Background: Anti-leukotriene (AL) agents are being considered as "add-on" therapy to inhaled corticosteroids (ICS), in chronic asthma.
Objectives: To examine the safety and efficacy of daily AL plus ICS compared to ICS alone, and determine the corticosteroid-sparing effect of AL when added to ICS in chronic asthma.
Search strategy: We searched Medline, Embase, Cinahl (all up to 2001), reference lists of review articles and trials, contacted international headquarters of AL manufacturers and ATS meeting abstracts (1998-2000).
Selection criteria: Randomised placebo-controlled trials of asthmatics aged 2 years and older lasting at least one month.
Data collection and analysis: Two reviewers assessed quality and extracted data independently. Trials were grouped by asthma control at baseline (symptomatic or well-controlled) and dose of ICS in the control group (same or double).
Main results: Of 336 citations, 11 trials (only adults) met inclusion criteria. Six were published in full-text, eight were high quality. Daily dose of ICS was 300-2000 mcg beclomethasone-equivalent. In symptomatic adults, AL (at 2-4 times licensed dose) combined with ICS reduced the number of patients with exacerbations that required systemic corticosteroids, compared to ICS alone [Relative Risk (RR) = 0.34; 95% Confidence Interval (CI) 0.13, 0.88]. This equates to 20 patients (95% CI 1,100 patients) treated to prevent one needing systemic corticosteroids. There was no difference in side effects. No trials tested the efficacy of licensed doses of ALs as add-on to ICS. In symptomatic adults, addition of zafirlukast to ICS did not reduce the number of exacerbations requiring systemic corticosteroids, compared to doubled dose ICS [RR= 1.39; 95% CI: 0.63, 3.08)]. There were no differences in any other measure of outcome. Higher doses of zafirlukast than currently licensed were associated with increased risk of liver enzyme elevation. In ICS-sparing trials of AL agents there was no difference in ICS dose after 12-16 weeks [Weighted Mean Difference (WMD) 1.9% change; 95% CI -3.5, 7.3], and no difference in lowest tolerated dose of ICS [WMD= 44 mcg/d; 95% CI -59, 148)].
Reviewer's conclusions: Used as add-on therapy to inhaled corticosteroids, high dose anti-leukotrienes reduced exacerbations, but there is no evidence to support their use at currently licensed doses. There is insufficient evidence to indicate whether they confer benefit over doubling the dose of corticosteroids. There is no evidence that they have any significant inhaled corticosteroid-sparing effect.