- Research article
- Open Access
- Open Peer Review
Extrafine Beclomethasone/formoterol compared to Fluticasone/salmeterol Combination Therapy in COPD
© Singh et al.; licensee BioMed Central Ltd. 2014
- Received: 22 August 2013
- Accepted: 3 March 2014
- Published: 12 March 2014
The study evaluated the efficacy of beclomethasone dipropionate/formoterol fumarate (BDP/FF) extrafine combination versus fluticasone propionate/salmeterol (FP/S) combination in COPD patients.
The trial was a 12-week multicentre, randomised, double-blind, double dummy study; 419 patients with moderate/severe COPD were randomised to BDP/FF 200/12 μg or FP/S 500/50 μg twice daily. The primary objective was to demonstrate the equivalence between treatments in terms of Transition Dyspnoea Index (TDI) score and the superiority of BDP/FF in terms of change from pre-dose in the first 30 minutes in forced expiratory volume in the first second (FEV1). Secondary endpoints included lung function, symptom scores, symptom-free days and use of rescue medication, St. George’s Respiratory Questionnaire, six minute walking test and COPD exacerbations.
BDP/FF was equivalent to FP/S in terms of TDI score and superior in terms of FEV1 change from pre-dose (p < 0.001). There were no significant differences between treatments in secondary outcome measures, confirming overall comparability in terms of efficacy and tolerability. Moreover, a clinically relevant improvement (>4 units) in SGRQ was detected in the BDP/FF group only.
BDP/FF extrafine combination provides COPD patients with an equivalent improvement of dyspnoea and a faster bronchodilation in comparison to FP/S.
- Chronic Obstructive Pulmonary Disease
- Chronic Obstructive Pulmonary Disease Patient
- Chronic Obstructive Pulmonary Disease Exacerbation
Chronic obstructive pulmonary disease (COPD) is a progressive disease estimated to become the third leading cause of death and the fifth cause of morbidity worldwide by 2020 . It is characterised by progressive airflow limitation which is not fully reversible and is associated with an enhanced pulmonary inflammatory response. Disease severity is determined by the degree of airflow limitation, the frequency of exacerbations, the severity of symptoms and the presence of co-morbidities. Current medical interventions are now increasingly focused on providing relief to symptoms that majorly impact on quality of life, such as dyspnoea and decreased exercise capacity . One particular focus is the effect of treatments in the morning, when COPD symptoms and patients’ ability to perform daily activities appear to be worst .
International guidelines recommend that treatment follows a stepwise approach, with the early introduction of bronchodilators for all patients with COPD, and the later addition of an inhaled corticosteroid (ICS) limited to patients with severe airflow limitation and/or frequent exacerbations . Treatment with a long-acting β2 agonist (LABA) and ICS can be administered through single combination inhalers. ICS/LABA combinations reduce the frequency of exacerbations and improve lung function to a greater degree than the monocomponents alone , and there are beneficial molecular interactions between these drugs that can potentiate their effectiveness [4, 5]. However, high ICS doses have been associated with an increased risk of pneumonia [6–8]. Hence, the dose–response relationship of ICS in COPD is currently a matter of debate , especially since head-to-head studies comparing different dosages of ICS in COPD are still lacking .
The ICS/LABA combination beclomethasone dipropionate 100 μg plus formoterol fumarate 6 μg (BDP/FF) is an extrafine formulation that optimises small particle deposition throughout the bronchial tree, including the small airways; It is licensed for use in asthma, and is being developed as a treatment for COPD [10, 11]. FF is a LABA with a rapid onset of action , while in contrast the LABA salmeterol has a slow onset of action. Consequently, a potential advantage of FF over salmeterol when used in combination inhalers is that the morning dose can more rapidly improve lung function, and so provide greater benefits for COPD patients who suffer with morning symptoms [13, 14].
The aim of the FUTURE trial was to compare the efficacy of two fixed combination therapies that deliver different ICS doses; extrafine BDP/FF versus fluticasone / salmeterol (FP/S) where the daily ICS doses are 400 μg and 1000 μg / day respectively. We measured symptoms and lung function after 12 weeks to compare the efficacy of these treatments. Furthermore, we also investigated the acute bronchodilator effects in the morning to study differences that might be due to the onset of action of the LABAs.
This study was carried out in 76 outpatient respiratory clinics throughout Europe and included patients aged ≥ 40 years with a diagnosis of moderate to severe COPD. Inclusion criteria were: smoking history ≥ 10 pack years; regular bronchodilator use in the previous 2 months; post-bronchodilator forced expiratory volume measured in the first second (FEV1) < 60% of predicted; post-bronchodilator FEV1/forced vital capacity (FVC) < 0.7; an increase in FEV1 ≥ 5% from baseline following administration of 400 μg of salbutamol; a Baseline Dyspnoea Index (BDI) focal score ≤ 10 at the screening and randomisation, and a history of ≤ one COPD exacerbation treated with antibiotics or systemic corticosteroids in the previous 12 months. Patients were excluded if they had been diagnosed with asthma, other respiratory disorders, or any other clinically relevant condition that could have interfered with the evaluation of results.
The study was performed in accordance with the principles of the Declaration of Helsinki and with the Good Clinical Practice guidelines recommended by the International Conference on Harmonization of Technical Requirements. The protocol was approved by the Institutional Review Board of each centre (a list is shown in Additional file 1), and informed written consent was obtained from each participant prior to study entry.
This was a randomised, double-blind, double-dummy, 2-arm parallel group study. After a screening visit, patients entered a 2-week run-in period, where they received inhaled ipratropium bromide (Atrovent® Inhaler CFC-Free 20 μg) as maintentance treatment administered 4 times / day. Patients were then randomised to a 12-week treatment period with either extrafine BDP/FF 100/6 μg in a hydrofluoralkane pressurised metered dose inhaler (pMDI; FOSTER®, Chiesi Farmaceutici, Parma, Italy) or FP/S 500/50 μg, in a dry-powder inhaler (DPI; Seretide®, Accuhaler® GlaxoSmithKline, Middlesex, UK). Randomization was performed according to a pre-determined balanced-block, computer generated, randomisation list stratified by country. BDP/FF was administered as two puffs twice daily (daily dose 400 μg BDP/24 μg FF), while FP/S was administered as one inhalation twice daily (daily dose 1000 μg FP/100 μg S). Clinic visits were performed at monthly intervals. Inhaled rescue salbutamol use was permitted during the whole study period (including run-in), but no other COPD medications were permitted.
Protocol outcome measures
The two co-primary efficacy variables were Transition Dyspnoea Index (TDI) score at the end of the study (week 12), and Area Under the Curve (AUC0-30min) standardized by time of change from pre-dose in FEV1 after drug inhalation during the morning of baseline visit. In order to demonstrate the equivalence between BDP/FF and FP/S in terms of TDI, dyspnoea was assessed at baseline with the Baseline Dyspnoea Index (BDI) score and by TDI score at week 12 . Pulmonary function tests (PFTs) were performed, in accordance with ATS/ERS standards , at the screening visit before (pre-bronchodilator) and after (post-bronchodilator) salbutamol inhalation and at each clinic visit. At baseline and week 12, PFTs were performed before study drug inhalation (pre-dose) and then 5, 15 and 30 minutes after (post-dose). At week 4 and 8, spirometry was performed at pre-dose only. PFTs were all performed at least 12 hours after the previous evening dose and 6 hours after previous salbutamol use. Each site was provided with the same spirometer FlowScreen® CT that directly transferred PFTs values to the e-CRF.
A diary card was used each morning at home to record COPD symptom scores, the number of inhalations of study medication (run-in medication included) and salbutamol use; the diary card is shown in Additional file 1. Symptoms assessed with the diary card included ability to perform usual daily activities, breathlessness, night waking caused by respiratory symptoms, breathlessness on rising, cough and sputum production; each was assigned a score ranging from 0 (no symptoms) to 3 (worst), giving a maximum total score of 18 / day; this questionnaire has been used previously in a COPD clinical trial , but has not been formally validated for this purpose.
Occurrence of COPD exacerbations and adverse events were evaluated by the Investigator at all visits, by diary review and asking the patient. Health status was assessed using the St. George’s Respiratory Questionnaire (SGRQ) [17, 18] at baseline and at week 12. All patient-reported outcomes were gathered pre-dose in the morning. The six-minute walking test (6MWT) was carried out following ATS guidelines  at pre-dose and post-dose, both at baseline and week 12.
Data are expressed as mean and standard deviation (SD), unless otherwise specified. The study was powered to detect a mean difference between treatments of 0.080 L in the AUC0-30min standardized by time of change from pre-dose in FEV1 at baseline visit, assuming a SD of 0.16 L and using a two-sample t-test with two-sided significance level of 0.05 (further details are in Additional file 1). Superiority for AUC0-30min was demonstrated if the two-sided 95% confidence interval (CI) for the adjusted mean difference between the two drugs lied entirely above 0. Equivalence in TDI score was demonstrated if the two-sided 95% CI for the adjusted mean difference lied entirely within the equivalence margins fixed at ± 1, assuming the true mean difference in TDI score between treatments is 0 and the standard deviation is 2.7.
For all parameters, the analysis of covariance, with treatment and country as factors, and baseline value (pre-dose at randomisation visit) as a linear covariate, was applied. All analyses were performed with SAS™ System (SAS Institute Inc, Cary, NC), version 9.2. Statistical significance was set at 0.05 two tailed, and all analyses were performed on the intention-to-treat population (ITT). Imputation of missing data was completed following last observation carried forward method for post-baseline data. According to the current indication for ICS/LABA use in COPD , a pre-defined analysis was performed in patients with FEV1 < 50% of predicted for all efficacy variables.
Demographics and baseline characteristics
(N = 211)
(N = 207)
BMI, kg/m 2
Current smokers (%)
No. of pack years
Previous treatments* (%)
ICS/LABA fixed combination
Pre-dose FEV1, litre
Pre-bronchodilator FEV1, litre †
Post- bronchodilator FEV1, litre †
Post- bronchodilator FEV1/FVC (%)†
Post- bronchodilator FEV1 (% predicted normal)†
FEV1 post-bronchodilator change (%)†
pre-dose 6MWT, metres
Symptom-free days (%)
Rescue medication-free days (%)
Patients with no exacerbations in the previous year
Comparisons between the groups at week 12: adjusted values from ANCOVA analysis
Between groups p value
(N = 211)
(N = 207)
Pre-dose morning FEV1, litre
0.08 (0.04 to 0.11)
0.06 (0.03 to 0.10)
Pre-dose morning FVC, litre
0.06 (-0.00 to 0.13)
0.05 (-0.01 to 0.12)
-5.92 (-7.75 to -4.08)
-3.80 (-5.70 to -1.90)
SGRQ decrease from baseline > 4, patients (%)
31.62 (15.18 to 48.06)
22.23 (6.30 to 38.16)
6MWT changea > 37 meters, patients (%)
-1.21 (-1.55 to -0.87)
-1.00 (-1.35 to -0.65)
Breathlessness on risingb
-0.26 (-0.35 to -0.18)
-0.24 (-0.32 to -0.16)
4.60 (1.79 to 7.41)
5.88 (2.99 to 8.76)
Use of rescue medicationb, puffs
-0.60 (-0.78 to -0.42)
-0.63 (-0.81 to -0.45)
Rescue medication-free daysc,%
13.50 (9.39 to 17.61)
13.11 (8.89 to 17.32)
FEV1 post-dose at week 12 improved significantly in both treatment groups (p < 0.001 at all time-points; Figure 3b), with a significantly greater effect observed with BDP/FF at all-time points (p < 0.001 at each time-point). The mean differences (95% CI) between groups at 5, 15 and 30 minutes were 0.09 (0.07-0.11); 0.08 (0.05-0.10) and 0.07 (0.05-0.10), respectively. Similar changes were seen in patients with FEV1 predicted <50%; see Additional file 1 for figure and statistical analysis.
COPD total symptom score decreased significantly (p < 0.001) from baseline in both treatment groups at all intermediate visits (data not shown) and at the end of the study (see Additional file 1), with no difference between treatments (see Table 2). The number of symptom-free days increased significantly in both groups (p < 0.001), with no difference between groups. There were similar findings in patients with FEV1 predicted <50% (see Additional file 1).
Six (2.8%) patients in the BDP/FF treatment group and 4 (1.9%) in the FP/S group reported exacerbations, with no difference between groups. The majority of exacerbations occurred in patients with FEV1% < 50% of predicted; 5 (4.2%) patients in the BDP/FF group and 3 (2.5%) in the FP/S group.
Treatment-emergent serious adverse events (SAEs) were significantly lower (p = 0.024) in the BDP/FF group (4 patients, 1.9%) than in the FP/S group (13 patients, 6.3%). Pneumonia was reported in 3 patients (1.4%) treated with FP/S and none treated with BDP/FF. Worsening of COPD was reported in 2 (1.0%) patients treated with FP/S and none treated with BDP/FF. Three patients (1.4%) treated with BDP/FF and 5 treated with FP/S (2.4%) discontinued the study due to adverse events (AEs). There were no differences between groups in terms of vital signs and ECG. Further details of adverse events are in Additional file 1.
This is the first head-to-head study comparing extrafine BDP/FF with one of the most commonly used drugs for COPD patients (FP/S), evaluating different ICS dosages in fixed combination therapies. The TDI findings demonstrate that the lower ICS dose in the extrafine BDP/FF combination compared to FP/S provides equivalent symptom control, while the lung function findings for AUC0-30min confirmed a faster onset of action of the formoterol component compared to salmeterol.
The co-primary endpoint measurement of TDI assessed changes in breathlessness that may have been due either to differences in the ICS or LABA in the combination inhalers. We have demonstrated that the BDP/FF combination with a lower ICS dose compared to the FP/S combination was associated with similar improvements in symptom control. This may be due to the effects of the LABAs within these combination inhalers [3, 20] as well as to better distribution of extrafine particles of ICS. There are differences between these LABAs, as we have demonstrated for the AUC0-30min, and others have also reported in COPD studies of combination inhalers [13, 14]. It is difficult in head to head studies of combination inhalers to be sure which effect is due to the LABA or ICS. Nevertheless, the similar results for both combinations suggests that the ICS dose used does not influence symptom control.
A major goal of COPD pharmacotherapy is to relieve subjective symptoms . The equivalence of the TDI score demonstrates that extrafine BDP/FF impacts COPD symptoms to the same degree as FP/S, despite using a lower ICS dose. A 1 unit change in TDI is recognised as a clinically meaningful difference, so we chose this magnitude of change for the equivalence limits [21, 22]. We also analysed the number of patients who improved by >1, and again did not find any difference between the treatments.
Early morning symptoms are very common in COPD patients [2, 23]. Rapid bronchodilation improves physical exercise tolerance upon wakening, which is one of the most common COPD-associated symptoms . The faster onset of action of formoterol compared to salmeterol has been clearly demonstrated in asthma , but results in COPD patients are less consistent, as previous studies comparing these drugs in COPD patients have often involved relatively small study populations [25, 26], or provided uncertain results [27, 28]. However, larger COPD studies have shown that the fixed combination of budesonide/formoterol has a faster onset of action in the morning compared to FP/S [13, 14]. We now also demonstrate this finding for extrafine BDP/FF, and show that this is present after the first dose and maintained after 12 weeks treatment. The benefit achieved after the first dose may be important in providing patients with reassurance regarding drug effectiveness, which will likely improve medication compliance . The maintained presence of a faster onset of action in the morning observed up to 12 weeks may benefit COPD patients who chronically suffer with early morning symptoms.
The secondary efficacy endpoint measurements, which included changes in FEV1 pre-dose, SGRQ and 6MWT, also showed no difference between treatments. Both treatments improved SGRQ scores and 6MWT compared to baseline, although only the mean SGRQ change from baseline for BDP/FF reached the clinical meaningful threshold (> 4 units). A large randomized controlled COPD study  reported similar efficacy of the BDP/FF extrafine combination to the higher ICS dose in the budesonide/formoterol combination on the 6MWT over 48 weeks. The important role of long acting bronchodilators in reducing hyperinflation and thus improving exercise tolerance is well established, and these 6MWT results are likely to reflect similarities in the degree of bronchodilation and benefit on hyperinflation achieved by the LABAs .
The effectiveness of the lower ICS dose in BDP/FF may be due to the extra-fine formulation that allows homogeneous distribution of the two drugs throughout the bronchial tree  entailing a greater efficacy per microgram of ICS, in agreement with previous studies on asthma [32–34]. The extra-fine BDP/FF formulation allows the treatment of both large and small airways; the latter are particularly relevant in COPD pathophysiology . Peripheral airway obstruction causes progressive “air trapping” during exercise and consequent limitation of exercise capacity in COPD patients . The effect of BDP/FF extrafine combination on small airways in COPD has been demonstrated in terms of reduction of air trapping measured as reduction in residual volume  and increase in FVC .
The use of a combination with a lower ICS dose can be of particular relevance in COPD patients since side effects of ICS are dose-dependent  and are linked to an increased risk of pneumonia, as highlighted in the TORCH study . Moreover, the approved dosage of FP/S in COPD patients is 500 μg/50 μg twice daily in the EU , while in the US only a lower dose (250 μg/50 μg twice daily) was approved on the basis of clinical trial results [38–40], and importantly because an efficacy advantage of the higher strength had not been demonstrated .
One limitation of this study may be the lack of a third arm as a control group (e.g. LABA alone). However, the superiority of both extrafine BDP/FF and FP/S over placebo and the monocomponents have been previously demonstrated [11, 20].
The COPD patients enrolled were required to have FEV1 < 60% of predicted, as ICS/LABA combination therapies are most commonly used in patients with more severe airflow obstruction, and the license for FP/S matches this pulmonary function criteria. ICS/LABA combinations are licensed for use in patients with greater than or equal to one exacerbation per year. We excluded patients with greater than one exacerbation per year, in order to avoid a high drop out rate due to exacerbations during the trial period. Patients were required to demonstrate an increase in FEV1 ≥ 5% after salbutamol at screening; this ensured that the patients had some degree of therapeutic response to beta-agonist treatment. We considered this to be a useful inclusion criteria when comparing long acting beta agonists [13, 28]. It should be noted that 73.5% of the patients included in this study were using ICS before entry into the study; the population enrolled therefore was highly representative of patients who use ICS in real life.
The present study shows that, despite its lower ICS dose, extrafine BDP/FF (200/12 μg twice daily) is equivalent in improving dyspnoea and has a faster onset of action with respect to FP/S (500/50 μg twice daily) in patients with COPD. The benefits for patients treated with extrafine BDP/FF compared to FP/S may be twofold: first, the lower concern related to ICS dosage and second, a faster onset of bronchodilation, which can reduce morning symptoms.
Editorial assistance for preparing manuscript was provided by Pencil and Papers. We are especially grateful to Àlvar Agustí, Andrea Bizzi, Stefano Petruzzelli, and Stefano Vezzoli for their contribution to the sample size calculation and the study design.
Coordinating Centres: Denmark: J Vestbo (Department of Cardiology and Respiratory Medicine, Copenhagen); France: JP Grignet (Centre Hospitalier de Denain); Germany: J Kampschulte (Praxis Dr. Jorg Kampschulte); Hungary: M Szilasi (Karolina Kórház és Rendelőintézet Tüdőgyógyászat); Italy: C Terzano (Policlinico Umberto I); Poland: W Pierzchała (Niepubliczny Zakład Opieki Zdrowotnej “PROFILAKTYKA”); Slovakia: S Hrebenár (Pľúcna ambulancia, Hrebenár s.r.o); Spain: À Agustí (Hospital Clínic de Barcelona); Turkey: A Sayiner (Ege Üniversitesi Tip Fakültesi); United Kingdom: D Singh (University Hospital of South Manchester).
Participating Centres: DENMARK: V Backer (Dept. of Pulmonary Research, Bispebjerg Hospital, Copenhagen), R Dahl (Aarhus University Hospital), N Seersholm (Gentofte Hospital), I Titlestad (Dept. Of Pulmonary Research, Odense University hospital, Odense), J Vestbo (Department of Cardiology and Respiratory Medicine, Copenhagen).
FRANCE: M Larrousse (Centre Hospitalier de Toulon).
GERMANY: F Kanniess (KLB Healthresearch Luebeck), J Kampschulte (Praxis Dr. Jorg Kampschulte), J Heider (SMO.MD GmbH Zentrum für klinische Studien), M Höfer (Pneumologische Gemeinschaftspraxis Saarbrücken); G Illies (SMO.MD GmbH Zentrum für klinische Studien), P Kühnelt (Fachinternistische Praxisgemeinschaft), A Ludwig-Sengpiel (KLB Healthresearch Luebeck), R Redlich (Pneumologische Praxis Dr. Redlich), H Teutemacher (Gemeinschaftspraxis für Pneumologie), M Unland (Gemeinschaftspraxis für Pneumologie), J Winkler (Praxis Dr. Jörg Winkler).
HUNGARY: B Bálint, Z Bártfai, A Bartha, V Csajbók, Z Csontos, Tì Kecskés, G Kelen, G Losonczy, I Mészáros (Szigetszentmiklós), M Póczi (Dr. Kenessey Albert Kórház-Rendelőintézet), V Obbágy (Jósa András Oktatókórház Egészségügyi Szolgáltató), G Pánczél (Bács-Kiskun Megyei Önkormányzat Kórháza Szegedi Tudományegyetem Általános Orvostudományi Kar Oktató Kórháza), M Szilasi (Karolina Kórház és Rendelőintézet Tüdőgyógyászat), Z Szalai (Centrum-Tüdőgyógyászati Klinika), Z Sztancsik (Békés Megyei Képviselő-testület Pándy Kálmán Kórház), P Szabo (Szabolcs-Szatmár-Bereg Megyei Önkormányzat Jósa András Oktató Kórház), S Vasas (Fővárosi Önkormányzat Szent János Kórháza és Észak-budai Egyesített Kórházai Tüdőgondozó Szakrendelő).
ITALY: M Caputi (Azienda Ospedaliera Monaldi), V Cardaci (IRCCS San Raffaele La Pisana), G Di Maria (A.O. Policlinico di Catania), S Nava (Ospedale Sant’Orsola-Malpighi), A Palla (Università di Pisa), A Pesci (A.O. S. Gerardo), C Terzano (Policlinico Umberto I). POLAND: A Antczak (Prywatny Gabinet Specjalistyczny), H Batura-Gabryel, A Fal (DOBROSTAN - Gabinety Lekarskie), E Gross-Tyrkin (NZOZ “Non Nocere”), P Kuna, I Grzelewska-Rzymowska (Gabinet Lekarski SERIA IWONA GRZELEWSKA-RZYMOWSKA), J Milanowski (Samodzielny Publiczny Szpital Kliniczny), P Nalepa (Szpital Specjalistyczny im Jana Pawła II), I Oddział (Chorób Płuc), E Niżankowska-Mogilnicka (Szpital Uniwersytecki w Krakowie), W Pierzchała (Niepubliczny Zakład Opieki Zdrowotnej “PROFILAKTYKA”), P Śliwiński (Instytut Gruźlicy i Chorób Płuc. Zakład Diagnostyki i Leczenia Niewydolności Oddychania), M Szmidt (Wojewódzki Szpital Specjalistyczny im. M. Curie-Skłodowskiej), S Wesołowski (Zakład Fizjopatologii Oddychania, Instytut Gruźlicy i Chorób Płuc), K Wytrychowski (NZOZ Lekarze Specjaliści J.Małolepszy i Partnerzy). SLOVAKIA: K Arpasova (Diunea, sro. Ambulancia PaF), Ľ Frajtová (PULMO, s.r.o,), A Golubov (Neštátna ambulancia pneumológie a ftizeológie, Nemocničná) , I Hlinka (ALERGOIMUNO s.r.o), H Horváthová (PNEUMO-CENTRUM, s.r.o, Poliklinika), S Hrebenár (Pľúcna ambulancia, Hrebenár s.r.o), D Kavková (Pľúcna ambulancia, Poliklinika ADUS), K Virčíková (PNEUMO-MED, s.r.o).
SPAIN: M Dominguez (Hospital del Mar), J Serra Batlles (Hospital General Vic), C Domingo Ribas (Hospital Parc Taulí).
TURKEY: A Akkoclu ( Dokuz Eylül Üniversitesi), A Cilli (Akdeniz Üniversitesi), R Demir (Erciyes Üniversitesi), Ö Dikensoy (Gaziantep Üniversitesi), F Ece (Bilim Üniversitesi), E Ege (Uludag Üniversitesi), S Karakurt (Marmara Üniversitesi), A Kocabas (Çukurova Üniversitesi), A Sayiner (Ege Universitesi), Z Yildirim (Fatih Üniversitesi).
UNITED KINGDOM: S Birring (Kings College Hospital), A Fisher (Freeman Hospital), L McGarvey (Belfast City Hospital).
This study was funded by Chiesi Farmaceutici S.p.A., Parma, Italy.
- Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R: Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease, GOLD Executive Summary. Am J Respir Crit Care Med. 2013, 187 (4): 347-365. 10.1164/rccm.201204-0596PP. 10.1164/rccm.201204-0596PPView ArticlePubMedGoogle Scholar
- Kessler R, Partridge MR, Miravitlles M, Cazzola M, Vogelmeier C, Leynaud D, Ostinelli J: Symptom variability in patients with severe COPD: a pan-European cross-sectional study. Eur Respir J. 2011, 37 (2): 264-272. 10.1183/09031936.00051110.View ArticlePubMedGoogle Scholar
- Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS: Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomized controlled trials. Thorax. 2013, 68 (1): 48-56. 10.1136/thoraxjnl-2012-201926.View ArticlePubMedGoogle Scholar
- Barnes PJ: Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J. 2002, 19: 182-191. 10.1183/09031936.02.00283202.View ArticlePubMedGoogle Scholar
- Caramori G, Ito K, Papi A, Adcock IM: Interactions between long-acting β2 agonists and glucocorticoids. Drug Discov Today Ther Strateg. 2006, 3: 261-268.View ArticleGoogle Scholar
- Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E: Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008, 300 (20): 2407-2416. 10.1001/jama.2008.717.View ArticlePubMedPubMed CentralGoogle Scholar
- Singh S, Amin AV, Loke YK: Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med. 2009, 169: 219-229. 10.1001/archinternmed.2008.550.View ArticlePubMedGoogle Scholar
- Singh S, Loke YK: Risk of pneumonia associated with long-term use of inhaled corticosteroids in chronic obstructive pulmonary disease: a critical review and update. Curr Opin Pulm Med. 2010, 16: 118-122. 10.1097/MCP.0b013e328334c085.View ArticlePubMedPubMed CentralGoogle Scholar
- Nannini LJ, Lasserson TJ, Poole P: Combined corticosteroid and long-acting beta(2) agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012, 12 (9): CD006829-Google Scholar
- Singh D, Kampschulte J, Wedzicha JA, Jones PW, Cohuet G, Corradi M, Higenbottam T, Petruzzelli S, Vestbo J: A trial of beclomethasone/formoterol in COPD using EXACT-PRO to measure exacerbations. Eur Respir J. 2013, 41 (1): 12-17. 10.1183/09031936.00207611.View ArticlePubMedGoogle Scholar
- Calverley PM, Kuna P, Monsó E, Costantini M, Petruzzelli S, Sergio F, Varoli G, Papi A, Brusasco V: Beclomethasone/formoterol in the management of COPD: a randomised controlled trial. Respir Med. 2010, 104: 1858-1868. 10.1016/j.rmed.2010.09.008.View ArticlePubMedGoogle Scholar
- Cazzola M, Paggiaro P, Palange P, Bjermer L, Ausin P, Carlsson LG, Ekelund J, Lotvall J: Onset of action of formoterol versus salmeterol via dry powder inhalers in moderate chronic obstructive pulmonary disease: a randomized, placebo-controlled, double-blind, crossover study. Clin Drug Investig. 2012, 32 (3): 147-155. 10.2165/11630880-000000000-00000.View ArticlePubMedGoogle Scholar
- Lindberg A, Szalai Z, Pullerits T, Radeczky E: Fast onset of effect of budesonide/formoterol versus salmeterol/fluticasone and salbutamol in patients with chronic obstructive pulmonary disease and reversible airway obstruction. Respirology. 2007, 12: 732-739. 10.1111/j.1440-1843.2007.01132.x.View ArticlePubMedGoogle Scholar
- Partridge MR, Schuermann W, Beckman O, Persson T, Polanowski T: Effect on lung function and morning activities of budesonide/formoterol versus salmeterol/fluticasone in patients with COPD. Ther Adv Respir Dis. 2009, 3 (4): 1-11.View ArticlePubMedGoogle Scholar
- Mahler DA, Weinberg DH, Wells CK, Feinstein AR: The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest. 1984, 85: 751-758. 10.1378/chest.85.6.751.View ArticlePubMedGoogle Scholar
- Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J: ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005, 2: 319-338.View ArticleGoogle Scholar
- Jones PW, Quirk FH, Baveystock CM, Littlejohns P: A self-complete measure for chronic airflow limitation - the St George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992, 145: 1321-1327. 10.1164/ajrccm/145.6.1321.View ArticlePubMedGoogle Scholar
- Schünemann HJ, Griffith L, Jaeschke R, Goldstein R, Stubbing D, Guyatt GH: Evaluation of the minimal important difference for the feeling thermometer and the St George’s Respiratory Questionnaire in patients with chronic airflow obstruction. J Clin Epidemiol. 2003, 56: 1170-1176. 10.1016/S0895-4356(03)00115-X.View ArticlePubMedGoogle Scholar
- Statement ATS: Guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002, 166: 111-117.View ArticleGoogle Scholar
- Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J: TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007, 356: 775-789. 10.1056/NEJMoa063070.View ArticlePubMedGoogle Scholar
- Witek TJ, Mahler DA: Meaningful effect size and patterns of response of the transition dyspnea index. J Clin Epidemiol. 2003, 56: 248-255. 10.1016/S0895-4356(02)00589-9.View ArticlePubMedGoogle Scholar
- Witek TJ, Mahler DA: Minimal important difference of the transition dyspnoea index in a multinational clinical trial. Eur Respir J. 2003, 21: 267-272. 10.1183/09031936.03.00068503a.View ArticlePubMedGoogle Scholar
- Partridge MR, Karlsson N, Small IR: Patient insight into the impact of chronic obstructive pulmonary disease in the morning: an internet survey. Curr Med Res Opin. 2009, 25 (8): 2043-2048. 10.1185/03007990903103006.View ArticlePubMedGoogle Scholar
- Van Noord JA, Smeets JJ, Raaijmakers JA, Bommer AM, Maesen FP: Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. Eur Respir J. 1996, 9 (8): 1684-1688. 10.1183/09031936.96.09081684.View ArticlePubMedGoogle Scholar
- Kottakis J, Cioppa GD, Creemers J, Greefhorst L, Lecler V, Pistelli R, Overend T, Till D, Rapatz G, Le Gros V, Bouros D, Siafakas N: Faster onset of bronchodilation with formoterol than with salmeterol in patients with stable, moderate to severe COPD: results of a randomized, double-blind clinical study. Can Respir J. 2002, 9 (2): 107-115.View ArticlePubMedGoogle Scholar
- Bouros D, Kottakis J, Le Gros V, Overend T, Della Cioppa G, Siafakas N: Effects of formoterol and salmeterol on resting inspiratory capacity in COPD patients with poor FEV(1) reversibility. Curr Med Res Opin. 2004, 20 (5): 581-586. 10.1185/030079904125003368.View ArticlePubMedGoogle Scholar
- Cazzola M, Santus P, Di Marco F, Boveri B, Castagna F, Carlucci P, Matera MG, Centanni S: Bronchodilator effect of an inhaled combination therapy with salmeterol + fluticasone and formoterol + budesonide in patients with COPD. Respir Med. 2003, 97 (5): 453-457. 10.1053/rmed.2002.1455.View ArticlePubMedGoogle Scholar
- Celik G, Kayacan O, Beder S, Durmaz G: Formoterol and salmeterol in partially reversible chronic obstructive pulmonary disease: a crossover, placebo-controlled comparison of onset and duration of action. Respiration. 1999, 66 (5): 434-439. 10.1159/000029427.View ArticlePubMedGoogle Scholar
- Bourbeau J, Bartlett SJ: Patient adherence in COPD. Thorax. 2008, 63 (9): 831-838. 10.1136/thx.2007.086041.View ArticlePubMedPubMed CentralGoogle Scholar
- Cazzola M, Page CP, Rogliani P, Matera MG: β2-agonist therapy in lung disease. Am J Respir Crit Care Med. 2013, 187 (7): 690-696. 10.1164/rccm.201209-1739PP.View ArticlePubMedGoogle Scholar
- Nicolini G, Scichilone N, Bizzi A, Papi A, Fabbri LM: Beclomethasone/formoterol fixed combination for the management of asthma: patient considerations. Ther Clin Risk Manag. 2008, 4: 855-864.PubMedPubMed CentralGoogle Scholar
- Scichilone N, Battaglia S, Sorino C, Paglino G, Martino L, Paternò A, Santagata R, Spatafora M, Nicolini G, Bellia V: Effects of extra-fine inhaled beclomethasone/formoterol on both large and small airways in asthma. Allergy. 2010, 65: 897-902. 10.1111/j.1398-9995.2009.02306.x.View ArticlePubMedGoogle Scholar
- Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM: Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J. 2007, 29: 682-689. 10.1183/09031936.00095906.View ArticlePubMedGoogle Scholar
- Huchon G, Magnussen H, Chuchalin A, Dymek L, Gonod FB, Bousquet J: Lung function and asthma control with beclomethasone and formoterol in a single inhaler. Respir Med. 2009, 103: 41-49. 10.1016/j.rmed.2008.09.002.View ArticlePubMedGoogle Scholar
- Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Paré PD: The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004, 350 (26): 2645-2653. 10.1056/NEJMoa032158.View ArticlePubMedGoogle Scholar
- Tzani P, Crisafulli E, Nicolini G, Aiello M, Chetta A, Clini EM, Olivieri D: Effects of beclomethasone/formoterol fixed combination on lung hyperinflation and dyspnea in COPD patients. Int J Chron Obstruct Pulmon Dis. 2011, 6: 503-509.PubMedPubMed CentralGoogle Scholar
- Allen & Hanburys: Seretide 100, 250, 500 Accuhaler. 2012, Available from URL: http://emc.medicines.org.uk Google Scholar
- Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, Shah T: The efficacy and safety of fluticasone propionate (250 μg)/salmeterol (50 μg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003, 124: 834-843. 10.1378/chest.124.3.834.View ArticlePubMedGoogle Scholar
- Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C: Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Respir Med. 2008, 102 (8): 1099-1108. 10.1016/j.rmed.2008.04.019.View ArticlePubMedGoogle Scholar
- Anzueto A, Ferguson GT, Feldman G, Chinsky K, Seibert A, Emmett A, Knobil K, O'Dell D, Kalberg C, Crater G: Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD. 2009, 6 (5): 320-329. 10.1080/15412550903140881.View ArticlePubMedGoogle Scholar
- Glaxo SK: Advair DiskusR 100/50, 250/50, 500/50 prescribing information [online]. 2012, Available from URL: http://us.gsk.com/products/assets/us_advair.pdf [Accessed 2012 Nov 21]Google Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/14/43/prepub
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