Step-up therapy for children with asthma not controlled by inhaled corticosteroids
In a controlled trial, ihaled long-acting beta-agonist (LABA) was more likely than increased inhaled corticosteroid (ICS) dose or leukotriene antagonist to be effective as step-up treatment in children with asthma not controlled with ICS, however many children responded better to ICS or leukotriene antagonist.
A significant proportion of children with asthma will not be controlled with low-dose ICS, however the evidence for the most effective step-up therapy is uncertain. This three-way crossover study was intended to determine whether inhaled LABA, increased ICS dose, or oral leukotriene antagonist would be most effective in such children. It involved children aged 6 to 17 years with mild to moderate asthma not adequately controlled on inhaled fluticasone 100 microgm twice daily. After a 2 – 8 week run-in to confirm poor control, they were randomised to receive inhaled fluticasone 250 microgm twice daily, or inhaled salmeterol 50 microgm plus fluticasone 100 microgm twice daily, or oral montelukast 5mg or 10mg daily plus inhaled fluticasone 100 microgm. Dummy inhalers and placebo tablets were used to ensure blinding.
Each treatment was continued for 16 weeks, at which point the patient was crossed over to ensure each received a period on each of the treatments. Primary outcome was differential response to each of the therapies based on a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second): a differential response was considered to have occurred if there was an improvement in at least one of the outcomes. Funding was from public sources and apart from donating the medications used, the manufacturers had no involvement in the study.
Of 480 patients initially enrolled, 182 were eligible and randomised: 25 dropped out during treatment (most commonly because lost to follow-up, unable to continue, or consent withdrawn) to leave 165 who completed at least two, and 157 who completed all three study periods. Overall adherence to treatment was fairly good (tablets 84%, inhalers 87%). Almost all the children (161 of 165) showed a differential response to each therapy, however on a three-way analysis of the primary outcome the response to LABA step-up was significantly more likely to be the best response, as compared with the response to leukotriene antagonist step-up (relative probability, 1.6; 95% CI, 1.1 to 2.3; P=0.004) and the response to ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002).
There were 7 serious adverse events, with no difference between the treatment groups.
The authors conclude that in children with mild to moderate asthma not controlled by ICS, many will show a ceiling effect to these drugs and alternative drugs must be added to treatment to achieve control. According to their results, addition of inhaled LABA is most likely to give best control, however there were many children who responded better to one of the other therapies. Analysis by race indicated that black patients were equally likely to have a best response to addition of LABA or ICS therapy and were least likely to have a best response to leukotriene antagonist addition. In contrast, in white subjects, LABA addition was most likely to provide the best response. Degree of asthma control and presence of eczema were also potentially predictive.
New Engl J Med, published early online 2 March 2010; doi: 10.1056/NEJMoa1001278 (link to abstract)