Twice-daily Salmeterol Research Articles

PRS10 Economic Evaluation of Umeclidinium/Vilanterol Versus Umeclidinium or Salmeterol in a UK COPD Population at Low Risk of Exacerbations Using the GALAXY Model

The 24-week EMAX trial in symptomatic patients with chronic obstructive pulmonary disease (COPD) and low exacerbation risk not receiving inhaled corticosteroids demonstrated clinical benefits of once-daily umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg versus once-daily UMEC 62.5 mcg and twice-daily salmeterol (SAL) 50 mcg. This post hoc analysis assessed cost-effectiveness of UMEC/VI versus UMEC or SAL from a UK payer perspective in patients with COPD and no exacerbation history in the EMAX trial. The validated GALAXY risk equation model was populated with EMAX patient characteristics, treatment effects, rescue medication use data, and 2020 UK costs. Treatment effects included forced expiratory volume in 1 second (FEV1) and St George’s Respiratory Questionnaire (SGRQ); no treatment effect was included for exacerbations. Model outputs included estimated exacerbation rates, survival, costs, life years (LYs), and quality-adjusted LYs (QALYs); incremental cost-effectiveness ratio (ICER) was calculated for cost per QALY gained. The base case used a 10-year time horizon, excluded treatment discontinuation, and discounted future costs and QALYs by 3.5% annually. Sensitivity and scenario analyses assessed robustness of model results. Despite greater incremental drug costs, UMEC/VI was the dominant treatment versus UMEC and SAL, providing an additional 0.090 LYs (95% CI: 0.035, 0.158) and 0.055 QALYs (-0.059, 0.168) with cost savings of £690 (-£1306, -£231) versus UMEC, and 0.174 LYs (0.076, 0.286) and 0.204 QALYs (0.079, 0.326) with cost savings of £1336 (-£2032, -£1006) versus SAL. In scenario and sensitivity analyses, ICERs for UMEC/VI versus UMEC were sensitive to time horizon (5 years: ICER=£4) and SGRQ treatment effect (upper CI: ICER=£12,337), while UMEC/VI was consistently dominant versus SAL. Based on model predictions from a UK NHS perspective, symptomatic patients with COPD and no exacerbation history receiving UMEC/VI are expected to have better outcomes (QALYs and survival) at lower costs versus UMEC and SAL. FUNDING: GSK (study 209845; EMAX study 201749/NCT03034915).

Salbutamol use in relation to maintenance bronchodilator efficacy in COPD: a prospective subgroup analysis of the EMAX trial

BackgroundShort-acting β2-agonist (SABA) bronchodilators help alleviate symptoms in chronic obstructive pulmonary disease (COPD) and may be a useful marker of symptom severity. This analysis investigated whether SABA use impacts treatment differences between maintenance dual- and mono-bronchodilators in patients with COPD.MethodsThe Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids 1:1:1 to once-daily umeclidinium/vilanterol 62.5/25 μg, once-daily umeclidinium 62.5 μg or twice-daily salmeterol 50 μg for 24 weeks. Pre-specified subgroup analyses stratified patients by median baseline SABA use (low, < 1.5 puffs/day; high, ≥1.5 puffs/day) to examine change from baseline in trough forced expiratory volume in 1 s (FEV1), change in symptoms (Transition Dyspnoea Index [TDI], Evaluating Respiratory Symptoms-COPD [E-RS]), daily SABA use and exacerbation risk. A post hoc analysis used fractional polynomial modelling with continuous transformations of baseline SABA use covariates.ResultsAt baseline, patients in the high SABA use subgroup (mean: 3.91 puffs/day, n = 1212) had more severe airflow limitation, were more symptomatic and had worse health status versus patients in the low SABA use subgroup (0.39 puffs/day, n = 1206). Patients treated with umeclidinium/vilanterol versus umeclidinium demonstrated statistically significant improvements in trough FEV1 at Week 24 in both SABA subgroups (59–74 mL; p < 0.001); however, only low SABA users demonstrated significant improvements in TDI (high: 0.27 [p = 0.241]; low: 0.49 [p = 0.025]) and E-RS (high: 0.48 [p = 0.138]; low: 0.60 [p = 0.034]) scores. By contrast, significant reductions in mean SABA puffs/day with umeclidinium/vilanterol versus umeclidinium were observed only in high SABA users (high: − 0.56 [p < 0.001]; low: − 0.10 [p = 0.132]). Similar findings were observed when comparing umeclidinium/vilanterol and salmeterol. Fractional polynomial modelling showed baseline SABA use ≥4 puffs/day resulted in smaller incremental symptom improvements with umeclidinium/vilanterol versus umeclidinium compared with baseline SABA use < 4 puffs/day.ConclusionsIn high SABA users, there may be a smaller difference in treatment response between dual- and mono-bronchodilator therapy; the reasons for this require further investigation. SABA use may be a confounding factor in bronchodilator trials and in high SABA users; changes in SABA use may be considered a robust symptom outcome.FundingGlaxoSmithKline (study number 201749 [NCT03034915]).

Add-on Tiotropium in Chinese Patients With Moderate Asthma: A Pooled Subgroup Analysis of MezzoTinA-Asthma 1 and 2.

PurposeAsthma affects approximately 30 million patients in China; however, tiotropium data for Chinese patients is limited. This study aimed to assess the efficacy and safety of tiotropium in Chinese patients with moderate symptomatic asthma.MethodsA post hoc subgroup analysis was conducted on 430 Chinese patients pooled from two 24-week, replicate phase 3 trials (NCT01172808 and NCT01172821), in which they received once-daily tiotropium 2.5 µg (Tio R2.5) or 5 µg (Tio R5) (n = 106 or 109, respectively), twice-daily salmeterol 50 µg (Sal 50) (n = 110), or placebo (n = 105), while maintaining inhaled corticosteroids (ICS). The co-primary endpoints assessed in week 24 were forced expiratory volume in 1 second (FEV1) peak0–3h response, trough FEV1 response, and responder rate as assessed using the Asthma Control Questionnaire (ACQ).ResultsFor both FEV1 peak0–3h responses and trough FEV1 responses, the mean treatment differences were greater for Tio R2.5, Tio R5, and Sal 50 compared with placebo at 0.249 L, 0.234 L, and 0.284 L, and 0.172 L, 0.180 L, and 0.164 L, respectively (P< 0.001). The ACQ responder rate in placebo, Tio R2.5, Tio R5, and Sal 50 was 58.7%, 62.3%, 59.3%, and 69.1%, respectively. Furthermore, 11 (2.6%) of 430 patients had serious adverse events (Tio R5, n = 4; Tio R2.5, n = 1; Sal 50, n = 1; and placebo, n = 5).ConclusionsOnce-daily tiotropium, as add-on to medium-dose ICS, was effective and well tolerated for Chinese patients with moderate symptomatic asthma, consistent with the main analysis.

Tiotropium Respimat Add-on Is Efficacious in Symptomatic Asthma, Independent of T2 Phenotype

Adding tiotropium to existing inhaled corticosteroid (ICS) maintenance therapy with or without a long-acting β2-agonist (LABA) has been shown to be beneficial in patients with symptomatic asthma. To assess whether responses to tiotropium Respimat add-on therapy were influenced by patients' T2 status. In this exploratory study, data from 4 phase III trials were analyzed: once-daily tiotropium 5 μg or placebo as add-on to ICS+ LABA (PrimoTinA-asthma; 2 replicate trials; NCT00772538/NCT00776984; n= 912); once-daily tiotropium 5 μg or 2.5 μg, twice-daily salmeterol 50 μg, or placebo as add-on to ICS (MezzoTinA-asthma; 2 replicate trials; NCT01172808/NCT01172821; n= 2100). The prespecified efficacy outcomes of these studies have been reported previously. Here, further exploratory subgroup analyses were performed to study whether these coprimary end points were influenced by serum IgE levels, blood eosinophil counts, and clinician judgment of allergic asthma. In addition, for the continuous parameters, namely, IgE and blood eosinophils, their influence on the treatment effect was modeled over the whole range of values. Tiotropium was efficacious in improving peak FEV1 within 3 hours postdose and trough FEV1, independent of T2 status. Tiotropium significantly reduced the risk of severe asthma exacerbations and asthma worsening, independent of T2 phenotype; Cox regression modeling supported a beneficial effect of tiotropium on exacerbations, independent of IgE levels or eosinophil counts. Numerical improvements in the 7-question Asthma Control Questionnaire (ACQ-7) responder rate with tiotropium versus placebo were observed in T2high and T2low patients; logistic regression modeling provided further evidence for improvement in ACQ-7 responder rates with tiotropium, independent of IgE levels or eosinophil counts. The results of our exploratory analyses suggest that the improvements seen with tiotropium Respimat as add-on to ICS ± LABA in patients with symptomatic asthma on lung function, exacerbation risk, and symptom control are independent of T2 phenotype.

The lung function profile of once-daily tiotropium and olodaterol via Respimat(®) is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler(®) (ENERGITO(®) study).

BackgroundTiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD. Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk. This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.ObjectiveThe study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.MethodsThis was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat® and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler® for 6 weeks. The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0–12) relative to the baseline after 6 weeks.ResultsTiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0–12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively). Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0–24).ConclusionOnce-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate. Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD.

The impact of treatment with indacaterol in patients with COPD: A post-hoc analysis according to GOLD 2011 categories A to D

BackgroundIndacaterol is an inhaled, once-daily, ultra-long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). We report on the effectiveness of indacaterol and other bronchodilators compared with placebo in patients across the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 categories A to D. MethodsA post-hoc, subgroup pooled analysis of 6-month efficacy data from three randomized, placebo-controlled, parallel-group studies involving 3862 patients was performed across GOLD 2011 categories A to D, according to baseline forced expiratory volume in 1 s (FEV1) % predicted, modified Medical Research Council (mMRC) dyspnea scale, and exacerbation history in the 12 months prior to entry. Efficacy of once-daily indacaterol 150 and 300 μg, open-label tiotropium 18 μg, twice-daily salmeterol 50 μg, and formoterol 12 μg was compared with placebo. End points analysed were trough FEV1, transition dyspnea index (TDI), and St George's Respiratory Questionnaire (SGRQ) total score, all at Week 26, and mean rescue medication use over 26 weeks. ResultsIndacaterol 150 and 300 μg significantly improved FEV1, compared with placebo across all GOLD groups. Indacaterol 150 and 300 μg also significantly improved TDI, SGRQ total score, and mean rescue medication use compared with placebo across most GOLD subgroups. ConclusionsTreatment selection according to patient's symptoms as well as lung function is an important consideration in maintenance treatment of COPD. Indacaterol 150 and 300 μg effectively improved lung function and symptoms in patients across all GOLD 2011 categories.

Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials

In patients with severe asthma, tiotropium improves lung function and exacerbation risk when added to high-dose inhaled corticosteroids plus long-acting β2 agonists. We aimed to assess the safety and efficacy of tiotropium in patients with moderate asthma who were symptomatic despite treatment with medium-dose inhaled corticosteroids. We did two 24-week, replicate, randomised, double-blind, placebo-controlled, parallel-group, active-comparator trials at 233 sites in 14 countries. Eligible patients were aged 18-75 years with symptomatic asthma and a pre-bronchodilator forced expiratory volume in 1 s (FEV1) of 60-90% predicted despite use of medium-dose inhaled corticosteroids, and had never smoked or were ex-smokers for 1 year or more with 10 pack-years or less. Patients were randomly assigned (1:1:1:1), with computer-generated pseudorandom numbers, to receive once-daily tiotropium 5 μg or 2·5 μg, twice-daily salmeterol 50 μg, or placebo, while maintaining inhaled corticosteroids. Patients and study investigators were masked to treatment allocation. Prespecified co-primary endpoints, assessed at week 24 in the full analysis set, were peak FEV1 response, measured within the first 3 h after evening dosing; trough FEV1 response; and responder rate assessed according to the seven-question Asthma Control Questionnaire (ACQ-7). These studies are registered with ClinicalTrials.gov, numbers NCT01172808 and NCT01172821. Between Aug 24, 2010, and Nov 13, 2012, we randomly assigned 2103 patients to the tiotropium 5 μg group (n=519), the tiotropium 2·5 μg group (n=520), the salmeterol group (n=541), or the placebo group (n=523); 1972 (94%) patients completed the study. Peak and trough FEV1 responses were significantly greater with tiotropium and salmeterol than with placebo and were similar in both studies. With pooled data, difference versus placebo in peak FEV1 was 185 mL (95% CI 146-223) in the tiotropium 5 μg group, 223 mL (185-262) in the tiotropium 2·5 μg group, and 196 mL (158-234) in the salmeterol group (all p<0·0001); difference in trough FEV1 was 146 mL (95% CI 105-188), 180 mL (138-221), and 114 mL (73-155; all p<0·0001), respectively. There were more ACQ-7 responders in the tiotropium 5 μg (OR 1·32, 95% CI 1·02-1·71; p=0·035) and 2·5 μg (1·33, 1·03-1·72; p=0·031) groups, and the salmeterol group (1·46, 1·13-1·89; p=0·0039), than in the placebo group. 48 (2%) of 2100 patients had serious adverse events (tiotropium 5 μg n=11, tiotropium 2·5 μg n=12, salmeterol n=11, placebo n=14). Once-daily tiotropium add-on to medium-dose inhaled corticosteroids reduces airflow obstruction and improves asthma control in patients with moderate symptomatic asthma. Patterns of response with both tiotropium doses were similar to those of salmeterol, and all active compounds had good safety and tolerability. Tiotropium is a safe and effective bronchodilator, and an alternative to salmeterol in this patient population. Boehringer Ingelheim.

Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol–fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study

QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease (COPD). It combines indacaterol (a longacting β2-agonist) with glycopyrronium (a longacting muscarinic antagonist) as a dual bronchodilator. We aimed to compare the efficacy, safety, and tolerability of QVA149 versus salmeterol-fluticasone (SFC) over 26 weeks in patients with moderate-to-severe COPD. In this multicentre double-blind, double-dummy, parallel-group study, 523 patients (age 40 years or older, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages II-III, without exacerbations in the previous year) were randomly assigned (1:1; via automated, interactive response technology and stratified for smoking status) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks. Efficacy was assessed in the full analysis set (randomised patients who received at least one dose of study drug); safety was assessed in all patients who received at least one dose of study drug. The primary endpoint was to demonstrate the superiority of QVA149 compared with SFC for the standardised area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second (FEV1 AUC0-12h) after 26 weeks of treatment. This trial was registered at ClinicalTrial.gov, NCT01315249. Between March 25, 2011, and March 12, 2012, 259 patients were randomly assigned to receive QVA149 and 264 to receive SFC. At week 26, FEV1 AUC0-12h was significantly higher with QVA149 than with SFC (treatment difference 0·138 L; 95% CI 0·100-0·176; p<0·0001). Overall incidence of adverse events (including COPD exacerbations) was 55·4% (143 of 258) for the QVA149 group and 60·2% (159 of 264) for the SFC group. Incidence of serious adverse events was similar between treatment groups (QVA149, 13 of 258 [5·0%]; SFC 14 of 264 [5·3%]); COPD worsening was the most frequent serious adverse event (one of 13 [0·4%] and three of 14 [1·1%], respectively). Once-daily QVA149 provides significant, sustained, and clinically meaningful improvements in lung function versus twice-daily SFC, with significant symptomatic benefit. These results indicate the potential of dual bronchodilation as a treatment option for non-exacerbating symptomatic COPD patients. Novartis Pharma AG.

Indacaterol

Indacaterol inhalation powder (Onbrez® Breezhaler®) is a long-acting, selective β(2)-adrenoceptor agonist that is indicated for the maintenance bronchodilator treatment of airflow obstruction in adults with chronic obstructive pulmonary disease (COPD). This article reviews the clinical efficacy and tolerability of indacaterol 150 and 300 μg once daily in adults with moderate to severe COPD, as well as reviewing indacaterol's pharmacological properties and results of a cost-utility analysis. Indacaterol has a fast onset of action after the first dose and is effective over 24 hours, allowing for once-daily administration. In short-term trials (≤21 days) in patients with COPD, once-daily indacaterol 150 or 300 μg significantly improved lung function, exercise endurance and lung hyperinflation relative to placebo. In large, longer-term clinical studies (12 weeks to 1 year) in patients with moderate to severe COPD, once-daily indacaterol 150 or 300 μg improved lung function (primary endpoint) significantly more than placebo, and improvements were significantly greater than twice-daily formoterol 12 μg or salmeterol 50 μg, and noninferior to once-daily tiotropium bromide 18 μg (all agents were administered via inhalation). Overall, indacaterol improved dyspnoea, use of rescue medication and general health status significantly more than placebo, salmeterol or tiotropium bromide, and the degree of improvement in these endpoints was similar to or greater than that achieved with formoterol. Improvements were sustained over the long term (1 year), with no evidence of tolerance. Combination therapy with indacaterol plus tiotropium bromide improved lung function, dyspnoea, rescue medication use and general health status significantly more than tiotropium bromide alone in patients with moderate to severe COPD. Indacaterol is generally well tolerated when used alone or in combination with tiotropium bromide in patients with COPD and has not been associated with any safety issues. The most common adverse event in clinical trials was COPD worsening, which occurred more commonly with placebo than indacaterol. Indacaterol was not associated with an increased risk of cardiovascular adverse events. In a cost-utility analysis from a German healthcare payer perspective, once-daily indacaterol 150 μg was dominant (i.e. more effective with lower total costs) to once-daily tiotropium bromide 18 μg and twice-daily salmeterol 50 μg in the treatment of patients with COPD. In conclusion, indacaterol provides a valuable option for the maintenance treatment of adults with COPD.

Efficacy of indacaterol in the treatment of patients with COPD

Effective bronchodilation is an important part of the management of patients with chronic obstructive pulmonary disease (COPD) and can improve breathlessness and ability to undertake physical activities. Indacaterol is a new once-daily, long-acting inhaled bronchodilator for COPD. We review here the efficacy of indacaterol as a bronchodilator, including its impact upon symptoms and health status. The evidence reviewed comprises four placebo-controlled clinical studies of indacaterol treatment, three of which included treatment arms with one of the other long-acting inhaled bronchodilators (once-daily tiotropium or twice-daily salmeterol or formoterol), in 4,833 patients with moderate-to-severe COPD. Indacaterol had a bronchodilator effect significantly greater than formoterol and salmeterol, and similar to tiotropium. Its effect on symptoms and health status was similar or significantly greater than the other bronchodilators. The safety profile was similar to placebo. Once-daily indacaterol is an effective and beneficial maintenance bronchodilator treatment for patients with moderate-to-severe COPD.

Indacaterol once-daily provides superior efficacy to salmeterol twice-daily in COPD: A 12-week study

Indacaterol is a novel, inhaled once-daily ultra-long-acting β(2)-agonist for the treatment of COPD. This 12-week randomised, parallel-group study compared the efficacy of indacaterol 150 μg once-daily to salmeterol 50 μg twice-daily in patients with moderate-to-severe COPD. Assessments included FEV(1) standardised area under curve (AUC) from 5 min to 11 h 45 min at Week 12 (primary endpoint), 24-h trough FEV(1) (mean of 23 h 10 min and 23 h 45 min post-dose) at Week 12 (key secondary endpoint), FEV(1) and FVC measured over 24-h, transition dyspnoea index (TDI) and rescue medication use. Of 1123 patients randomised 92.1% completed. Mean ± SD age was 62.8±8.78 years, post-bronchodilator FEV(1) 51.8±12.32% predicted, FEV(1)/FVC 50.6±9.54%. At Week 12, FEV(1) AUC(5 min-11 h 45 min) for indacaterol was statistically superior (p<0.001) to salmeterol (adjusted mean difference [95% CI] 57 [35, 79] mL), as was 24-h trough FEV(1) (60 [37, 83] mL, p<0.001). Indacaterol also showed statistical superiority over salmeterol in terms of FEV(1) and FVC measured over 24-h at Week 12. For TDI at Week 12, the mean total score was statistically superior for indacaterol versus salmeterol (difference 0.63 [0.30, 0.97], p<0.001), as was the percentage of patients with a clinically relevant (i.e., ≥1 point) change from baseline (69.4% vs 62.7%, p<0.05). For rescue medication, patients on indacaterol used fewer puffs/day (difference -0.18 [-0.36, 0.00] puffs/day, p<0.05) and had a greater percentage of days with no rescue use (difference 4.4 [0.6, 8.2], p<0.05). Once-daily indacaterol provided statistically superior bronchodilation with an improvement in breathlessness and rescue use compared with twice-daily salmeterol. ClinicalTrials.gov NCT00821093.

Indacaterol once-daily is equally effective dosed in the evening or morning in COPD

Indacaterol is a novel, inhaled, long-acting β(2)-agonist providing 24-h bronchodilation with once-daily (o.d.) dosing in patients with COPD. In this double-blind, incomplete block crossover study, patients with moderate-to-severe COPD were randomised to receive three treatment cycles from: indacaterol 300μg o.d. dosed PM or AM, salmeterol 50μg twice daily or placebo, each for 14 days. Trough FEV(1) was measured 24h after indacaterol, and 12h after salmeterol. Ninety-six patients (mean age: 64 years; post-bronchodilator FEV(1) 57% predicted, FEV(1)/FVC 55%) were randomised; 83 completed. After 14 days, the difference vs. placebo in trough FEV(1) for PM indacaterol was 200mL (p<0.001 [primary analysis]) and for AM indacaterol was 200mL (p<0.001). Compared with salmeterol, trough FEV(1) for PM indacaterol was 110mL higher (p<0.001), and for AM indacaterol was 50mL higher (p=NS). Over 14 days, vs. placebo, both PM and AM indacaterol improved the % of nights with no awakenings (by 11.9 and 8.1 points; p<0.01); the % of days with no daytime symptoms (by 6.7 and 5.5 points; p<0.05); and the % of days able to perform usual activities (by 6.7 and 7.8 points; p<0.05). Indacaterol provided 24-h bronchodilation and improvement in symptoms regardless of whether taken regularly in the morning or evening. ClinicalTrials.gov NCT00615030.

Indacaterol maleate for the treatment of chronic obstructive pulmonary disease

Importance of the field: Chronic obstructive pulmonary disease (COPD) is a partially reversible, progressive obstructive disorder. Bronchodilators are the mainstay of treatment since they improve lung function and patient-reported outcomes and reduce acute exacerbations. Long-acting inhaled bronchodilators (at present including the once-daily antimuscarinic tiotropium, and the twice-daily β2-agonists formoterol and salmeterol) are recommended as first-line treatment for patients with persistent symptoms. Indacaterol maleate has been developed as a new once-daily inhaled β2-selective agonist.Areas covered in this review: This article reviews the published literature on the pharmacologic properties and the Phase II and III trials that have evaluated the safety and efficacy of this new agent.What the reader will gain: The reader will obtain an appreciation of the safety and efficacy of indacaterol and the role that it might play in the future management of COPD of varying severity.Take home message: Indacaterol is a new, once-daily β2-agonist with an onset of action within 5 min and a duration of bronchodilation of at least 24 h. In doses of 150 and 300 μg, it has sustained benefits over 6 – 12 months with respect to both bronchodilation and patient-reported outcomes and is well-tolerated with an acceptable safety profile.

Is a long-acting inhaled bronchodilator the first agent to use in stable chronic obstructive pulmonary disease?

Purpose of review This article reviews findings from recently published randomized controlled clinical trials to address the question whether a long-acting inhaled bronchodilator should be the initial choice for maintenance therapy in patients with stable, symptomatic chronic obstructive pulmonary disease (COPD). Recent findings Results of recent clinical trials suggest that a long-acting inhaled bronchodilator, either once-daily tiotropium or twice-daily salmeterol or formoterol, has advantages over a regularly-scheduled short-acting anticholinergic inhaled bronchodilator (ipratropium) as initial maintenance therapy in patients with at least moderate, stable, symptomatic COPD (forced expired volume in 1 second ≤ 60-70% predicted; mean, ~37-45% predicted). For tiotropium, these advantages encompass several important outcomes, including lung function, rescue inhaler use, dyspnea, frequency of exacerbations, and hospitalization for COPD, in addition to greater convenience and therefore potentially better adherence to prescribed therapy, whereas side effects are similar except for a greater incidence of dry mouth. Summary Current evidence supports the recommendation of the Global Initiative for Chronic Obstructive Lung Disease guidelines of at least one of the two classes of long-acting inhaled bronchodilators as initial maintenance therapy for symptomatic COPD. In patients who do not respond satisfactorily to tiotropium or a long-acting inhaled β-agonist as the initially prescribed single maintenance agent, the Global Initiative for Chronic Obstructive Lung Disease guidelines recommend the addition of the alternate class of long-acting inhaled bronchodilator as the next step. Further clinical trials are required to investigate whether this recommendation is preferable to that of adding an inhaled corticosteroid, which has been shown to have additive benefits to those of a long-acting β-agonist with respect to bronchodilation and, variably, dyspnea, rescue bronchodilator use, and quality of life. The choice of agents will depend ultimately on how well the patient responds to a trial of the drug in terms of both efficacy and side effects, and patient preference and cost.

Is a long-acting inhaled bronchodilator the first agent to use in stable chronic obstructive pulmonary disease?

This article reviews findings from recently published randomized controlled clinical trials to address the question whether a long-acting inhaled bronchodilator should be the initial choice for maintenance therapy in patients with stable, symptomatic chronic obstructive pulmonary disease (COPD). Results of recent clinical trials suggest that a long-acting inhaled bronchodilator, either once-daily tiotropium or twice-daily salmeterol or formoterol, has advantages over a regularly-scheduled short-acting anticholinergic inhaled bronchodilator (ipratropium) as initial maintenance therapy in patients with at least moderate, stable, symptomatic COPD (forced expired volume in 1 second </= 60-70% predicted; mean, approximately 37-45% predicted). For tiotropium, these advantages encompass several important outcomes, including lung function, rescue inhaler use, dyspnea, frequency of exacerbations, and hospitalization for COPD, in addition to greater convenience and therefore potentially better adherence to prescribed therapy, whereas side effects are similar except for a greater incidence of dry mouth. Current evidence supports the recommendation of the Global Initiative for Chronic Obstructive Lung Disease guidelines of at least one of the two classes of long-acting inhaled bronchodilators as initial maintenance therapy for symptomatic COPD. In patients who do not respond satisfactorily to tiotropium or a long-acting inhaled beta-agonist as the initially prescribed single maintenance agent, the Global Initiative for Chronic Obstructive Lung Disease guidelines recommend the addition of the alternate class of long-acting inhaled bronchodilator as the next step. Further clinical trials are required to investigate whether this recommendation is preferable to that of adding an inhaled corticosteroid, which has been shown to have additive benefits to those of a long-acting beta-agonist with respect to bronchodilation and, variably, dyspnea, rescue bronchodilator use, and quality of life. The choice of agents will depend ultimately on how well the patient responds to a trial of the drug in terms of both efficacy and side effects, and patient preference and cost.

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

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

Effectiveness and Safety of Salmeterol in Nonspecialist Practice Settings

To evaluate the effectiveness and safety of inhaled salmeterol in patients managed in nonspecialist practice settings. A randomized, double-blind, 6-month, parallel-group study involving 253 centers. Primarily nonspecialist practices (n = 232). A total of 911 subjects (417 men; 494 women) who met American Thoracic Society asthma criteria were enrolled and randomized to treatment with either twice-daily salmeterol aerosol (50 microg; n = 455) or matching placebo twice daily (n = 456). Both groups were allowed to take salbutamol as needed. All subjects were previously treated with anti-inflammatory maintenance therapy that was continued throughout the study. The primary outcome variable was the proportion of subjects with serious asthma exacerbations defined as an exacerbation requiring hospitalization, emergency department visit, or use of prednisone during the treatment period. A total of 712 subjects competed the study. There was no significant difference in the proportion of subjects experiencing serious exacerbations between the salmeterol and placebo groups (20.8% vs 20.9%, respectively; p = 0.935; power > 88%). Peak expiratory flow was significantly higher in the salmeterol group (398 L/min vs 386 L/min for placebo; p < 0.01). Median daily use of salbutamol was two inhalations for the salmeterol group and three inhalations for placebo (p < 0.001). The proportion of subjects sleeping through the night was significantly higher in the salmeterol group (74%) as compared to placebo (68%; p = 0.028). Salmeterol treatment is effective in subjects typically cared for in the primary-care setting and does not increase the frequency of severe exacerbations.

Changes in malondialdehyde levels in bronchoalveolar fluid and serum by the treatment of asthma with inhaled steroid and beta2-agonist.

Oxidative stress plays an important role in the pathogenesis of asthma. Recent data suggest that clinical indices of the patients with asthma may not correlate with the underlying inflammatory process. We aimed to measure the level of malondialdehyde (MDA), which is a marker of lipid peroxidation, a free radical-mediated process, before and after a well-accepted treatment of asthma. Nine non-smoking females and five non-smoking males with mild-moderate asthma were included. Twenty-four age- and sex-matched, non-smoking healthy people (17 females and seven males, mean age 32.1 years, range 20-59) were included for control. After initial evaluation, spirometry, bronchoscopy with bronchoalveolar lavage (BAL), and blood sample were maintained. The patients were treated with twice-daily salmeterol inhaler (100 microg/d) and fluticasone propionate inhaler (500 microg/d). One month later the investigations were repeated. Serum MDA levels before treatment were compared with both the levels after treatment and levels of controls. Malondialdehyde levels of BAL were compared before and after treatment. Serum MDA level of the patient before treatment was 6.7+/-0.8 nmol/mL, significantly higher than that of healthy controls; 3.8+/-0.4, P < 0.001. One month after the treatment, serum MDA level decreased to 5.3+/-0.7 nmol/mL (P < 0.001). However, this level is still significantly higher than healthy controls (P < 0.0001). Forced expiratory volume in 1 s level of the patients increased from 2.43+/-0.79 L to 3.50+/-1.21 L after the treatment (P < 0.001). Although treatment with beta2-agonist and corticosteroid inhalers for the duration of 1 month reduced lipid peroxidation significantly, it was still at a level significantly higher than healthy controls. The treatment may need a longer duration to improve lipid peroxidation or an alternative regimen which is more effective in controlling inflammation may be warranted.

Effect of Long-term Salmeterol Therapy Compared With As-Needed Albuterol Use on Airway Hyperresponsiveness

To determine the effect of long-term salmeterol aerosol therapy on airway hyperresponsiveness measured by methacholine challenge. Randomized, double-blind, placebo-controlled, multicenter study. Thirty-one clinical centers in the United States. Four hundred eight asthmatic patients > or = 12 years of age with baseline FEV1 of > or = 70% of predicted values. Patients were not using inhaled corticosteroids. Twice-daily salmeterol aerosol, 42 microg, or placebo via metered-dose inhaler for 24 weeks. Backup albuterol was available. Pulmonary function tests were performed before, during, and after treatment. Subjects recorded asthma-related symptoms, morning and evening peak expiratory flow (PEF) levels, and use of supplemental albuterol daily on diary cards. Methacholine challenges were performed 10 to 14 h postdose at weeks 4, 12, and 24, and 3 and 7 days posttreatment. Over 24 weeks of treatment, salmeterol provided significant (p < 0.001) protection against methacholine-induced bronchoconstriction of approximately one doubling dose of methacholine when compared to placebo with no evidence for a progressive decrease in protection. A rebound increase in airway hyperresponsiveness was not observed 3 and 7 days after cessation of salmeterol therapy. Salmeterol treatment resulted in sustained improvements of 0.21 to 0.26 L in morning premedication FEV1 and an improvement of 26.2 L/min in morning PEF when compared to placebo (p < 0.001). The use of salmeterol significantly reduced combined daytime asthma symptoms by 20% when compared to placebo (p = 0.005). A total of 34 and 48 exacerbations, respectively, were reported in the Salmeterol and placebo groups, and no evidence was present for a difference in the severity of asthma exacerbations between groups. Adverse event profiles were similar for the salmeterol and placebo groups. Regular long-term use of salmeterol aerosol resulted in sustained improvements in pulmonary function and asthma symptom control over the 24-week treatment period. There was no increase in bronchial hyperresponsiveness or loss of bronchoprotection at 24 weeks from that seen following 4 weeks of therapy. There was no evidence of rebound airway hyperresponsiveness after cessation of salmeterol treatment. Regular treatment with the long-acting beta-agonist salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks.

Long-term Cardiovascular Safety of Salmeterol Powder Pharmacotherapy in Adolescent and Adult Patients With Chronic Persistent Asthma: A Randomized Clinical Trial

This study investigates the long-term cardiovascular safety of salmeterol powder vs placebo in adolescent and adult patients with mild persistent asthma. Multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eighteen US clinical centers. Three hundred fifty-two patients (> or = 12 years) with mild persistent asthma (duration > or = 6 months) requiring pharmacotherapy; with FEV1 of 70 to 90% of predicted and without abnormal ECG/continuous ambulatory ECG (Holter). Randomized to twice-daily salmeterol powder (50 microg) or placebo via breath-actuated device for 52 weeks. Backup albuterol was available to control asthma symptoms. Cardiovascular safety was regularly assessed by 12-lead ECG with a 15-s lead II rhythm strip, 24-h continuous ambulatory ECG (Holter) monitoring, serial vital sign measurements, and review of adverse cardiovascular events. No deaths occurred during the study. No clinically significant between-group differences were observed in pulse rate, ECG QTc interval, median number of ventricular or supraventricular ectopic events, incidence of ventricular ectopic couplets and runs, or incidence of > 100 ventricular or supraventricular ectopic events in 24 h. No clinically significant between-group differences were observed in arterial BP or incidence of adverse cardiovascular events. Salmeterol was well tolerated throughout the 52-week study period, with a cardiovascular safety profile similar to that of placebo. Long-term, twice-daily pharmacotherapy with salmeterol powder is safe and is not associated with unfavorable clinically significant changes in cardiac function or increases in cardiovascular adverse effects.