Long-acting Beta2-agonist Salmeterol Research Articles

Indacaterol–Glycopyrronium versus Salmeterol–Fluticasone for COPD

BackgroundMost guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA–LAMA regimen in these patients is unclear.MethodsWe conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily. The primary outcome was the annual rate of all COPD exacerbations.ResultsA total of 1680 patients were assigned to the indacaterol–glycopyrronium group, and 1682 to the salmeterol–fluticasone group. Indacaterol–glycopyrronium showed not only noninferiority but also superiority to salmeterol–fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol–glycopyrronium group than in the salmeterol–fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol–glycopyrronium group had a longer time to the first exacerbation than did the salmeterol–fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol–glycopyrronium group than in the salmeterol–fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol–glycopyrronium group than in the salmeterol–fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P=0.046). The effect of indacaterol–glycopyrronium versus salmeterol–fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol–glycopyrronium group and 4.8% in the salmeterol–fluticasone group (P=0.02).ConclusionsIndacaterol–glycopyrronium was more effective than salmeterol–fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.)

Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone

BackgroundThe safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate.MethodsIn this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone–salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation.ResultsOf 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone–salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone–salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone–salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone–salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001).ConclusionsPatients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone–salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721.)

Long term therapy and outcome of chronic obstructive pulmonary disease with or without co-morbidity: the TORCH study

BACKGROUND COPD affects over 5% of the adult population, and it is the only major cause of mortality that is increasing worldwide. Patients with COPD don’t die usually of respiratory failure: indeed lung cancer and cardiovascular diseases are the leading causes of mortality in patients with mild to moderate COPD. Pulmonary and systemic inflammations are prominent. Inhaled corticosteroids have little effect on the rate of decline of lung function, but they reduce the frequency of exacerbations, especially when combined with an inhaled long-acting beta-agonist. AIM OF THE STUDY The combination of the long-acting beta-agonist salmeterol (SM) and the inhaled corticosteroid fluticasone propionate (FP) would reduce mortality among patients with COPD, as compared with usual care. The primary end-point was the time to death from any cause by 3 years. Secondary end-points were the frequency of exacerbations and health status. PATIENTS AND METHODS Of 8,554 patients recruited, 6,184 underwent randomization; the mean age was 65 years, and the mean value of postbronchodilator FEV1 was 44% of the predicted value. This double-blind study was conducted in 444 centers of 42 countries. After a 2-week run-in period, eligible patients were randomly assigned to treatment with the combination of SM at a dose of 50 μg and FP at a dose of 500 μg or SM alone at a dose of 50 μg, FP alone at a dose of 500 μg, or placebo, all taken as a dry powder with the use of an inhaler bid for 3 years. RESULTS There were 875 deaths within 3 years after randomization. The proportions of deaths from any cause at 3 years were 12.6% in the combination therapy group, 15.2% in the placebo group, 13.5% in the SM group, and 16.0% in the FP group. The absolute risk reduction for death in the combination-therapy group as compared with the placebo group was 2.6%, and the hazard ratio was 0.825 (95% confidence interval [CI], 0.681 to 1.002; p = 0.052), corresponding to a reduction in the risk of death at any time in the 3 years of 17.5% (95% CI, –0.2 to 31.9). DISCUSSION In this trial, the reduction in mortality from any cause did not meet the level of statistical significance (p = 0.052), but the treatment with the combination regimen resulted in significantly fewer exacerbations and improved health status and lung function, as compared with placebo. Mortality could be influenced mainly by factors unresponsive to the study drugs, or it is possible that this study was underpowered to detect this effect. There was also a high withdrawal rate, which was highest among patients in the placebo group. CONCLUSIONS Even though p = 0.052 is not statistically significant, 126 deaths for every 1,000 treated in the combination-therapy group, after 3 years, instead of 152 in the placebo group, is anyway an important result? Further investigation is needed in future large, prospective trials.

Chronic obstructive pulmonary disease: a slowly progressive cardiovascular disease masked by its pulmonary effects?

Chronic obstructive pulmonary disease: a slowly progressive cardiovascular disease masked by its pulmonary effects?

Intra-Individual Variability in the Urine Concentrations of Inhaled Salmeterol in Male Subjects with Reference to Doping Analysis–Impact of Urine Specific Gravity Correction

Since 2010, the World Anti-Doping Agency (WADA) has introduced urinary thresholds for some beta2-agonists. In doping analysis urine samples of beta2-agonists are not corrected for the Urine Specific Gravity (USG) by the WADA laboratories. Several studies have observed high differences in the urine concentrations of beta2-agonists when correction for USG is compared with no correction, as well as high inter-individual variability between subjects. However, no studies have measured the intra-individual variability after inhalation of the long-acting beta2-agonist salmeterol. As such, the purpose of this study was to measure the intra-individual variability in the urine concentrations of salmeterol and its metabolite α-hydroxysalmeterol. Furthermore, to highlight the variability between corrected and uncorrected urine samples for USG. Urine samples from 20 subjects were analyzed for USG, urine excretion and urine concentrations of salmeterol and α-hydroxysalmeterol. Seven of the subjects underwent a second visit with the same procedures. At each visit 100 μg salmeterol was administered by inhalation. Urine samples were collected before administration of the drug (T0) and 4 (T4), 8 (T8) and 12 (T12) hours after administration. The mean relative differences in the urine concentrations of salmeterol and α-hydroxysalmeterol between USG corrected and uncorrected samples were 43 ± 44, 27 ± 42 and 56 ± 87% at T4, T8 and T12, respectively. The intra-individual variability in the urine excretion of salmeterol and α-hydroxysalmeterol during visits one and two were 12.6 and 21.8%, respectively. The intra-individual variability of salmeterol and α-hydroxysalmeterol in the urine concentrations were significantly higher when uncorrected for USG with 43.0 and 43.7% versus 20.4% (p<0.01) and 28.0% (p<0.05), respectively. Correction for USG reduces inter-individual and intra-individual variability in urine concentrations of salmeterol and α-hydroxysalmeterol.

Engineering of Crystalline Combination Inhalation Particles of a Long-Acting β2-agonist and a Corticosteroid

Engineering of inhalation particles incorporating, in each individual particle, a combination of a long-acting beta-agonist and a glucocorticosteroid in a pre-determined and constant ratio for delivery via a dry powder inhaler (DPI). Individual crystalline particles containing both the glucocorticosteroid fluticasone propionate (FP) and long-acting beta-agonist salmeterol (SX) were prepared, in a ratio of 10:1, using the solution atomization and crystallization by sonication (SAX) process. Combination drug particles were characterized by particle size, morphology, crystallinity and aerosolisation efficiency using inertial impaction. Combination drug particles were spherical and crystalline, with a median diameter of 4.68 +/- 0.01 microm. Aerosolisation of formulations containing combination drug particles resulted in greater uniformity in delivery ratios of both actives across all stages of the impactor before and after storage. Actives in a pre-determined dose ratio can be crystallised in a single particle using the SAX process.

Acute and chronic lung function responses to salmeterol and salmeterol plus fluticasone propionate in relation to Arg16Gly β2-adrenergic polymorphisms

ABSTRACTObjective: There is conflicting clinical evidence describing the response to long-acting beta-agonist (LABA) bronchodilators for patients with Arg16Gly β2-adrenergic receptor (ADRB2 ) genotype differences. Furthermore, the role of inhaled corticosteroids (ICS) in modulating Arg16Gly clinical responses is not well understood. The objective of this study was to investigate the effects of Arg16Gly polymorphism on the 12 hour post-dose bronchodilator response to the LABA salmeterol (SAL) or SAL plus fluticasone propionate (FSC) on first administration and following 12 weeks of treatment.Research design and methods: Genotyping was retrospectively performed in patients with persistent asthma randomized to SAL or FSC who were participating in three similar double-blind clinical trials of 12 week duration. The primary outcome was area under the curve (AUC) for 12 hour serial FEV1 by treatment and Arg16Gly genotype, recorded on Day 1 and Week 12. In addition, other single nucleotide polymorphisms (SNPs) associated with asthma outcomes we assessed at positions −47, +79 and +491 as well as common ADRB2 haplotypes.Results: No statistically significant associations between Arg16Gly genotypes and serial FEV1 clinical responses to SAL and FSC were observed following acute assessment. In addition, the FEV1 response was preserved following 12 weeks of treatment with SAL and FSC and was not altered by Arg16Gly genotypes analyzed. These results may not be generalizable to other ethnic groups since they are derived predominantly from Caucasians.Conclusions: In subjects with persistent asthma, the ADRB2 Arg16Gly polymorphism does not alter lung function responses to SAL or FSC over the 12 hour dosing interval following acute and chronic dosing.

Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma

Obesity may contribute to the development and clinical expression of asthma. However, how obesity can influence response to asthma medications is still uncertain. To examine the relationship between body mass index (BMI) and the response to an inhaled corticosteroid (ICS), fluticasone propionate, with or without the long-acting beta2-agonist salmeterol (LABA). Achievement of asthma control as defined by the global initiative on asthma guidelines (GINA) was examined in 1242 asthmatic patients not currently using ICS, enrolled in five clinical trials comparing fluticasone propionate and the combination of fluticasone and salmeterol. In both obese and non-obese subjects, fluticasone propionate combined with salmeterol was more effective in controlling asthma than fluticasone alone. However, for both treatments the odds of achieving well-controlled asthma were significantly lower in obese subjects, particularly among those with a BMI of >or=40 kg/m2. Reported prevalence of atopy increased with BMI. Age did not influence the effect of obesity in response to asthma medications. Obese patients are less likely than the non-obese to achieve asthma control with an ICS or an ICS combined with a LABA. The causes of such reduced response to asthma medication in obese subjects should be studied, and their implications for asthma therapy determined.

Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma

Theophylline and long acting beta-2 agonists are bronchodilators used for the management of persistent asthma symptoms, especially nocturnal asthma. They represent different classes of drug with differing side-effect profiles. To assess the comparative efficacy, safety and side-effects of long-acting beta-2 agonists and theophylline in the maintenance treatment of adults and adolescents with asthma. We searched the Cochrane Airways Group trials register and reference lists of articles. We also contacted authors of identified RCTs for other relevant published and unpublished studies and pharmaceutical manufacturers. Most recent search: November 2006. All included studies were RCTs involving adults and children with clinical evidence of asthma. These studies must have compared oral sustained release and/or dose adjusted theophylline with an inhaled long-acting beta-2 agonist. In original review, two reviewers independently assessed trial quality and extracted data, similarly in this update two reviewers undertook this. Study authors were contacted for additional information. Thirteen studies with a total of 1344 participants met the inclusion criteria of the review. They were of varying quality. There was no significant difference between salmeterol and theophylline in FEV(1) predicted (6.5%; 95% CI -0.84 to 13.83). However, salmeterol treatment led to significantly better morning PEF (mean difference 16.71 L/min, 95% CI 8.91 to 24.51) and evening PEF (mean difference 15.58 L/min, 95% CI 8.33 to 22.83). Salmeterol also reduced the use of rescue medication. Formoterol, used in two studies was reported to be as effective as theophylline. Bitolterol, used in only one study, was reported to be less effective than theophylline. Participants taking salmeterol experienced fewer adverse events than those using theophylline (Parallel studies: Relative Risk 0.44; 95% CI 0.30 to 0.63, Risk Difference -0.11; 95% CI -0.16 to -0.07, Numbers Needed to Treat (NNT) 9; 95% CI 6 to 14). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.50; 95% CI 0.29 to 0.86, Risk Difference -0.07; 95% CI -0.12 to -0.02, NNT 14; 95% CI 8 to 50) and gastrointestinal adverse events (Relative Risk 0.30; 95% CI 0.17 to 0.55, Risk Difference -0.11; 95% CI -0.16 to -0.06, NNT 9; 95% CI 6 to 16). Long-acting beta-2 agonists, particularly salmeterol, are more effective than theophylline in improving morning and evening PEF, but are not significantly different in their effect on FEV1. There is evidence of decreased daytime and nighttime short-acting beta-2 agonist requirement with salmeterol. Fewer adverse events occurred in participants using long-acting beta-2 agonists (salmeterol and formoterol) as compared to theophylline.

The controversy over long-acting beta agonists: examining the evidence.

In the Salmeterol Multicenter Asthma Research Trial (SMART), patients receiving the long-acting beta agonist salmeterol--particularly African Americans--had a statistically significantly higher risk of fatal or potentially fatal asthma episodes. As a result, medications that contain salmeterol (Serevent, Advair) or formoterol (Foradil) carry a "black box warning." However, the benefits of these drugs continue to outweigh the risks, if they are used appropriately.

Combination therapy with a long-acting beta-agonist and a leukotriene antagonist in moderate asthma.

Long-acting beta-agonists (LABAs) and inhaled corticosteroids administered together appear to be complementary in terms of effects on asthma control. The elements of asthma control achieved by LABAs (improved lung function) and leukotriene receptor antagonists (LTRAs; protection against exacerbations) may be complementary as well. We sought to determine whether the combination of the LTRA montelukast and the LABA salmeterol could provide an effective therapeutic strategy for asthma. In a randomized, placebo-controlled, crossover study of 192 subjects with moderate asthma, we compared the clinical efficacy of regular treatment over 14 weeks with the combination of montelukast and salmeterol to that with the combination of beclomethasone and salmeterol in moderate asthma. The primary efficacy outcome was time to treatment failure. Three months after the randomization of the last subject, the Data and Safety Monitoring Board determined that the primary research question had been answered and terminated the trial. The combination of montelukast and salmeterol was inferior to the combination of beclomethasone and salmeterol as judged by protection against asthma treatment failures (p = 0.0008), lung function (26 L/min difference in a.m. peak expiratory flow rate, p = 0.011), asthma control score (0.22 difference in Asthma Control Questionnaire score, p = 0.038), and markers of inflammation and airway reactivity. Patients with moderate asthma similar to those we studied should not substitute the combination of an LTRA and an LABA for the combination of inhaled corticosteroid and an LABA.

Effect of inhaled glucocorticoid treatment on placental 11β‐hydroxysteroid dehydrogenase type 2 activity and neonatal birthweight in pregnancies complicated by asthma

Asthma is a common disease affecting 12% of Australian women with 55% of women experiencing at least one exacerbation during pregnancy. Exacerbations during pregnancy are associated with low birthweight neonates and stillbirth. One of the main reasons for maternal exacerbations during pregnancy is non-compliance with inhaled glucocorticoid treatment due to the misconception that inhaled glucocorticoids are harmful to the fetus. We have therefore assessed whether the commonly used inhaled glucocorticoids reduce placental glucocorticoid metabolising capacity, by measuring 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2) activity. As these treatments potentially increase the exposure of the fetus to the growth-inhibiting effects of glucocorticoids, we also examined the question of whether inhaled glucocorticoid use was associated with reduced birthweight. Pregnant women using budesonide (n = 18), fluticasone propionate alone (n = 14) and fluticasone propionate in combination with the long-acting beta2 agonist salmeterol (n = 9) were compared to a non-asthmatic control group (n = 20). The use of inhaled budesonide was associated with significantly increased placental 11beta-HSD-2 activity relative to the control group. Inhaled glucocorticoid use for the treatment of asthma was associated with normal birthweight. In the small number of women using combination therapy (fluticasone and salmeterol), there was reduced birthweight compared to the control group. Inhaled glucocorticoids alone do not adversely affect fetal growth and placental function.

Evidence of tachyphylaxis associated with salmeterol treatment of chronic obstructive pulmonary disease patients

Bronchodilator therapy is lifelong mandatory for chronic obstructive pulmonary disease patients. There is evidence of loss of bronchodilator effectiveness over time with beta2-agonists but not with anticholinergics. The aim of this study was to examine the development of tachyphylaxis to the long-acting beta2-agonist salmeterol using as a control therapeutic regimen the combination of ipratropium bromide and salbutamol sulphate. Fifty-six subjects participated in a 20-week, crossover randomised clinical trial. The parameters forced expiratory volume at 1 s (FEV1), peak expiratory flow rate (PEFR) and FEV1/forced vital capacity were measured via spirometry and the parameters triangle DeltaFEV1%pre, triangle DeltaPEFR%pre and triangle DeltaAUC(0-2 h) were calculated. FEV1 increased significantly after two weeks of treatment with the combination treatment but not with the salmeterol. The observed diminished increase could be attributed to the development of tolerance to the long acting beta2-agonist. Salmeterol seems to be an effective bronchodilator, however, its duration of action over time and its peak effect might be subject to tachyphylaxis.

Antiinflammatory Effects of Salmeterol/Fluticasone Propionate in Chronic Obstructive Lung Disease

No currently available treatment is reported to reduce the exaggerated airway wall inflammation of chronic obstructive pulmonary disease. We tested the hypothesis that inhaled combined long-acting beta2-agonist (salmeterol) and corticosteroid (fluticasone propionate) will reduce inflammation. Bronchial biopsies and induced sputum were taken from 140 current and former smokers (mean age, 64 yr) with moderate to severe disease, randomized in a 13-wk double-blind study to placebo (n = 73) or salmeterol/fluticasone propionate 50/500 microg (n = 67) twice daily. Biopsies were repeated at 12 wk and sputa at 8 and 13 wk. After adjustment for multiplicity, comparisons between active and placebo were made for median change from baseline in the numbers of biopsy CD8+ and CD68+ cells/mm2 and sputum neutrophils. Combination therapy was associated with a reduction in biopsy CD8+ cells of -118 cells/mm2 (95% confidence interval [CI], -209 to -42; p = 0.02), a reduction of 36% over placebo (p = 0.001). CD68+ cells were unaffected by combination treatment. Sputum differential (but not total) neutrophils reduced progressively and, at Week 13, significantly with combination treatment (median treatment difference, 8.5%; 95% CI, 1.75%-15.25%; p = 0.04). The combination also significantly reduced biopsy CD45+ and CD4+ cells and cells expressing genes for tumor necrosis factor-alpha and IFN-gamma and sputum total eosinophils (all p < or = 0.03). These antiinflammatory effects were accompanied by a 173-ml (95% CI, 104-242; p < 0.001) improvement in prebronchodilator FEV1. The combination of salmeterol and fluticasone propionate has a broad spectrum of antiinflammatory effects in both current and former smokers with chronic obstructive pulmonary disease, which may contribute to clinical efficacy.

The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma

For children older than 5 years with asthma who remain symptomatic despite inhaled corticosteroid (ICS) therapy, the preferred treatment is to add an inhaled long-acting beta2-agonist vs increasing the ICS dose. To compare the safety of twice-daily treatment with inhaled fluticasone propionate plus the inhaled long-acting beta2-agonist salmeterol with that of fluticasone propionate used alone in children aged 4 to 11 years with persistent asthma. A randomized, multicenter, double-blind, active-controlled, parallel-group study in 203 children with persistent asthma who were symptomatic during ICS therapy. Patients received fluticasone propionate-salmeterol (100/50 microg) or fluticasone propionate (100 microg) alone twice daily for 12 weeks. The safety profile of fluticasone propionate-salmeterol was similar to that of fluticasone propionate alone. The overall incidence of adverse events was 59% for fluticasone propionate-salmeterol and 57% for fluticasone propionate. Both treatments were well tolerated. Two patients receiving fluticasone propionate-salmeterol and 5 receiving fluticasone propionate withdrew from the study because of worsening asthma. Changes in heart rate, blood pressure, and laboratory variables were infrequent and were similar between treatments. No patients had clinically significant abnormal electrocardiographic findings during treatment. Geometric mean 24-hour urinary cortisol excretion at baseline and after 12 weeks of treatment was comparable within and between groups; no patient in either group had abnormally low 24-hour urinary cortisol excretion after 12 weeks of treatment. The incidence of withdrawals due to asthma exacerbations was 2% in the fluticasone propionate-salmeterol group and 5% in the fluticasone propionate group. In pediatric patients with persistent asthma, fluticasone propionate-salmeterol twice daily was well tolerated, with a safety profile similar to that of fluticasone propionate used alone.

Improved daytime spirometric efficacy of tiotropium compared with salmeterol in patients with COPD

Background The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends long-acting bronchodilators as first-line maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). A study was conducted comparing the long-acting anticholinergic tiotropium with the long-acting beta-agonist salmeterol to confirm the significant improvements in daytime bronchodilator efficacy seen with tiotropium in previous studies. Methods Randomized, double-blind, double-dummy, parallel-group study, comparing daytime bronchodilator efficacy of tiotropium 18 mcg once daily with salmeterol 50 mcg twice daily in patients with COPD. Serial spirometry was performed over 12 h after 12 weeks of treatment. Co-primary endpoints were average (over 12 h) and peak FEV 1 at 12 weeks. Results 653 patients were randomized (328 tiotropium, 325 salmeterol): mean age 64 years; 66% male; mean baseline FEV 1 1.05 l (37.7% predicted). After 12 weeks, the average post-dose FEV 1 over 12 h was significantly higher with tiotropium compared with salmeterol (167 vs. 130 mL, respectively, p=0.03), as was peak FEV 1 (262 vs. 216 ml, respectively, p=0.01). The average FEV 1 responses from 0–6 h and 6–12 h were higher in the tiotropium group compared with salmeterol ( p<0.05). Peak and average FVC were significantly higher with tiotropium compared with salmeterol ( p<0.01). Morning pre-dose FEV 1 responses were not significantly different; however, tiotropium demonstrated a significantly higher pre-dose FVC than salmeterol ( p<0.05). Conclusion Tiotropium demonstrated significantly greater post-dose improvements in spirometric parameters compared with salmeterol. These improvements were sustained over 12 h.

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.

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.

The 24 h duration of bronchodilator action of the salmeterol/fluticasone combination inhaler

The duration of bronchodilator action of the long-acting beta agonist salmeterol when administered in the evening has not been investigated. In this study we have investigated whether a single evening dose of salmeterol, administered from the combination salmeterol/fluticasone (SFC) Accuhaler significantly attenuates the circadian rhythm in airway tone over 24 h. Eighteen subjects with mild to moderate asthma (mean FEV1 84% predicted) participated in a double-blind, double dummy, placebo controlled, cross-over study. Subjects inhaled, in random order, placebo, salbutamol (200 microg) or SFC (50/100 microg) administered in the evening (2000 h) on three separate occasions. Lung function measurements including FEV1, specific airways conductance (sGaw) and maximum expiratory flow at 25-75% of vital capacity (MEF(25-75%)) were assessed at baseline, at 1 h and subsequently every 4 h post-dose for 24 h. Compared with placebo, SFC significantly improved the three measures of airways function throughout the 24 h period, with a difference in FEV1 at 24 h of 0.24 l (0.00-0.47 l). SFC abolished the biphasic pattern of the circadian rhythm in airway tone. In contrast, salbutamol had a significant bronchodilator action of 4-8 h, depending on the lung function parameter measured. The single evening administration of SFC via the Accuhaler resulted in a duration of bronchodilation of at least 24 h, with the abolition of the accentuated biphasic circadian variation in airway tone observed in asthma.

Long acting beta-agonists versus theophylline for maintenance treatment of asthma.

Theophylline and long acting beta-2 agonists are bronchodilators used for the management of persistent asthma symptoms, especially nocturnal asthma. They represent different classes of drug with differing side-effect profiles. To assess the comparative efficacy, safety and side-effects of long-acting beta-2 agonists and theophylline in the maintenance treatment of asthma. Randomised, controlled trials (RCTs) were identified using the Cochrane Airways Group register. The register was searched using the following terms: asthma and theophylline and long acting beta-agonist or formoterol or foradile or eformoterol or salmeterol or bambuterol or bitolterol. Date of last search was April 2003. Titles and abstracts were then screened to identify potentially relevant studies. The bibliography of each RCT was searched for additional RCTs. Authors of identified RCTs were contacted for other relevant published and unpublished studies. All included studies were RCTs involving adults and children with clinical evidence of asthma. These studies must have compared oral sustained release and/or dose adjusted theophylline with an inhaled long-acting beta-2 agonist. Potentially relevant trials, identified by screening titles and/or abstracts, were obtained. Two reviewers independently assessed full text versions of these trials to decide whether the trial should be included in the review, and assessed its methodological quality. Where there was disagreement between reviewers, this was resolved by consensus, or reference to a third party. Data were extracted by two independent reviewers. Inter-rater reliability was assessed by simple agreement. Study authors were contacted to clarify randomisation methods, provide missing data, verify the data extracted and identify unpublished studies. Relevant pharmaceutical manufacturers were also contacted. Six trials originally met the inclusion criteria. Five used salmeterol and one, bitolterol. In an updated version of the review, six more trials were included. Four trials used salmeterol and two used formoterol. They were of varying quality. Salmeterol improved FEV1 significantly more than theophylline in five studies and salmeterol use was associated with significantly more symptom free nights in all the studies comparing these agents. Formoterol, used in two studies was reported to be as effective as theophylline. Bitolterol, used in only one study, was reported to be less effective than theophylline. Subjects taking salmeterol experienced fewer adverse events than those using theophylline (Parallel studies: Relative Risk 0.44; 95% CI: 0.30 to 0.63), Risk Difference -0.11 (95%CI: -0.16 to -0.07), NNT 9 (6, 14). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.50; 95%Confidence Intervals 0.29, 0.86), Risk Difference -0.07(95% CI -0.12, -0.02), NNT 14(8, 50) and gastrointestinal adverse events (Relative Risk 0.30; 95%Confidence Intervals 0.17, 0.55), Risk Difference -0.11(-0.16, -0.06), NNT 9(6, 16). Long-acting beta-2 agonists are at least as effective than theophylline in reducing asthma symptoms including night waking and improving lung function. Fewer adverse events occurred in subjects using long-acting beta-2 agonists(salmeterol and formoterol) as compared to theophylline.