Salmeterol/fluticasone Propionate Combination Research Articles

The Effects of Switching from Fluticasone/Salmeterol Aerosol to Fluticasone/Formoterol Aerosol in Patients with Severe Asthma

Objective: Two pressurized Metered Dose Inhalers (pMDIs) containing a combination of a corticosteroid and long acting β2 agonist: Fluticasone propionate/Salmeterol Combination (FSC), and Fluticasone propionate/Formoterol Combination (FFC), are currently available in Japan. In order to examine the usefulness of the FFC pMDI, we sought to investigate the efficacy, adverse events, and handling after switching to the FFC pMDI from the FSC in patients with asthma. Methods: Fifty-six outpatients who were using the FSC pMDI (250/50 μg) twice daily were enrolled in the study. The following items were evaluated before and after the use of the FFC pMDI (250/10 μg) twice daily for 8 weeks: Asthma Control Test (ACT) Questionnaire; Asthma Health Questionnaire (AHQ)-33-Japan; spirometry; and forced oscillation technique. On the final day of the study, the original questionnaire was administered for a subjective evaluation between the FSC pMDI and FFC pMDI. Results: We found improvements in ACT (22.54 to 22.98, p=0.0076) and AHQ-33 Japan (16.27 to 14.23, p=0.0162) scores after FFC use. In addition, inspiratory capacity (p <0.0001) and forced expiratory volume in 1 second (p=0.0122) significantly increased. Further, 51.8% of patients preferred the FFC, while 12.5% preferred the FSC. Conclusion: There was a subjective and objective improvement in patients after switching to FFC pMDI from FSC pMDI. These findings indicate that FFC is more useful for patients with asthma. Further studies are needed to confirm the results of this study.

Which inhaled corticosteroid and long-acting β-agonist combination is better in patients with moderate-to-severe asthma, a dry powder inhaler or a pressurized metered-dose inhaler?

Two main types of devices are used to facilitate the administration of inhaled corticosteroid (ICS) and long-acting β-agonist (LABA) in combination, dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs). There are few reports comparing the effects of the two devices, and it is unknown which should be recommended for asthma patients with given sets of characteristics. In the current study, the beneficial effects and side effects associated with DPIs and pMDIs were compared, and the question of which device should be recommended for asthma patients was investigated. A prospective, randomized, crossover, comparative study in adult outpatients with asthma was conducted using salmeterol/fluticasone propionate combination (SFC) 50 μg/250 μg, one inhalation of Adoair® 250 Diskus® twice daily or two inhalations of Adoair® 125 Aerosol twice daily, for 8 weeks. Questionnaires, exhaled nitric oxide (FeNO) tests and pulmonary function tests were administered after the use of each device for 8 weeks, and the results derived from each device were compared. Sixty-eight subjects were included in the final analysis. There were no significant differences between quality-of-life scores, FeNO, spirometry test results and forced oscillation results. With regard to patient preferences, 57.4% preferred the Adoair® Aerosol and 35.3% preferred the Adoair® Diskus®, as determined via the comparative evaluation questionnaire. Although DPI prescription accounts for the predominant market share of combined ICS/LABA in Japan, patients preferred a pMDI device to a DPI device. Compared to DPIs, pMDIs may be the preferential choice for patients with asthma.

Assessment of the efficacy and safety of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler in patients with asthma

BackgroundIn developing countries, there is a need for access to affordable inhaled respiratory medicines. This study tested the clinical non-inferiority of fluticasone propionate/salmeterol combination (FSC) 50/250 μg Rotacaps®/Rotahaler® compared with FSC 50/250 μg Diskus®. MethodsA multi-centre, randomised, double-blind, double-dummy study evaluated 12 weeks, twice daily treatment of FSC 50/250 μg administered using Rotacaps/Rotahaler or Diskus inhaler in a crossover design in patients with asthma (pre-bronchodilator forced expiratory volume in 1 s (FEV1) 40%–85% of predicted, FEV1 reversibility ≥12%, prior stable dose with inhaled corticosteroid (ICS) or ICS/long acting beta-agonist). The primary efficacy endpoint, change from baseline in trough morning FEV1 at Day 85, was analysed using a model for repeated measures analysis. The pre-defined criterion for non-inferiority was the lower limit of the CI (0.025, one-sided significance level) for the treatment difference (Rotacaps/Rotahaler-Diskus) in least squares (LS) mean change from baseline, being greater than −125 mL. Secondary endpoints included serial FEV1 measurements, morning peak expiratory flow (PEF), rescue medication use, day- and night-time asthma symptoms, Asthma Control Test (ACT) scores, and serial cortisol measured over 12 h (area under the curve (AUC0-12)). ResultsTreatment with FSC 50/250 μg via Rotacaps/Rotahaler or Diskus resulted in a similar LS mean increase from baseline in trough FEV1 at Day 85 (231 mL and 203 mL respectively). The difference in the model-adjusted LS mean change was 28 mL (95% CI -24 mL, 80 mL), fulfilling the criterion for non-inferiority. Data for all secondary endpoints were similar for the two treatments, supporting the primary endpoint findings. Both treatments were well tolerated and demonstrated similar safety profiles. ConclusionThis study demonstrated the clinical non-inferiority of FSC 50/250 μg when administered using Rotacaps/Rotahaler compared with administration using Diskus in patients with asthma, and suggests there is no difference in the risk:benefit profile between the two FSC inhalers.

Economic evaluations of fluticasone-propionate/salmeterol combination therapy for chronic obstructive pulmonary disease: a review of published studies

ABSTRACTThis review identifies and evaluates the comprehensive reporting of peer-reviewed economic evaluations of the effectiveness of fluticasone-propionate/salmeterol combination (FSC) therapy for maintenance treatment of chronic obstructive pulmonary disease (COPD). Economic evaluations were included if published in English since 2003. Evaluation categories included in the review were cost-effectiveness, cost-utility, and cost-consequence analyses. FSC is cost-effective in comparison to short-acting bronchodilators (SABDs). Cost and outcome differences between FSC and other long-acting therapies were modest. Studies exhibited large variations in populations, designs and environment, limiting the ability to draw conclusions. Many new maintenance treatments for COPD have been approved since 2010. Most have yet to be compared to older treatments like FSC. Evaluations are needed that consider costs and outcomes from a societal perspective (e.g., patients’ ability to keep working) and evaluations that include subgroup analyses to investigate differential impacts according to clusters of patient characteristics.

Mortality and drug therapy in patients with chronic obstructive pulmonary disease: a network meta-analysis.

BackgroundIncreasing evidence suggests pharmacological treatments may impact on overall survival in Chronic Obstructive Pulmonary Disease (COPD) patients. Individual clinical trials are rarely powered to detect mortality differences between treatments and may not include all treatment options relevant to healthcare decision makers.MethodsA systematic review was conducted to identify RCTs of COPD treatments reporting mortality; evidence was synthesised using network meta-analysis (NMA). The analysis included 40 RCTs; a quantitative indirect comparison between 14 treatments using data from 55,220 patients was conducted.ResultsThe analysis reported two treatments reducing all-cause mortality; salmeterol/fluticasone propionate combination (SFC) was associated with a reduction in mortality versus placebo in the fixed effects (HR 0.79; 95 % Crl 0.67, 0.94) but not the random effects model (0.79; 0.56, 1.09). Indacaterol was associated with a reduction in mortality versus placebo in fixed (0.28; 0.08 to 0.85) and random effects (0.29; 0.08, 0.89) models. Mean estimates and credible intervals for hazard ratios for indacaterol versus placebo are based on a small number of events; estimates may change when the results of future studies are included. These results were maintained across a variety of assumptions and provide evidence that SFC and indacaterol may lead to improved survival in COPD patients.ConclusionResults of an NMA of COPD treatments suggest that SFC and indacaterol may reduce mortality. Further research is warranted to strengthen this conclusion.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-015-0138-4) contains supplementary material, which is available to authorized users.

Comparison of the Pharmacokinetics of Salmeterol and Fluticasone Propionate 50/100 µg Delivered in Combination as a Dry Powder Via a Capsule-Based Inhaler and a Multi-Dose Inhaler.

The Rotacaps(®)/Rotahaler(®) system is a single unit dose inhaler being developed to deliver inhaled salmeterol/fluticasone propionate combination (SFC) as an alternative treatment option to the metered dose inhaler and the multi-dose dry powder inhaler, Diskus(®). The aim of this study was to compare the systemic exposure of SFC 50/100 µg following delivery via the Rotacaps(®)/Rotahaler(®) and the Diskus(®). This was an open-label, randomized, cross-over, repeat-dose (3.5 days of twice-daily dosing) study comparing salmeterol and fluticasone propionate systemic exposure following inhaled SFC 50/100 µg delivered via the Rotacaps(®)/Rotahaler(®) and Diskus(®), in healthy subjects. Pharmacokinetic sampling was conducted over 12 h post-dose on the last day of each treatment. Pharmacokinetic samples were analysed using solid phase extraction followed by high performance liquid chromatography/tandem mass spectrometry. Co-primary endpoints were fluticasone propionate area under the concentration-time curve over the dosing interval (AUC0-τ ) and salmeterol maximum plasma concentration (C max) on the last day of treatment. Following SFC 50/100 µg Rotacaps(®)/Rotahaler(®), fluticasone propionate and salmeterol systemic exposures were comparable with Diskus(®) in terms of both AUC0-τ [geometric mean ratio (GMR) with 90 % confidence interval (CI) of Rotahaler(®)/Diskus(®) for fluticasone propionate: 0.98 (0.91, 1.06) and salmeterol: 1.04 (0.99, 1.10)] and C max [GMR (90 % CI) for fluticasone propionate: 1.04 (0.94, 1.15) and salmeterol: 0.97 (0.87, 1.08)], meeting the pre-defined criteria for comparability (upper limit of the 90 % CI for the GMRs (Rotahaler(®)/Diskus(®)) ≤1.25]. SFC delivered from both inhalers was well tolerated. SFC 50/100 µg Rotacaps(®)/Rotahaler(®) showed comparable fluticasone propionate and salmeterol systemic exposure to Diskus(®) for all pharmacokinetic endpoints with GMR and both upper and lower limits of 90 % CIs within conventional acceptance criteria for bioequivalence (0.8, 1.25), sufficient for considering progression of the Rotacaps(®)/Rotahaler(®) product for further clinical development.

Comparative Effectiveness of Budesonide-Formoterol Combination and Fluticasone-Salmeterol Combination for Asthma Management: A United States Retrospective Database Analysis

Comparative effectiveness of the budesonide-formoterol fumarate dihydrate combination (BFC) and the fluticasone propionate-salmeterol combination (FSC) therapy on asthma exacerbation has not been assessed in real-world settings in the United States. To compare exacerbation rates and health care utilization for patients with asthma who initiate BFC versus FSC therapy. This retrospective cohort comparative effectiveness study queried medical and pharmacy data for patients with asthma from a large managed care data repository that covers major US population centers. The patients were 12 to 64 years old, with ≥12 months of pre- and postindex enrollment and ≥1 pharmacy claim(s) for BFC or FSC initiated during June 1, 2007, and September 30, 2010; the first prescription fill date was defined as the index date. Patients with other respiratory diseases and/or cancer were excluded. Exacerbation was defined as asthma-related hospitalization, emergency department visit, and/or oral corticosteroid prescription fill. Cohorts were matched by using propensity scores. A total of 3043 patients per cohort were matched and balanced. During the 12 months following the initiation the BFC cohort had lower adjusted exacerbations per person year versus the FSC cohort (0.85 vs 0.93; RR 0.92, 95% CI [0.85-0.99]), lower oral corticosteroid fill rates, and fewer asthma-related emergency department visits but comparable asthma-related hospitalization. Asthma exacerbation was lower for BFC versus FSC initiators due to lower rates of oral corticosteroid use and asthma-related emergency department visits, which indicate better treatment effectiveness of those patients initiated with BFC compared with FSC.

Pharmacokinetics of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler

AimTo compare salmeterol (SALM) and fluticasone propionate (FP) systemic exposure following inhaled salmeterol/fluticasone propionate combination (SFC) from a unit-dose capsule-based inhaler (Rotacaps®/Rotahaler®) and a multi-dose dry powder inhaler (Diskus®) in healthy volunteers. MethodsAn open-label, randomised, repeat-dose, cross-over, adaptive design study (n = 36 in each part) evaluated SFC 50/250 μg and SFC 50/100 μg in Rotacaps used with two types of Rotahaler inhalers (airflow resistance similar to (S) and lower than (L) Diskus) versus the Diskus. Primary endpoints were area under the concentration-time curve over the dosing interval [AUC0–τ] and maximum plasma concentration [Cmax]. ResultsSFC 50/250 μg Rotacaps/Rotahaler (S) showed 1.2–1.9-fold greater FP and SALM systemic exposure compared with Diskus. FP and SALM systemic exposure were comparable to DISKUS following SFC 50/250 μg Rotacaps/Rotahaler (L) (90% CI of ratio of Rotahaler to DISKUS within 0.8–1.25) for salmeterol (AUC0–τ and Cmax) and FP (AUC0–τ). Following SFC 50/100 μg Rotacaps/Rotahaler (L), FP and SALM systemic exposures were 1.2–1.4 fold higher in terms of FP (AUC0–τ and Cmax) and salmeterol (Cmax) compared with Diskus. SFC at both doses and via both inhalers was well tolerated. ConclusionsSFC 50/250 μg Rotacaps/Rotahaler (L) showed comparable systemic exposure to Diskus in terms of FP AUC and SALM AUC and Cmax. These results merit further progression of SFC 50/250 μg Rotacaps/Rotahaler (L) to phase 3 clinical evaluation in asthma and COPD patients. The lack of pharmacokinetic comparability between the inhalers for SFC 50/100 μg requires further evaluation.

A Prescription event monitoring (PEM) study to assess safety and health outcomes of Airtec SF (Salmeterol Fluticasone propionate combination) in Indian population

Background: Asthma management has been fraught with several challenges especially for partly or uncontrolled cases. Incremental dosage strategy with salmeterol, fluticasone propionate combination offers stable yet effective control of symptoms preventing further exacerbations. However, there is limited evidence available on the need and safety profile of this incremental dosage strategy with the combination especially in Indian settings. To examine the safety and adverse clinical outcomes of Airtec SF when prescribed in patients with well- or poorly controlled persistent asthma. Methods: Based on the principle of prescription event monitoring (PEM) for safety reporting, this study was conducted at 20 centers across India. PEM study booklets with study questionnaire were provided to capture information related to adverse “events” during the observation period of 30 days. Results: Data of 384 patients were analyzed, with a mean age 44.5 years. 39% (n=150) were newly diagnosed and 61% (n=234) being in poorly controlled asthma status (i.e., partly or uncontrolled asthma). Of them, 42% (161), 44% (n=169) and 14% (54) patients were diagnosed with mild, moderate or severe persistent asthma, respectively. These were prescribed with metered-dose inhaler (n=187) or dry powder inhaler (n=197) formulations. 56% (n=216) patients suffered from concomitant allergic rhinitis. Among newly diagnosed patients with moderate to severe asthma dosage were tapered in 5.5% (n=3) cases. Dosage consistency was well-maintained in 98.2% (n=155) among partial or uncontrolled asthmatics with moderate to severe asthma with exacerbation rate of 1.9% (n=3). Adverse events including infective pneumonitis and upper respiratory tract infection were transient with none requiring treatment withdrawal. Conclusion: Use of Airtec SF was safe and well-tolerated with a negligible rate of exacerbations in Indian population especially amongst poorly controlled asthma patients.

Effect of fluticasone propionate/salmeterol plus tiotropiumversustiotropium on walking endurance in COPD

To the Editor: Exercise intolerance is a hallmark feature of chronic obstructive pulmonary disease (COPD) and is associated with premature mortality [1]. Tiotropium (TIO) is effective in improving cycling exercise tolerance [2, 3] and walking endurance time in COPD [4]; these properties are thought to be associated with reductions in operating lung volume and the perception of dyspnoea during exercise [2, 3, 5]. What is less certain, however, is the extent to which these benefits of TIO on exercise duration can be further improved with the use of additional inhalational therapy. We examined whether the addition of fluticasone propionate/salmeterol combination (FSC) to TIO improved endurance time during the endurance shuttle walking test (ESWT) more than TIO alone in patients with COPD. Our specific objectives were to compare endurance time during the ESWT and evaluate the impact on lung function of TIO alone or in combination with FSC. We hypothesised that the addition of FSC to TIO would improve endurance time during the ESWT compared to TIO alone. This was an 8-week, multicentre, placebo-controlled, double-blind, randomised, parallel group study. Patients received either FSC (Advair/Seretide; GlaxoSmithKline, Research Triangle Park, NC, USA) 250/50 μg administered via DISKUS twice daily plus TIO (Spiriva; Boehringer Ingelheim GmbH and Co.KG, Ingelheim, Germany) 18 μg administered via Handihaler once daily or placebo DISKUS twice daily plus TIO 18 μg once daily. The study was conducted at 24 sites in the USA and Canada between July 19, 2010 and May 2, 2011. Eligible patients were aged ≥40 years and …

Effects of Tiotropium and Salmeterol/Fluticasone Propionate on Airway Wall Thickness in Chronic Obstructive Pulmonary Disease

Background: Triple inhalation therapy with tiotropium (Tio) and salmeterol/fluticasone propionate combination (SFC) is widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, the effects of triple therapy on airway structural changes remain unknown. Objective: The aim of the study was to assess the effects of Tio, salmeterol (SM), SFC and Tio plus SFC on airway dimensions in COPD. Methods: A randomized, open-label, 4-way study (n = 60) was conducted comparing 16-week treatment periods of Tio (18 μg once daily), SM (50 μg twice daily), SFC (50/250 μg twice daily) and Tio (18 μg once daily) plus SFC (50/250 μg twice daily). Airway dimensions were assessed by a validated CT technique, and airway wall area (WA) corrected for body surface area (BSA), percentage WA (WA%), wall thickness/√BSA and luminal area (Ai)/BSA at the right apical segmental bronchus were measured. Pulmonary function and the St. George's Respiratory Questionnaire (SGRQ) were evaluated. Results: Tio plus SFC resulted in a significant decrease in WA corrected for BSA and WA% compared with Tio, SM and SFC (p < 0.05 for all). The changes in WA% and Ai/BSA were significantly correlated with changes in forced expiratory volume in 1 s (r = -0.86, p < 0.001, and r = 0.48, p < 0.05, respectively). There were more significant improvements in SGRQ scores after treatment with triple therapy than after the 3 other treatments. Conclusions: Tio plus SFC therapy is more effective than Tio, SM and SFC for reducing airway wall thickness in COPD.

Clinical and economic outcomes in an observational study of COPD maintenance therapies: multivariable regression versus propensity score matching

PurposeTo investigate equivalency of results from multivariable regression (MR) and propensity score matching (PSM) models, observational research methods used to mitigate bias stemming from non-randomization (and consequently unbalanced groups at baseline), using, as an example, a large study of chronic obstructive pulmonary disease (COPD) initial maintenance therapy.MethodsPatients were 32,338 health plan members, age ≥40 years, with COPD initially treated with fluticasone propionate/salmeterol combination (FSC), tiotropium (TIO), or ipratropium (IPR) alone or in combination with albuterol. Using MR and PSM methods, the proportion of patients with COPD-related health care utilization, mean costs, odds ratios (ORs), and incidence rate ratios (IRRs) for utilization events were calculated for the 12 months following therapy initiation.ResultsOf 12,595 FSC, 9126 TIO, and 10,617 IPR patients meeting MR inclusion criteria, 89.1% (8135) of TIO and 80.2% (8514) of IPR patients were matched to FSC patients for the PSM analysis. Methods produced substantially similar findings for mean cost comparisons, ORs, and IRRs for most utilization events. In contrast to MR, for TIO compared to FSC, PSM did not produce statistically significant ORs for hospitalization or outpatient visit with antibiotic or significant IRRs for hospitalization or outpatient visit with oral corticosteroid. As in the MR analysis, compared to FSC, ORs and IRRs for all other utilization events, as well as mean costs, were less favorable for IPR and TIO.ConclusionIn this example of an observational study of maintenance therapy for COPD, more than 80% of the original treatment groups used in the MR analysis were matched to comparison treatment groups for the PSM analysis. While some sample size was lost in the PSM analysis, results from both methods were similar in direction and statistical significance, suggesting that MR and PSM were equivalent methods for mitigating bias.

Systemic bioavailability of hydrofluoroalkane formulations containing fluticasone and salmeterol: a reply

Daley-Yates & Parkins cite data comparing relative lung dose of fluticasone propionate/salmeterol combination (FP/SM) from dry power inhalers which are more flow rate and resistance dependent than pressurized metered dose inhalers (pMDIs), and as such are not pertinent to the interpretation of our data[1]. Daley-Yates & Parkins focus particularly on the extra fine particle fraction deposited on stages 6–7. For the in vitro data it is the overall fine particle dose (in µg) deposited on stages 3–7 (i.e. <4.7 µm) which will determine the total lung absorption profile and in this regard it is evident that the test : reference (T : R) ratios for the two formulations were clearly close to unity. With regard to deposition of extra fine particles on stages 6–7 one has to place any differences in the T : R ratios in the context of the overall fine particle dose. Thus for pMDI alone the relative deposition of FP on stages 6–7 as a proportion of the overall fine particle dose was 3.08% and 1.82% (i.e. a difference of 1.26%) for test and reference products, respectively, and with spacer was 2.98% and 1.67% (i.e. a difference of 1.31%). Corresponding values for SM were 7.38% and 1.31% with pMDI alone (i.e. a difference of 6.07%), 6.11% and 1.20% with spacer (i.e. a difference of 4.91%). An absolute difference between test and reference products in extra fine particle dose of SM amounting to 1.04 µg with pMDI and 1.0 µg with spacer (i.e. at the usual single dose of two puffs) is unlikely to be of any clinical relevance in terms of meaningful systemic adverse effects on potassium and heart rate when used at the standard recommended dose. Moreover in terms of bronchodilator efficacy since airway β2-adrenoceptors are mostly located centrally, the topical impact of such a small difference in extra fine particles would be rather irrelevant in terms of disease control for patients. Daley-Yates & Parkins also criticize our abbreviated 2 h sampling period for FP in study 2 suggesting we may have missed the true total lung exposure, along with possible effects on Cmax due to time delay by using multiple puffs via the spacer. For the FP moiety in study 1 over a 24 h sampling period using four puffs, the T : R ratio was 0.91 for Cmax while for AUC(0,last) the ratio was 1.05. The ratios from study 1 were similar to those obtained in study 2 also using four puffs, which were 1.11 for Cmax and 1.07 for AUC(0,2 h). Given that we employed a crossover design in study 2, any putative impact of delay would be the same for test and reference formulations. From a clinical view point one also has to bear in mind that in real life patients will inevitably not be using their inhaler correctly, such that any small differences in extra fine particle dose will become rather trivial. We were required for regulatory purposes to be able to show assay sensitivity and as such we had to use artificially high single doses of FP/SM in our study, whereas in everyday prescribing the recommended maximum single dose is two puffs which is taken twice daily. The administered single dose of eight puffs in study 2 was four fold higher than the usual recommended dose, such that any small differences in β2- adrenoceptor mediated response would become accentuated. To put this in context even at a high single dose of eight puffs the mean difference in maximal chronotropic response of 6.4 beats min–1 or in hypokalaemia of 0.09 mmol l–1 is not clinically relevant. Indeed at the usual single dose of two puffs one would not expect to see any detectable systemic β2-adrenoceptor mediated adverse effects, as this does not coincide with the steep part of the dose–response curve. Moreover as patients take FP/SM on a regular twice daily basis, β2-adrenoceptor down regulation, uncoupling and associated sub-sensitivity of response would occur, such that any small putative differences in potassium or heart rate response between test and reference formulations would be diminished [2]. Daley-Yates & Parkins are also incorrect in suggesting that overnight urinary cortisol/creatinine is insensitive for detecting adrenal suppression in response to FP, as this measure has consistently been shown to be a sensitive measure of HPA-axis suppression compared with other markers of basal or stimulated adrenal function [3–7]. Thus, we stand firmly by our conclusions that the observed differences in systemic pharmacodynamic β2 responses at the conventional dose of two puffs twice daily would not have any clinically meaningful impact in terms of safety for patients switching from the reference to test formulation of FP/SM. As such we consider the two formulations to be clinically interchangeable at recommended doses.

A Review of Salmeterol&amp;ndash;Fluticasone Propionate in Combination: Its Use in the Treatment of Chronic Obstructive Pulmonary Disease

Tiotropium bromide (TIO), a long-acting anticholinergic bronchodilator, is now used world-wide for the treatment of Chronic Obstructive Pulmonary Disease (COPD). However, the GOLD guidelines recommend another, or additional medication for symptomatic patients with GOLD stage III or IV disease, forced expiratory volume in 1 second (FEV1) less than 50% of the predicted value, and repeated exacerbations. Several lines of evidence such as the TRISTAN study have shown the synergistic effects of a salmeterol–fluticasone propionate combination (SFC), with significant improvements of pulmonary function, health status, exacerbation rates, and quality of life in patients with COPD, compared with using individual components of SFC. But they didn’t obtain any improvement in the data for mortality, which is our major clinical concern. The TORCH study is a major study which investigated all-cause mortality rates, but it showed no significant difference of mortality among SFC, individual drugs and placebo groups. The INSPIRE study showed significant improvement of mortality in the SFC treatment group, compared with the TIO. However, the higher incidence of pneumonia in the SFC group remains a subject of debate. Some studies showed that SFC therapy has lower medical costs with good patient compliance, which may become a reason for choosing the therapy. The new 2010 NICE GOLD Guideline recommends the “triple” therapy with SFC and TIO, when the FEV1% predicted is less than 50% in the presence of persistent exacerbations or breathlessness. The advantages of “triple” therapy may outweigh the disadvantages of each medication. This review focuses upon the therapeutic potential of SFC for the treatment of COPD.

Long-term treatment with fluticasone propionate/salmeterol via Diskus improves asthma control versus fluticasone propionate alone

This 52-week study was designed to assess the safety and efficacy of fluticasone propionate/salmeterol combination (FSC) 250/50 micrograms versus fluticasone propionate (FP) 250 micrograms in subjects with persistent asthma symptomatic on open-label FP 100 micrograms. The primary objective of this study was to show that FSC 250/50 micrograms was superior to FP 250 micrograms at increasing pulmonary function as measured by forced expiratory volume in 1 second over a 52-week treatment period. A secondary objective was to compare the rate of asthma attacks defined as (1) a sustained 2-day decrease in morning peak expiratory flow or increase in albuterol use for 2 consecutive days, (2) an asthma exacerbation requiring systemic corticosteroids, or (3) an unscheduled clinic or hospital visit for acute asthma symptoms. Three hundred six subjects received FSC 250/50 micrograms and 315 subjects received FP 250 micrograms. Both treatments were administered twice daily. Treatment with FSC 250/50 micrograms resulted in a significant improvement in lung function compared with FP 250 micrograms (p < 0.001). Additionally, treatment with FSC 250/50 micrograms resulted in a reduction in the rate of exacerbations of asthma (i.e., requiring systemic corticosteroids or unscheduled urgent care intervention) compared with FP 250 micrograms (0.170 versus 0.273, respectively; p = 0.017). There was no differentiation between treatments for less severe attacks of asthma. FSC 250/50 micrograms showed consistently greater improvement in lung function, symptom control, and decreased albuterol use. In addition, FSC 250/50 micrograms-treated subjects experienced fewer severe asthma exacerbations than subjects treated with FP 250 micrograms.

Effects of adding salmeterol/fluticasone propionate to tiotropium on airway dimensions in patients with chronic obstructive pulmonary disease

Although salmeterol/fluticasone propionate combination (SFC) therapy has been widely used for the treatment of COPD, the relationship between airway dimensions and improvement in pulmonary function remains unknown. The aim of this study was to compare the effects of SFC in combination with tiotropium (Tio) and Tio alone, on airway dimensions and pulmonary function in COPD patients. Thirty COPD patients were randomized to receive inhaled Tio (18 µg once daily) or inhaled SFC (50/250 µg twice daily) plus Tio for 12 weeks. Spirometry and CT were performed, and the St. George's Respiratory Questionnaire (SGRQ) was completed, before and after the trial. Airway dimensions were assessed by a validated CT technique, and airway wall area (WA) corrected for body surface area (BSA), percentage wall area (WA%), absolute wall thickness T/√BSA, and luminal area Ai/BSA at the right apical segmental bronchus, were measured. Treatment with SFC plus Tio significantly decreased WA/BSA (P < 0.05), WA% (P < 0.01) and T/√BSA (P < 0.01), and increased Ai/BSA (P < 0.01), whereas treatment with Tio alone had no effect. The changes in WA/BSA and Ai/BSA were significantly correlated with increases in FEV1 (r = 0.48, P < 0.05, and r = 0.36, P < 0.05, respectively). There were significant improvements in SGRQ scores after treatment with SFC plus Tio. Airway wall thickening and airway narrowing decreased after treatment with SFC plus Tio, and the changes in airway dimensions were proportional to the improvements in FEV1 . These results suggest that SFC plus Tio is more effective than Tio alone in the management of COPD patients.

Bias due to withdrawal in long‐term randomised trials in COPD: Evidence from the TORCH study

Randomised controlled trials (RCTs) are considered the least biased method for evaluating drug efficacy and several large long-term RCTs in chronic obstructive pulmonary disease have been published. These usually include drugs with symptomatic benefits and have significant withdrawal rates. We aimed at examining bias due to differential withdrawal in the Towards a Revolution in COPD Health (TORCH) trial. We did an observational study nested in the TORCH trial, a placebo-controlled trial of salmeterol/fluticasone propionate combination (SFC) therapy in chronic obstructive pulmonary disease. We included 3057 patients randomly allocated to placebo or SFC in the analyses. We examined rates of withdrawal from the study and analysed change in effect parameters over time and in relation to withdrawal, as well as medication uptake after withdrawal. There was differential withdrawal with a significantly higher withdrawal rate from the group allocated to placebo than to SFC, 44% compared with 34%. Regardless of treatment group, withdrawal was associated with worse baseline lung function and more frequent exacerbations, leading to selection of a study population in better health than those originally recruited. As a result, annualized exacerbation rates in the first 6 months of the study compared with the last 6 months of the study decreased from 6.8 to 0.9 in the placebo group and from 3.0 to 0.8 in the SFC group. Also, use of medications under test in the study was frequent in patients after withdrawal. Significant bias may occur in long-term RCTs of registered medications with symptomatic benefits as a result of differential withdrawal.

Triple Therapy of Fluticasone Propionate/Salmeterol Combination 250/50 mcg and Tiotropium Improves Lung Function Compared to Tiotropium Monotherapy

PURPOSE: Fluticasone Propionate/Salmeterol Combination (FSC) and Tiotropium (Tio) are frequently co-prescribed in clinical practice in COPD. However, few studies have examined the effects of combining these medications. This study is the first to examine the effects of FSC (250/50) combined with Tio on outcomes in subjects with COPD.

Fluticasone propionate/salmeterol combination in children with asthma: Key cardiac and overall safety results

This study studied the safety of fluticasone propionate/salmeterol combination (FSC) 100/50 HFA (2 inhalations of 50/25 mcg) twice daily, compared with fluticasone propionate (FP) 100 HFA (two inhalations of 50 mcg) twice daily, over a 12-week treatment period in subjects aged 4–11 years with persistent asthma. Of the 350 subjects randomized to receive double-blind treatment, 173 received FSC 100/50 HFA and 177 received FP 100 HFA. The two treatment groups were comparable in adverse events profiles, vital signs, asthma exacerbations, oropharyngeal examinations, clinical laboratory tests and urinary cortisol levels. The use of spacer did not meaningfully modify cortisol levels. The pre-specified analysis of 12-lead electrocardiograms (ECGs) identified abnormalities during screening as well as post-randomization in both study treatments, even though randomized subjects were without pre-existing cardiovascular disorders. An ad hoc analysis of the ECG data found no clinically relevant ECG abnormalities either...

Cost-effectiveness of combination fluticasone propionate&amp;ndash;salmeterol 250/50 &amp;mu;g versus salmeterol in severe COPD patients

To estimate the cost-effectiveness of fluticasone propionate-salmeterol combination (FSC) compared to salmeterol for maintenance therapy in severe chronic obstructive pulmonary disease (COPD). Pooled economic analysis. We performed an economic analysis of pooled data from two randomized clinical trials (combined N = 1554) that evaluated the effect of maintenance therapy with FSC (250/50 microg twice daily) or salmeterol (50 microg twice daily) on exacerbation rates in patients with severe COPD. We calculated exacerbation rates and applied standardized costs to exacerbation-related health care utilization reported in the trials (office, urgent care, and emergency department visits; hospitalizations; and oral corticosteroids and antibiotics) to determine cost differences between FSC and salmeterol treatment outcomes. Annual rates of any exacerbation and moderate/severe exacerbation were lower in the FSC group than the salmeterol group (4.91 vs 5.78 and 1.32 vs 2.00 respectively, both P < 0.05). Total adjusted annual COPD related exacerbation and therapeutic costs were $4,842 (95% CI; $4,731-$4,952) in the FSC group and $5,066 (95% CI; $4,937-$5,195) in the salmeterol group. FSC combination therapy is associated with reduced risk of any exacerbation and moderate/severe exacerbation, and incurs lower annual COPD-related health care costs compared to treatment with salmeterol. This analysis demonstrates that FSC therapy may be advantageous from both a clinical and cost-benefit standpoint for patients with severe COPD.