Joseph Blonski, MD

BACKGROUND: Many asthmatics do not have adequate symptom control despite using inhaled corticosteroids. This study evaluates the effectiveness of salmeterol and montelukast as second-line agents added to inhaled corticosteroids.

POPULATION STUDIED: The authors enrolled 20 patients with moderate persistent asthma (forced expiratory volume in 1 second = 79.1; forced expiratory flow = 25-50, 51.5% predicted). All were suboptimally controlled despite monotherapy with at least 400 mg per day of inhaled corticosteroid (median dose = 800 mg/day). The subjects were required to have persistent asthma symptoms requiring 2 puffs per day of a short-acting b2-agonist as rescue therapy, to have at least 10% diurnal variation in their morning and evening peak expiratory flow (PEF) rates, and to be responsive to adenosine monophosphate (AMP) bronchial challenge testing. The study population is likely to be similar to that subset of primary care patients with suboptimally controlled asthma symptoms, although no information is given about those excluded from the study.

STUDY DESIGN AND VALIDITY: The study was a randomized placebo-controlled single-blind double-dummy crossover design. In addition to receiving their usual maintenance dose of inhaled corticosteroid throughout the study, the patients were randomized to receive either inhaled salmeterol 50 mg twice daily plus a placebo tablet once daily, or oral montelukast 10 mg once daily plus a placebo inhaler twice daily. There was a 1-week run-in period where all subjects received double placebo, followed by 2 weeks of active treatment. The patients then had another week of double placebo after which they were switched over to the opposite active drug and placebo combination for the final 2 weeks. Standardized instructions, as well as written instructions, were given by a third party. All laboratory measurements were performed at 8 AM. Data from patients with greater than 90% compliance were considered evaluable. The major strengths of this study were the randomization and crossover design that allowed patients to serve as their own control. This greatly increased the ability of the study to detect a difference if one existed, despite the small number of patients. Weaknesses included the strong emphasis placed on disease-oriented outcomes, being only single blinded, and the crudeness of the scale used to measure symptoms (a 4-point scale from no symptoms to severe symptoms).

OUTCOMES MEASURED: The primary endpoint was the effect on AMP bronchial challenge (PC20), which causes bronchoconstriction indirectly by release of inflammatory mediators. Secondary outcomes included exhaled nitric oxide, blood eosinophil count, daily symptom control, rescue bronchodilator requirements, PEF, and lung function.

RESULTS: Montelukast was found to produce a significant difference in PC20 after the first dose, as well as at the end of 2 weeks (last dose). Salmeterol produced a significant difference in PC20 after the first dose but not after the last dose. Montelukast was superior to salmeterol in lowering blood eosinophil counts. There was no difference in nitric oxide measurements. Compared with placebo, salmeterol significantly improved daytime and nighttime symptom scoring and need for rescue therapy, as well as morning PEF rate. Montelukast showed significant improvement in daytime and nocturnal need for rescue therapy and morning PEF rate but not in symptom control.

BACKGROUND: Many asthmatics do not have adequate symptom control despite using inhaled corticosteroids. This study evaluates the effectiveness of salmeterol and montelukast as second-line agents added to inhaled corticosteroids.

POPULATION STUDIED: The authors enrolled 20 patients with moderate persistent asthma (forced expiratory volume in 1 second = 79.1; forced expiratory flow = 25-50, 51.5% predicted). All were suboptimally controlled despite monotherapy with at least 400 mg per day of inhaled corticosteroid (median dose = 800 mg/day). The subjects were required to have persistent asthma symptoms requiring 2 puffs per day of a short-acting b2-agonist as rescue therapy, to have at least 10% diurnal variation in their morning and evening peak expiratory flow (PEF) rates, and to be responsive to adenosine monophosphate (AMP) bronchial challenge testing. The study population is likely to be similar to that subset of primary care patients with suboptimally controlled asthma symptoms, although no information is given about those excluded from the study.

STUDY DESIGN AND VALIDITY: The study was a randomized placebo-controlled single-blind double-dummy crossover design. In addition to receiving their usual maintenance dose of inhaled corticosteroid throughout the study, the patients were randomized to receive either inhaled salmeterol 50 mg twice daily plus a placebo tablet once daily, or oral montelukast 10 mg once daily plus a placebo inhaler twice daily. There was a 1-week run-in period where all subjects received double placebo, followed by 2 weeks of active treatment. The patients then had another week of double placebo after which they were switched over to the opposite active drug and placebo combination for the final 2 weeks. Standardized instructions, as well as written instructions, were given by a third party. All laboratory measurements were performed at 8 AM. Data from patients with greater than 90% compliance were considered evaluable. The major strengths of this study were the randomization and crossover design that allowed patients to serve as their own control. This greatly increased the ability of the study to detect a difference if one existed, despite the small number of patients. Weaknesses included the strong emphasis placed on disease-oriented outcomes, being only single blinded, and the crudeness of the scale used to measure symptoms (a 4-point scale from no symptoms to severe symptoms).

OUTCOMES MEASURED: The primary endpoint was the effect on AMP bronchial challenge (PC20), which causes bronchoconstriction indirectly by release of inflammatory mediators. Secondary outcomes included exhaled nitric oxide, blood eosinophil count, daily symptom control, rescue bronchodilator requirements, PEF, and lung function.

RESULTS: Montelukast was found to produce a significant difference in PC20 after the first dose, as well as at the end of 2 weeks (last dose). Salmeterol produced a significant difference in PC20 after the first dose but not after the last dose. Montelukast was superior to salmeterol in lowering blood eosinophil counts. There was no difference in nitric oxide measurements. Compared with placebo, salmeterol significantly improved daytime and nighttime symptom scoring and need for rescue therapy, as well as morning PEF rate. Montelukast showed significant improvement in daytime and nocturnal need for rescue therapy and morning PEF rate but not in symptom control.

BACKGROUND: Many asthmatics do not have adequate symptom control despite using inhaled corticosteroids. This study evaluates the effectiveness of salmeterol and montelukast as second-line agents added to inhaled corticosteroids.

POPULATION STUDIED: The authors enrolled 20 patients with moderate persistent asthma (forced expiratory volume in 1 second = 79.1; forced expiratory flow = 25-50, 51.5% predicted). All were suboptimally controlled despite monotherapy with at least 400 mg per day of inhaled corticosteroid (median dose = 800 mg/day). The subjects were required to have persistent asthma symptoms requiring 2 puffs per day of a short-acting b2-agonist as rescue therapy, to have at least 10% diurnal variation in their morning and evening peak expiratory flow (PEF) rates, and to be responsive to adenosine monophosphate (AMP) bronchial challenge testing. The study population is likely to be similar to that subset of primary care patients with suboptimally controlled asthma symptoms, although no information is given about those excluded from the study.

STUDY DESIGN AND VALIDITY: The study was a randomized placebo-controlled single-blind double-dummy crossover design. In addition to receiving their usual maintenance dose of inhaled corticosteroid throughout the study, the patients were randomized to receive either inhaled salmeterol 50 mg twice daily plus a placebo tablet once daily, or oral montelukast 10 mg once daily plus a placebo inhaler twice daily. There was a 1-week run-in period where all subjects received double placebo, followed by 2 weeks of active treatment. The patients then had another week of double placebo after which they were switched over to the opposite active drug and placebo combination for the final 2 weeks. Standardized instructions, as well as written instructions, were given by a third party. All laboratory measurements were performed at 8 AM. Data from patients with greater than 90% compliance were considered evaluable. The major strengths of this study were the randomization and crossover design that allowed patients to serve as their own control. This greatly increased the ability of the study to detect a difference if one existed, despite the small number of patients. Weaknesses included the strong emphasis placed on disease-oriented outcomes, being only single blinded, and the crudeness of the scale used to measure symptoms (a 4-point scale from no symptoms to severe symptoms).

OUTCOMES MEASURED: The primary endpoint was the effect on AMP bronchial challenge (PC20), which causes bronchoconstriction indirectly by release of inflammatory mediators. Secondary outcomes included exhaled nitric oxide, blood eosinophil count, daily symptom control, rescue bronchodilator requirements, PEF, and lung function.

RESULTS: Montelukast was found to produce a significant difference in PC20 after the first dose, as well as at the end of 2 weeks (last dose). Salmeterol produced a significant difference in PC20 after the first dose but not after the last dose. Montelukast was superior to salmeterol in lowering blood eosinophil counts. There was no difference in nitric oxide measurements. Compared with placebo, salmeterol significantly improved daytime and nighttime symptom scoring and need for rescue therapy, as well as morning PEF rate. Montelukast showed significant improvement in daytime and nocturnal need for rescue therapy and morning PEF rate but not in symptom control.