Salmeterol Group Research Articles

Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease

Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied. To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone. Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006. 27 academic and community medical centers in Canada. 449 patients with moderate or severe COPD. 1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol. The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics. The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo. More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists. Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041.

Nebulized arformoterol in patients with COPD: A 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial

Objective: The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate (a selective, long-acting β 2-adretlergic agonist that is the [ R,R] isomer of formoterol) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease (COPD). Methods: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial was conducted at 60 centers across the United States. Male and female patients aged ≥35 years with physician-diagnosed COPD received arformoterol (15 μg BID, 25 μg BID, or 50 μg QD via nebulizer), saleterol (42 μg BID via metered dose inhaler), or placebo. Pulmonary function was assessed by spirotnetry; dyspnea, by the Transitional Dyspnea Index (TDI); and health status, by the St. George's Respiratory Questionnaire (SGRQ). Adverse events (AEs) were assessed by site personnel at all clinic visits (screening, first dose at week 0, and at weeks 3, 6, 9, 12, and follow-up). COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit. Results: A total of 717 patients received study medication.The demographic composition of all treatment arms was similar. The mean age was 62.9 years, 58% were men, and mean baseline forced expiratory volume in 1 second (FEV 1) was 1.2 L (41% predicted). Mean improvement in trough FEV 1 over 12 weeks was significantly greater with all 3 arfortttoterol doses (15 μg BID, +16.9%; 25 μg BID, +18.9%;,50 μg QD, +14.9%) and for salmeterol (+17.4%) relative to placebo (+6.0%; P < 0.001). There were significantly greater improvements in the mean percentage change in FEV 1 AUC 0–12h from the predose value over 12 weeks (15 μg BID, 12.7%, 25 μg BID, 13.9%, 50 μg QD, 18.9%; salmeterol, 9.8%) versus placebo (2.7%; P ≤ 0.001); all doses of arfortnoterol were statistically different from salmeterol for this end point ( P ≤ 0.024). At week 12, TDI focal scores were significantly greater with all arformoterol doses compared with placebo (mean [95% CI]: 15 μg BID, 0.97 [0.25–1.69]; 25 μg BID, 1.08 [0.3–1.86]; 50 μg QD, 1.04 [0.32–1.771), suggesting treatment-associated improvement in dyspnea, however, the difference between salmeterol and placebo was not statistically significant (0.36 [-0.40 to 1.12]). Improvements in health status, as measured using SGRQ total scores, were -2.6 to -3.6 U in the arforinoterol groups, -4.4 U for saltneterol, and -1.2 U for placebo; 95% CI of differences versus placebo suggested significant improvement for the arfortnoterol 25 μg BID and salmeterol groups. There was a similar frequency of AEs and COPD exacerbations across all groups, including placebo. Conclusions: In this trial, patients with moderate tosevere COPD administered nebulized arformoterol over 12 weeks were observed to have significant and sustained improvements in airway function and dyspnea compared with placebo. The results also suggest that all doses of arforrnoterol, including the lowest dose (15 μg BID), were effective. Overall, nebulized arformoterol was well tolerated.

Impact of Salmeterol/Fluticasone Propionate versus Salmeterol on Exacerbations in Severe Chronic Obstructive Pulmonary Disease

Exacerbations of chronic obstructive pulmonary disease (COPD) greatly contribute to declining health status and the progression of the disease, thereby incurring significant direct and indirect health care costs. The prevention of exacerbations, therefore, is an important treatment goal. To assess the impact of combination therapy with salmeterol/fluticasone propionate compared with salmeterol alone on moderate and severe exacerbations in patients with severe COPD and a history of repeated exacerbations. Randomized, double-blind, parallel-group study. After a 4-wk run-in period, 994 clinically stable patients were randomized to one of two treatment groups: 507 patients received the salmeterol/fluticasone combination 50/500 micro g twice daily and 487 received salmeterol 50 micro g twice daily for 44 wk. The total number of exacerbations was 334 in the combination therapy and 464 in the salmeterol group (p < 0.0001). The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group, corresponding to a 35% decrease. In addition, the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group (128 vs. 93 d, p < 0.0001). Other endpoints, including health-related quality of life, peak expiratory flow, and use of rescue medication, were significantly improved in the combination therapy group. Both treatments were well tolerated. This study demonstrates that combination therapy with salmeterol/fluticasone compared with salmeterol monotherapy significantly reduces the frequency of moderate/severe exacerbations in patients with severe COPD.

Comparable spirometric efficacy of tiotropium compared with salmeterol plus fluticasone in patients with COPD: A pilot study

Background International guidelines recommend the long-acting anticholinergic, tiotropium, or long-acting β 2-agonists as maintenance therapy in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). The efficacy of long-acting β 2-agonists combined with inhaled corticosteroids (ICS) in the treatment of COPD has also been confirmed for severe and very severe COPD, but data comparing tiotropium with the combination of a long-acting β 2-agonist and an ICS are lacking. Methods This 6-week multicentre, randomised, double-blind, triple-dummy pilot study compared the bronchodilator effects of tiotropium 18 μg once daily ( n=56) vs. the combination of salmeterol 50 μg plus fluticasone 250 μg twice daily ( n=51) in patients with moderate-to-very severe COPD. Serial spirometry was performed over 12 h after 6 weeks of treatment. The primary endpoint was forced expiratory volume in 1 s (FEV 1) area under the curve from 0 to 12 h (AUC 0−12 h ) on Day 43. Results Randomization failed to provide treatment groups with comparable baseline characteristics for smoking history, current smokers, duration of COPD, FEV 1, forced vital capacity (FVC) and reversibility. Mean±SD FEV 1 was 1.31±0.47 l in the tiotropium group vs. 1.46±0.53 l in the salmeterol plus fluticasone group. Fewer patients in the tiotropium showed a 12% and 200 ml acute increase to short-acting bronchodilators at baseline. However, treatment with tiotropium alone resulted in comparable bronchodilation compared with salmeterol plus fluticasone, as measured by all the spirometric parameters at the end of the 6-week study period. FEV 1 AUC 0–12 h was 1.55±0.03 l in the tiotropium group vs. 1.57±0.04 l in the salmeterol plus fluticasone groups ( p=0.63). Trough (predose) FEV 1 was 1.54±0.03 l in the tiotropium group vs. 1.46±0.03 l in the combination group ( p=0.07), and peak FEV 1 was 1.68±0.04 l vs. 1.66±0.04 l, respectively, ( p=0.77). FVC AUC 0–12 h , trough and peak were also comparable between groups at study end ( p>0.05, for all). Further, rescue salbutamol use was similar in the tiotropium and combination groups and both treatment regimens were well tolerated. Conclusions Six weeks of treatment with tiotropium resulted in comparable bronchodilation compared with salmeterol plus fluticasone in patients with moderate-to-very severe COPD, despite tiotropium patients having lower lung function and fewer patients considered reversible at baseline. The results of this pilot study will aid planning for further large-scale comparative studies.

Effect of Fluticasone Propionate/Salmeterol on Lung Hyperinflation and Exercise Endurance in COPD

To examine the effect of fluticasone propionate, 250 microg/salmeterol, 50 microg combination (FSC 250/50) twice daily on lung hyperinflation and associated measures of exercise performance in patients with COPD. This was a randomized, double-blind, parallel-group study. Eligible patients were > or = 40 years old with a diagnosis of COPD, prealbuterol FEV(1) < 70% of predicted, FEV1/FVC ratio > or = 0.70, and functional residual capacity (FRC) > or = 120% of predicted normal. Patients were randomized to FSC 250/50; salmeterol, 50 microg; or placebo twice daily for 8 weeks. Predose and postdose spirometry, plethysmography, and constant-load cycle cardiopulmonary exercise test evaluations were compared. The primary comparison was FSC 250/50 with placebo. The salmeterol group was included for exploratory comparisons with FSC 250/50. A total of 185 patients (mean baseline FEV1 of 41% predicted) were enrolled. At rest, FSC 250/50 significantly reduced postdose FRC and increased inspiratory capacity (IC) compared with placebo (differences of - 0.35 +/- 0.12 L and 0.33 +/- 0.06 L [mean +/- SE], respectively, at week 8; p > or = 0.003) and increased exercise endurance time (difference, 132 +/- 45 s; p = 0.004). At a standardized time during exercise (isotime), FSC 250/50 increased postdose IC by 0.20 +/- 0.05 L over placebo with associated improvements in tidal volume and minute ventilation (p < 0.05 vs placebo at week 8). Improvement in exercise time was significantly correlated with the increase in IC (r = 0.45, p < 0.001) but not FEV1 (r = 0.23, p = 0.08). Predose comparisons of FSC 250/50 with salmeterol and placebo favored FSC 250/50. We conclude that FSC 250/50 decreases lung hyperinflation at rest and during exercise with an associated increase in exercise endurance time when compared with placebo.

Comparison of the Clinical Efficacy of Salmeterol and Sustained-Release Tulobuterol (Patch) on Inadequately Controlled Asthma Patients on Inhaled Corticosteroids

Patients with inadequately controlled asthma on inhaled corticosteroid (400 to 1,600 μg/day chlorofluorocarbon beclomethasone equivalent) were treated with concomitant salmeterol (n = 18) or sustained-release tulobuterol (patch) (n = 18), or the inhaled corticosteroid dose was doubled (add-on) (n = 13) to compare clinical efficacy. () At 8 weeks, morning and evening peak expiratory flow rates were significantly improved in the salmeterol group only (p < 0.01). () Symptom and sleeplessness scores improved in the order, salmeterol (symptom score; p < 0.0001), inhaled corticosteroid add-on, and tulobuterol groups. () Only the salmeterol group showed significant improvement in the total Asthma Quality of Life Questionnaire score (p < 0.05). () No adverse reactions considered related to the study drugs were observed.

Salmeterol Does Not Alter Increased Bronchial Responsiveness Caused by Organic Dust Exposure

Exposure in a swine house induces airway inflammation and increases bronchial responsiveness to methacholine in healthy subjects. The aim was to investigate whether a long-acting beta2-agonist, salmeterol, alters the increased bronchial responsiveness induced in healthy subjects following exposure to organic dust in a swine barn. The study includes three separate parts. In the first part (part 1), healthy subjects inhaled salmeterol (50 microg bid, n = 8) or placebo (n = 8) over 2 weeks. In part 2, healthy subjects inhaled one single dose of salmeterol (100 microg, n = 6) or placebo (n = 6) 1 h prior to exposure in a swine barn, which was followed by a bronchial methacholine challenge. In part 3, eight healthy individuals inhaled placebo or salmeterol (100 microg), 2 h or 8 h prior to a bronchial methacholine provocation, without being exposed in the swine barn. Exposure caused an increase of bronchial responsiveness to methacholine by 3.2 doubling concentration steps (25 to 75th percentiles, 2.8 to 4.1) and 2.6 doubling concentration steps (25 to 75th percentiles, 1.4 to 3.7) in the placebo and salmeterol groups (2 weeks), respectively, with no significant differences between the groups (p = 0.3; part 1). Similar results were obtained when salmeterol was administered as a single dose (part 2) prior to exposure. However, salmeterol significantly attenuated the bronchial responsiveness to methacholine by 1.2 doubling concentration steps (0.8 to 1.7) 8 h after inhalation (part 3). Salmeterol inhalation did not protect against the increased bronchial responsiveness induced in healthy subjects following exposure to organic dust when administered for 2 weeks or as a single dose prior to exposure. This lack of protection cannot be explained by homologous beta2-adrenoceptor desensitization. We hypothesize that exposure to organic material may alter the airway response to beta2-agonists.

Comparison of the Short-term Effects of Salmeterol and Formoterol on Heart Rate Variability in Adult Asthmatic Patients

We investigated the effects of beta2-adrenergic agonists salmeterol and formoterol on heart rate variability (HRV) in adult asthmatic patients using time-domain measures of HRV. Thirty-nine adult patients with asthma were studied. All patients showed a mild-to-moderate decrease in baseline FEV1. Any diseases that might have influenced the autonomic function were excluded. All patients underwent a complete physical examination and medical history that revealed no cardiovascular disease or medication. The beta2-adrenergic inhaled agonists salmeterol, 50 microg, and formoterol, 12 microg, were used in the study. HRV analysis was performed for each 5-min segment: 5 min and 10 min before inhalation of the study drug, and 5, 10, 15, 20, 25, and 30 min after inhalation. Time-domain parameters of HRV were calculated: (1) the SD all normal-to-normal intervals; (2) the SD of the mean of all normal-to-normal intervals in all 5-min segments of the entire recording; (3) the root mean square of differences between adjacent normal-to-normal intervals; (4) the mean of the SD of all normal-to-normal intervals in all the 5-min intervals; and (5) the SD of the SD of all normal-to-normal intervals in all the 5-min intervals. Baseline HRV parameters were not significantly different between formoterol and salmeterol groups. There were no significant differences in HRV parameters after formoterol and salmeterol inhalation. The HRV parameters in each 5-min segment in the formoterol group were not statistically significant different when compared to the same segment in the salmeterol group. Salmeterol and formoterol have no short-term adverse effects on HRV.

Effects of long-acting bronchodilators and placebo on histamine-induced asthma symptoms and mild bronchusobstruction

Accurate perception of airway caliber remains an important issue in asthma management. The way bronchodilation is perceived is partly related to the perception of the efficacy of bronchodilators in relieving complaints. In the present study, we compared the effects of salmeterol, formoterol and placebo on relief of histamine-induced asthma symptoms and mild bronchusobstruction. In this randomized controlled, double blind study, 30 asthmatics were challenged with histamine until forced expiratory volume in 1s (FEV(1)) fell with > or =20%. Subjects received salmeterol, formoterol or placebo after the histamine provocation. Pulmonary function (FEV(1)) and asthma symptoms (Asthma Symptom Checklist, Borg Dyspnea Scale) were assessed 5 and 20 min later. FEV(1) improved significantly more in the salmeterol and formoterol group than in the placebo group (P<0.001, P<0.001 and P<0.05, respectively). Salmeterol and formoterol were not different with regard to the pulmonary function recovery. No significant differences were found between the effects of salmeterol, formoterol and placebo on any of the symptom responses at the different time points. We conclude that after a histamine-induced mild bronchusobstruction, a similar asthma symptom recovery occurred when inhaling salmeterol, formoterol or placebo, despite better recovery of pulmonary function in the active drug conditions.

Clinical Efficacy and Safety of Transdermal Tulobuterol in the Treatment of Stable COPD: An Open-Label Comparison with Inhaled Salmeterol

Long-acting bronchodilators are recommended for the management of stable COPD to relieve symptoms and improve quality of life. The tulobuterol patch (Hokunalin) is a transdermal patch preparation of the beta2-adrenoceptor agonist (beta2-agonist) tulobuterol designed to yield sustained beta(2)-agonistic effects for 24 hours when applied once daily. To compare the effectiveness of tulobuterol patch and inhaled salmeterol (Serevent Diskus) in the treatment of stable COPD. Clinically stable COPD patients (age > or = 40 years, postbronchodilator FEV1/FVC <70%, and postbronchodilator FEV1 <80% predicted) were enrolled in a multicenter, open-label randomized study. After a 2-week run-in period, patients were administered either tulobuterol (2mg once-daily applied as a patch) or salmeterol (50 microg per inhalation, twice a day) for 12 weeks. Data for 92 patients (46 each for each treatment group) were analyzed. There were no significant differences in baseline characteristics in the tulobuterol versus salmeterol groups: age, 69.2 +/- 7.4 vs 71.6 +/- 7.3 years; male, 91% versus 96%; and patients with stage II (III) COPD, 32.6% (67.4%) versus 50% (50%). FEV1, FVC, and PEF improved during treatment in both groups compared with baseline, with no significant between group differences. The total St George's Respiratory Questionnaire (SGRQ) score was significantly improved relative to baseline in the tulobuterol group at 8 weeks (-4.7 units [U]), but not in the salmeterol group at all timepoints. Domain analysis of the SGRQ scores revealed significant improvement in the symptom score relative to baseline in the tulobuterol group at weeks 4 (-6.9U), 8 (-12.0U), and 12 (-11.7U), but not in the salmeterol group in any of the domains tested. Medical Research Council dyspnea scale score improved during treatment in both groups, with no significant differences between groups. Compliance with the treatment regimen was significantly better in the tulobuterol than in the salmeterol group (98.5% vs 94.1%; p < 0.05). These findings indicate that once-daily transdermal sustained-release tulobuterol is as effective or better than the inhaled long-acting beta2-agonist salmeterol in the management of stable COPD, with significant effects on quality of life.

Probabilistic Markov Model to Assess the Cost-Effectiveness of Bronchodilator Therapy in COPD Patients in Different Countries

Objectives The development of a probabilistic Markov model with a time horizon of 1 year to compare the cost-effectiveness of three bronchodilators: 1) the new long-acting anticholinergic tiotropium; 2) the short-acting anticholinergic ipratropium; and 3) the long-acting beta 2-agonist salmeterol, for the treatment of patients with chronic obstructive pulmonary disease (COPD) in different countries. In this article we compare the Netherlands and Canada. Methods The Markov model was structured along disease severity states and exacerbations. Transition probabilities between disease states and exacerbation probabilities were derived from patient-level data from six randomized controlled trials assessing the efficacy and safety of tiotropium. Resource utilization during exacerbations and maintenance treatment for the Netherlands were derived from two clinical trials, whereas for Canada these data were obtained from a countrywide observational study that used similar inclusion criteria as the trials. Second-order Monte Carlo simulations were undertaken in which values were randomly drawn from distributions of these parameters. Outcomes of the model are yearly treatment costs, exacerbations, and quality-adjusted life months. Results The mean difference in the number of exacerbations was 0.17 (95% uncertainty interval: −0.02–0.37) in favor of tiotropium when compared with salmeterol and the difference between salmeterol and ipratropium was 0.12 (−0.17–0.44) in favor of salmeterol. The number of quality-adjusted life months did not substantially differ between treatment groups and varied from 8.42 (SE 0.41) in the tiotropium group to 8.17 (0.46) in the salmeterol group and 8.11 (0.50) in the ipratropium group. In the Netherlands, costs in the tiotropium group were 42 € (−484–353) lower than in the salmeterol group, whereas costs in the salmeterol group were 128€ (−795–457) lower than in the ipratropium group. In Canada, costs were consistently lower than in the Netherlands and nearly the same in all treatment groups. Differences between the two countries were primarily a result of a higher length of hospital stay in case of an exacerbation in the Netherlands. The cost-effectiveness acceptability frontier of exacerbations showed that tiotropium was associated with the maximum expected net benefit for all values of the ceiling ratio above 0€ (the Netherlands) and 10€ (Canada) in the base case analysis. Conclusions This probabilistic model-based economic evaluation demonstrates how clinical trial data can be combined and integrated with country-specific information about resource utilization and unit cost to assess the cost-effectiveness of bronchodilators in COPD patients. Quality-adjusted life months did not substantially differ between treatment groups. In terms of exacerbations, tiotropium was associated with maximum expected net benefit for plausible values of the ceiling ratio. In sensitivity analyses, this outcome was most sensitive to changes in exacerbation rates.

Outcomes Associated with Initiation of Different Controller Therapies in a Medicaid Asthmatic Population: A Retrospective Data Analysis

Background. Outcomes in asthmatic patients may vary depending on the controller medication used. Observational studies of outcomes of asthma therapy are needed to understand the implications of choice of controller in different populations. Objectives. To determine whether there are differences in health care use and costs of asthma treatment in asthma patients treated with montelukast compared with fluticasone proponiate 44 µg. Method. Using data from the North Carolina Medicaid program, we compared continuously enrolled asthmatic patients starting either fluticasone propionate 44 µg (FP44), an inhaled corticosteroid (ICS) (n = 312), or montelukast 5 and 10 mg, an oral leukotriene modifier (LM) (n = 398) between the years 1998 and 1999. A secondary analysis compared continuously enrolled asthmatic patients already using ICS as controller therapy initiating either salmeterol (long-acting β-agonist) (n = 97) or montelukast (n = 101) in the year 1998. Patients were followed for 1 year pre- and postcontroller or additional controller initiation for health care service use, medication refill patterns, and costs. Results. There were no significant differences in the adjusted asthma-related health care costs between the montelukast and FP44 groups. In both groups, physician visits were significantly higher in year 2 (p < 0.01) than in year 1. We found montelukast users to be more adherent with prescription refills (using measures of medication possession) even after allowing for a wider adherence range for FP (RR = 2.53; 95% CI = 1.50–4.26), although patients using montelukast were more likely than patients with fluticasone to switch controller pharmacotherapy (RR = 1.53; 95% CI = 1.12–2.09). Similarly, there were no differences in health care service use and costs between the montelukast and salmeterol groups, with the exception of a 33% reduction (p < 0.01) in number of inhaled corticosteroid refills in the second year in the salmeterol group. Conclusion. There were no cost and major health care use differences between the two primary or secondary controller therapies in the postinitiation year. Although FP was associated with lower rate of controller switch, montelukast use was associated with significantly better treatment adherence in patients with treatment persistence in this population of Medicaid-enrolled asthmatic patients. The addition of salmeterol as additional controller was associated with a significant decrease in inhaled corticosteroid use, suggesting decreased adherence in patients on the two-drug regimen.

A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge

Objectives: To compare the effects of addition of montelukast or salmeterol to inhaled corticosteroids (ICS) on the response to rescue beta2-agonist use after exercise-induced bronchoconstriction. Methods: A double-blind, placebo-controlled study was performed at 16 centers in the United States. Patients with asthma ( n=122, ages 15–58) whose symptoms were uncontrolled on low-dose inhaled fluticasone and who had a history of exercise-induced worsening of asthma were randomized to receive either montelukast (10 mg once daily), salmeterol (50 μg twice daily), or placebo for 4 weeks. Standardized spirometry after exercise challenge and beta2-agonist rescue was performed at baseline, week 1 and 4. Results: Maximum achievable forced expiratory volume in 1 s (FEV 1) percent predicted after rescue beta2-agonist improved in the montelukast (+1.5%) and placebo (+1.2%) groups at 4 weeks, but diminished in the salmeterol (−3.9%) group ( P<0.001). Although pre-exercise FEV 1 was greatest with salmeterol ( P=0.10), patients taking montelukast had significantly greater protection from an exercise-induced decrease in FEV 1 than those taking salmeterol ( P<0.001). Both the magnitude and rate of rescue bronchodilation were greater with montelukast compared with salmeterol ( P<0.001). Five minutes after rescue beta2-agonist, 92% of patients taking montelukast and 68% of those taking placebo had recovered to pre-exercise levels, whereas only 50% of those taking salmeterol had recovered to pre-exercise levels. Conclusion: In patients whose asthma symptoms remain uncontrolled using ICS, addition of montelukast permits a greater and more rapid rescue bronchodilation with a short-acting beta2-agonist than addition of salmeterol and provides consistent and clinically meaningful protection against exercise-induced bronchoconstriction.

Addition of montelukast or salmeterol to fluticasone for protection against asthma attacks: a randomized, double-blind, multicenter study

For patients whose asthma is uncontrolled with low-dose inhaled corticosteroids, addition of alternative therapy instead of increasing the steroid dose is recommended by current treatment guidelines. To compare montelukast, a once-daily leukotriene receptor antagonist, and salmeterol, a twice-daily, long-acting beta-agonist, concomitantly administered with inhaled fluticasone, according to the percentage of patients without an asthma attack for 1 year. A randomized, double-blind, double-dummy, multicenter study was conducted. Adult patients with moderate-to-severe persistent asthma (ages 14-73 years) receiving inhaled fluticasone (220 microg/d) who remained symptomatic during a 4-week run-in period were randomized to the addition of salmeterol (84 microg/d) or montelukast (10 mg/d) for 48 weeks. Of the 1,473 randomized patients, 743 were randomized to montelukast and 730 to salmeterol; 1,059 patients completed the study. Eighty percent of patients in the montelukast group and 83.3% of patients in the salmeterol group remained attack free during the 48 weeks of treatment (relative risk, 1.20; 95% confidence interval, 0.96-1.49). Montelukast significantly reduced blood eosinophil counts compared with salmeterol, whereas salmeterol significantly increased prealbuterol forced expiratory volume in 1 second, asthma-specific quality of life, morning peak expiratory flow rate, and decreased nocturnal awakenings compared with montelukast. Differences between treatments were small, and both treatments were generally well tolerated. Addition of montelukast or salmeterol to an inhaled corticosteroid similarly protected most patients from experiencing an asthma attack during a 1-year period, but, based on noninferiority limits, the study was inconclusive with regard to a difference between treatment groups.

Effect of inhaled fluticasone with and without salmeterol on airway inflammation in asthma

Background: The clinical benefit of combining long-acting β2-agonists with inhaled corticosteroids rather than doubling the dose of corticosteroid has been well-documented. However, there are concerns that this might result in a masking of underlying airway inflammation. Objective: The aim of this study was to test the hypothesis that the addition of the long-acting β2-agonist salmeterol (SALM) to a low dose of the inhaled corticosteroid fluticasone propionate (FP) has a steroid-sparing effect and does not result in a worsening of bronchial inflammation compared to doubling the dose of inhaled corticosteroid. Methods: Fifty-six asthmatic subjects, previously not well-controlled on inhaled corticosteroids, were randomized to receive 3 months of treatment with inhaled FP 500 μg twice a day (FP 1000) or FP 200 μg twice a day plus SALM 50 μg twice a day (FP 400 + SALM). Fluticasone propionate 200 μg twice a day served as the control (FP400). Bronchial mucosal biopsy specimens, bronchial washings (BW), and bronchoalveolar lavage were obtained before and after treatment. The primary end points for the study were submucosal mast cell and eosinophil counts. Results: There was a significant improvement in FEV1 in the FP400 + SALM group compared to both the FP400 and FP1000 groups. This was accompanied by a significant improvement in peak expiratory flow in the FP400 + SALM group in both the morning and evening compared to the FP1000 group. There were no significant between treatment differences in the change in the number of submucosal mast cells or eosinophils. However, in the FP400 + SALM group there was a significant decrease in submucosal mast cells after 12 weeks of treatment. The addition of SALM to FP was not associated with any increases in airway inflammation in the biopsy specimens, bronchoalveolar lavage, or bronchial washings. Conclusion: These findings confirm that addition of SALM to FP has clinical benefits but does not mask or exacerbate airway inflammation and suggest that long-acting β2-adrenoceptor agonists might influence mast cell numbers. (J Allergy Clin Immunol 2003;112:72-8.)

Cost–effectiveness of salmeterol in patients with chronic obstructive pulmonary disease: an economic evaluation

Chronic obstructive pulmonary disease (COPD) is associated with a large economic and social burden. Few economic studies have examined the benefits of inhaled therapy for patients with COPD. This 16-week study examined the cost–effectiveness of salmeterol in this patient group. Patients with a history of COPD were randomised to treatment with salmetrol 50mcg (229 patients) or placebo (227 patients) twice daily, administered by metered-dose inhaler in addition to normal therapy. Forced expiratory volume (FEV 1) was measured and patients recorded the impact of their symptoms in a daily diary. Health status was assessed using the St George's Respiratory Questionnaire. A significantly higher proportion of salmeterol-treated patients had an increase of >15% in FEV 1. Salmeterol patients had a higher mean proportion of symptom-free days and nights than those in the placebo group. More salmeterol patients had a clinically significant improvement in health status. Total healthcare costs were increased in the salmeterol group, but hospital and GP visit costs and concurrent COPD medication costs were lower. The reduction in hospital costs was sufficient to offset a substantial portion of the acquisition cost of salmeterol. Addition of salmeterol to COPD patients' current therapy improved lung function, health status at the expense of a modest increase in costs compared with usual therapy.

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Effect of Salmeterol on Seasonal Changes in Airway Responsiveness and Exhaled Nitric Oxide in Pollen-Sensitive Asthmatic Subjects

Using a model of natural allergen exposure, we examined the effect of regular treatment with salmeterol on allergen-induced changes in airway responsiveness and exhaled nitric oxide (ENO). Double-blind, randomized, parallel-group study. Specialist allergy unit in a university hospital. Asthmatic patients sensitized to pollen allergens were randomly allocated to monotherapy with salmeterol (n = 14) or placebo (n = 13). Salmeterol, 25 micro g, and placebo inhalers, two puffs bid, for 6 weeks. Spirometry, the level of a provocative concentration of a substance (methacholine) causing a 20% fall in FEV(1) (PC(20)), the PC(20) level for adenosine 5'-monophosphate (AMP), and ENO were measured before the pollen season and were repeated at the height of the pollen season after 6 weeks of treatment with salmeterol or placebo. The decrease in FEV(1) during the pollen season was significantly larger in the placebo group than in the salmeterol group, the mean difference in the change between the groups being 0.20 L (95% confidence interval, 0.03 to 0.35; p = 0.047). Changes in PC(20) for methacholine, PC(20) for AMP, and ENO levels were not significantly different between treatment groups. However, a mean (+/- SEM) decrease in the PC(20) for methacholine of -1.0 +/- 0.4 doubling concentrations was observed within the placebo group (p = 0.03), whereas no significant changes were observed within the salmeterol group. A significant decrease in PC(20) for AMP (doubling concentrations) was observed within the placebo group (-2.1 +/- 0.6; p = 0.003) and the salmeterol group (-1.5 +/- 0.4; p = 0.003). ENO concentrations increased significantly among the placebo and the salmeterol groups during natural pollen exposure. These observations indicate that natural allergen exposure and the regular use of salmeterol are not associated with a greater increase in ENO and airway responsiveness than allergen exposure alone.

Salmeterol Powder Provides Significantly Better Benefit than Montelukast in Asthmatic Patients Receiving Concommitant Inhaled Corticosteroid Therapy

Purpose of the Study. To compare inhaled salmeterol powder to oral montelukast in patients with persistent asthma who are not well-controlled on inhaled corticosteroids (ICS).Study Population. Male and nonlactating, nonpregnant females ≥15 years of age with the diagnosis of asthma for at least 6 months were recruited from 71 private and university clinics in the United States and Puerto Rico. The group included 948 subjects (61% female, 85% Caucasian). All subjects were symptomatic with their asthma for at least 6 weeks before screening and at a constant dose of ICS for 30 days before screening. Baseline forced expiratory volume in 1 second (FEV1) was 50% to 80% and all subjects had at least 12% improvement in FEV1 postbronchodilator.Methods. Two multicenter, randomized, double-blind, parallel-group clinical trials were conducted comparing 50 μg bid of salmeterol by dry powder inhaler (n = 476) versus 10 mg po daily of montelukast (n = 472). All subjects underwent baseline history and physical, and pulmonary function tests including FEV1 reversibility. After a 7- to 14-day run-in period to assess symptoms, diary card completion, and patient proficiency with inhaler use, patients whose FEV1 remained within 50% to 80% of normal were eligible for enrollment. Subjects also had to meet at least 1 of the following criteria during the 7 days before randomization: use of an average of ≥4 puffs per day of albuterol, a symptom score of ≥2 on ≥3 days, and/or ≥3 nights of nocturnal asthma symptoms. The subjects remained on their current ICS dose throughout the study and rescue albuterol, but no other asthma medications were allowed other than study drug. Subjects were asked to record am and pm peak flows (PEF), nocturnal awakenings, albuterol use, asthma symptoms, and daily study drug use. Symptoms were rated using a 5-point scale and were targeted to affects on activity level. Subjects returned for assessments at 1, 4, 8, and 12 weeks of treatment. The subjects completed a satisfaction survey at the end of the 12-week study.Results. A total of 476 subjects received inhaled salmeterol and 472 received montelukast. The treatment groups had similar demographics and disease characteristics at baseline, with 61% women, >80% Caucasian, >70% with asthma ≥10 years, mean baseline FEV1 68% of predicted, and mean baseline PEF of 370 l/m. Morning PEF in the salmeterol treated group increased more significantly (mean = 35 l/m) than the montelukast treated group (mean = 21.7 l/m). The bronchodilator properties of salmeterol were superior than montelukast over all treatment weeks. Patients in the salmeterol group had a significantly greater increase in symptom-free days than the montelukast group (24% vs 16%; P < .001). Symptom scores for all parameters except wheezing were significantly improved in the salmeterol group vs the montelukast group. Subjects in the salmeterol group used significantly less rescue albuterol than the montelukast group. Regarding patient satisfaction with the drug, the salmeterol group had greater satisfaction other than in how long the medication worked, where there was no difference in scores. The number of asthma exacerbations and the number of adverse events was similar in both groups, with 13 in each group withdrawing from the study because of adverse events.Conclusion. The addition of salmeterol in moderate to severe persistent adult asthmatics poorly controlled on ICS was superior to the addition of montelukast in improvement in PEF and overall symptom control.Reviewer’s Comments. The addition of inhaled salmeterol in subjects who were not adequately controlled on ICS showed significantly greater improvement in lung function and control of symptoms (other than wheezing) compared with oral montelukast. Other groups have compared salmeterol as an additive agent versus doubling the ICS dose and versus another leukotriene modifier, but not all in that study were on baseline ICS. Future studies are needed to determine if these findings will hold true over longer study periods and whether either long-acting β-agonists or leukotriene modifiers have a bearing on the natural history of asthma. In addition, similar studies in children are needed to see if the same patterns of response occur in all age groups.

A 6-Month, Placebo-Controlled Study Comparing Lung Function and Health Status Changes in COPD Patients Treated With Tiotropium or Salmeterol

Tiotropium, a once-daily anticholinergic, and salmeterol represent two inhaled, long-acting bronchodilators from different pharmacologic classes. A trial was designed to examine the efficacy and safety of both compounds with multiple outcome measures, including lung function, dyspnea, and health-related quality of life (HRQoL) in patients with COPD. A 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group study of tiotropium, 18 microg once daily via dry-powder inhaler, compared with salmeterol, 50 microg bid via metered-dose inhaler, was conducted in patients with COPD. Efficacy was assessed by 12-h monitoring of spirometry, transition dyspnea index (TDI), and the St. George's Respiratory Questionnaire (SGRQ). A total of 623 patients participated (tiotropium, n= 209; salmeterol, n = 213; and placebo, n = 201). The groups were similar in age (mean, 65 years), gender (75% men), and baseline FEV(1) (mean, 1.08 +/- 0.37 L; percent predicted, 40 +/- 12% [+/- SD]). Compared with placebo treatment, the mean predose morning FEV(1) following 6 months of therapy increased significantly more for the tiotropium group (0.14 L) than the salmeterol group (0.09 L; p < 0.01). The average FEV(1) (0 to 12 h) for tiotropium was statistically superior to salmeterol (difference, 0.08 L; p < 0.001). Tiotropium improved TDI focal score by 1.02 U compared with placebo (p = 0.01), whereas there was no significant change in TDI focal score with salmeterol (0.24 U). Tiotropium was superior to salmeterol in improving TDI focal score (p < 0.05). At 6 months, the mean improvement in SGRQ total score vs baseline was tiotropium, - 5.14 U (p < 0.05 vs placebo); salmeterol, - 3.54 U (p = 0.4 vs placebo); and placebo, - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo. Both active drugs reduced the need for rescue albuterol (p < 0.0001). Tiotropium once daily produces superior bronchodilation, improvements in dyspnea, and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD.