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14th March 2011
A randomised controlled trial (RCT) suggests that inhaled corticosteroids (ICS) plus salbutamol as reliever therapy might be an effective step-down strategy for children (>5years of age) with well controlled, mild asthma on regular ICS. However, the study had a number of limitations and this option is not currently recommended in the British asthma guideline.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Action
Health professionals should continue to follow the British asthma guideline with regard to the management of asthma in children. Regular ICS should be used (at Step 2) where children have persistent asthma, as first-choice preventer therapy at a dose according to the severity of the disease (usual starting dose 200 micrograms/day beclometasone [BDP] equivalent at Step 2 in children 5–12 years). Because of concerns about adverse systemic effects (e.g. reduced growth), the lowest maintenance dose of ICS compatible with maintaining disease control should be used.
In some children with mild persistent asthma who remain well controlled on a low dose of ICS, the guideline allows for stepping down of the ICS dose, decreasing the dose by approximately 25–50% each time. If appropriate, the guideline allows for discontinuation of the ICS altogether, with rescue salbutamol being used alone to control symptoms (Step 1) in some children. This study suggests an alternative means of stepping down the ICS dose, by use of as-needed ICS in addition to salbutamol for symptom relief. This might be considered as an alternative step-down option for some children with very intermittent symptoms, especially where there problems with adherence to regular ICS dosing. However, this option is not currently recommended in the British asthma guideline, and more studies are required before this can be considered routinely.
What is the background to this?
Regular ICS is the first-choice preventer therapy for adults and children with mild persistent asthma at Step 2 of the British asthma guideline. For well controlled patients at Step 2, the guideline recommends stepping down the dose, and eventually discontinuing the ICS where appropriate, and using a short-acting beta 2 agonist (SABA, e.g. salbutamol or terbutaline) alone to control symptoms as needed (Step 1). The investigators of this study considered that many parents or children have difficulty adhering to twice daily treatment during long asymptomatic periods, and either use the ICS sparingly or interrupt treatment altogether. This study compared the effectiveness of as-needed BDP for symptom relief instead of, or in addition to twice daily BDP, compared with twice daily BDP alone and placebo (all in addition to as-needed salbutamol for symptom relief).
What does this study claim?
This was a double-blind, placebo-controlled RCT of 288 children, aged 5 to 18 years, with well controlled persistent asthma. It included four treatment groups:
1) BDP twice daily as preventer, BDP plus salbutamol as needed (combined group)
2) BDP twice daily as preventer, salbutamol as needed (daily BDP group)
3) Placebo preventer, BDP plus salbutamol as needed (rescue BDP group)
4) Placebo preventer, salbutamol as needed (placebo group).
Over a period of 44 weeks, the probability of a first exacerbation (requiring oral prednisone) in the placebo group (salbutamol alone as needed) was 49% (95% confidence interval [CI] 37 to 61), 28% (95%CI 18 to 40) in the daily BDP group, 31% (95%CI 21 to 43) in the combined group, and 35% (95%CI 24 to 47%) in the rescue BDP group. Only in the case of the daily BDP group (i.e. equivalent to Step 2 in the British guideline) was the difference from the placebo group (i.e. equivalent to Step 1 in the British Guideline) statistically significant after adjustment for multiple comparisons (P=0.033). However, in all BDP groups the frequencies of treatment failure (requirement for a second dose of prednisone within a six-month period was the only criterion met) was statistically significantly lower than in the placebo group (see study details below). Compared with the placebo group, children in the groups receiving BDP twice daily (combined and daily BDP groups) grew by less than 1.1cm on average (P<0.0001) during the study period. There was no significant difference in growth between the placebo and rescue BDP groups.
How does this relate to other studies?
For patients who step down from regular ICS therapy, there are theoretical advantages for as-needed ICS plus SABA over as-needed SABA alone as reliever therapy (see Papi et al 2009). However, few studies have investigated this or other step-down procedures.
An earlier double-blind RCT in adult patients with mild asthma, with four treatment groups similar to the present study, evaluated the effect of as-needed BDP and salbutamol for symptom relief over a six-month period. This study suggested that as-needed combined BDP and salbutamol was more effective than as-needed salbutamol alone with regard to morning PEF and some other outcomes, including time to first exacerbation. Although not appropriately powered to show a difference, the study also indicated the use of as-needed BDP might be no less effective as BDP twice daily, despite requiring a lower 6-month cumulative dose of the ICS.
A previous Finish study (see MeReC Rapid Review No.189) compared stepping down to as-needed budesonide with continued budesonide in children with mild persistent asthma aged 5–10 years. Similar to the present study, this demonstrated a small but statistically significant (0.6cm/year) greater rate of growth of children receiving as-needed budesonide over the last 12 months of the study. In contrast to the present study, this study found that the as-needed group was associated with a significantly greater number of asthma exacerbations — about one per patient on average (P=0.008).
Although the studies are not directly comparable, e.g. patient groups, outcomes and designs of the studies were different, the results of the studies are not inconsistent with that of the present study.
So what?
ICS are effective treatments for reducing symptoms and preventing exacerbations in asthma. This study clearly demonstrates the benefits of continuing regular ICS in children with mild persistent asthma, who are well controlled with regular ICS, compared with stepping down to use of as-needed salbutamol alone. In the study, 21% fewer patients who continued use of regular ICS preventer therapy in addition to as-needed salbutamol (daily group) had at least one exacerbation requiring use of oral corticosteroid (prednisone) during the 44-week treatment period compared with those patients who stepped down to as-needed salbutamol alone (number needed to treat [NNT]=5). This benefit was also reflected by the difference in the number of treatment failures in these two groups (3% vs. 23%, P=0.009, NNT=5). Therefore, clinicians need to carefully consider risks and benefits of withdrawing ICS completely in children, i.e. stepping down from step 2 to step 1
The number of children who suffered an exacerbation requiring prednisone in the group who stepped down to as-needed BDP and salbutamol (rescue group) was not significantly higher that those continuing twice daily BDP (35% vs. 28%). However, there was also no statistically significant difference with regard to exacerbations between those children using as-needed BDP and salbutamol, and those using as-needed salbutamol alone. Nevertheless, use of as-needed BDP and salbutamol, was shown to significantly reduce treatment failures (secondary outcome) compared with as-needed salbutamol alone (9% vs. 23%, P=0.024, NNT=7). The numbers of children in each treatment group is small, and it appears that the investigators underestimated the number of patients who would an experience an exacerbation on as-needed BDP and salbutamol in the study. The study was effectively underpowered to demonstrate a difference in its primary outcome. The large number of children excluded during the run-in phase, suggests that the population studied might not be representative of normal clinical practice.
The present study only considered twice daily ICS preventer therapy, and it should be remembered that the British asthma guidelines states that stepping down to once daily ICS can be an option for patients with mild disease. We do not know how once daily regular low-dose BDP therapy would compare with the regimens considered in the present study.
Although there are limitations to this study, and further studies are required, this study, taken together with the Finish study, suggests that as-needed ICS may not be as effective as continuing with twice daily ICS for prevention of exacerbations requiring oral corticosteroids in children. However, although not currently recommended in British guidelines, or appropriate for routine use, it might be considered a step-down option, as an alternative to complete discontinuation of the ICS, particularly for those patients with very intermittent symptoms where adherence to regular ICS treatment is problematic.
In the present study, as-needed BDP use was associated with 15 to 25% of the ICS dose received by the children on regular BDP, which was reflected by statistically significantly greater child growth in the as-needed group compared with those receiving regular BDP. Any benefit with regard to growth needs to balanced against any loss of asthma control and possible increased frequency of exacerbations. Although the exact level of ICS needed to produce long-term clinically significant effects on growth are unknown, for children with mild asthma controlled with low regular doses of ICS according to Step 2 of the British asthma guideline, the long-term effects on growth are unlikely to be of clinical significance.
Design
Forty-four week, double-blind RCT, with four treatment groups. All enrolled patients entered a 4-week run in period during which they received BDP (40microgram twice daily) and rescue salbutamol. Only those whose disease remained well controlled and who did not have exacerbations during the run-in period were included in the 44-week treatment phase.
Patients
843 children (aged 5 to 18 years) with a history of mild persistent asthma during the previous 2 years and who qualified for interruption or discontinuation of preventer treatment because they were well controlled. 555 were excluded during the run-in phase and 288 were randomised to receive one of the four treatments (approximately 70 per treatment group)
Interventions and comparisons
During the randomised treatment phase patients received one of four treatment groups: twice daily BDP with as-needed BDP plus salbutamol for symptom relief (combined group); twice daily BDP with as-needed placebo plus salbutamol for symptom relief (daily BDP group); twice daily placebo with as-needed BDP plus salbutamol as rescue (rescue BDP group); and twice daily placebo with as-needed placebo plus salbutamol for symptom relief (placebo group). Twice daily BDP treatment was one puff of BDP (40 microgram per puff) or placebo given in the morning and evening. Rescue BDP treatment was two puffs of BDP or placebo for each two puffs of salbutamol (180 microgram) needed for symptom relief.
Outcomes and results
Compared with the placebo group (49%, 95%CI 37 to 61), the frequency of exacerbations was lower in the daily (28%, 95%CI 18 to 40, P=0.03), combined (31%, 95%CI 21 to 43, P=0.07), and rescue (35%, 95%CI 24 to 47, P=0.07) groups. Frequency of treatment failure was 23% (95%CI 14 to 43) in the placebo group, compared with 5.6% (95%CI 1.6 to 14) in the combined (P=0.012), 2.8% (95%CI 0 to 10) in the daily (P=0.009), and 8.5% (2 to 15) in the rescue (P=0.024) BDP groups. Compared with the placebo group, linear growth was 1.1 cm (standard deviation 0.3) less in the combined and daily arms (P<0.0001), but not the rescue group (P=0.26). Children in the rescue BDP group received 15 to 25% of the daily inhaled ICS dose that children in the combined and daily BDP groups received. The proportion of asthma control days was high (80–90%) during the trial and did not differ significantly between groups.
Sponsorship
The study was funded by the U.S. National Heart, Lung, and Blood Institute, part of the National Institutes of Health
More information on asthma can be found in the respiratory section of NPC
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Related PJ Online articles: Rescue steroids may be a valid step-down option and Inhaled corticosteroids assessed for children with mild asthma
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