Amanda Emmett

The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma

BACKGROUND Current treatment guidelines define inhaled corticosteroids such as fluticasone propionate (FP) as the cornerstone of anti-inflammatory therapy for asthma. OBJECTIVE The objective was to evaluate the efficacy and safety of adding salmeterol therapy to patients who remain symptomatic while receiving FP as compared with increasing the dose of FP. METHODS In a multicenter, double-blind study conducted over 24-weeks, 437 patients aged 12 years and older and receiving FP 88 microg twice daily for 2 to 4 weeks were randomly assigned to receive either salmeterol (42 microg twice daily) or FP 220 microg twice daily. The primary efficacy endpoint was morning peak expiratory flow. Secondary measures included FEV1, symptom scores, nighttime awakenings, and supplemental albuterol use. Safety was assessed by reported adverse events and asthma exacerbations. RESULTS The addition of salmeterol resulted in significantly greater improvements in lung function and symptom control as compared with increasing the dose of FP. Over weeks 1 to 24, morning peak expiratory flow was increased by 47 L/min from baseline with salmeterol treatment as compared with 24 L/min with FP 220 microg twice daily (P < .001) while the percent of symptom-free days increased from baseline by 26% of days as compared with 10% of days (P < .001). The adverse event profiles were similar between groups and fewer exacerbations were reported with salmeterol treatment. CONCLUSIONS The addition of salmeterol therapy to patients who remain symptomatic while using a low dose of FP was clinically and statistically superior to increasing the dose of FP.

Effect of fluticasone propionate/salmeterol (250/50 μg) or salmeterol (50 μg) on COPD exacerbations

OBJECTIVES 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. METHODS 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. RESULTS 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%). CONCLUSIONS 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.

Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations.

OBJECTIVES 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. METHODS 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. RESULTS 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%). CONCLUSIONS 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.

β2-Receptor Polymorphisms in Patients Receiving Salmeterol with or without Fluticasone Propionate

RATIONALE Retrospective pharmacogenetic studies have questioned whether patients with asthma who are arginine homozygous at the beta(2-)adrenergic receptor (position 16) should use long-acting beta-agonists. OBJECTIVES To examine whether the response to salmeterol alone or in combination with an inhaled corticosteroid is influenced by beta- receptor polymorphisms. METHODS Subjects using only as-needed albuterol were screened and completed two sequential open-label run-in periods (8 wk on as-needed albuterol; 8 wk on as-needed ipratropium). Five hundred forty-four subjects were randomized by Arg16Gly genotype to salmeterol alone or with fluticasone propionate for 16 weeks. Change from baseline in morning peak expiratory flow was the primary endpoint. MEASUREMENTS AND MAIN RESULTS Lung function responses were sustained over treatment and no statistically significant changes from baseline between genotypes within treatments were observed. Overall mean changes in morning peak flow for salmeterol with fluticasone propionate were 32.6 L/min (Arg/Arg vs. Gly/Gly, 95% confidence interval [CI], -6.3, 22.1), 25.9 L/min (Arg/Arg vs. Arg/Gly, 95% CI, -7.1, 21.3), and 24.9 L/min (Arg/Gly vs. Gly/Gly, 95% CI, -13.0, 14.6), and for salmeterol alone were 19.4 L/min (Arg/Arg vs. Gly/Gly, 95% CI, -1.7, 21.4), 24.6 L/min (Arg/Arg vs. Arg/Gly, 95% CI, -13.0, 10.6), and 12.4 L/min (Arg/Gly vs. Gly/Gly, 95% CI, -0.2, 22.3) for Arg/Arg, Arg/Gly, and Gly/Gly genotypes, respectively. Other measures of asthma control showed similar responses. CONCLUSIONS The results showed no evidence of a pharmacogenetic effect of beta-receptor variation on salmeterol response. Clinical trial registered with www.clinicaltrials.gov (NCT 00102882).

Concurrent use of salmeterol with inhaled corticosteroids is more effective than inhaled corticosteroid dose increases.

This randomized, double-blind, parallel, multi-center study was designed to determine whether the addition of salmeterol to existing inhaled corticosteroid therapy provides greater therapeutic benefit than doubling the dose of inhaled corticosteroids in symptomatic patients with asthma. A total of 514 adults were randomized to either beclomethasone 168 micrograms plus salmeterol 42 micrograms twice daily or beclomethasone 336 micrograms twice daily for 24 weeks. Both treatments resulted in significantly improved symptom control and increased pulmonary function. However, beclomethasone plus salmeterol provided greater improvements than doubling the dose of beclomethasone (p < or = 0.05) in FEV1 and in daily-recorded measurements of morning (38 L/minute versus 20 L/minute after treatment with higher dose beclomethasone) and evening peak expiratory flow, asthma symptom scores, symptom-free days, supplemental albuterol use, and days and nights not requiring albuterol. There were no significant differences between treatment groups in the number of patients with abnormal response to corticotropin stimulation at Treatment Week 24. No treatment differences in asthma exacerbation and adverse event frequency rates were seen. Beclomethasone 168 micrograms plus salmeterol 42 micrograms administered twice daily was superior to beclomethasone 336 micrograms taken twice daily in patients symptomatic on beclomethasone 168 micrograms, with no added safety risks.

Salmeterol Added to Inhaled Corticosteroid Therapy Is Superior to Doubling the Dose of Inhaled Corticosteroids: A Randomized Clinical Trial

This randomized, double-blind, double-dummy, parallel group clinical trial compared the efficacy and safety of adding salmeterol xinafoate to concurrent inhaled beclomethasone dipropionate therapy with doubling the dose of beclomethasone dipropionate in patients experiencing symptoms on low-dose beclomethasone. Salmeterol added to low-dose beclomethasone was superior (p < or = 0.05) to doubling the dose of beclomethasone in improving peak expiratory flow (PEF) and forced expiratory volume in 1 sec (FEV1), and in reducing symptoms of asthma, sleep loss, nighttime awakenings, and use of albuterol. Both treatment regimens had comparable safety profiles. In asthma patients inadequately controlled despite the use of low-dose inhaled corticosteroids (i.e., less than 400 microg per day), the addition of salmeterol may be a more effective treatment option than doubling the dose of inhaled corticosteroids.

Body Mass Index and Response to Asthma Therapy: Fluticasone Propionate/Salmeterol versus Montelukast

We studied the relationship between body mass index (BMI) on responses to asthma therapy using a retrospective analysis of four previously reported clinical trials. Fluticasone propionate (FP)/salmeterol via Diskus 100/50 μg twice daily and montelukast (MON) 10 mg daily were compared. BMI was classified as underweight (less than 20 kg/m2), normal (20–24.9 kg/m2), overweight (25–29.9 kg/m2), obese-1 (30–34.9 kg/m2), obese-2 (35–39.9 kg/m2), or obese-3 (at least 40 kg/m2). Outcomes assessed included forced expiratory volume in one second (FEV1), asthma symptom score, and albuterol use. FP/salmeterol produced greater improvements compared to MON in each of the asthma outcomes studied over the entire BMI range at the week-12 endpoint, with statistically significant differences noted among normal, overweight, obese-1, and obese-3 subjects. The within-treatment responses to FP/salmeterol across BMI ranges at the week-12 endpoint was statistically significantly greater in normal compared to obese-3 for FEV1 and albuterol use, and in overweight compared to the obese-3 for each outcome studied. The within-treatment comparisons of MON across BMI ranges were significant for albuterol use in normal and underweight compared to obese-3 at the week-12 endpoint. Compared to subjects with normal BMI, the onset to peak FEV1 may require longer treatment exposure in the very obese. Treatment responses to FP/salmeterol were consistently greater compared to MON and persisted at higher BMI.

Fluticasone propionate/salmeterol combination compared with montelukast for the treatment of persistent asthma

BACKGROUND Asthma is a chronic disease characterized by inflammation and bronchoconstriction. Medications that are able to effectively treat both components are advantageous. OBJECTIVE To compare the efficacy of an inhaled corticosteroid and a long-acting beta2-agonist combination product with a leukotriene antagonist for initial maintenance therapy in patients who were symptomatic while receiving short-acting beta2-agonists alone. METHODS A 12-week, randomized, double-blind, double-dummy, multicenter study was conducted in 432 patients 15 years of age and older with persistent asthma who were symptomatic on short-acting beta2-agonists alone. Fluticasone propionate 100 microg and salmeterol 50 microg combination product (FSC) twice daily or montelukast 10 mg once daily was administered. RESULTS At endpoint, compared with montelukast, FSC significantly increased morning predose forced expiratory volume in 1 second (0.61 +/- 0.03 L vs 0.32 +/- 0.03 L), morning peak expiratory flow rate (peak expiratory flow rate; 81.4 +/- 5.9 L/minute vs 41.9 +/- 4.8 L/minute), evening peak expiratory flow rate (64.6 +/- 5.3 L/minute vs 38.8 +/- 4.7 L/minute), the percentage of symptom-free days (40.3 +/- 2.9% vs 27.0 +/- 2.7%), the percentage of rescue-free days (53.4 +/- 2.8% vs 26.7 +/- 2.5%), and the percentage of nights with no awakenings (29.8 +/- 2.5% vs 19.6 +/- 2.1%) (P < or = 0.011, all comparisons). At endpoint, FSC significantly reduced asthma symptom scores (-1.0 +/- 0.1 vs -0.7 +/- 0.1) and rescue albuterol use (-3.6 +/- 0.2 puffs/day vs -2.2 +/- 0.2 puffs/day) compared with montelukast (P < 0.001). At endpoint, patients treated with FSC also had a significantly greater improvement in quality of life scores and were more satisfied with their treatment compared with montelukast-treated patients (P < or = 0.001). Both treatments were well tolerated. CONCLUSIONS Initial maintenance therapy with FSC provides greater improvement in asthma control and patient satisfaction than montelukast.

Effect of fluticasone/salmeterol administered via a single device on exercise-induced bronchospasm in patients with persistent asthma

BACKGROUND Exercise is a common trigger of asthma symptoms in patients with persistent asthma. OBJECTIVE To evaluate the protective effect of fluticasone/salmeterol against exercise-induced bronchospasm. METHODS Multicenter, randomized, double-blind, parallel-group trial of 192 asthma patients who used moderate-dose inhaled corticosteroids. Patients (aged 12-50 years; mean forced expiratory volume in 1 second [FEV1], 78% of predicted at baseline) were randomized to receive fluticasone/salmeterol (250/50 microg twice daily) or fluticasone alone (250 microg twice daily) via Diskus for 4 weeks. Exercise challenge tests were performed 1 and 8.5 hours after administration of the first (day 1) and last (week 4) doses of blinded study medication. RESULTS On day 1 and at week 4, mean +/- SEM values for the maximal percentage decline in FEV1 1 hour after drug administration were 11.4% +/- 1.5% and 10.9% +/- 1.5% for fluticasone/salmeterol compared with 20.0% +/- 1.7% and 18.4% +/- 1.8% for fluticasone (P < .001). At 8.5 hours, mean +/- SEM values on day 1 and at week 4 were 11.6% +/- 1.4% and 8.9% +/1.1%, respectively, for fluticasone/salmeterol and 12.6% +/- 1.6% and 12.9% +/- 1.4%, respectively, for fluticasone (P = .01 at week 4). More fluticasone-treated patients did not complete the 8.5-hour exercise challenges (36% on day 1 and 33% at week 4) compared with the fluticasone/salmeterol group (18% each) (P < or = .01). Improvements in peak expiratory flow rate and albuterol rescue-free days were significantly greater with fluticasone/salmeterol vs fluticasone over weeks 1 to 4 (P < or = .03). CONCLUSIONS Consistent with the improvements in other measures of asthma control, long-term fluticasone/salmeterol therapy also provided protection against exercise-induced bronchospasm in patients with persistent asthma.

Lung function and symptom improvement with fluticasone propionate/salmeterol and ipratropium bromide/albuterol in COPD: Response by beta-agonist reversibility ☆

This retrospective analysis of data from two multi-center, randomized, double-blind, parallel group studies compared the efficacy of fluticasone propionate/salmeterol (FSC) 250/50 mcg twice daily with ipratropium bromide/albuterol (IB/ALB) 36/206 mcg four times daily in albuterol-reversible (n=320 [44%]) and non-reversible (n=399 [56%]) patients with COPD. In reversible and non-reversible patients, both treatments significantly increased FEV(1)AUC(0-6h) from baseline and the magnitude of improvement was larger in reversible patients. FSC increased FEV(1)AUC(0-6h) by 1.46+/-0.08 and 1.98+/-0.13 l-h at Day 1 and Week 8, respectively, in reversible patients, compared with 0.71+/-0.06 and 0.94+/-0.10 l-h in non-reversible patients (p<0.001). With IB/ALB, increases were 1.46+/-0.08 and 1.19+/-0.11 l-h at Day 1 in reversible patients and Week 8, respectively, and 0.89+/-0.06 and 0.74+/-0.09 l-h (p < or = 0.041) in non-reversible patients. After 8 weeks, in both the reversible and non-reversible populations, the FEV(1) AUC(0-6h) significantly increased with FSC treatment (p < or = 0.002) and significantly decreased with IB/ALB (p < or = 0.010). In both reversibility groups, improvement in Transition Dyspnea Index (TDI) scores, overall daytime diary symptom scores and nocturnal symptom measures were significantly greater with FSC treatment compared with IB/ALB (p < or = 0.044). Reversibility status was not predictive of the magnitude of reduction in symptom scores. We conclude that both reversible and non-reversible patients receive greater clinical benefit with FSC compared with IB/ALB and acute bronchodilator reversibility is not useful for differentiating patients based on symptomatic responses to FSC compared with IB/ALB.