06–1·41]; p=0·006), but reduced oral corticosteroid exposure (77·5 mg prednisone [240·5] vs 126·6 mg prednisone [382·1], respectively; p=0·011), with no significant difference in composite systemic corticosteroid exposure (793·7 mg prednisone equivalent per year [893·1] vs 772·1 mg prednisone equivalent per year [1062·7], respectively; 1·03 [0·86–1·22]; p=0·76). Participants in the SMART group had fewer severe asthma exacerbations (35 [weighted mean rate per year 0·53] vs 66 [0·97]; relative rate 0·54 [0·36–0·82]; p=0·004).

Interpretation
The SMART regimen has a favourable risk-to-benefit profile and can be recommended for use in adults at risk of severe asthma exacerbations.

Journal Article Type Article
Publication Date Mar 4, 2013
Journal Lancet Respiratory Medicine
Print ISSN 2213-2600
Electronic ISSN 2213-2619
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 1
Issue 1
Pages 32-42
Institution Citation Patel, M., Pilcher, J., Pritchard, A., Perrin, K., Travers, J., Shaw, D., …Beasley, R. (2013). Efficacy and safety of maintenance and reliever combination budesonide–formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. Lancet Respiratory Medicine, 1(1), 32-42. doi:10.1016/S2213-2600(13)70007-9
DOI https://doi.org/10.1016/S2213-2600%2813%2970007-9
Publisher URL http://www.sciencedirect.com/science/article/pii/S2213260013700079
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
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