The addition of salmeterol 50 microg bid to anticholinergic treatment in patients with COPD: a randomized, placebo controlled trial. Chronic obstructive pulmonary disease. Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD) Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Efficacy of inhaled salmeterol in the management of smokers with chronic obstructive pulmonary disease: a single centre randomised, double blind, placebo controlled, crossover study. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. Comparison of the efficacy of formoterol and salmeterol in patients with reversible obstructive airway disease: a multicenter, randomized, open-label trial. Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Efficacy of salmeterol xinafoate in the treatment of COPD. EXCEL: A randomised trial comparing salmeterol/fluticasone propionate and formoterol/budesonide combinations in adults with persistent asthma. Eformoterol Turbohaler compared with salmeterol by dry powder inhaler in asthmatic children not controlled on inhaled corticosteroids.
In the past, the role of long-acting beta(2-) agonists in chronic obstructive pulmonary disease (COPD) relative to other agents has been unclear.
                To compare the effect of adding salmeterol (50 microg bid) or placebo to concurrent anticholinergic therapy on symptom scores, quality of life, prebronchodilator lung function and exacerbations in patients with moderately severe COPD.
                This was a double-blind, randomized, parallel-group study in patients aged 40 years or older receiving anticholinergic medication. Patients were randomly assigned to treatment with placebo (n=207) or salmeterol (n=201) via a Diskus/Accuhaler inhaler for 24 weeks.
                The morning trough (prestudy drug) forced expiratory volume in 1 s (FEV(1)) increased significantly above baseline levels among the salmeterol-treated patients. Improvement in FEV(1) was greater in the salmeterol group than in the placebo group at four weeks (difference 0.06 L, P<0.005), eight weeks (0.06 L, P<0.005) and 16 weeks (0.05 L, P<0.05) after the start of treatment. There was a nonsignificant trend in favour of salmeterol after 24 weeks of treatment (P=0.198). Improvements in morning peak flow were significantly greater in the salmeterol group over 24 weeks (P<0.01). Although symptom scores were numerically higher in the salmeterol group than in the placebo group and there was less requirement for rescue bronchodilator use, these differences were not statistically significant. In the salmeterol group, fewer patients had exacerbations of COPD, and there was a trend toward an improved quality of life. The safety profile of the two groups was similar.
                Salmeterol has a beneficial effect when added to existing anticholinergic therapy in patients with COPD. The regular use of salmeterol for six months was not associated with worsening of the underlying airflow obstruction; rather, there was a tendency for the trough FEV1 to improve above the baseline levels over the treatment period. Prevention and treatment of COPD exacerbations are recognized as key goals in disease management. This randomized, double-blind, parallel-group, multicenter study evaluated the effect of fluticasone propionate/salmeterol 250 mcg/50 mcg (FSC 250/50) and salmeterol 50 mcg (SAL) twice-daily on moderate/severe exacerbations. Subjects received treatment with FSC 250/50 during a one month run-in, followed by randomization to FSC 250/50 or SAL for 52 weeks. Moderate/severe exacerbations were defined as worsening symptoms of COPD requiring antibiotics, oral corticosteroids and/or hospitalization. In 797 subjects with COPD (mean FEV(1) = 0.98L, 34% predicted normal), treatment with FSC 250/50 significantly reduced the annual rate of moderate/severe exacerbations by 30.4% compared with SAL (1.10 and 1.59 per subject per year, respectively, p < 0.001), the annual rate of exacerbations requiring oral corticosteroids by 34% (p < 0.001) and the annual rate of moderate/severe exacerbations requiring hospitalization by 36% (p = 0.043). Clinical improvements observed during run-in treatment with FSC 250/50 were better maintained over 52 weeks with FSC 250/50 compared to SAL. Statistically significant reductions in albuterol use, dyspnea scores, and nighttime awakenings and numerical benefits on quality of life were seen with FSC 250/50 compared with SAL. The incidence of adverse events was similar across groups. Pneumonia was reported more frequently with FSC 250/50 compared with SAL (7% vs. 2%). FSC 250/50 is more effective than SAL at reducing the rate of moderate/severe exacerbations. These data confirm the beneficial effect of FSC on the management of COPD exacerbations and support the use of FSC in patients with COPD. The objectives of this study were to compare the efficacy and safety of salmeterol xinafoate (50 and 100 microg b.i.d.) with that of placebo, when added to existing therapy, in the treatment of patients with chronic obstructive pulmonary disease (COPD). Six hundred and seventy four patients were randomized to receive either salmeterol 50 microg b.i.d., salmeterol 100 microg b.i.d., or placebo treatment for a period of 16 weeks. The results showed a significant improvement in daily symptom scores noted for patients taking either 50 microg (p=0.043) or 100 microg b.i.d. salmeterol (p=0.01) compared with placebo, with a corresponding decrease in additional daytime salbutamol requirements for both salmeterol groups. The same pattern was reflected for night-time symptoms and additional salbutamol use. During treatment, forced expiratory volume in one second (FEV1) measurements improved significantly in each salmeterol group, with up to a 7% improvement observed at the end of the study. Although no difference was observed between treatment groups for the distance walked in 6 min, patients treated with salmeterol 50 microg b.i.d. were significantly less breathless than those treated with placebo after their 6 min walk, after 8 weeks (p=0.024) and 16 weeks (p=0.004) of therapy. Adverse events were similar in all three groups except for tremor, which was significantly higher in the 100 microg b.i.d. salmeterol group (p=0.005) compared both with 50 microg b.i.d. salmeterol and placebo. Salmeterol offered further positive improvement to the effect of therapy in patients with chronic obstructive pulmonary disease when added to their existing regimens. This clinical improvement was similar both with 50 and 100 microg b.i.d. dosage, although the group receiving 50 microg b.i.d. tolerated the drug better than those receiving 100 microg b.i.d. salmeterol. Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease (COPD), whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status. We postulated that a combination of these treatments would be better than each component used alone.
                1465 patients with COPD were recruited from outpatient departments in 25 countries. They were treated in a randomised, double-blind, parallel-group, placebo-controlled study with either 50 microg salmeterol twice daily (n=372), 500 microg fluticasone twice daily (n=374), 50 microg salmeterol and 500 microg fluticasone twice daily (n=358), or placebo (n=361) for 12 months. The primary outcome was the pretreatment forced expiratory volume in 1s (FEV1) after 12 months treatment' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h. Secondary outcomes were other lung function measurements, symptoms and rescue treatment use, the number of exacerbations, patient withdrawals, and disease-specific health status. We assessed adverse events, serum cortisol concentrations, skin bruising, and electrocardiograms. Analysis was as predefined in the study protocol.
                All active treatments improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV1 significantly more than did placebo (treatment difference 133 mL, 95% CI 105-161, p<0.0001), salmeterol (73 mL, 46-101, p<0.0001), or fluticasone alone (95 mL, 67-122, p<0.0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in daily symptoms. All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls in serum cortisol concentration.
                Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function, with no greater risk of side-effects than that with use of either component alone, this combination treatment should be considered for patients with COPD. The acute response to bronchodilators in patients with chronic obstructive pulmonary disease (COPD) is modest; it has, however, been suggested that these patients may benefit from long term treatment.
                To investigate the efficacy of salmeterol in smokers with moderate to severe COPD a double blind, randomised, crossover comparison was performed between salmeterol (50 micrograms twice daily) and placebo in 63 patients with stable COPD (mean age 65 years). Prior to inclusion, all patients had a forced expiratory volume in one second (FEV1) of < 60% of predicted and an improvement in FEV1 of < 15% following 400 micrograms inhaled salbutamol. Patients received four weeks of therapy with each of the treatment regimens. Assessment of efficacy was made with recording of morning and evening peak expiratory flow rates (PEF), respiratory symptoms, and use of rescue salbutamol. FEV1 was measured before and after nebulised salbutamol prior to randomisation and at the end of each treatment period.
                Morning PEF values were higher during the salmeterol than during the placebo period, although the mean treatment difference was small (12 l/min (95% confidence limits 6 to 17)). No difference in mean evening PEF values was found. Diurnal variation in PEF, assessed as the difference between the morning PEF and that of the previous evening, was more pronounced during the placebo than during the salmeterol period. The mean spirometric values (including reversibility in FEV1) obtained at the end of the two treatment periods were similar. Compared with placebo, treatment with salmeterol was associated with lower daytime and night time symptom scores and less use of rescue salbutamol both during the day and the night. The patients rated the treatment with salmeterol better than treatment with placebo.
                This study shows that, compared with placebo, treatment with salmeterol produces an improvement in respiratory symptoms and morning PEF values in patients with moderate to severe COPD. Treatment with long acting beta agonists may therefore result in an improvement in functional status, even in patients suffering from apparently nonreversible 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. 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. Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD.
                In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year.
                A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group.
                These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.). Beta2-adrenergic agonists are frequently used for the prevention and relief of bronchospasm in patients with reversible obstructive airway disease. Formoterol and salmeterol are long-acting beta2-agonists. In addition to its long duration of action, formoterol has been reported to have an onset of action similar to that of albuterol.
                This study compared the effects on lung function of regular twice-daily inhalation of formoterol or salmeterol in adults with moderate to moderately severe persistent asthma who were receiving daily inhaled corticosteroids.
                In this 6-month, multicenter, open-label, parallel-group study, patients with moderate or moderately severe asthma were randomized to receive either formoterol 12 microg BID or salmeterol 50 microg BID. The primary end point was mean morning peak expiratory flow (PEF) measured 5 minutes after dosing and entered in a patient diary each day during the first 4 weeks of treatment. Secondary end points included mean morning and evening predose PEF and number of episode-free days recorded in the patient diaries during the first 4 weeks of treatment, use and time of rescue medication, symptom scores, and overall mean morning predose PEF (spirometric measurements made by the physician during scheduled visits) for the entire treatment period. Safety assessments included spontaneously reported adverse events and vital signs.
                A total of 528 patients were randomized to study treatment, 262 to formoterol and 266 to salmeterol. There were no significant differences in demographic or baseline characteristics between treatment groups, except in the proportion of current smokers in the formoterol group (4.6%) compared with the salmeterol group (1.5%; P = 0.039). Based on the information recorded in patients' diaries, those receiving formoterol showed significant improvement in mean morning PEF measured 5 minutes after dosing (P < 0.001), reduced use of rescue medication (P < 0.03), and an increased number of episode-free days (P < 0.04) compared with patients receiving salmeterol. Mean predose morning and evening PEF and symptom scores based on diary data and mean morning predose PEF based on measurements obtained during office visits were comparable between the 2 treatment groups throughout the study.
                In this open-label trial, patients randomized to formoterol treatment had greater improvement in mean PEF 5 minutes after dosing, required significantly less rescue medication (fewer actuations of albuterol), and experienced more episode-free days compared with patients receiving salmeterol. Thus, although both formoterol and salmeterol are long-acting beta2-agonists, formoterol had a more rapid onset of action. COPD exacerbations are associated with significant morbidity and mortality. This randomized, double-blind, parallel-group, multicenter study evaluated the effect of fluticasone propionate/salmeterol 250/50 and salmeterol 50 microg twice daily on moderate to severe exacerbations.
                Patients received standardized treatment with fluticasone propionate/salmeterol 250/50 during a 1-month run-in, followed by randomization to fluticasone propionate/salmeterol 250/50 or salmeterol for 12 months. Moderate to severe exacerbations were defined as worsening symptoms of COPD requiring treatment with oral corticosteroids, antibiotics, or hospitalization.
                In 782 patients with COPD (mean FEV(1)=0.94+/-0.36 L, 33% predicted normal), treatment with fluticasone propionate/salmeterol 250/50 significantly reduced (1) the annual rate of moderate to severe exacerbations by 30.5% compared with salmeterol (1.06 and 1.53 per subject per year, respectively, p<0.001), (2) the risk of time to first exacerbation by 25% (hazard ratio=0.750, p=0.003) and (3) the annual rate of exacerbations requiring oral corticosteroids by 40% (p<0.001). Clinical improvements observed during run-in treatment with fluticasone propionate/salmeterol 250/50 were better maintained over 12 months with fluticasone propionate/salmeterol 250/50 than salmeterol. Adverse events were reported for a similar percentage of subjects across groups. A higher reporting of pneumonia was observed with fluticasone propionate/salmeterol 250/50 than salmeterol (7% vs. 4%).
                We conclude that fluticasone propionate/salmeterol 250/50 is more effective than salmeterol at reducing the rate of moderate to severe exacerbations over 1 year. The benefits of this reduction relative to the risk of a higher incidence of reported pneumonia should be considered. This study supports the use of fluticasone propionate/salmeterol 250/50 for the reduction of COPD exacerbations in patients with COPD. To examine and compare the efficacy and safety of salmeterol xinafoate, a long-acting inhaled beta2-adrenergic agonist, with inhaled ipratropium bromide and inhaled placebo in patients with COPD.
                A stratified, randomized, double-blind, double-dummy, placebo-controlled, parallel group clinical trial.
                Multiple sites at clinics and university medical centers throughout the United States.
                Four hundred eleven symptomatic patients with COPD with FEV1 < or = 65% predicted and no clinically significant concurrent disease. Interventions: Comparison of inhaled salmeterol (42 microg twice daily), inhaled ipratropium bromide (36 microg four times a day), and inhaled placebo (2 puffs four times a day) over 12 weeks.
                Salmeterol xinafoate was significantly (p < 0.0001) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; this improvement was associated with reduced use of supplemental albuterol. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (p < 0.05). Adverse effects were similar among the three treatments.
                These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD. This multicentre, parallel group, double-blind, double-dummy, randomised 24-week study was designed to compare the efficacy of salmeterol/fluticasone propionate combination (SFC) 50/250 microg one inhalation twice daily (bid) with formoterol/budesonide combination (FBC) 6/200 microg two inhalations bid in patients with persistent asthma, currently receiving 1000-2000 microg/day of inhaled corticosteroids.
                The intent-to-treat population comprised 694 patients in the SFC group and 697 patients in the FBC group.
                The primary endpoint, mean rate of all exacerbations over 24 weeks, was similar in both treatment groups (SFC: 2.69; FBC: 2.79; SFC/FBC ratio 0.96; 95% CL 0.84, 1.10; P=0.571). A reduction in the rate of exacerbations over time was observed in both treatment groups. Overall, there was a 30% lower annual rate of moderate/severe exacerbations in the SFC group compared with the FBC group (95% CI 0-49%, 52% reduction vs. 1% increase; P=0.059). This effect increased with time: in weeks 17-24 the moderate/severe exacerbation rate was 57% lower in the SFC group compared with the FBC group (95% CI 21-77% reduction; P=0.006). Similar improvements in lung function, asthma symptoms and rescue medication usage were seen with both treatments and both were well tolerated.
                Twice-daily treatment with SFC and FBC over 6 months significantly improved asthma symptoms and lung function in patients with persistent asthma. The rate of exacerbations was significantly reduced over time on both treatments but SFC was found to be significantly superior to FBC in reducing the rate of moderate/severe exacerbations with sustained treatment. The aim of the study was to compare the efficacy of the inhaled long-acting beta2-agonists eformoterol and salmeterol when added to existing inhaled corticosteroid (ICS) therapy in symptomatic asthmatic children. This randomized, 12-week, parallel-group study, performed in a primary care setting, included 156 children and adolescents (aged 6-17 years) with moderate persistent asthma. Patients were randomized to open-label eformoterol (Oxis) Turbohaler 9 microg (delivered dose) or salmeterol Accuhaler 50 microg, both b.i.d, added to current ICS. Assessments included: changes in daytime reliever beta2-agonist therapy (primary variable), total 24-h reliever use, lung function, clinic and diary symptom scores, patient and carer health-related quality of life (HRQL) and adverse events. Daytime reliever use decreased significantly (p < 0.001) from baseline by 65% and 52%, respectively in the eformoterol and salmeterol treatment groups. Compared with salmeterol, eformoterol produced a greater decrease in daytime (-0.46 inhalations/day; p = 0.081) and 24-h (-0.70 inhalations/day; p = 0.043) reliever use. The percentage of patients who did not require any reliever medication during the study was significantly higher in the eformoterol group (p < 0.05 vs. salmeterol at weeks 8 and 12). Clinic and diary card peak expiratory flow and symptom measures all improved from baseline in both treatment arms. There was a significantly greater effect in favour of eformoterol for the reduction in clinic-assessed overall night-time symptoms (p < 0.05 vs. salmeterol). Clinically relevant improvements in patient-assessed HRQL occurred during treatment with eformoterol and salmeterol, but carer-assessed HRQL was improved to a clinically relevant extent, only with eformoterol. Both treatments were well tolerated. In children and adolescents with moderate persistent asthma, add-on therapy with eformoterol was well tolerated and at least as effective as salmeterol.
This review shows that the treatment of patients with COPD with salmeterol 50 mcg produces modest increases in lung function. There were varying effects for other important outcomes such as health related quality of life or reduction in symptoms. However, there was a consistent reduction in exacerbations which may help people with COPD who suffer frequent deterioration of symptoms prompting healthcare utilisation. The strength of evidence for the use of salmeterol 100 mcg, formoterol 12 mcg, 18 mcg, 24 mcg was insufficient to provide clear indications for practice.