Montelukast as Monotherapy for Pediatric Asthma

Montelukast has emerged as an effective therapy for childhood asthma. However, its role as a monotherapy is still unclear. U.S. [1] and international guidelines [2] view leukotriene receptor antagonist (LTRA) medications as alternative therapies for mild persistent asthma secondary to inhaled corticosteroids (ICS); however, recent Practall guidelines[3] place it as an acceptable alternate first-line therapy. As an alternative first-line therapy, any asthma medication must prove to be efficacious versus placebo and have efficacy comparable to the current standard therapy, inhaled corticosteroids (ICS). While montelukast does fulfill the criteria for efficacy compared with placebo, it has never been shown to be superior or equivalent to common choices of ICS.

Several studies have established safety and efficacy of montelukast monotherapy in randomized placebo controlled trials in children and adults [4; 5; 6; 7; 8]. In a 1-year study of preschool aged children with virally-induced intermittent asthma, montelukast decreased asthma exacerbation rates and time to first exacerbation. However, there was no sparing of courses of oral steroids for the intervention group compared to placebo [6]. This study, along with pilot data showing improvement in symptomatic outcomes following RSV bronchiolitis in infants [9] was initially very promising for montelukast's ability to intervene in viral induced wheezing illnesses. Subsequent post-RSV bronchiolitis data from Bisgaard, et al [10] contrasted with the previous findings when the study protocol was applied to a larger sample size. It is difficult to recommend chronic montelukast therapy to children with viral wheeze without clear efficacy in controlling respiratory symptoms after RSV bronchiolitis and the lack of steroid sparing effect in viral-induced intermittent asthma.

For young children with persistent asthma, placebo controlled trials of montelukast have been promising. Knorr, et al. [7] studied the efficacy of montelukast in 689 children, aged 2-5 years, with persistent asthma in a randomized, double blind, placebo controlled trial with 12 week follow-up. Montelukast decreased asthma symptom scores (−0.23, P value=0.015) and days with β-agonist use (49% vs. 55%, P = 0.001) and increased days without asthma (34% vs. 28%, P = 0.002) more than did placebo. Objective outcomes in this age group are also encouraging. Measured airway resistance in asthmatic children [5] are significantly improved with montelukast, as are exhaled nitric oxide (eNO) values, a marker for airway inflammation, in those with elevated eNO at baseline [4]. Similar efficacy has been shown in older children aged 6-14 years [11].

Showing efficacy against placebo is important, but any alternative first line therapy for asthma must be shown to have equal efficacy to low dose inhaled corticosteroids. Head to head trials, primarily in school aged children and adults, have consistently shown ICS to be superior to montelukast in both clinical and laboratory outcomes [12; 13; 14; 15; 16; 17]. In children aged 2-8 years old, Szefler, et al. [15] showed a lower exacerbation rate for children taking daily nebulized budesonide (0.5mg) compared with montelukast. Notably, the primary outcome of time to requiring step-up of asthma medication therapy at 52 weeks was not significantly different between groups, but this may have been due to lack of power as the study suffered a 29% study dropout rate and poor medication compliance to the study drugs. Ostrom, et al. [14] showed improved FEV1 and decreased asthma symptom scores in 6-12 year old children with persistent asthma who used fluticasone propionate 50mcg twice daily compared with those taking montelukast 5mg daily. Similarly, the PACT (Pediatric Asthma Controller Trial, NIH Childhood Asthma Research Education [CARE] funded) study found an 11% difference in asthma control days (64% vs. 53%, P=0.004) in favor of fluticasone 100mcg twice daily over montelukast in school aged children with persistent asthma. A recent meta-analysis of 5 randomized controlled trials in school aged children with mild to moderate persistent asthma by Jartti [13] confirms a clear superiority of fluticasone over montelukast in head to head, long term (>4week), trials. This study found a highly significant 4.6% (p< 0.0001) difference in mean percent predicted FEV1 and a 5.6% (p< 0.0001) difference in asthma control days in favor of fluticasone.

The only study, to our knowledge, to claim equivalent effect between montelukast and fluticasone has been the Mosaic study [18], which enrolled 994 school aged children with mild-moderate persistent asthma for a non-inferiority study comparing the two medications. A ‘non-inferiority’ study design starts with an assumption of what is a clinically important difference in outcome and uses that as the standard to compare two interventions. Montelukast was found to be ‘not inferior’ to fluticasone based on the a priori clinical parameters defined by the authors, despite statistically significant symptom and spirometry outcomes favoring fluticasone. The magnitude of difference in effect, 2.8% improvement in rescue free days, did not reach the authors' preconceived criteria of 7% difference in rescue free days, the practical equivalent of about 2 rescue free days per month. While statistical significance does not necessarily imply clinical significance, taking each of these head to head trials into consideration, we feel ICS offers significant improvement in clinically relevant outcomes when compared to montelukast.

While the superiority of fluticasone to montelukast seems clear, there may be children in whom montelukast is the preferred drug. Five percent of the subjects in the CLIC (Characterizing the response to a Leukotriene receptor antagonist and Inhaled Corticosteroid) trial's analysis had a favorable response to montelukast but not to inhaled fluticasone [19; 20]. These children were of lower age and had shorter disease duration at study start. When the outcome of asthma control days (ACD) was analyzed, only fewer ACDs at baseline predicted more ACDs after montelukast therapy [20]. Other researchers have used genetic polymorphisms in the 5-lipoxygenase biosynthetic pathway [21] and urinary leukotrienes [22] to predict clinical effect of LTRAs. The prospect of testing for genotype specific responses and the non-invasive measurement of urinary biomarkers is exciting and may lead to truly individualized asthma care. These markers need further development and testing before becoming a clinically useful tool to determine appropriate candidates for montelukast therapy.

It is largely agreed in the medical community and medical literature that children with persistent asthma of any degree should be treated with a regimen of chronic anti-inflammatory medication. The current first-line agent, inhaled corticosteroids, has proven to be efficacious, but the known adverse effect on growth velocity [23] has pediatricians hoping for an alternative medication for their patients. Montelukast has established safety down to 6 months of age [8]. In premarket studies there were few adverse effects noted, however, the US FDA is currently investigating reports of adverse mood and behavioral outcomes possibly associated with montelukast in post-market analysis [24]. Overall, the safety disparities between montelukast and placebo [6; 7; 8] and montelukast and low dose ICS in head to head trials [17] do not appear to be significant and should not influence the choice of medication.

A closer look at the current Practall, GINA and NAEPP guidelines reveals that most diagnostic and management recommendations for asthma are similar. The Practall guidelines reference several placebo controlled trials to support its' recommendation for montelukast as alternative first line therapy with less emphasis on comparative trials of montelukast with ICS. In contrast, the GINA and NAEPP guidelines site both placebo controlled studies as well as head to head trials between montelukast and ICS. This likely explains the discrepancy between the recommendations in regard to montelukast.

The current evidence does not support the use of montelukast as first line monotherapy for children with persistent asthma. However, as montelukast has been shown to improve some clinical and laboratory asthma outcomes, there may be circumstances in which this drug could be used as an alternate to inhaled corticosteroids, such as in children unable to properly use an ICS or in whom the risk of growth velocity decline with ICS is unacceptable. Further research is needed to determine patient specific responses to therapy, whether it be montelukast or any other asthma medication, in order to provide the most appropriate and least toxic medication. As inhaled corticosteroids remain the most efficacious medicine for asthma with a relatively tolerable side effect profile, new asthma therapies will have to be similarly efficacious and safe to be considered an alternate first line therapy. At this time, montelukast should be considered a second-line monotherapy and an appropriate add-on therapy to ICS for asthmatic children poorly controlled on ICS, alone.