The salmeterol/fluticasone combination is more effective than fluticasone plus oral montelukast in asthma. Salmeterol plus fluticasone propionate versus fluticasone propionate plus montelukast: a randomised controlled trial investigating the effects on airway inflammation in asthma. Comparison of inhaled salmeterol and oral zafirlukast in asthmatic patients using concomitant inhaled corticosteroids. Addition of montelukast or salmeterol to fluticasone for protection against asthma attacks: a randomized, double-blind, multicenter study. Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness. [A fixed combination of fluticasone and salmeterol permits better control of asthma than a beclomethasone dipropionate and montelukast combination]. A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge. Addition of formoterol or montelukast to low-dose budesonide: an efficacy comparison in short- and long-term asthma control. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial. Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma: a pragmatic trial. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids.
The aim of this study was to compare the efficacy and safety of salmeterol/fluticasone propionate combination product (SFC) with fluticasone propionate (FP) plus oral montelukast (M) over 12 weeks in symptomatic asthma patients. The study was a multinational, randomised, double-blind, double-dummy, parallel-group design in patients aged > or = 15 years. After a 4-week run-in during which all patients received FP 100 microg twice daily, patients were randomised to inhaled SFC (50/100 microg) twice daily or inhaled FP 100 microg twice daily and oral M 10 mg once daily. Patients kept daily records of their peak expiratory flow (PEF) symptom scores and use of rescue medication. Over the 12-week treatment period, the adjusted increase in mean morning PEF was significantly greater in the SFC group (36 l/min) than the FP/M group (19 l/min; P < 0.001). The improvement in FEV1 was also significantly greater in the SFC group (mean treatment difference 0.11 l; P < 0.001). SFC provided significantly better control of daytime and night-time symptoms and there were fewer exacerbations. Patients in the SFC group were also significantly more likely to have a rescue-free day. Both treatments were equally well tolerated. Combination therapy with FP plus salmeterol (SFC) produced significantly greater improvements in lung function and asthma control than the addition of montelukastto FP. Few studies have compared treatment strategies in patients with asthma poorly controlled on low dose inhaled corticosteroids, and little is known about the effects of different treatments on airway inflammation. In this double-blind, placebo-controlled, parallel group study, we compared the effects of salmeterol plus fluticasone propionate (FP) (Seretide; SFC) and FP plus montelukast (FP/M) on sputum inflammatory markers, airway responsiveness, lung function, and symptoms in adult asthmatics.
                Sixty-six subjects were randomised to SFC or FP/M for 12 weeks. The primary outcome was changes in neutrophil, eosinophil, macrophage, lymphocyte, and epithelial cell levels in induced sputum. Additional outcomes included the change in other sputum markers of airway inflammation, airway responsiveness, symptom control, and lung function.
                Both treatments had no significant effect on induced sputum inflammatory cells, although there was a trend for a reduction in sputum eosinophils. Both treatments significantly improved airway responsiveness, whereas SFC generally led to greater improvements in symptom control and lung function than FP/M. FP/M led to significantly greater reductions in sputum cysteinyl leukotrienes than SFC (treatment ratio 1.80; 95% CI 1.09, 2.94).
                Both treatments led to similar control of eosinophilic airway inflammation, although PEF and symptom control were better with SFC. STUDY NUMBER: SAM40030 (SOLTA). For asthmatic patients who remain symptomatic on inhaled corticosteroids, augmenting the therapy with additional long-term control medication is advocated. Long-acting beta2-adrenergic agonists and leukotriene modifiers are 2 therapeutic alternatives in the long-term controller class.
                To compare the addition of a long-acting beta2-adrenergic agonist to the addition of an oral leukotriene modifier for asthma therapy in patients who remain symptomatic on inhaled corticosteroids.
                Double-blind, double-dummy, parallel-group, multicenter clinical studies.
                54 outpatient clinical centers.
                429 male and female patients with asthma 12 years of age and older who were symptomatic while taking inhaled corticosteroids.
                Salmeterol xinafoate 42 mcg via metered dose inhaler twice daily or oral zafirlukast 20 mg twice daily.
                Pulmonary function, asthma symptoms, supplemental albuterol use, asthma quality of life scores, and adverse events.
                Inhaled salmeterol provided significantly greater improvement in pulmonary function as well as significantly greater relief of both daytime and nighttime asthma symptoms compared with oral zafirlukast in patients concurrently treated with inhaled corticosteroids. The use of supplemental albuterol was reduced to a greater extent with salmeterol compared with zafirlukast. Patients treated with salmeterol showed significantly greater improvement in Asthma Quality of Life Questionnaire (AQLQ) scores and were satisfied with how fast, how long, and how well the medication worked compared with patients in the zafirlukast group. Both treatments were well tolerated and demonstrated similar safety profiles.
                In patients with moderate to severe persistent asthma not sufficiently controlled with inhaled corticosteroids alone, the combination of inhaled salmeterol and inhaled corticosteroids is superior to the combination of oral zafirlukast and inhaled corticosteroids as stepwise therapy. 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. Asthma is a disease of chronic inflammation and bronchoconstriction. Inhaled corticosteroids (ICSs) provide important anti-inflammatory treatment but may not provide optimal control of asthma when taken alone. Two therapeutic alternatives for enhanced asthma control are to substitute the combination of fluticasone propionate (FP) and salmeterol (FP/Salm Combo) through the Diskus inhaler or to add montelukast to existing ICS therapy.
                We compared the efficacy and safety of FP/Salm Combo through the Diskus inhaler versus montelukast added to FP (FP + montelukast) in patients whose symptoms were suboptimally controlled with ICS therapy.
                We performed a multicenter, double-blind, double-dummy, parallel-group, 12-week study in 447 patients with asthma who were symptomatic at baseline while receiving low-dose FP. Patients were treated for 12 weeks with one of the following: (1) combination of FP 100 microg plus salmeterol 50 microg twice daily through the Diskus inhaler, or (2) FP 100 microg twice daily through the Diskus inhaler plus oral montelukast 10 mg once daily.
                FP/Salm Combo treatment provided better overall asthma control than FP + montelukast with significantly greater improvements in morning peak expiratory flow (+24.9 L/min vs +13.0 L/min, P <.001), evening peak expiratory flow (+18.9 L/min vs +9.6 L/min, P <.001), and forced expiratory volume in 1 second (+0.34 L vs +0.20 L, P <.001), as well as a change in the percentage of days with no albuterol use (+26.3% vs +19.1%, P =.032) and the shortness of breath symptom score (-0.56 vs -0.40, P =.017). The groups had comparable improvements in chest tightness, wheeze, and overall symptom scores. Asthma exacerbation rates were significantly lower (P =.031) in the FP/Salm Combo group (4 patients, 2%) than in the FP + montelukast group (13 patients, 6%). Adverse event profiles were comparable.
                Symptomatic patients on low-dose ICS therapy had significantly greater improvement in asthma control when switched to the FP/Salm Combo than when montelukast was added to ICS therapy. There is increasing evidence that the assessment of eosinophilic airway inflammation using induced sputum and measurement of airway hyperresponsiveness provides additional, clinically important information concerning asthma control. The aim of this study was to directly compare the effects of different treatments on these markers in patients with asthma and persistent symptoms, despite the use of low-dose inhaled corticosteroids. A double-blind four-way crossover study was performed, which compared a 1-month treatment with budesonide 400 mug b.i.d., additional formoterol, additional montelukast and placebo in 49 patients with uncontrolled asthma despite budesonide 100 mug b.i.d., with each treatment separated by a 4-week washout period. The change in sputum eosinophil count with formoterol (2.4 to 3.8% change, 0.6-fold reduction, 95% confidence interval (CI) 0.5-0.9) differed significantly from placebo (2.8 to 2.5% change, 1.1-fold reduction, 95% CI 0.7-1.6) and high-dose budesonide (2.7 to 1.6% change, 1.6-fold reduction, 95% CI 1.2-2.2). The effects of montelukast did not differ from placebo. The changes in methacholine airway responsiveness were small and did not differ between treatments. High-dose budesonide had the broadest range of beneficial effects on other outcomes, including symptom scores, morning peak expiratory flow and forced expiratory volume in one second. In conclusion, treatment given in addition to low-dose inhaled corticosteroids results in modest benefits. Formoterol and high-dose budesonide have contrasting effects on eosinophilic airway inflammation. It is now recommended to add an inhaled long-acting beta 2-agonist, or as an alternative, to add a leukotriene-antagonist, in patients whose asthma is insufficiently controlled with an inhaled corticosteroid alone. A randomised, multicentre, open-label, parallel-group study was carried out in 246 patients of at least 15 years, whose asthma was not adequately controlled with a medium dose of an inhaled corticosteroid. They received either fluticasone/salmeterol combination 250/50 micrograms one inhalation twice daily or CFC beclomethasone dipropionate 250 micrograms two puffs twice daily plus montelukast 10 mg in the evening for 12 weeks. The mean morning PEFR (main criterion) was significantly (p = 0.017) more improved with fluticasone/salmeterol (+44.2 L/min) than with beclomethasone dipropionate plus montelukast (+31.0 L/min). Other outcomes showed significantly better improvements (p 0.022 Pound) with fluticasone/salmeterol than with beclomethasone plus montelukast. The two treatments were well tolerated. Fluticasone/salmeterol provided a better asthma control than beclomethasone dipropionate plus montelukast in patients insufficiently controlled with an inhaled corticosteroid alone. 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.
                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 (50microg twice daily), or placebo for 4 weeks. Standardized spirometry after exercise challenge and beta2-agonist rescue was performed at baseline, week 1 and 4.
                Maximum achievable forced expiratory volume in 1 s (FEV1) 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 FEV1 was greatest with salmeterol (P = 0.10), patients taking montelukast had significantly greater protection from an exercise-induced decrease in FEV1 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.
                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. Asthma is a chronic inflammatory disease of the airways. Inhaled corticosteroids are very important in anti-inflammatory treatment, but to a great extent they cannot control asthma alone. In addition to corticosteroids, long-acting beta2 agonists and leukotriene antagonists are used for asthma control.
                In this study, the effect of the addition of formoterol and montelukast on asthma control in patients with moderately persistent asthma who were symptomatic while using a low dose of inhaled budesonide was compared.
                At the beginning of the study, 40 symptomatic patients with moderately persistent asthma used 400 microg/day budesonide for a 4-week training period, and were then divided randomly into two groups, each composed of 20 persons. For the first group's treatment regime, inhaled formoterol (9 microg) twice a day was added, and for the second group's treatment regime, one-dose oral montelukast (10 microg) was added. These patients were followed up for 8 weeks. The patients' peak expiratory flow (PEF) values measured in the morning and at night, changes in PEF, forced expiratory volume in 1 s, asthma symptom score and the symptom-relieving therapy used during the 12-week study period were recorded and evaluated in the clinic at the very beginning and at the end of each period.
                Before the study, the morning PEF value of the group for whom formoterol was added to budesonide (FB) was 266.3 +/- 59.3 liters/min, and in the group for whom montelukast was added to budesonide (MB), it was 262.8 +/- 53.8 liters/min (p > 0.05). After the 8-week treatment period, the morning PEF values were found to be 320.5 +/- 54.4 liters/min in the FB group and 293.3 +/- 52.4 liters/min in the MB group; at the end of the study, it was seen that although there was an increase in morning PEF of 54.2 +/- 15.2 liters/min in the FB group, there was an increase of only 30.5 +/- 25.3 liters/min in the MB group (p < 0.0001). Before the study, night PEF values were 287 +/- 56.6 liters/min in the FB group and 283 +/- 48.5 liters/min in the MB group (p > 0.05). At the end of the treatment, the night PEF values were found to be 331.5 +/- 56.1 liters/min in the FB group and 310 +/- 53.1 liters/min in the MB group. At the end of the study, it was observed that although there was an increase in night PEF of 44.5 +/- 23.3 liters/min in the FB group, there was an increase of only 27 +/- 24.1 liters/min in the MB group (p < 0.001). Although asthma symptom scores and the use of symptom-relieving drugs showed similarities between the two groups at the beginning of the study, after treatment, the FB group had better results than the MB group with respect to these two parameters (p < 0.0001 for both). It was also seen that the two treatments are tolerated equally well.
                FB treatment, which causes a considerable improvement in lung function, showed better asthma control than MB treatment in patients with moderately persistent asthma. Comparison of inhaled salmeterol powder vs oral montelukast treatment in patients with persistent asthma who remained symptomatic while receiving inhaled corticosteroids.
                Randomized, double-blind, double-dummy, parallel-group, multicenter trials of 12-week duration.
                Outpatients in private and university-affiliated clinics.
                Male and female patients > or = 15 years of age with a diagnosis of asthma (baseline FEV(1) of 50 to 80% of predicted) and symptomatic despite receiving inhaled corticosteroids.
                Inhaled salmeterol xinafoate powder, 50 microg bid, or oral montelukast, 10 mg qd. Measurements and results: Treatment with salmeterol powder resulted in significantly greater improvements from baseline compared with montelukast for most efficacy measurements, including morning peak expiratory flow (35.0 L/min vs 21.7 L/min; p < 0.001), percentage of symptom-free days (24% vs 16%; p < 0.001), and the percentage of rescue-free days (27% vs 20%; p = 0.002). Total supplemental albuterol use was decreased significantly more in the salmeterol group compared with the montelukast group (- 1.90 puffs per day vs - 1.66 puffs per day; p = 0.004) and nighttime awakenings per week decreased significantly more with salmeterol than with montelukast (- 1.42 vs - 1.32; p = 0.015). Patients treated with inhaled salmeterol were significantly more satisfied with their treatment regimen and how well, how fast, and how long it worked than were patients who were treated with oral montelukast. The safety profiles for the two treatments were similar.
                In patients with persistent asthma who remain symptomatic while receiving inhaled corticosteroids, adding inhaled salmeterol powder provided significantly greater improvement in lung function and asthma symptoms and was preferred by patients over oral montelukast. To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone. Design and setting A 52 week, two period, double blind, multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol.
                Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for > or = 1 year, a baseline forced expiratory volume in one second (FEV1) value 50-90% predicted, and a beta agonist improvement of > or = 12% in FEV1.
                The primary end point was the percentage of patients with at least one asthma exacerbation.
                20.1% of the patients in the group receiving montelukast and fluticasone had an asthma exacerbation compared with 19.1% in the group receiving salmeterol and fluticasone; the difference was 1% (95% confidence interval -3.1% to 5.0%). With a risk ratio (montelukast-fluticasone/salmeterol-fluticasone) of 1.05 (0.86 to 1.29), treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone. Salmeterol and fluticasone significantly increased FEV1 before a beta agonist was used and morning peak expiratory flow compared with montelukast and fluticasone (P < or = 0.001), whereas FEV1 after a beta agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups. Montelukast and fluticasone significantly (P = 0.011) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone. Both treatments were generally well tolerated.
                The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol. Information is lacking on the relative effectiveness and cost effectiveness--in a real-life primary-care setting--of leukotriene receptor antagonists (LTRAs) and long-acting beta2 adrenergic receptor agonists (beta2 agonists) as add-on therapy for patients whose asthma symptoms are not controlled on low-dose inhaled corticosteroids (ICS).
                To estimate the cost effectiveness of LTRAs compared with long-acting beta2 agonists as add-on therapy for patients whose asthma symptoms are not controlled on low-dose ICS.
                An economic evaluation was conducted alongside a 2-year, pragmatic, randomized controlled trial set in 53 primary-care practices in the UK. Patients aged 12-80 years with asthma insufficiently controlled with ICS (n = 361) were randomly assigned to add-on LTRAs (n = 176) or long-acting beta2 agonists (n = 185). The main outcome measures were the incremental cost per point improvement in the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), per point improvement in the Asthma Control Questionnaire (ACQ) and per QALY gained from perspectives of the UK NHS and society.
                Over 2 years, the societal cost per patient receiving LTRAs was pounds sterling 1157 versus pounds sterling 952 for long-acting beta2 agonists, a (significant, adjusted) increase of pounds sterling 214 (95% CI 2, 411) [year 2005 values]. Patients receiving LTRAs experienced a non-significant incremental gain of 0.009 QALYs (95% CI -0.077, 0.103). The incremental cost per QALY gained from the societal (NHS) perspective was pounds sterling 22,589 (pounds sterling 11,919). Uncertainty around this point estimate suggested that, given a maximum willingness to pay of pounds sterling 30,000 per QALY gained, the probability that LTRAs are a cost-effective alternative to long-acting beta2 agonists as add-on therapy was approximately 52% from both societal and NHS perspectives.
                On balance, these results marginally favour the repositioning of LTRAs as a cost-effective alternative to long-acting beta2 agonists as add-on therapy to ICS for asthma. However, there is much uncertainty surrounding the incremental cost effectiveness because of similarity of clinical benefit and broad confidence intervals for differences in healthcare costs.
                UK National Research Register N0547145240; Controlled Clinical Trials ISRCTN99132811. For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.
                We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 microg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 microg of fluticasone twice daily (ICS step-up), 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily (LABA step-up), or 100 microg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%.
                A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P=0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P=0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P=0.005).
                Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy. (ClinicalTrials.gov number, NCT00395304.)
                2010 Massachusetts Medical Society
In adults with asthma that is inadequately controlled on low doses of inhaled steroids and showing significant reversibility with beta2-agonists, LABA is superior to LTRA in reducing oral steroid treated exacerbations. Differences favouring LABA in lung function, functional status and quality of life scores are generally modest. There is some evidence of increased risk of SAEs with LABA. The findings support the use of a single inhaler for the delivery of LABA and inhaled corticosteroids. We are unable to draw conclusions about which treatment is better as add-on therapy for children.