Leukotriene Receptor Antagonists

Marzena E. Krawiec, MD, Nizar J. Jarjour, MD

Disclosures

Semin Respir Crit Care Med. 2002;23(4) 

In This Article

Clinical Trials

Placebo-Controlled Studies

Multiple double-blind, placebo-controlled trials of the LTRAs have been completed in adults. These studies primarily involve patients with mild to moderate asthma and consistently show benefit of LTRA use compared with placebo over periods of time ranging from 6 weeks to 6 months. In contrast to the various adult studies,[81,82,83] pediatric studies are limited in number,[84,85] but support the adult data.

Several published comparison studies of LTRA therapies versus older therapies including various ICSs in adult asthmatics have been published, whereas few exist in the pediatric population. In a double-blind, open-label, crossover study, Volovitz and colleagues demonstrated that montelukast (5 mg) for 1 month in 23 children with moderate to severe asthma (FEV1 60-85%, 6-11 years) resulted in significant decreases in nasal concentrations of LTC4 and eosinophilic cationic protein, in association with reductions in beta2-agonist use and clinical improvement compared with cromolyn (2 mg q.i.d.).[86] In contrast to the clinical efficacy reported by the above pediatric study, a comparison of zafirlukast (20 mg b.i.d.) with cromolyn sodium (1.6 mg q.i.d.) in adult asthmatics reported minimal differences in outcome with either of these treatments, although both were more effective than placebo.[87]

Comparison studies of the LTRA class of drugs compared with various ICSs uniformly favor the steroid group. An important randomized, double-blind, double- dummy, placebo-controlled, parallel-group, 12-week study compared the efficacy of beclomethasone (400 mg/day) with montelukast (10 mg) in 895 chronic mild to moderate adult asthmatics (age 15-85 years). Beclomethasone therapy resulted in a nearly two-fold improvement in % change from baseline FEV1 compared with montelukast (13.1% and 7.4%, respectively).[88] A trial of similar duration in 451 mild asthmatics (≥ 12 years) symptomatic on prn beta2-agonists compared fluticasone proprionate (FP) 88 µg with zafirlukast 20 mg b.i.d. Treatment with the ICS was significantly more effective than the LTRA in increasing am FEV1 (p < 0.001), morning and evening PEF (p < 0.001). Furthermore, statistically significant treatment differences in FEV1 and am and pm PEF favored FP by weeks 4 and 2, respectively. Additional parameters of efficacy favoring the ICS over zafirlukast included mean change in % symptom-free days (28.5% vs 15.6% of days, p < 0.001) and rescue-free days (40.4% vs 24.2% of days, p < 0.001) and reduction in daily albuterol use and night-time awakening.[89] Busse and colleagues reported similar efficacy in all of the above paramenters with first-line treatment with FP (88 µg b.i.d.) compared with montelukast (10 mg > 15 years) symptomatic on baseline short-acting beta2-agonists.[90] In fact, additional comparison studies in adults with moderate persistent asthma consistently report that treatment with low-dose ICS is superior to treatment with the LTRA drugs based on improvements in FEV1.[91,92] Of significance, however, is that the asthmatics in these multicenter trials may not reflect the response of individuals with mild persistent disease but, rather, disease of a more moderate nature. Therefore, although the ICS class of drugs appear to provide increased benefit to the individual with persistent symptoms of a moderate nature, studies are still needed to better define first-line therapy in the individual with persistent disease of a truly "mild" nature, especially in the pediatric population. Secondly, open-label extensions of 1 to 2 years comparing beclomethasone and montelukast have suggested that outcomes may change when a patient is removed from a double-blind, placebo-controlled study. In open-label extensions, the differences in FEV1 seen during the double-blind portion of the study disappear because the FEV1 in the ICS-treated group fell during the course of this portion of the study. It is unlikely that this was related to a "loss of efficacy," but could be explained by diminished compliance in the beclomethasone group. Such results may have significant clinical implications for chronic asthma treatment where compliance remains less than ideal.

Multiple studies with long-acting beta2-agonists and theophylline have suggested that the addition of a second long-term controller medication to low- to moderate-dose ICS is more effective than increasing the ICS dose.[93,94,95] Evidence is also emerging to support the use of LTRAs in this role. Adding montelukast to ICS (baseline ~1000 µg/day at double-blind initiation) resulted in a 47% further reduction in ICS therapy compared with placebo.[96] Pranlukast has demonstrated similar steroid sparing effects. Moderately severe asthmatics whose ICS dose was cut in half and had pranlukast added to their therapy were able to maintain baseline pulmonary function and symptom stability compared to patients with the addition of placebo.[97]

There are, however, very few existing studies defining the best "add-on" therapy for persistent asthmatics still symptomatic on baseline ICS therapy ( Table 1 ). A 3-month study evaluating the addition of montelukast to the treatment of moderate asthmatics still symptomatic on 336 µg/day of beclomethasone suggested that the combination therapy was more effective than solely continuing beclomethasone, but a comparison to doubling the dose of beclomethasone was not included.[98] The addition of zafirlukast (80 mg b.i.d.) to high-dose ICS (1000 to 4000 mg/day) improved mean am PEF (p < 0.001), pm PEF (p < 0.01), FEV1 (p < 0.05), daytime symptom scores, and beta2-agonist use (p < 0.001)[99] (Fig. 3). Zafirlukast also significantly reduced the risk of asthma exacerbation and the requirement for further increase in asthma controller therapy. Similar additive benefit with montelukast compared with placebo was noted in a multicenter, double-blind, crossover study in 279 children on 200 µg b.i.d. budesonide. Although the additive effect of montelukast use on lung function was small, but significant, greater benefit was demonstrated clinically based on a marked reduction in asthma exacerbation days compared to the placebo additive group.[100] Similar to the Laviolette et al[98] study, no comparison of the efficacy of adding montelukast versus doubling the budesonide dose was included.

Figure 3.

Changes from baseline in pulmonary function, symptoms, and rescue beta2-agonist use in patients treated with high-dose inhaled corticosteroids plus zafirlukast at 80 mg twice daily or with high-dose inhaled corticosteroids plus placebo. All data are presented as the mean change at endpoint as a percent of the starting mean baseline value in each treatment group. All p values indicated significance for the between-treatment comparisons at endpoint, through analysis of covariance. Note that a treatment difference in favor of zafirlukast for mornings with asthma was significant according to an analysis of median change at endpoint (p = 0.015; Wilcoxon's rank sum test). (Adapted from Virchow et al[99] with permission.)

Although addition of an LTRA to patients still symptomatic on ICS therapy appears to be beneficial compared with placebo, the question remains whether this is the best additive measure for improved control in persistent asthmatic patients who remain symptomatic. A recent multicenter, double-blind, double-dummy, parallel group, 12-week study was conducted in 447 asthmatic patients symptomatic at baseline despite low-dose FP (100 mg Diskus b.i.d.). The group treated with the combination FP (100 µg) and Salmeterol (50 µg) Diskus b.i.d. had improved asthma control compared with the FP (100 µg b.i.d.) and montelukast (10 mg) group in terms of am and pm PEF, FEV1 (0.34 L vs 0.20 L, respectively, p < 0.001), change in % days not requiring albuterol intervention, shortness of breath, and overall symptom scores.[101] Despite these findings, further study, especially over longer periods of evaluation, is necessary to determine the best "add-on" therapy for the asthmatic patient who remains symptomatic despite baseline controller therapy.

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