Addition of anti-leukotriene agents to inhaled corticosteroids in children with persistent asthma.

BACKGROUND In the treatment of children with mild persistent asthma, low-dose inhaled corticosteroids (ICS) are recommended as the preferred monotherapy (referred to as step 2 of therapy). In children with inadequate asthma control on low doses of ICS (step 2), asthma management guidelines recommend adding an anti-leukotriene agent to existing ICS as one of three therapeutic options to intensify therapy (step 3). OBJECTIVES To compare the efficacy and safety of the combination of anti-leukotriene agents and ICS to the use of the same, an increased, or a tapering dose of ICS in children and adolescents with persistent asthma who remain symptomatic despite the use of maintenance ICS. In addition, we wished to determine the characteristics of people or treatments, if any, that influenced the magnitude of response attributable to the addition of anti-leukotrienes. SEARCH METHODS We identified trials from the Cochrane Airways Group Specialised Register of Trials (CAGR), which were derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, AMED, and CINAHL; and the handsearching of respiratory journals and meeting abstracts, as well as the www.clinicaltrials. gov website. The search was conducted until January 2013. SELECTION CRITERIA We considered for inclusion randomised controlled trials (RCTs) conducted in children and adolescents, aged one to 18 years, with asthma, who remained symptomatic despite the use of a stable maintenance dose of ICS and in whom anti-leukotrienes were added to the ICS if they were compared to the same, an increased, or a tapering dose of ICS for at least four weeks. DATA COLLECTION AND ANALYSIS We used standard methods expected by The Cochrane Collaboration. MAIN RESULTS Five paediatric (parallel group or cross-over) trials met the inclusion criteria. We considered two (40%) trials to be at a low risk of bias. Four published trials, representing 559 children (aged ≥ six years) and adolescents with mild to moderate asthma, contributed data to the review. No trial enrolled preschoolers. All trials used montelukast as the anti-leukotriene agent administered for between four and 16 weeks. Three trials evaluated the combination of anti-leukotrienes and ICS compared to the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (N = 268 participants; risk ratio (RR) 0.80, 95% confidence interval (CI) 0.34 to 1.91). There was also no statistically significant difference in percentage change in FEV₁ (forced expiratory volume in 1 second) with mean difference (MD) 1.3 (95% CI -0.09 to 2.69) in this trial, but a significant group difference was observed in the morning (AM) and evening (PM) peak expiratory flow rates (PEFR): N = 218 participants; MD 9.70 L/min (95% CI 1.27 to 18.13) and MD 10.70 (95% CI 2.41 to 18.99), respectively. One trial compared the combination of anti-leukotrienes and ICS to a higher-dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over 16 weeks (N = 182 participants; RR 0.82, 95% CI 0.54 to 1.25), nor was there any significant difference in exacerbations requiring hospitalisation. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding anti-leukotrienes as a means to taper the dose of ICS. AUTHORS' CONCLUSIONS The addition of anti-leukotrienes to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared to the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although anti-leukotrienes have been licensed for use in children for over 10 years, the paucity of paediatric trials, the absence of data on preschoolers, and the variability in the reporting of relevant clinical outcomes considerably limit firm conclusions. At present, there is no firm evidence to support the efficacy and safety of anti-leukotrienes as add-on therapy to ICS as a step-3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low-dose ICS.