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Intermittent, rather than continuous, inhaled corticosteroids (ICS) increases the risk of exacerbations of asthma in children, without clear evidence of long-term safety benefits.
Action
Prescribers should not change practice as a result of this study and should continue to follow the SIGN/BTS British Asthma Guideline. For children aged 5–12 years who require preventative therapy, regular ICS should be prescribed at a dose appropriate to the severity of disease. A reasonable starting dose is beclometasone (BDP) 200mcg per day (or equivalent). The dose should be given initially in two divided doses, but once a day dosing of the same total daily dose can be considered if good control is established. The dose should be titrated to the lowest dose at which effective asthma control is maintained. Although the dose or duration of ICS required to place a child at risk of clinical adrenal insufficiency is unknown, it is likely to occur at >800mcg per day BDP (or equivalent). Therefore, such doses should only be prescribed if the child is under the care of a specialist paediatrician.
What is the background to this?
When prescribing ICS, it is important to balance efficacy benefits with regard to asthma control against safety risks. For children, systemic effects including growth failure and adrenal suppression are of particular concern and may be associated with doses at or above BDP 400mcg per day (or equivalent). There is merit in a regimen that provides equivalent control of asthma, with lower systemic exposure to steroids, and a clinically significant reduction in adverse effects. Turpeinen and colleagues conducted a small study in children with mild persistent asthma to evaluate the anti-asthmatic efficacy and systemic effect of continuing regular ICS (budesonide) beyond a six-month period, compared with stopping regular ICS after six months treatment and just providing as-needed ICS to treat exacerbations.
What does this study claim?
The authors claim that the dose of ICS can be reduced in children once their symptoms are controlled, and some children with mild persistent asthma do not seem to need continuous ICS treatment but may be managed by use of the as-needed ICS regimen.
What is the claim based on?
This claim is based on showing a faster normalisation of growth rate over a year in children given as-needed ICS, rather than continuous ICS, following withdrawal of treatment with high doses (800mcg then 400mcg per day) for six months. However, this was at the expense of more asthma exacerbations.
What did the study actually show?
The claim for a safety benefit of as-needed treatment comes from identifying a small but statistically significant (0.6cm/year) difference in the rate of growth of children between the two budesonide groups over the last 12 months of the study (i.e. when the as-needed group was only using ICS to treat exacerbations). It is unlikely that this difference is of any long-term clinical significance (see below). Although there were no differences identified between the budesonide groups with regard to lung function measurements, the as-needed group was associated with a significantly greater number of asthma exacerbations —about one per patient on average (P=0.008). However, as detailed below, there are many limitations to the study, including the atypical budesonide regimen used initially, which question the significance of the safety claims and their relevance to routine clinical practice.
What are the limitations?
The study was small (<60 per group) and only statistically powered to detect changes in a lung function measurement (morning peak expiratory flow). In patients with mild asthma, lung function measurements are poor predictors of the risk of having an asthma exacerbation. Moreover, their correlation to clinical measures such as quality of life, impairment during physical activities, daily symptoms, or more comprehensive scores of daily asthma control, is poor or non-existing (see Perspectives article). Nevertheless, statistically significant benefits of continuous over as-needed budesonide treatment were demonstrated with regard to exacerbations. Although there are indications of a possible safety benefit in terms of growth for the as-needed ICS regimen, the results of study should only be considered hypothesis generating at this stage. As the accompanying Perspectives article points out, the change in growth rate during one to two years of treatment is a poor predictor of long-term growth or attained adult height.
The relevance of the study regimen to routine clinical practice is also uncertain. The study appears to have been conducted in a single secondary care setting in Finland and the population studied may not be representative of children in primary care in the UK. The authors of the article themselves recognise the “artificial nature of the research protocol” used for the study. The particular ICS regimen used in this study does not reflect current recommended practice for initiating doses of ICS in children. The study initiated patients at budesonide 800mcg per day and then reduced dosage according to protocol, without consideration of individual patient circumstances. The SIGN/BTS British Asthma Guideline recommends (STEP 2) 200mcg per day as an appropriate starting dose for children of this age, with the dose being increased, or other drugs added in, as necessary to control symptoms. It is not known what if any differences would have been detected if the groups had been treated according to this guideline, as opposed to the rigid ICS regimen used in the study.
Most of the growth changes occurring in the study occurred in the first six-months of treatment. Therefore, at the start of the randomised budesonide treatment, bone growth was already significantly reduced. Furthermore, as there was no selection of patients in the study, in terms of those who were likely to require such a high dose of ICS for asthma control, it is likely that those patients whose asthma would have been adequately controlled with lower doses of steroid were over-treated with steroid during the study.
Study details – This double-blind, single-centre, randomised controlled study enrolled 178 children aged five to ten years (mean age seven years) in Finland who presented with symptoms of asthma for at least a month beforehand. Most were categorised as mild persistent asthma according to lung function tests and symptoms. After a run-in period of two weeks, in which they received terbutaline as needed, they were randomised into one of three groups and received either: 1) continuous budesonide 400mcg twice daily for one month, then 200mcg twice daily for five months, and then 100mcg, twice daily for 12 months 2) budesonide as for group 1 for the first six months, then placebo for 12 months, or 3) open label disodium cromoglycate (DSCG) 10mg three times daily for 18 months. Exacerbations for all groups were treated with budesonide 400mcg twice daily for two weeks.
There were no significant differences between groups with regard to the change in morning peak expiratory flow (the primary efficacy variable) at any time point (18 month improvements were between 10.0 and 12.5%; all three groups). Patients treated with DSCG experienced significantly more exacerbations of asthma per patient during the study compared with the other groups during the first six months (1.24 vs. 0.32; P<0.001), and with the continuous ICS group during the last 12 months (1.58 vs. 0.97; P=0.023). Patients treated with continuous ICS experienced significantly fewer exacerbations than those receiving placebo (as-needed treatment) during the last twelve months (0.97 vs. 1.69, P=0.008).
During the first 6 months, the mean standing-height velocity in the budesonide groups was 2cm/year slower than in the DSCG group (P<0.001). During the following twelve months, height velocity increased in both budesonide groups, with the mean height velocity being greater in the as-needed group compared with the continuous group (6.2 vs. 5.6 cm; P=0.016). After 18 months, children in the DSCG as-needed budesonide group grew, on average, by 1.0cm more than those in the continuous budesonide group (8.8 vs. 7.8cm; P=0.008) and 0.6cm more than those in the as-needed budesonide group (8.8 vs. 8.2cm, P=0.048).
Sponsorship
This study was funded by the Helsinki University Central Hospital and AstraZeneca.
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