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Montelukast reduces asthma exacerbations in 2- to 5- year old children with intermittent asthma

Background: Montelukast is an effective therapy for the control of asthma exacerbations in adults and children with persistent asthma, which makes it a potential treatment modality for children with intermittent asthma.

Objective: The purpose of the study was to investigate the role of montelukast in the prevention of viral-induced asthma exacerbations in children aged 2 to 5 years with a history of intermittent asthma symptoms.

Methods: This was a multicenter, double-blind, parallel-group randomized study. Patients were enrolled from 68 sites in 23 countries. Patients were included in the study if they were between 2-5 years old with a clinical history of intermittent asthma symptoms resulting from an upper respiratory infection. The exacerbations had to be characterized by the absence of symptoms and b-agonist use in a typical week over 3 months before the first visit. Five hundred forty-nine patients were randomized to receive either montelukast 4mg or 5mg chewable tablets (278 patients) or placebo (271 patients) for 12 months. The primary efficacy measure of the study was the number of asthma exacerbation episodes defined as any three consecutive days with daytime symptoms and at least two treatments of b-agonist per day, or rescue use of oral/inhaled corticosteroids during one or more days, or a hospitalization because of asthma. Secondary endpoints were the duration and severity of exacerbation episodes, blood eosinophil counts, number of treatment courses of corticosteroids, percentage of days without asthma, time to first exacerbation episode, proportion of patients with an exacerbation episode, and asthma-related resource utilization. A safety analysis was also conducted on all patients. Investigators used the Poisson regression model, Kaplan-Meier curves, log-rank tests and ANOVA models for statistical analysis. All efficacy results were based on an intent-to-treat analysis.

Results: Five hundred twenty-two patients completed the study (265 patients receiving montelukast and 257 patients receiving placebo). The average asthma exacerbation rate was 1.60 for the montelukast group compared to 2.34 for the placebo group (P<0.001). The relative exacerbation rate for montelukast compared to placebo was 0.68 (95% CI, 0.56—0.83). The overall rate per year of steroid use in the montelukast group was 1.19 compared to placebo, which was 1.74 (P=0.024). The overall rate per year of inhaled steroid use in the montelukast group was 0.66 compared to placebo, which was 1.10 (P=0.027). Oral steroid use was similar between groups, as was the duration and severity of asthma exacerbations. Also similar in both groups was the proportion of drug related adverse effects, occurring in 14 (5%) patients in the montelukast group and 11 (4.1%) patients in the placebo group. The percentage of days without asthma symptoms was 75.8% in the montelukast group and 72.7% in the placebo group. The mean difference between groups was 3.48% (95% CI, -0.13—7.08) (P=0.059). The placebo group saw a 3.7% increase in blood eosinophils compared with a 4% decrease in the montelukast group, a difference in medians of 7.7% (P=0.010). The proportion of patients with asthma episodes was higher in the placebo group (56%) compared to the montelukast group (45%) (P=0.008). The time to first exacerbation was longer for patients receiving montelukast (median = 206 days) compared with placebo (median = 147 days) (P=0.024). Throughout the study, 5% of all patients were hospitalized for asthma (5.8% in the placebo group and 4.2% in the montelukast group). The proportion of patients with at least one unscheduled visit to a physician for asthma was 42.2% in patients taking placebo and 37% in patients taking montelukast. The authors concluded that montelukast effectively reduced asthma exacerbations in 2 to 5-year-old patients with intermittent asthma over 12 months of treatment and was generally well tolerated.

Strengths: This study was the first to evaluate asthma treatments in preschool children (between ages 2 and 5). Additionally, the study design was appropriate to assess the outcomes measured. To help maintain blinding, an image-matched placebo of the actual drug was used.

Weaknesses: All of the authors were associated with or employees of the manufacturer of montelukast (Merck & Co.), who also financially supported the study. This may have biased the reporting of the study results. It is possible that some of the patients included in the study may have suffered from mild persistent asthma rather than intermittent asthma, which could have affected results. When reporting results, the authors were inconsistent with the measures used to define outcomes. This could indicate that the authors were using the most positive results for each of the outcome measures in order to make montelukast look more beneficial. Under-reporting of symptoms may have occurred as a result of the young age of the patients and this could have made montelukast look more efficacious. Finally, in the study’s discussion the limitations were explained; however, the overall conclusion of the study was biased in how it interpreted results.

Conclusion: Although the authors reported the results as being significant, the clinical significance of the results is lacking. Additionally, the number of limitations and vagueness in the description of methods weakens the study as a whole, which makes the interpretation and extrapolation of results questionable. More studies need to be conducted to determine the place of montelukast in children with intermittent asthma.

Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, et al. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med. 2005 Feb 15; 171 (4): 315-22.

Michelle Kovach, Pharm. D. candidate