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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

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Summary

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.

Funding

Health Research Council of New Zealand.

Introduction

Inhaled corticosteroid plus long-acting β agonist delivered from a combination inhaler is the mainstay of treatment in patients with moderate to severe asthma.1, 2 It can be prescribed either in accordance with a standard fixed-dose maintenance regimen with a short-acting β agonist for relief of symptoms, or according to the SMART (Single combination budesonide–formoterol inhaler Maintenance And Reliever Therapy) regimen, in which a combination budesonide–formoterol inhaler is used for both maintenance and as-needed reliever use. Results of randomised controlled trials show that in patients with moderate to severe asthma, the SMART regimen leads to a reduction in severe exacerbations compared with the standard regimen.3, 4 However, the generalisability of this finding is restricted because patients who had high baseline use of their reliever medication were not eligible for inclusion in these studies.3, 4 Because there are no robust data for the actual patterns of medication use, it is not possible to ascertain whether the reduction in severe exacerbations with the SMART regimen is due to more regular exposure to inhaled corticosteroid through as-needed reliever use in otherwise poorly adherent patients or use of self-titrated budesonide–formoterol during worsening of asthma. Also, whether the SMART regimen leads to delays in patients seeking medical care during severe asthma exacerbations or whether it might result in a greater systemic corticosteroid load is not known.

We report the results of a randomised controlled trial in patients with asthma at risk of severe exacerbations. We used electronic monitoring to assess patterns of actual medication use and this method allowed us to apply β agonist overuse as a marker of the risk of life-threatening asthma.5, 6, 7, 8 Our hypothesis was that treatment of patients with the SMART regimen would lead to a reduction in the risk of high-use episodes of β agonist, but when such episodes did occur the patients would be less likely to seek medical review and that any reduction in severe asthma exacerbations would be at a higher burden of systemic corticosteroid.

Section snippets

Study design and participants

The study was a 24-week, open-label, parallel-group, randomised, controlled, trial undertaken at four primary health-care practices and one hospital in New Zealand (appendix p 2; study protocol).

Participants were eligible for participation in the study if they were aged 16–65 years, had a physician's diagnosis of asthma, a current prescription for inhaled corticosteroid, and at least one asthma exacerbation in the preceding year. This exacerbation was defined as a presentation to a general

Results

303 participants were enrolled between June 29, 2010 (study start), and Sept 14, 2011, with the last participant completing the study on Feb 29, 2012. The characteristics of participants are shown in table 1 and their flow is shown in figure 1. A final-visit assessment was completed for 21 (75%) of 28 participants who had withdrawn from the study. 282 466 actuations from 2642 monitors were recorded in the database over 49 149 days of treatment. After removal of actuations on visit days (11 576

Discussion

The results of this study show that combination budesonide–formoterol delivered through an inhaler and prescribed according to the SMART regimen has favourable safety and efficacy profiles compared with the standard regimen of fixed-dose maintenance budesonide–formoterol and salbutamol as reliever therapy in adult patients with asthma at risk of severe exacerbations. The SMART regimen reduces the risk of severe asthma exacerbations without increasing the risk of β-agonist overuse without

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