Leukotriene Antagonist Therapy Anti-leukotrienes as Add-on Therapy to Inhaled Glucocorticoids in Patients with Asthma: Systematic Review of Current Evidence

Purpose of the Study. To examine the evidence for the efficacy and glucocorticoid-sparing effect of oral anti-leukotrienes taken daily as add-on therapy to inhaled glucocorticoids in patients with asthma. Study Population. Systematic review of randomized, controlled trials of children and adults with asthma comparing the addition of anti-leukotrienes or placebo to inhaled glucocorticoids. Methods. Medline, Embase, Cinahl, and Central databases up to August 2001 were used. Trials were included if they were randomized, controlled trials, if they pertained to children and adults with asthma who were taking inhaled glucocorticoids for maintenance, if they compared the addition of anti-leukotrienes or placebo daily to inhaled glucocorticoids for a minimum of 28 days, and if they documented measures of efficacy other than compliance. Primary outcome measures were number of asthma exacerbations when the intervention was compared with the same or increased dose of inhaled glucocorticoids. It also included the change from baseline dose of inhaled glucocrticoids required to maintain control when the intervention was aimed to establish the steroid-sparing effect. Secondary outcomes were changes in pulmonary function tests, symptoms, use of rescue 2-agonists, quality of life, exacerbations requiring hospital admission, adverse effects, and withdrawals. Results. Of 376 citations, 13 were included (12 in adult patients; 1 in children). The addition of licensed doses of anti-leukotrienes to inhaled glucocorticoids resulted in a nonsignificant reduction in the risk of exacerbations requiring systemic steroids (2 trials; relative risk: 0.61; 95% confidence interval: 0.36–1.05). No trials comparing the use of anti-leukotrienes with double the dose of inhaled glucocorticoids could be pooled. The use of anti-leukotrienes resulted in no overall group difference in the lowest achieved dose of inhaled glucocrticoids (3 trials; weighted mean difference: 44.43 g/day, 147.87 to 59.02: random effect model) but was associated with a reduction in withdrawals owing to poor asthma control (four trials; relative risk: 0.56; 95% confidence interval: 0.35–0.89) Conclusions. The addition of anti-leukotrienes to inhaled glucocorticoids may modestly improve asthma control compared with inhaled glucocorticoids alone but this strategy cannot be recommended as a substitute for increasing the dose of inhaled glucocrticoids. The addition of anti-leukotrienes is possibly associated with superior asthma control after tapering of glucocorticoids, but the glucocorticoid-sparing effect cannot be quantified at present. Reviewer’s Comments. This systematic review summarizes the evidence available through August 2001 and emphasizes the shortage of relevant trials testing the role of anti-leukotrienes as add-on therapy to inhaled glucocorticoids. Although no firm conclusion can be made, the addition of anti-leukotrienes to inhaled glucocorticoids may modestly improve the control of asthma, but there is little evidence to consider their use as a substitute for increasing doses of inhaled glucocrticoids. There is also one pediatric trial showing modest benefit, and extrapolation of adult data to children remains speculative. Additional studies are needed to evaluate the true role of anti-leukotrienes as a steroid-sparing agent, and until more evidence is available, the gold standard should remain that clinicians use inhaled corticosteroids at the lowest effective dose to maintain asthma control.