Long-acting beta2 agonists for childhood asthma
- Peter Paul van Asperen
- Aust Prescr 2012;35:111-3
- 1 August 2012
- DOI: 10.18773/austprescr.2012.049
Long-acting beta2 agonists are currently overprescribed in children. They are also often used inappropriately as first-line therapy and are not recommended for children aged five years or less.
Due to the paucity of paediatric clinical trials, the evidence for the efficacy and safety of long-acting beta2 agonists in children is limited. There is little evidence that they reduce the risk of severe exacerbations and some evidence that they may actually increase the risk.
The regular use of long-acting beta2 agonists may also result in a loss of protection against exercise-induced bronchoconstriction, and the development of tolerance to short-acting beta2 agonists. Long-acting beta2 agonists are only one option for children whose asthma is not adequately controlled with inhaled corticosteroids alone – the other options being an increase of inhaled corticosteroid dose or the addition of a leukotriene receptor antagonist.
For children whose major ongoing symptoms are activity related, the addition of a leukotriene receptor antagonist is the preferred option.
There is limited evidence for the efficacy of long-acting beta2 agonists in children,2 but combination therapy (inhaled corticosteroids and long-acting beta2 agonists) is commonly prescribed as first-line when preventer therapy is needed. Combination therapy now represents over 40% of prescribed preventer therapy in children. Based on the frequency of asthma patterns in children and the stepwise approach advocated by the current National Asthma Council of Australia guidelines,1 combination therapy should represent no more than 10% of prescribed preventer therapy in children and probably less, given the availability of alternative step-up options.
A greater concern is that combination therapy now represents 20% of all prescribed asthma medication (preventers and relievers) in pre-school children.3 This is outside the prescribing indications for combination therapy and no evidence exists for the efficacy or safety of long-acting beta2 agonists in this age group. Combination therapy is also often inappropriately prescribed for intermittent, rather than regular, use.
There were 24 comparisons of adding long-acting beta2 agonists or placebo to a constant dose of inhaled corticosteroids. These trials showed a predictable small and probably not patient-important improvement in lung function. There was no significant reduction in exacerbations in the children taking regular long-acting beta2 agonists.
Seven studies compared the addition of long-acting beta2 agonists with an increased dose of inhaled corticosteroids. The children on long-acting beta2 agonists had significantly improved lung function and short-term linear growth when compared to those on higher dose inhaled corticosteroids. However, there was a non-significant increase in exacerbations requiring oral corticosteroids and hospitalisation (which the authors concluded required further examination).
Another Cochrane review highlighted the difference in the effectiveness of long-acting beta2 agonists in children versus adults.4 This review compared the addition of long-acting beta2 agonists to inhaled corticosteroids versus higher dose inhaled corticosteroids, in both adults and children with suboptimal asthma control despite low-dose inhaled corticosteroids. In adolescents and adults the combination of long-acting beta2 agonists and inhaled corticosteroids was modestly more effective in reducing the risk of exacerbation requiring oral corticosteroids than a higher dose of inhaled corticosteroids. However, in children, combination therapy did not lead to a significant reduction, but rather a trend toward an increased risk of severe exacerbations and hospital admission.4
A further Cochrane review examined the addition of long-acting beta2 agonists to inhaled corticosteroids versus inhaled corticosteroids alone as first-line therapy for persistent asthma in adults and children who had previously taken steriods. This review concluded that the ‘current evidence does not support the use of combination therapy as first-line preventive treatment, without a prior trial of inhaled corticosteroids’.5 While the combination of budesonide and eformoterol is approved for patients aged 12 years and over, there are limited paediatric data.
Before intensifying the treatment of poorly controlled asthma it is important to first exclude other factors contributing to poor control. These include incorrect diagnosis, poor adherence, inappropriate delivery device and poor inhaler technique.
When comparing the addition of long-acting beta2 agonists to an increased dose of inhaled corticosteroids, current evidence suggests that while regular use of long-acting beta2 agonists will predictably improve lung function, the risk of exacerbation appears, if anything, to increase.2,4
A randomised triple crossover study in 182 children aged 6–17 years of age who had uncontrolled asthma on 100 microgram of fluticasone propionate twice daily also provides relevant comparative information.1 These children received 16 weeks on each of the following therapies, in random order:
The response was assessed by a composite index comprising exacerbations requiring oral corticosteroids, asthma-control days and forced expiratory volume in one second. Overall the probability of the long-acting beta2 agonist step-up providing the best response was higher (45%), but the probability of having a best response to leukotriene receptor antagonist (28%) or inhaled corticosteroid (27%) step-up was also significant. This highlights the variability of children’s responses to these drugs, plus the need to regularly monitor and appropriately adjust each child’s therapy.9
What is clear is that leukotriene receptor antagonists are superior to long-acting beta2 agonists in protecting against exercise-induced bronchoconstriction as add-on therapy in children already receiving inhaled corticosteroids.7 Further, in contrast to regular use of long-acting beta2 agonists, leukotriene receptor antagonists are not associated with the development of tolerance to either protection against exercise-induced bronchoconstriction, nor responsiveness to short-acting beta2 agonists.7 Montelukast has now been listed in the Australian Pharmaceutical Benefits Scheme for add-on treatment (as an alternative to long-acting beta2 agonists) for children aged 6–14 years, who despite inhaled corticosteroids, have ongoing activity (exercise)-related asthma.
Recommendations on step-up options11
The addition of a leukotriene receptor antagonist is the preferred option for children with ongoing activity-related asthma. Long-acting beta2 agonists are not recommended for children five years or younger.
Professor Peter van Asperen is currently a member of the MSD (Aust) Paediatric Respiratory Physician Advisory Board and has received speaker fees from MSD for presentations on management of asthma and wheeze in children. He is a member of the GlaxoSmithKline Paediatric Respiratory Taskforce which has been convened to ensure appropriate prescribing of Seretide in children. His department has received research funding in the past from GlaxoSmithKline, Astra Zeneca, MSD, Boehringer Ingelheim and Altana for involvement in clinical trials but is not currently receiving funding from these companies.
Van Asperen PP, Mellis CM, Sly PD, Robertson CF. Evidence-based asthma management in children – what’s new? [editorial]. Med J Aust 2011;194:383-4 .
Van Asperen P. What’s new in the management of asthma in children? Med Today 2011;12:53-64 .
Head, Department of Respiratory Medicine, The Children’s Hospital at Westmead Sydney Children’s Hospitals Network
Macintosh Professor of Paediatric Respiratory Medicine, Discipline of Paediatrics and Child Health, Sydney Medical School University of Sydney