The Study to Understand Mortality and Morbidity in COPD (SUMMIT) study protocol Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee ADRB2 polymorphisms and budesonide/formoterol responses in COPD. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial Inhaled corticosteroids in COPD and the risk of serious pneumonia Inhaled Steroids Modulate Extracellular Matrix Composition in Bronchial Biopsies of COPD Patients: A Randomized, Controlled Trial Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Efficacy and Tolerability of Budesonide/Formoterol in One Hydrofluoroalkane Pressurized Metered-Dose Inhaler in Patients with Chronic Obstructive Pulmonary Disease Effect on lung function and morning activities of budesonide/formoterol versus salmeterol/fluticasone in patients with COPD Health status deterioration in patients with chronic obstructive pulmonary disease. Which patients with chronic obstructive pulmonary disease benefit from the addition of an inhaled corticosteroid to their bronchodilator? A cluster analysis Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. The TORCH (TOwards a Revolution in COPD Health) survival study protocol Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Randomised controlled trial of inhaled corticosteroids in patients with chronic obstructive pulmonary disease. Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations Effect of Fluticasone Propionate/Salmeterol (250/50) on COPD Exacerbations and Impact on Patient Outcomes Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study Effects of fluticasone propionate in COPD patients with bronchial hyperresponsiveness Budesonide/formoterol via Turbuhaler® versus formoterol via Turbuhaler® in patients with moderate to severe chronic obstructive pulmonary disease: phase III multinational study results. Effects of long-term treatment with corticosteroids in COPD. Effects of fluticasone propionate on inflammatory cells in COPD: an ultrastructural examination of endobronchial biopsy tissue Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Effect of an inhaled glucocorticoid on reactive oxygen species production by bronchoalveolar lavage cells from smoking COPD patients. Inhaled corticosteroids in COPD: quantifying risks and benefits A randomised trial of fluticasone furoate/vilanterol (50/25 μg; 100/25 μg) on lung function in COPD. Predictive value and utility of oral steroid testing for treatment of COPD in primary care: the COOPT study Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting β2 agonist: observational matched cohort study (PATHOS) Impact of preventing exacerbations on deterioration of health status in COPD Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial Maintenance therapy with budesonide and formoterol in chronicobstructive pulmonary disease Withdrawal from treatment as an outcome in the ISOLDE study of COPD. Is treatment with ICS and LABA cost-effective for COPD? Multinational economic analysis of the TORCH study Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease Cardiovascular events in patients with COPD: TORCH Study results Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease Does addition of inhaled steroid to combined bronchodilator therapy affect health status in patients with COPD? Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Long-term mortality follow-up of the ISOLDE participants: causes of death during 13 years after trial completion. The effect of inhaled corticosteroids on bronchoalveolar lavage cells and IL-8 levels in stable COPD patients. Rapid Fall in Lung Density Following Smoking Cessation in COPD Cost effectiveness of budesonide/formoterol in a single inhaler for COPD compared with each monocomponent used alone Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study. A double‐blind placebo‐controlled study of the effect of inhaled beclomethasone dipropionate for 2 years in patients with nonasthmatic chronic obstructive pulmonary disease Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis. Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler® Short- and long-term efficacy of fluticasone propionate in subjects with early signs and symptoms of chronic obstructive pulmonary disease. Results of the DIMCA study. Gender does not influence the response to the combination of salmeterol and fluticasone propionate in COPD. Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomised trial. Estimating the cost-effectiveness of fluticasone propionate for treating chronic obstructive pulmonary disease in the presence of missing data. Indirect comparisons of competing interventions. The European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): recruitment methods and strategies. Methods for therapeutic trials in COPD: lessons from the TORCH trial Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): hypothesis and design. Beclomethasone/formoterol in the management of COPD: a randomised controlled trial. The Effect of Inhaled Corticosteroids on the Development of Emphysema in Smokers Assessed by Annual Computed Tomography Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. Steroid reversibility test followed by inhaled budesonide or placebo in outpatients with stable chronic obstructive pulmonary disease. The Danish Society of Respiratory Medicine. An observational study of inhaled corticosteroid withdrawal in stable chronic obstructive pulmonary disease. ISOLDE Study Group. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial Bias due to withdrawal in long‐term randomised trials in COPD: Evidence from the TORCH study
Chronic obstructive pulmonary disease ( COPD ) often coexists with other chronic diseases and comorbidities that can markedly influence patients ' health status and prognosis . This is particularly true for cardiovascular disease ( CVD ) . However , there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases . The “ Study to Underst and Mortality and Morbidity in COPD ” ( SUMMIT ) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD . SUMMIT is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled trial of 16 000 patients with moderate COPD r and omly assigned to once daily treatment with fluticasone furoate/vilanterol ( 100/25 & mgr;g ) , fluticasone furoate ( 100 & mgr;g ) , vilanterol ( 25 & mgr;g ) or matched placebo ; mortality is the primary end-point . The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo . Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point . This article describes the design of the SUMMIT study Background : TORCH ( Towards a Revolution in COPD Health ) is an international multicentre , r and omised , placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease ( COPD ) . The primary outcome is all-cause mortality . Cause-specific mortality and deaths related to COPD are additional outcome measures , but systematic methods for ascertainment of these outcomes have not previously been described . Methods : A Clinical Endpoint Committee ( CEC ) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic , unbiased and independent manner . The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD -relatedness ; the independent review of cases by all members with development of a consensus opinion ; and a substantial infrastructure to collect medical information . Results : 911 deaths were review ed and consensus was reached in all . Cause-specific mortality was : cardiovascular 27 % , respiratory 35 % , cancer 21 % , other 10 % and unknown 8 % . 40 % of deaths were definitely or probably related to COPD . Adjudications were identical in 83 % of blindly re-adjudicated cases ( κ = 0.80 ) . COPD -relatedness was reproduced 84 % of the time ( κ = 0.73 ) . The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52 % of cases . Conclusion : A CEC can provide st and ardised , reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators BACKGROUND Effects of β(2)-adrenergic receptor gene ( ADRB2 ) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials . We aim ed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD . METHODS Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I ( NCT00206167 ) or the 6-month trial II ( NCT00206154 ) were r and omly assigned to bid budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9 μg or 160/9 μg , budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg ( trial II ) , budesonide pMDI 320 μg ( trial II ) , formoterol dry powder inhaler 9 μg , or placebo . The effect of Gly16Arg on predose FEV(1 ) and 1-h postdose FEV(1 ) , exacerbations , diary variables , and adverse events were analyzed . RESULTS No significant interaction between genotype and treatment response was observed for predose ( P ≥ .197 ) or postdose FEV(1 ) ( P ≥ .125 ) in either pharmacogenetic study ( n = 2,866 ) . The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups ( both studies ) . Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment . CONCLUSION Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD Background : Airway inflammation in chronic obstructive pulmonary disease ( COPD ) is characterised by infiltration of CD8 + T cells and CD68 + macrophages and an increased number of neutrophils , whereas few studies have described the presence of eosinophils . Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear , recent studies suggest that combination therapy could be beneficial . A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate ( SFC ) and fluticasone propionate ( FP ) alone on inflammatory cells in the airways of patients with COPD . Methods : Patients were treated in a r and omised , double blind , parallel group , placebo-controlled trial with either a combination of 50 µg salmeterol and 500 µg FP twice daily  ( SFC , n = 19 , 19 men , mean age 62 years ) , 500 µg FP twice daily ( n = 20 , 15 men , mean age 64 years ) or placebo  ( n = 21 , 17 men , mean age 66 years ) for 3 months . At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8 + T lymphocytes , CD68 + macrophages , neutrophils and eosinophils were measured . Results : CD8 + cells were significantly reduced by SFC compared with placebo ( difference −98.05 cells/mm2 ; 95 % CI −143.14 to −52.9 ; p<0.001 ) . Such a marked effect was not seen with FP alone ( −44.67 cells/mm2 ; 95 % CI −90.92 to 1.57 ; p = 0.06 ) . CD68 + macrophages were also reduced by SFC compared with placebo ( difference −31.68 cells/mm2 ; 95 % CI −61.07 to −2.29 ; p = 0.03 ) but not by FP . SFC did not significantly change neutrophils and eosinophils compared with placebo . Conclusions : SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone Background Inhaled corticosteroids ( ICS ) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease ( COPD ) . It is unclear whether the risk of pneumonia varies for different inhaled agents , particularly fluticasone and budesonide , and increases with the dose and long-term duration of use . Methods We formed a new-user cohort of patients with COPD treated during 1990–2005 . Subjects were identified using the Quebec health insurance data bases and followed through 2007 or until a serious pneumonia event , defined as a first hospitalisation for or death from pneumonia . A nested case – control analysis was used to estimate the rate ratio ( RR ) of serious pneumonia associated with current ICS use , adjusted for age , sex , respiratory disease severity and comorbidity . Results The cohort included 163 514 patients , of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up ( incidence rate 2.4/100/year ) . Current use of ICS was associated with a 69 % increase in the rate of serious pneumonia ( RR 1.69 ; 95 % CI 1.63 to 1.75 ) . The risk was sustained with long-term use and declined gradually after stopping ICS use , disappearing after 6 months ( RR 1.08 ; 95 % CI 0.99 to 1.17 ) . The rate of serious pneumonia was higher with fluticasone ( RR 2.01 ; 95 % CI 1.93 to 2.10 ) , increasing with the daily dose , but was much lower with budesonide ( RR 1.17 ; 95 % CI 1.09 to 1.26 ) . Conclusions ICS use by patients with COPD increases the risk of serious pneumonia . The risk is particularly elevated and dose related with fluticasone . While residual confounding can not be ruled out , the results are consistent with those from recent r and omised trials Rationale Smoking and inflammation contribute to the pathogenesis of chronic obstructive pulmonary disease ( COPD ) , which involves changes in extracellular matrix . This is thought to contribute to airway remodeling and airflow obstruction . We have previously observed that long-term treatment with inhaled corticosteroids can not only reduce bronchial inflammation , but can also attenuate lung function decline in moderate-severe COPD . We hypothesized that inhaled corticosteroids and current smoking modulate bronchial extracellular matrix components in COPD . Objective To compare major extracellular matrix components ( elastic fibers ; proteoglycans [ versican , decorin ] ; collagens type I and III ) in bronchial biopsies 1 ) after 30-months inhaled steroids treatment or placebo ; and 2 ) between current and ex-smokers with COPD . Methods We included 64 moderate-severe , steroid-naive COPD patients ( 24/40 (ex)-smokers , 62±7 years , 46 ( 31–54 ) packyears , post-bronchodilator forced expiratory volume in one second ( FEV1 ) 62±9 % predicted ) at baseline in this r and omized , controlled trial . 19 and 13 patients received 30-months treatment with fluticasone or placebo , respectively . Bronchial biopsies collected at baseline and after 30 months were studied using (immuno)histochemistry to evaluate extracellular matrix content . Percentage and density of stained area were calculated by digital image analysis . Results 30-Months inhaled steroids increased the percentage stained area of versican ( 9.6 % [ CI 0.9 to 18.3 % ] ; p = 0.03 ) and collagen III ( 20.6 % [ CI 3.8 to 37.4 % ] ; p = 0.02 ) compared to placebo . Increased collagen I staining density correlated with increased post-bronchodilator FEV1 after inhaled steroids treatment ( Rs = 0.45 , p = 0.04 ) . There were no differences between smokers and ex-smokers with COPD in percentages and densities for all extracellular matrix proteins . Conclusions These data show that long-term inhaled corticosteroids treatment partially changes the composition of extracellular matrix in moderate-severe COPD . This is associated with increased lung function , suggesting that long-term inhaled steroids modulate airway remodeling thereby potentially preventing airway collapse in COPD . Smoking status is not associated with bronchial extracellular matrix proteins . Trial Registration Clinical Trials.gov BACKGROUND Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2 ) agonist is more protective than a once-daily longacting β(2 ) agonist alone against exacerbations of chronic obstructive pulmonary disease ( COPD ) is unknown . We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone . METHODS We did two replicate double-blind parallel-group 1 year trials . Both studies began on Sept 25 , 2009 . Study 1 ended on Oct 31 , 2011 , and study 2 on Oct 17 , 2011 . Eligible patients were aged 40 years or older , had a history of COPD , a smoking history of 10 or more pack-years , a ratio of forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity of 0·70 or less after bronchodilators ( and an FEV(1 ) of 70 % or less of predicted ) , and a documented history of one or more moderate or severe disease exacerbations in the year before screening . Patients were r and omly assigned ( 1:1:1:1 ) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg , 100 μg , or 200 μg fluticasone furoate once daily . Our primary endpoint was the yearly rate of moderate and severe exacerbations . The trials were analysed separately and a pooled analysis was also done . These trials are registered with Clinical Trials.gov ( NCT01009463 and NCT01017952 ) . FINDINGS 1622 patients in study 1 and 1633 patients in study 2 were r and omly assigned . In study 1 , no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group ( mean 0·90 events vs 1·05 events per year ; ratio 0·9 [ 95 % CI 0·7 - 1·0 ] ) . Because of the statistical hierarchy used , we could not infer significance for the 50 μg and 100 μg groups . In study 2 , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( p=0·0398 for the 50 μg group , 0·0244 for the 100 μg group , and 0·0004 for the 200 μg group ) . In the pooled analysis , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( 0·0141 for the 50 μg group , < 0·0001 for the 100 μg group , and 0·0003 for the 200 μg group ) . Nasopharyngitis was the most frequently reported adverse event in both studies . Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone . Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group . INTERPRETATION Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD  in patients with a history of exacerbation , but was also associated with an increased pneumonia risk . FUNDING GlaxoSmithKline Background : Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid ( ICS ) is recommended in patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations . The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler ( DPI ) in a 1-year study and when administered via the hydrofluoroalkane ( HFA ) pressurized metered-dose inhaler ( pMDI ) in a 6-month study . Objective : This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD . Methods : This was a 12-month , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled , multicentre study ( NCT00206167 ) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US , Europe and Mexico . After 2 weeks of treatment based on previous therapy ( ICSs , short-acting bronchodilators allowed ) , patients received one of the following treatments twice daily : budesonide/formoterol pMDI 160/4.5 μg × two inhalations ( 320/9 μg ) ; budesonide/formoterol pMDI 80/4.5 μg × two inhalations ( 160/9 μg ) ; formoterol DPI 4.5 μg × two inhalations ( 9 μg ) ; or placebo . Main outcome measures : The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV1 ) and 1-hour post-dose FEV1 . Results : Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1  versus formoterol ( p = 0.008 ) , and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1  versus placebo ( p < 0.001 ) . The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo ( p ≤ 0.004 ) . Both budesonide/formoterol doses were more effective  than placebo ( p ≤ 0.006 ) for controlling dyspnoea and improving health status ( St George ’s Respiratory Question naire ) . All treatments were generally well tolerated . The incidence of pneumonia was not different for active ( 3.4–4.0 % ) and placebo ( 5.0 % ) groups . Conclusions : Budesonide/formoterol pMDI ( 320/9 μg and 160/9 μg ) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD .  Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co- primary variables compared with formoterol DPI 9 μg . Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo Background : Patients with chronic obstructive pulmonary disease ( COPD ) often experience symptoms and problems with activities early in the morning . This is the first study to compare the effect of budesonide/formoterol and salmeterol/fluticasone on lung function , symptoms and activities early in the morning . Methods : Lung function ( peak expiratory flow [ PEF ] and forced expiratory volume in 1 second [ FEV 1 ] ) and symptoms were measured at bedside and activities were measured during the morning using a six-item question naire concerning basic morning routines . In a r and omised , double-blind , multicentre , cross-over study , 442 patients with COPD aged ≥40 years ( pre-bronchodilator FEV1 ≤50 % ; FEV1/vital capacity < 70 % )  received budesonide/formoterol ( 320/9 µg , one inhalation twice daily ) dry powder inhaler ( DPI ) or salmeterol/fluticasone ( 50/500 µg , one inhalation twice daily ) DPI daily , for 1 week each , separated by a 1- to 2-week washout . Lung function ( PEF and FEV1 ) shortly after rising from bed in the morning , symptoms and basic morning activities were assessed by electronic diary ( e-Diary ) recordings . Results : Budesonide/formoterol and salmeterol/fluticasone treatment increased morning PEF 5 minutes post-dose , measured as a mean improvement from baseline over the full study period ( primary endpoint ; adjusted mean change : 15.1 l/min and 14.2 l/min , respectively [ difference 1.0 l/min ; p = 0.603 ] ) . Mean morning FEV1 improved more following budesonide/ formoterol treatment versus salmeterol/fluticasone at 5 minutes ( 0.12 l versus 0.09 l ; p = 0.090 ) and 15 minutes ( 0.14 l versus 0.10 l ; p < 0.05 ) post-dose . Budesonide/formoterol demonstrated a more rapid onset of effect as reflected by increases in e-Diary-recorded PEF and FEV 1 from pre-dose to 5 and 15 minutes post-dose ( all p < 0.001 ) and spirometry at the clinic measured after the first dose ( FEV1 p < 0.001 ; 5 minutes post-dose ) . Improvements in symptom scores within 15 minutes after drug administration were similar for both drugs , but budesonide/formoterol treatment result ed in significantly greater improvements in total morning activities score ( getting washed , dried , dressed , eating breakfast and walking around the home ; 0.22 versus 0.12 respectively , p < 0.05 ) . Both treatments were well tolerated . Conclusions : Short-term treatment with budesonide/formoterol DPI or salmeterol/fluticasone DPI was effective in patients with COPD .  Budesonide/formoterol had a more rapid onset of effect compared with salmeterol/fluticasone and result ed in greater improvements in ability to perform morning activities despite the lower inhaled corticosteroid dose This study examined health status decline in patients with chronic obstructive pulmonary disease ( COPD ) . Data are from the Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) trial . After an 8-wk run-in , 751 patients ( 566 male ) , mean age 64 yr , were r and omized to receive fluticasone propionate ( FP ) 500 microg twice daily ( 376 patients ) or placebo ( 375 patients ) . Mean baseline postbronchodilator FEV1 was 50 + /- 15 % predicted . Patients completed the St George 's Respiratory Question naire ( SGRQ ) and the Short-Form 36 ( SF-36 ) at baseline and every 6 mo for 3 yr . FEV1 and smoking status were assessed at baseline and at 3-mo intervals . A total of 387 ( 212 FP ) patients completed the trial . All SGRQ components ( p = 0.03 to 0.004 ) and Physical Function , Mental Health , Energy/ Vitality , and Physical Role Limitation scales of the SF-36 ( p = 0.05 to 0.005 ) deteriorated faster in the placebo group . FEV1 and SGRQ scores correlated at baseline values ( r = -0.25 , p < 0.0001 ) , as did change in FEV1 and change in SGRQ ( Delta r = -0.24 , p < 0.0001 ) . At baseline values smokers had worse SGRQ Total , Symptoms , and Impacts scores than ex-smokers . This difference was maintained throughout the study . Smoking status did not influence the rate of decline in health status . The SGRQ Total scores of FP-treated patients took 59 % longer than placebo to deteriorate by a clinical ly significant amount . We conclude that health status decline in moderate to severe COPD can be reduced by high-dose fluticasone Objective To identify subsets of chronic obstructive pulmonary disease ( COPD ) patients who are more protected from exacerbations with the use of an  inhaled corticosteroid/long-acting β2 agonist ( ICS/LABA ) combination , compared with the use of LABA monotherapy . Design Post hoc cluster analysis of patients from two r and omised clinical trials of  salmeterol/fluticasone propionate ( SFC ) and salmeterol ( SAL ) that had primary endpoints of moderate/severe exacerbation rates . Setting Centres in North America . Participants 1543 COPD patients were studied . Interventions SFC 50/250 µg or SAL 50 µg , twice daily . Primary and secondary outcome measures The analysis identified clusters of COPD patients more responsive to SFC versus SAL with respect to the annual rate of moderate/severe exacerbations and compared their baseline clinical characteristics . Results Overall , SFC significantly reduced the annual rate of moderate/severe exacerbations as compared with SAL alone ( rate ratio (RR)=0.701 , p<0.001 ) . Three-patient clusters were identified : COPD patients receiving diuretics ( RR=0.56 , p<0.001 ) ; patients not receiving diuretics but with forced expiratory volume in 1 s ( FEV1 ) reversibility ≥12 % ( RR=0.67 , p<0.001 ) exhibited a substantial reduction in the annual rate of moderate/severe exacerbations relative to SAL . A third cluster , consisting of patients not receiving diuretics and without FEV1 reversibility , demonstrated no difference for SFC versus SAL . Patients receiving diuretics had a significantly higher prevalence of comorbid cardiovascular disease . Conclusions COPD patients receiving diuretics and those not receiving diuretics but with FEV1 reversibility > 12 % at baseline were significantly more likely to experience a reduction in COPD -associated exacerbations with SFC versus SAL alone . Trial registration NCT00115492 , RATIONALE Chronic obstructive pulmonary disease ( COPD ) is characterized by an accelerated decline in lung function . No drug has been shown conclusively to reduce this decline . OBJECTIVES In a post hoc analysis of the Toward a Revolution in COPD Health ( TORCH ) study , we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg , either component alone or placebo , on the rate of post-bronchodilator FEV(1 ) decline in patients with moderate or severe COPD . METHODS A r and omized , double-blind , placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries . Of 6,112 patients from the efficacy population , 5,343 were included in this analysis . MEASUREMENTS AND MAIN RESULTS Spirometry was measured every 24 weeks for 3 years . There were 26,539 on-treatment observations . The adjusted rate of decline in FEV(1 ) was 55 ml/year for placebo , 42 ml/year for salmeterol , 42 ml/year for fluticasone propionate , and 39 ml/year for salmeterol plus fluticasone propionate . Salmeterol plus fluticasone propionate reduced the rate of FEV(1 ) decline by 16 ml/year compared with placebo ( 95 % confidence interval [ CI ] , 7 - 25 ; P < 0.001 ) . The difference was smaller for fluticasone propionate and salmeterol compared with placebo ( 13 ml/year ; 95 % CI , 5 - 22 ; P = 0.003 ) . Rates of decline were similar among the active treatment arms . FEV(1 ) declined faster in current smokers and patients with a lower body mass index , and varied between world regions . Patients who exacerbated more frequently had a faster FEV(1 ) decline . CONCLUSIONS Pharmacotherapy with salmeterol plus fluticasone propionate , or the components , reduces the rate of decline of FEV(1 ) in patients with moderate-to-severe COPD , thus slowing disease progression . Clinical trial ( GSK Study Code SCO30003 ) registered with www . clinical trials.gov ( NCT00268216 ) Only long-term home oxygen therapy has been shown in r and omised controlled trials to increase survival in chronic obstructive pulmonary disease ( COPD ) . There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators , alone or in combination , on mortality in patients with COPD , despite their known benefit in reducing symptoms and exacerbations . The “ TOwards a Revolution in COPD Health ” ( TORCH ) survival study is aim ing to determine the impact of salmeterol/fluticasone propionate ( SFC ) combination and the individual components on the survival of COPD patients . TORCH is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled study . Approximately 6,200 patients with moderate-to-severe COPD were r and omly assigned to b.i.d . treatment with either SFC ( 50/500 µg ) , fluticasone propionate ( 500 µg ) , salmeterol ( 50 µg ) or placebo for 3 yrs . The primary end-point is all-cause mortality ; secondary end-points are COPD morbidity relating to rate of exacerbations and health status , using the St George 's Respiratory Question naire . Other end-points include other mortality and exacerbation end-points , requirement for long-term oxygen therapy , and clinic lung function . Safety end-points include adverse events , with additional information on bone fractures . The first patient was recruited in September 2000 and results should be available in 2006 . This paper describes the “ TOwards a Revolution in COPD Health ” study and explains the rationale behind it The aim of this double-blind single center study ( the COPE study ) was to investigate the effect of discontinuation of the inhaled corticosteroid fluticasone propionate ( FP ) on exacerbations and health-related quality of life in patients with chronic obstructive pulmonary disease . After 4 months of treatment with FP ( 1,000 microg/day ) , 244 patients were r and omized to either continue FP or to receive placebo for 6 months : 123 patients continued FP ( FP group ) , and 121 received placebo ( placebo group ) . In the FP group , 58 ( 47 % ) patients developed at least one exacerbation compared with 69 ( 57 % ) in the placebo group . The hazard ratio of a first exacerbation in the placebo group compared with the FP group was 1.5 ( 95 % confidence interval [ CI ] 1.1 - 2.1 ) . In the placebo group 26 patients ( 21.5 % ) experienced rapid recurrent exacerbations and were subsequently unblinded and prescribed FP compared with 6 patients ( 4.9 % ) in the FP group ( relative risk = 4.4 ; 95 % CI 1.9 - 10.3 ) . Over a 6-month period , a significant difference in favor of the FP group was observed in the total score ( + 2.48 95 % CI 0.37 - 4.58 ) , activity domain ( + 4.64 95 % CI 1.60 - 7.68 ) , and symptom domain ( + 4.58 95 % CI 1.05 - 8.10 ) of the St. George 's Respiratory Question naire . This study indicates that discontinuation of FP in patients with chronic obstructive pulmonary disease is associated with a more rapid onset and higher recurrence-risk of exacerbations and a significant deterioration in aspects of Health-Related Quality of Life BACKGROUND Inhaled corticosteroids are known to be beneficial for patients with asthma , but their role in treating patients with stable chronic obstructive pulmonary disease ( COPD ) remains controversial . A study was undertaken to determine whether inhaled corticosteroids are of functional benefit in patients who did not show improvement with a trial of oral corticosteroids . METHODS In phase I patients with stable COPD were given a two week course of oral placebo followed by two weeks of prednisone 40 mg per day in a single blind manner to distinguish between responders and non-responders to oral corticosteroids . In phase II a double blind , r and omised , parallel group trial of inhaled budesonide 1600 micrograms per day versus placebo was carried out in 79 nonresponders to oral corticosteroids .  The primary outcome measure was forced expiratory volume in one second ( FEV1 ) , and secondary outcome measures were exercise capacity , dyspnoea with exertion , quality of life , peak expiration flow rate , and respiratory symptoms . RESULTS R and omisation allocated 39 subjects to inhaled corticosteroids and 40 to placebo .  There was no difference in the change in FEV1 from baseline between the treatment and placebo groups ; mean difference -12 ml ( 95 % CI -88 to 63 ) at three months and -4 ml ( 95 % CI -95 to 87 ) at six months . The proportion of patients with a 15 % or greater improvement was no higher among those receiving inhaled corticosteroids than in the placebo group at any of the follow up visits . Changes in secondary outcomes were also no different . CONCLUSIONS Inhaled corticosteroids , even at high doses , were of no physiological or functional benefit in these patients with advanced COPD Exacerbations of chronic obstructive pulmonary disease ( COPD ) are associated with worse health and increased healthcare utilisation . The Inhaled Steroids in Obstructive Lung Disease in Europe ( ISOLDE ) study in COPD showed a 26 % reduction in the yearly rate of exacerbations in patients treated with fluticasone propionate ( FP ) compared to placebo , but did not indicate which patients showed greatest benefit . In this study the patients were stratified into mild and moderate‐to‐severe COPD using the American Thoracic Society criterion of forced expiratory volume in one second ( FEV1 ) 50 % predicted , and the total number of exacerbations and those requiring treatment with oral corticosteroids were examined . There were 391 ( 195 FP ) patients with mild COPD and 359 ( 180 FP ) patients with moderate‐to‐severe disease .  The exacerbation rate was highly skewed in mild disease , but more normally distributed in moderate‐to‐severe disease . FP reduced the overall exacerbation rate in moderate‐to‐severe disease ( FP median rate 1.47 yr−1 , placebo 1.75 yr−1 ) , but not in mild disease ( FP 0.67 yr−1 , placebo 0.92 yr−1 ) . FP use was associated with fewer patients with ≥1 exacerbation·yr−1 being treated with oral corticosteroids ( mild : FP 8 % , placebo 16 % ; moderate‐to‐severe : FP 17 % , placebo 30 % ) . Effects  of fluticasone propionate  on exacerbations were seen predominantly in patients with a postbronchodilator forced expiratory volume in one second < 50 % predicted . These data support recommendations in the Global Initiative for Chronic Obstructive Disease treatment guidelines that inhaled corticosteroids should be considered in patients with moderate‐to‐severe chronic obstructive pulmonary disease who experience recurrent exacerbations Prevention and treatment of COPD exacerbations are recognized as key goals in disease management . This r and omized , double-blind , parallel-group , multicenter study evaluated the effect of fluticasone propionate/salmeterol 250 mcg/50 mcg ( FSC 250/50 ) and salmeterol 50 mcg ( SAL ) twice-daily on moderate/severe exacerbations . Subjects received treatment with FSC 250/50 during a one month run-in , followed by r and omization to FSC 250/50 or SAL for 52 weeks . Moderate/severe exacerbations were defined as worsening symptoms of COPD requiring antibiotics , oral corticosteroids and /or hospitalization . In 797 subjects with COPD ( mean FEV1 = 0.98L , 34 % predicted normal ) , treatment with FSC 250/50 significantly reduced the annual rate of moderate/severe exacerbations by 30.4 % compared with SAL ( 1.10 and 1.59 per subject per year , respectively , p < 0.001 ) , the annual rate of exacerbations requiring oral corticosteroids by 34 % ( p < 0.001 ) and the annual rate of moderate/severe exacerbations requiring hospitalization by 36 % ( p = 0.043 ) . Clinical improvements observed during run-in treatment with FSC 250/50 were better maintained over 52 weeks with FSC 250/50 compared to SAL . Statistically significant reductions in albuterol use , dyspnea scores , and nighttime awakenings and numerical benefits on quality of life were seen with FSC 250/50 compared with SAL . The incidence of adverse events was similar across groups . Pneumonia was reported more frequently with FSC 250/50 compared with SAL ( 7 % vs. 2 % ) . FSC 250/50 is more effective than SAL at reducing the rate of moderate/severe exacerbations . These data confirm the beneficial effect of FSC on the management of COPD exacerbations and support the use of FSC in patients with COPD Background : A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease ( COPD ) , with the subsequent “ response ” determining the treatment selected . This approach assumes that patients can be reliably divided into responder and non-responder groups . We have assessed whether such a separation is statistically valid , which factors influence the change in forced expiratory volume in 1 second ( FEV1 ) after prednisolone , and whether the prednisolone response predicts 3 year changes in FEV1 , health status , or number of exacerbations during placebo or fluticasone propionate treatment . Methods : Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before r and omised treatment for 3 years with fluticasone propionate or placebo . Factors relating to change in FEV1 after prednisolone were investigated using multiple regression . The response to prednisolone was entered into separate mixed effects models of decline in FEV1 and health status during the 3 years of the study . Results : The post-bronchodilator FEV1 increased by a mean 60 ml ( CI 46 to 74 ) after prednisolone with a wide unimodal distribution . Current smoking was the factor most strongly associated with the change in FEV1 after prednisolone , with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers ( p<0.001 ) . There was no relationship between the change in FEV1 after prednisolone  and the response to inhaled bronchodilators , baseline FEV1 , atopic status , age , or sex . The response to prednisolone  , however expressed , was unrelated to the subsequent change in FEV1 over the following 3 years on either placebo or fluticasone propionate . Regression to the mean effects explained much of the apparent prednisolone response . The significant effect of treatment on decline in health status was not predicted by the prednisolone response . Conclusion : Patients with COPD can not be separated into discrete groups of corticosteroid responders and non-responders . Current smoking reduces the FEV1 response to prednisolone . Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients Background : Treatment of chronic obstructive pulmonary disease ( COPD ) with inhaled corticosteroids does not appear to be as effective as similar treatment of asthma . It seems that only certain subgroups of patients with COPD benefit from steroid treatment . A study was undertaken to examine whether inhaled fluticasone propionate ( FP ) had an effect on lung function and on indices of inflammation in a subgroup of COPD patients with bronchial hyperresponsiveness ( BHR ) . Methods : Twenty three patients with COPD were studied . Patients had to be persistent current smokers between 40 and 70 years of age . Non-specific BHR was defined as a PC20 for histamine of ≤8 mg/ml . Patients received either 2 × 500 μg FP or placebo for 6 months . Expiratory volumes were measured at monthly visits , BHR was determined at the start of the study and after 3 and 6 months , and bronchial biopsy specimens were taken at the start and after 6 months of treatment . Biopsy specimens from asymptomatic smokers served as controls . Results : In contrast to asthma , indices of BHR were not significantly influenced by treatment with FP  . Forced expiratory volume in 1 second ( FEV1 ) showed a steep decline in the placebo group but remained stable in patients treated with FP . FEV1/FVC , and maximal expiratory flows at 50 % and 25 % FVC ( MEF50 , MEF25 ) were significantly increased in the FP treated patients compared with the placebo group . Biopsy specimens were analysed for the presence of CD3 + , CD4 + , CD8 + , MBP+ , CD15 + , CD68 + , CD1a , and tryptase cells  . FP treatment result ed in marginal reductions in these indices of inflammation . Conclusion : In patients with COPD and BHR  , FP has a positive effect on indices of lung function  compared with placebo . Bronchial inflammation analysed in bronchial biopsy specimens is only marginally reduced BACKGROUND AND OBJECTIVE The efficacy and tolerability of budesonide/formoterol versus formoterol in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) was evaluated . METHODS In this r and omized , double-blind , parallel-group , phase III study ( NCT01069289 ) , patients with moderate to severe COPD for ≥2 years received either budesonide/formoterol 160/4.5 μg two inhalations twice daily via Turbuhaler ® or formoterol 4.5 μg two inhalations twice daily via Turbuhaler ® for 12 weeks . Salbutamol was available as reliever medication . Primary outcome variable : change from baseline to average during treatment in pre-dose forced expiratory volume in 1 s ( FEV1 ) . RESULTS One thous and two hundred ninety-three patients were r and omized  ( budesonide/formoterol n = 636 ; formoterol n = 657 ) .  Both budesonide/formoterol and formoterol increased pre-dose FEV1 versus baseline ( improvements of 4.6 % and 1.5 % over baseline , respectively ) , with the increase from baseline being significantly greater with budesonide/formoterol versus formoterol ( budesonide/formoterol : formoterol ratio 1.032 ; 95 % confidence interval : 1.013 - 1.052 ; P = 0.0011 ) . The budesonide/formoterol group had a significantly prolonged time to first exacerbation versus the formoterol group ( hazard ratio : 0.679 ; 95 % confidence interval : 0.507 - 0.909 ; P = 0.0094 ) and significantly greater improvements in many secondary outcome measures . Both treatments were well tolerated ; the incidence and type of adverse events were similar : most commonly reported ( budesonide/formoterol vs formoterol ) : COPD ( 8.0 % vs 9.4 % ) and nasopharyngitis ( 5.5 % vs 4.9 % ) . CONCLUSIONS Budesonide/formoterol 160/4.5 μg two inhalations twice daily was effective and well tolerated in patients with moderate to severe COPD , offering benefits over formoterol alone in terms of improved lung function and reduced risk of exacerbation STUDY OBJECTIVE To determine the effectiveness of treatment with corticosteroids in patients with COPD . METHODS In this study , we investigated the effect of a 2-year treatment with corticosteroids on clinical symptoms and the decline of lung function in 58 nonallergic patients with COPD . Subjects were treated in a double-blind , r and omized , placebo-controlled , parallel way with inhaled budesonide ( bud ) , 1,600 micrograms/d ; inhaled budesonide , 1,600 micrograms/d , plus oral prednisolone , 5 micrograms/d ( bud + pred ) ; or placebo ( plac ) .  Clinical assessment ( history , physical examination , and spirometry ) was carried out every 2 months . The rate of decline in FEV1 was assessed by calculating individual regression co-efficients from linear regression of FEV1 on time for each subject . RESULTS Eleven patients dropped out . The number of withdrawals due to pulmonary problems was significantly higher in the plac group ( n = 5 out of 18 ) than in the actively treated groups ( n = 2 out of 40 ) . Treatment with corticosteroids significantly reduced pulmonary symptoms . Median decline of FEV1 was 60 mL/yr in the plac group , 40 mL/yr in the bud + pred group , and 30 mL/yr in the bud group . Variation was large and differences were not statistically significant . No treatment effect was found on frequency or duration of exacerbations , possibly because of the high number of withdrawals due to pulmonary deterioration in the plac group . Treatment with a combination of inhaled plus oral corticosteroids was not more effective than inhaled corticosteroids alone . Morning plasma cortisol levels remained within the normal range in all three groups . CONCLUSIONS Our study shows beneficial effects of long-term daily treatment with inhaled corticosteroids in patients with COPD with regard to symptoms and drop out due to pulmonary problems . Lung function decline tends to decrease during treatment with inhaled corticosteroids . The observed effects are limited but warrant further studies on the effectiveness of corticosteroids in larger numbers of patients with COPD Background : Inhaled corticosteroids ( ICS ) markedly reduce bronchial mucosal inflammation in asthma but whether they have an anti-inflammatory effect in airway tissue in chronic obstructive pulmonary disease ( COPD ) is unknown . Methods : A study of endobronchial biopsy sample s was conducted as part of a double blind , placebo controlled , r and omised trial of parallel design . Patients had mild to moderately severe COPD ( FEV1 25–80 % of predicted ) and were given 3 months treatment with ICS , fluticasone propionate ( FP ; 500 μg twice daily , n=14 ) or placebo ( n=10 ) . Biopsy tissue taken at baseline and after treatment was examined by transmission electron microscopy to count the numbers of all ultrastructurally distinct inflammatory cells . Results : Compared with their baseline values , FP result ed in a significant decrease ( on average 65 % ) in the numbers of mucosal mast cells ( median 7.8 ( range 1–33 ) v 2.8 ( 1–14 ) , p<0.05 ) . The reductive effect of FP held true when the post-treatment values of the placebo and FP groups were compared : 8.8 ( 1–24 ) v 2.8 ( 1–14 ) ( p<0.05 ) . Unexpectedly , there were significantly more neutrophils in the FP than in the placebo group : 4.0 ( 0–23 ) v 1.7 ( 0–8 ) , respectively ( p<0.05 ) . There were no alterations to other cell types including mononuclear cells . Symptoms markedly improved in the patients treated with FP for 3 months . Conclusion : Fluticasone propionate given for 3 months to patients with COPD has selective effects on the inflammatory cells in the bronchial mucosa : the reduction in mast cell numbers may account for the improvement in symptoms over this time Background Guidelines recommend inhaled corticosteroids ( ICS ) for patients with severe chronic obstructive pulmonary disease ( COPD ) . Most COPD patients are managed in primary care and receive ICS long-term and irrespective of severity . The effect of withdrawing ICS from COPD patients in primary care is unknown . Methods In a pragmatic r and omised , double-blind , placebo-controlled trial in 31 practice s , 260 COPD patients stopped their usual ICS ( median duration of use 8 years ) and were allocated to 500 mcg fluticasone propionate twice daily ( n = 128 ) , or placebo ( n = 132 ) . Follow-up assessment s took place at three monthly intervals for a year at the patients ' practice . Our primary outcome was COPD exacerbation frequency . Secondary outcomes were time to first COPD exacerbation , reported symptoms , peak expiratory flow rate and reliever inhaler use , and lung function and health related quality of life . Results In patients r and omised to placebo , COPD exacerbation risk over one year was RR : 1.11 ( CI : 0.91–1.36 ) . Patients taking  placebo were more likely to return to their usual ICS following exacerbation , placebo : 61/128 ( 48 % ) ; fluticasone : 34/132 ( 26 % ) , OR : 2.35 ( CI : 1.38–4.05 ) . Exacerbation risk whilst taking r and omised treatment was significantly raised in the placebo group 1.48 ( CI : 1.17–1.86 ) . Patients taking placebo exacerbated earlier ( median time to first exacerbation : placebo ( days ) : 44 ( CI : 29–59 ) ; fluticasone : 63 ( CI : 53–74 ) , log rank 3.81 , P = 0.05 ) and reported increased wheeze . In a post-hoc analysis , patients with mild COPD taking placebo had increased exacerbation risk RR : 1.94 ( CI : 1.20–3.14 ) . Conclusion Withdrawal of long-term ICS in COPD patients in primary care  increases risk of exacerbation shortens time to exacerbation and causes symptom deterioration . Patients with mild COPD may be at increased risk of exacerbation after withdrawal . Trial Registration Clinical Trials.gov BACKGROUND Treatment with an inhaled corticosteroid ( ICS ) and long-acting bronchodilator is recommended for severe/very severe chronic obstructive pulmonary disease ( COPD ) patients with repeated exacerbations . This r and omized , double-blind , double-dummy , parallel-group , 12-month multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) on COPD exacerbations . METHODS Following a 2-week run-in during which COPD patients aged ≥40 years with an exacerbation history discontinued medications except ICSs , 1219 patients were r and omized 1:1:1 to twice-daily budesonide/formoterol pMDI 320/9 μg , budesonide/formoterol pMDI 160/9 μg , or formoterol dry powder inhaler 9 μg . An exacerbation was defined as COPD worsening requiring oral corticosteroids and /or hospitalization . A post hoc analysis , with antibiotic treatment added to the exacerbation definition , was also performed . RESULTS Budesonide/formoterol 320/9 and 160/9 reduced exacerbation rates ( number per patient-treatment year ) by 34.6 % and 25.9 % , respectively , versus formoterol ( p ≤ 0.002 ) . Budesonide/formoterol 320/9 prolonged time to first exacerbation versus formoterol , corresponding to a 21.2 % reduction in hazard ratio ( 0.788 [ 95 % CI : 0.639 , 0.972 ] ; p = 0.026 ) . Exacerbation rates ( number per patient-treatment year ) including antibiotic treatment ( post hoc analysis ) were reduced by 25.9 % and 18.7 % with budesonide/formoterol 320/9 and 160/9 , respectively , versus formoterol ( p ≤ 0.023 ) . Both budesonide/formoterol doses were well tolerated with safety profiles similar to formoterol . Pneumonia adverse events occurred in 6.4 % , 4.7 % , and 2.7 % of patients in the budesonide/formoterol 320/9 , 160/9 , and formoterol groups . CONCLUSIONS Over 12 months , both budesonide/formoterol doses reduced the exacerbation rate ( defined with or without antibiotic treatment ) versus formoterol . Budesonide/formoterol pMDI is an appropriate treatment for reducing exacerbations in COPD patients with a history of exacerbations . ( NCT00419744 ) Oxidative stress in the lung is important in the pathogenesis of COPD . Published data indicate that glucocorticoids inhibit blood cells in their capacity to produce reactive oxygen species ( ROS ) . We investigated the effect of Fluticasone propionate ( FP ) on the ROS production capabilities of pulmonary cells . Bronchoalveolar lavage ( BAL ) was performed in smoking COPD patients , before and after a six month , placebo-controlled treatment with FP . BAL cells were stimulated with phorbol myristrate acetate ( PMA ) alone , and together with superoxide dismutase ( SOD ) . From kinetic plots of ferricytochrome-c conversion we calculated the maximal rate of superoxide production : V(max ) . We also examined BAL cell subsets and performed correlation analyses on ROS production and relevant clinical determinants . Paired results were obtained from 6 FP- and 9 placebo-treated patients . No significant change of V(max ) was found in both patient groups . Also BAL cellularity was unchanged . Correlation analyses showed a significant ( inverse ) association of V(max ) with the number of cigarettes smoked per day . We concluded that a potent inhaled glucocorticoid had no effect on the ROS production capability of BAL cells from smoking COPD patients . Apparently , heavy smoking impaired the ability of alveolar macrophages to produce ROS , which was not further decreased by FP It is by no means straightforward to analyse the change in the rate of  chronic obstructive pulmonary disease ( COPD ) exacerbations in clinical trials . Exacerbation rates do not follow a normal distribution , nor do they occur at r and om . High exacerbation rates in a few patients can make average rates difficult to calculate and interpret . So , surely , transforming exacerbation rates into numbers needed to treat ( NNT ) should help . Not necessarily so — this is the message from Professor Suissa 's paper.1 He points out that the simplistic transformation from annual exacerbation rates to NNT in some published papers is misleading . He then goes on to present an alternative way of calculating NNT from survival curves showing time to first exacerbation , and a model to estimate such curves even if they are not presented . I have used the exponential model suggested by Suissa , with the data from two of the arms of the Towards a Revolution in Chronic obstructive pulmonary disease Health ( TORCH ) trial2 to show how this works in practice . I chose the arms in TORCH , that compared combination fluticasone/salmeterol therapy with salmeterol alone , as this seems to me to be a fair way to estimate the impact of additional inhaled corticosteroids . Figure 1 shows pairs of modelled survival curves for pneumonia ( in the upper part ) , and for COPD exacerbation ( in the lower part ) . BACKGROUND Fluticasone furoate (FF)/vilanterol ( VI ) is a novel once-daily inhaled corticosteroid/long-acting β2-agonist combination therapy for COPD . We aim ed to assess the efficacy and safety of two strengths of FF/VI ( 100/25 μg ; 50/25 μg ) vs. individual components ( FF 100 μg , VI 25 μg ) and placebo over 24 weeks . METHODS Multicentre , r and omised , placebo-controlled , double-blind , parallel-group study of patients ( N = 1030 ) with moderate-to-severe COPD . All medication was administered once daily in the morning . Co- primary efficacy endpoints were : ( 1 ) weighted mean ( wm ) FEV1 ( 0 - 4 h post-dose on day 168 ) to assess acute lung function effects ; and ( 2 ) trough FEV1 ( 23 - 24 h post-dose on day 169 ) to assess long-lasting effects . Symptom-related outcomes were analysed and adverse events ( AEs ) assessed . RESULTS Main findings were : ( 1 ) the combination of FF/VI at a strength of 100/25 μg significantly ( p < 0.001 ) improved wm FEV1 ( 173 ml ) and trough FEV1 ( 115 ml ) vs. placebo . Similar effects were observed with FF/VI 50/25 μg ; ( 2 ) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 ( 48 ml , p = 0.082 ) , while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV1 ( 120 ml , p < 0.001 ) ; ( 3 ) VI 25 μg over 24 weeks improved lung function  vs. placebo significantly for wm FEV1 ( 103 ml , p < 0.001 ) and trough FEV1 ( 67 ml , p = 0.017 ) ; and ( 4 ) no safety signal was observed . CONCLUSIONS In subjects with moderate-to-severe COPD , FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks . Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg . All treatments were well tolerated . GSK study number : HZC112206 . Clinical Trials.gov : NCT01053988 Background The oral prednisolone test is widely used to distinguish chronic obstructive pulmonary disease ( COPD ) patients who might benefit from inhaled steroid treatment . Previous studies used selected patient groups that did not represent the large COPD population in primary care . Methods The study included smokers and exsmokers with chronic bronchitis or COPD from primary care , who underwent prednisolone testing ( 30 mg for 14 days ) before r and omization in a three-year follow-up r and omized controlled trial ( COOPT Study ) .  Spirometry  was performed before and after the test . Responders and nonresponders were classified according to international criteria . Effectiveness of inhaled fluticasone relative to placebo was compared in terms of health status ( Chronic Respiratory Disease Question naire ) , exacerbations , and postbronchodilator forced expiratory volume in one second ( FEV1 ) , using repeated measurement analysis . Results Two hundred eighty-six patients recruited from 44 primary care practice s were r and omized . Nine percent to 16 % of the COPD population was classified as responder , depending on the international guideline criteria used . On average , responders did not reach the minimum clinical ly important difference in health status ( 0.29 points/year , P = 0.05 ) , although a borderline significant effect of inhaled fluticasone was noted . Possible clinical ly relevant reductions in exacerbation rate ( rate ratio 0.67 ) and FEV1 decline ( 39 mL/year ) occurred in responders , but did not reach statistical significance . Conclusions Oral steroid testing identifies a limited proportion of COPD patients , but does not reveal any clinical ly relevant benefit from inhaled steroid treatment on health status . No significant effects on exacerbation rate and lung function decline occurred Objective To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease ( COPD ) treated with two different fixed combinations of inhaled corticosteroid/long acting β2 agonist .  Design Observational retrospective pairwise cohort study matched ( 1:1 ) for propensity score . Setting Primary care medical records data linked to Swedish hospital , drug , and cause of death registry data for years 1999 - 2009 . Participants Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol .  Main outcome measures Yearly pneumonia event rates , admission to hospital related to pneumonia , and mortality . Results 9893 patients were eligible for matching ( 2738 in the fluticasone/salmeterol group ; 7155 in the budesonide/formoterol group ) , yielding two matched cohorts of 2734 patients each . In these patients , 2115 ( 39 % ) had at least one recorded episode of  pneumonia  during the study period , with 2746 episodes recorded during 19 170 patient years of follow up . Compared with budesonide/formoterol , rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol : rate ratio 1.73 ( 95 % confidence interval 1.57 to 1.90 ; P<0.001 ) and 1.74 ( 1.56 to 1.94 ; P<0.001 ) , respectively . The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 ( 10.4 to 11.8 ) versus 6.4 ( 6.0 to 6.9 ) and the rate of admission to hospital was 7.4 ( 6.9 to 8.0 ) versus 4.3 ( 3.9 to 4.6 ) . The mean duration of admissions related to pneumonia was similar for both groups , but mortality related to pneumonia was higher in the fluticasone/salmeterol group ( 97 deaths ) than in the budesonide/formoterol group ( 52 deaths ) ( hazard ratio 1.76 , 1.22 to 2.53 ; P=0.003 ) . All cause mortality did not differ between the treatments ( 1.08 , 0.93 to 1.14 ; P=0.59 ) . Conclusions There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting β2 agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD . Trial registration Clinical Trials.gov NCT01146392 Exacerbations of chronic obstuctive pulmonary disease ( COPD ) are associated with worse health status . The Inhaled Steroids in Obstructive Lung Disease in Europe ( ISOLDE ) study showed that treatment with fluticasone propionate ( FP ) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo . The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations . Rates of deterioration in St George 's Respiratory Question naire ( SGRQ ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs . Exacerbation rates were skewed and could not be normalised , therefore , patients were stratified into three exacerbation groups : none , infrequent ( < 1.65 exacerbations·yr−1 ) and frequent ( > 1.65 exacerbations·yr−1 ) . There were 91 patients with no exacerbations , 285 with infrequent exacerbations and 235 with frequent exacerbations . Frequent exacerbations were independently associated with a worse baseline SGRQ score ( p<0.0001 ) and a more rapid rate of deterioration in health status ( p=0.0003 ) . Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score . Statistical modelling showed the beneficial effect of fluticasone propionate  on deterioration in health status to be largely due to its effect on exacerbation frequency The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo , budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . In a 12-month , r and omised , double-blind , placebo-controlled , parallel-group study in 812 adults ( mean age 64 yrs , mean forced expiratory volume in one second ( FEV1 ) 36 % predicted normal ) , patients received two inhalations twice daily of either budesonide/formoterol ( Symbicort ® ) 160/4.5 µg ( delivered dose ) , budesonide 200 µg ( metered dose ) , formoterol 4.5 µg or placebo . Severe exacerbations and FEV1 ( primary variables ) , peak expiratory flow ( PEF ) , COPD symptoms , health-related quality of life ( HRQL ) , mild exacerbations , use of reliever β2‐agonist and safety variables were recorded .  Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24 % versus placebo and 23 % versus formoterol . FEV1 increased by 15 % versus placebo and 9 % versus budesonide . Morning PEF improved significantly on day 1 versus placebo and budesonide ; after 1 week , morning PEF was improved versus placebo , budesonide and formoterol . Improvements in morning and evening PEF versus comparators were maintained over 12 months . Budesonide/formoterol decreased all symptom scores and use of reliever β2‐agonists significantly versus placebo and budesonide , and improved HRQL versus placebo . All treatments were well tolerated . These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease BACKGROUND Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease ( COPD ) , whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status . We postulated that a combination of these treatments would be better than each component used alone . METHODS 1465 patients with COPD were recruited from outpatient departments in 25 countries . They were treated in a r and omised , double-blind , parallel-group , placebo-controlled study with either 50 microg salmeterol twice daily ( n=372 ) , 500 microg fluticasone twice daily ( n=374 ) , 50 microg salmeterol and 500 microg fluticasone twice daily ( n=358 ) , or placebo ( n=361 ) for 12 months . The primary outcome was the pretreatment forced expiratory volume in 1s ( FEV1 ) after 12 months treatment ' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h . Secondary outcomes were other lung function measurements , symptoms and rescue treatment use , the number of exacerbations , patient withdrawals , and disease-specific health status . We assessed adverse events , serum cortisol concentrations , skin bruising , and electrocardiograms . Analysis was as predefined in the study protocol . FINDINGS All active treatments improved lung function , symptoms , and health status and reduced use of rescue medication and frequency of exacerbations . Combination therapy improved pretreatment FEV1 significantly more than did placebo ( treatment difference 133 mL , 95 % CI 105 - 161 , p<0.0001 ) , salmeterol ( 73 mL , 46 - 101 , p<0.0001 ) , or fluticasone alone ( 95 mL , 67 - 122 , p<0.0001 ) . Combination treatment produced a clinical ly significant improvement in health status and the greatest reduction in daily symptoms . All treatments were well tolerated with no difference in the frequency of adverse events , bruising , or clinical ly significant falls in serum cortisol concentration . INTERPRETATION Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function , with no greater risk of side-effects than that with use of either component alone , this combination treatment should be considered for patients with COPD Lung function in chronic obstructive pulmonary disease ( COPD ) can be improved acutely by oral corticosteroids and bronchodilators . Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown . COPD patients ( n=1,022 , mean prebronchodilator forced expiratory volume in one second ( FEV1 ) 36 % predicted ) initially received formoterol ( 9 µg b.i.d . ) and oral prednisolone ( 30 mg o.d . ) for 2 weeks . After this time , patients were r and omised to b.i.d . inhaled budesonide/formoterol 320/9 µg , budesonide 400 µg , formoterol 9 µg or placebo for 12 months . Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George 's Respiratory Question naire ( SGRQ ) by 4.5 units after run-in . Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide , formoterol or placebo . Budesonide/formoterol patients had a prolonged time to first exacerbation ( 254 versus 96 days ) and maintained higher FEV1 ( 99 % versus 87 % of baseline ) , both primary variables versus placebo . They had fewer exacerbations ( 1.38 versus 1.80 exacerbations per patient per year ) , had higher prebronchodilator peak expiratory flow , and showed clinical ly relevant improvements in SGRQ versus placebo ( −7.5 units ) . Budesonide/formoterol was more effective than either monocomponent in both primary variables . Budesonide/formoterol in a single inhaler ( Symbicort ® ) maintains the benefit of treatment optimisation , stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo OBJECTIVES To investigate the determinants of patient withdrawal from our study , and the effect of these withdrawals on the outcome of treatment with inhaled corticosteroids in patients with COPD . DESIGN A double-blind , placebo-controlled , r and omized trial . SETTING Eighteen outpatient centers in the United Kingdom . PARTICIPANTS Seven hundred fifty-one patients with stable COPD defined clinical ly and as baseline postbronchodilator FEV(1 ) > or = 0.8 L and < 85 % predicted , FEV(1)/FVC ratio < 70 % , and FEV(1 ) change after albuterol < 10 % of predicted . INTERVENTION R and om assignment of either 500 microg bid of inhaled fluticasone propionate ( FP ) using a spacer device or an identical placebo inhaler . Treatment was continued for 3 years or until patients withdrew from follow-up . MEASUREMENTS AND RESULTS Postbronchodilator FEV(1 ) was measured on three occasions before r and omization and every 3 months thereafter . Health status was assessed by the disease-specific St. George Respiratory Question naire ( SGRQ ) and the modified short-form 36 question naire ( SF-36 ) at baseline and every 6 months . Three hundred thirty-nine patients withdrew , of whom 156 patients received FP .  Prescription of frequent courses of oral prednisolone was the most common reason for withdrawing as specified in the protocol ( 69 patients in the FP group withdrew due to respiratory symptoms , compared with 93 patients in the placebo group ) . This explained the significantly greater dropout of placebo-treated patients that was most evident when FEV(1 ) was < 50 % predicted . Patients withdrawing had a significantly more rapid decline in health status , measured by both the SGRQ and the SF-36 ( p < 0.001 ) . Those withdrawing from the placebo group had a more rapid decline in FEV(1 ) and more exacerbations than the FP-treated groups . Baseline FEV(1 ) was lower in dropouts than in patients completing the study receiving placebo , but there was no difference between the respective groups receiving FP . CONCLUSIONS Patients who withdrew from follow-up were those with the most rapidly deteriorating health status and lung function . Losing these patients from the final analysis can reduce the power of a study to achieve its primary end point The TOwards a Revolution in COPD Health ( TORCH ) study was a 3-yr multicentre trial of 6,112 patients r and omised to salmeterol ( Salm ) , fluticasone propionate ( FP ) , a Salm/FP combination ( SFC ) or placebo ( P ) .  Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed . For four regions , 3-yr all-cause hospitalisation , medication and outpatient care costs were calculated . The sample was restricted to the 21 countries ( n = 4,237 ) in which European quality of life five-dimension ( EQ-5D ) data were collected in order to estimate the number of quality -adjusted life years ( QALYs ) . Regression models were fitted to survival , study medication cost , other medication cost and EQ-5D data in order to estimate total cost , number of QALYs and cost per QALY , adjusted for missing data and region . SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars ( USD ) compared with P ( 95 % confidence interval 21,400–123,500 USD ) . Estimates for Salm versus P ( 197,000 USD ) and FP versus P ( 78,000 USD ) were less favourable . The US estimates were greater than those from other regions ; for SFC versus P , the cost per QALY was 77,100 ( 46,200–241,700 ) USD compared to 24,200 ( 15,200–56,100 ) USD in Western Europe . Compared with P , SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone , and is , therefore , preferred to these monotherapies on the grounds of cost-effectiveness BACKGROUND The efficacy of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease ( COPD ) remains controversial because of a lack of placebo-controlled studies . We compared the effect of inhaled fluticasone propionate with placebo in the treatment of patients with COPD . METHODS We used a r and omised , double-blind , placebo-controlled design . We enrolled from 13 European countries , New Zeal and , and South Africa , 281 outpatient current or ex-smokers , aged between 50 and 75 years . They had a forced expiratory volume in 1 s ( FEV1 ) of between 35 % and 90 % of predicted normal values , a ratio of FEV1 to forced vital capacity of 70 % or less and bronchodilator reversibility of less than 15 % , as well as a history of chronic bronchitis . Patients were r and omly assigned fluticasone propionate 500 microg ( n=142 ) or placebo ( n=139 ) twice daily via a metered-dose inhaler for 6 months . The main outcome measures were the number of patients who had at least one exacerbation by the end of treatment , the number and severity of exacerbations , clinic lung function , diary card symptoms and peak expiratory flow and 6 min walking distance . FINDINGS 51 ( 37 % ) patients in the placebo group compared with 45 ( 32 % ) in the fluticasone propionate group had had at least one exacerbation by the end of treatment ( p=0.449 ) . Significantly more patients had moderate or severe exacerbations in the placebo group than in the fluticasone propionate group ( 86 % vs 60 % , p<0.001 ) . Diary-card and clinic morning peak expiratory flows improved significantly in the fluticasone propionate group ( p<0.001 , p=0.048 , respectively ) , as did clinic FEV1 ( p<0.001 ) , forced vital capacity ( p<0.001 ) , and mid-expiratory flow ( p=0.01 ) . Symptom scores for median daily cough and sputum volume were significantly lower with fluticasone propionate treatment than with placebo ( p=0.004 and p=0.016 , respectively ) . At the end of treatment , patients on fluticasone propionate had increased their 6 min walking distance significantly more than those on placebo ( p=0.032 ) . Fluticasone propionate was tolerated as well as placebo , with few adverse effects and without a clinical ly important effect on mean serum cortisol concentration . INTERPRETATION Fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months .  Inhaled corticosteroids may have an important role in the long-term treatment of COPD Background Previous studies have suggested that long-term use of β agonists to treat chronic obstructive pulmonary disease ( COPD ) may increase the risk of cardiovascular adverse events . In this post hoc analysis , data from the TOwards a Revolution in COPD Health ( TORCH ) study were used to investigate whether use of the long-acting β2 agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD . Methods TORCH was a r and omised , double-blind , placebo controlled study conducted at 444 centres in 42 countries . Patients ( n=6184 ; safety population ) received twice daily combined salmeterol 50 μg plus fluticasone propionate 500 μg ( SFC ) , either component alone , or placebo . Adverse events were recorded every 12 weeks for 3 years . Results The probability of having a cardiovascular adverse event by 3 years was 24.2 % for placebo , 22.7 % for salmeterol , 24.3 % for fluticasone propionate and 20.8 % for SFC . Although a history of myocardial infa rct ion doubled the probability of cardiovascular adverse events , the event rates remained similar across treatment groups . Conclusion Post hoc analysis of the 3-year TORCH data set showed that salmeterol alone or in combination ( SFC ) did not increase the risk of cardiovascular events in patients with moderate to severe COPD Background : Guidelines recommend inhaled corticosteroids ( ICS ) as maintenance treatment for patients with chronic obstructive pulmonary disease ( COPD ) with a post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 50 % predicted and frequent exacerbations , although they have only a small preventive effect on the accelerated decline in lung function . Combined treatment with ICS and long acting β2 agonists ( LABA ) may provide benefit to the stability of COPD , but it is unknown if withdrawal of ICS will result in disease deterioration . Methods : The effects of 1 year withdrawal of the ICS fluticasone propionate ( FP ) after a 3 month run-in treatment period with FP combined with the LABA salmeterol ( S ) ( 500 μg FP + 50 μg S twice daily ; SFC ) were investigated in patients with COPD in a r and omised , double blind study . 497 patients were enrolled from 39 centres throughout the Netherl and s ; 373 were r and omised and 293 completed the study . Results : The drop out rate after r and omisation was similar in the two groups . Withdrawal of FP result ed in a sustained decrease in FEV1 : mean ( SE ) change from baseline −4.4 (0.9)% ( S ) v −0.1 (0.9)% ( SFC ) ; adjusted difference 4.1 ( 95 % CI 1.6 to 6.6 ) percentage points ( p<0.001 ) . Corresponding figures for the FEV1/FVC ratio were −3.7 (0.8)% ( S ) v 0.0 (0.8)% ( SFC ) ( p = 0.002 ) . The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups , respectively ( adjusted rate ratio 1.2 ; 95 % CI 0.9 to 1.5 ; p = 0.15 ) . The mean annual incidence rate of mild exacerbations was 1.3 ( S ) v 0.6 ( SFC ) , p = 0.020 . An immediate and sustained increase in dyspnoea score ( scale 0–4 ; mean difference between groups 0.17 ( 0.04 ) , p<0.001 ) and in the percentage of disturbed nights ( 6 ( 2 ) percentage points , p<0.001 ) occurred after withdrawal of fluticasone . Conclusions : Withdrawal of FP  in COPD patients using SFC result ed in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights . This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration , even under treatment with a LABA Background : Combined treatment with inhaled corticosteroids and long acting β2 agonists is approved for the treatment of chronic obstructive pulmonary disease ( COPD ) , but little is known about the onset of effect of the combination . Methods : Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow ( PEF ) and symptom scores . Results : PEF was significantly higher after 1 day in patients treated with salmeterol 50 μg twice daily or the salmeterol/fluticasone propionate combination 50/500 μg twice daily than placebo . In patients treated with fluticasone propionate 500 μg twice daily alone , PEF differed from placebo after 2 days . The differences after 2 weeks compared with placebo were 16 l/min ( 95 % confidence interval ( CI ) 11 to 21 ) , 11 l/min ( 95 % CI 6 to 16 ) , and 27 l/min ( 95 % CI 22 to 33 ) for salmeterol , fluticasone propionate , and the salmeterol/fluticasone propionate combination , respectively . For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study . The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second ( FEV1 ) . Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group . The 2 week change in FEV1 was only partly indicative of a long term response in individual patients . Conclusions : The effects of salmeterol and fluticasone propionate , alone or in combination , on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks OBJECTIVE Withdrawal of corticosteroid is associated with a deterioration of health status in COPD . In this study the aim was to determine whether high dose inhaled corticosteroid improves quality of life in patients with COPD . METHODOLOGY In total , 38 male patients with moderate COPD were included in the study . Baseline quality of life scores were determined using a Turkish version of the St George 's Respiratory Question naire ( SGRQ ) . Patients were r and omly divided into two groups . Group 1 consisted of 20 patients who received existing bronchodilator therapy plus inhaled corticosteroid ( 800 micro g budesonide ) for 12 weeks , while 18 patients in group 2 received bronchodilator and placebo . The SGRQ was repeated after the treatment period . RESULTS All patients were male and mean age was 67 + /- 8.2 years .  Symptom , activity , impact , and total scores were assessed and a difference of four units with treatment was considered to be clinical ly significant . Total score and activity score were decreased by six units and eight units , respectively , in the placebo group while symptom and impact scores did not change significantly . Total scores and the three component scores improved significantly in the corticosteroid group compared to the placebo group ( Deltatotal score : -22 in corticosteroid group , -6 in placebo group , P < 0.01 ) . CONCLUSION Inhaled corticosteroid improved quality of life scores in patients with COPD , without significant improvement in airflow obstruction parameters . Since improvement of health status is one of the important aims in COPD treatment , use of inhaled corticosteroids should be considered from this perspective BACKGROUND Inhaled corticosteroids ( ICSs ) and long-acting beta(2)-agonists ( LABAs ) are used to treat moderate to severe chronic obstructive pulmonary disease ( COPD ) . OBJECTIVE To determine whether long-term ICS therapy , with and without LABAs , reduces inflammation and improves pulmonary function in COPD . DESIGN R and omized , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00158847 ) SETTING 2 university medical centers in The Netherl and s. PATIENTS 114 steroid-naive current or former smokers with moderate to severe COPD . MEASUREMENTS Cell counts in bronchial biopsies and sputum ( primary outcome ) ; methacholine responsiveness at baseline , 6 , and 30 months ; and clinical outcomes every 3 months . INTERVENTION R and om assignment by minimization method to receive fluticasone propionate , 500 microg twice daily , for 6 months ( n = 31 ) or 30 months ( n = 26 ) ; fluticasone , 500 microg twice daily , and salmeterol , 50 microg twice daily , for 30 months ( single inhaler ; n = 28 ) ; or placebo twice daily ( n = 29 ) . RESULTS 101 patients were greater than 70 % adherent to therapy . Fluticasone therapy decreased counts of mucosal CD3(+ ) cells ( -55 % [ 95 % CI , -74 % to -22 % ] ; P = 0.004 ) , CD4(+ ) cells ( -78 % [ CI , -88 % to 60 % ] ; P < 0.001 ) , CD8(+ ) cells ( -57 % [ CI , -77 % to -18 % ] ; P = 0.010 ) , and mast cells ( -38 % [ CI , -60 % to -2 % ] ; P = 0.039 ) and reduced hyperresponsiveness ( P = 0.036 ) versus placebo at 6 months , with effects maintained after 30 months . Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium , with accompanying reductions in sputum neutrophil , macrophage , and lymphocyte counts and improvements in FEV(1 ) decline , dyspnea , and quality of life . Reductions in inflammatory cells correlated with clinical improvements . Discontinuing fluticasone therapy at 6 months increased counts of CD3(+ ) cells ( 120 % [ CI , 24 % to 289 % ] ; P = 0.007 ) , mast cells ( 218 % [ CI , 99 % to 407 % ] ; P < 0.001 ) , and plasma cells ( 118 % [ CI , 9 % to 336 % ] ; P = 0.028 ) and worsened clinical outcome . Adding salmeterol improved FEV(1 ) level . LIMITATIONS The study was not design ed to evaluate clinical outcomes . Measurement of primary outcome was not available for 24 % of patients at 30 months . CONCLUSION ICS therapy  decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD . Adding LABAs does not enhance these effects . This r and omized controlled trial examined the benefits of combining an inhaled corticosteroid , fluticasone propionate ( F ) , with an inhaled long-acting beta(2)-agonist , salmeterol ( S ) , to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease ( COPD ) . A total of 691 patients with COPD received the combination of F and S ( FSC ) , S ( 50 mcg ) , F ( 500 mcg ) , or placebo twice daily via the Diskus device for 24 weeks . A significantly greater increase in predose FEV(1 ) at the endpoint was observed after FSC ( 156 ml ) compared with S ( 107 ml , p = 0.012 ) and placebo ( -4 ml , p < 0.0001 ) . A significantly greater increase in 2-hour postdose FEV(1 ) at the endpoint was observed after treatment with FSC ( 261 ml ) compared with F ( 138 ml , p < 0.001 ) and placebo ( 28 ml , p < 0.001 ) . There were greater improvements in the Transition Dyspnea Index with FSC ( 2.1 ) compared with F ( 1.3 , p = 0.033 ) , S ( 0.9 , p < 0.001 ) , and placebo ( 0.4 , p < 0.0001 ) . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and F ) was similar among the treatment groups . We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo The Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) study was a trial that r and omised 752 patients with moderate to severe COPD to fluticasone propionate 1000 mcg/day or placebo for three years . We aim ed to examine the causes of death of the ISOLDE participants after the original three up to 13 years post-r and omisation . Death certificates were obtained either from the NHS Strategic Tracing Service or from the Office of National statistics . Deaths were classified according to the trial protocol . In the sub sample of 375 participants from the seven ISOLDE original centers where complete extended follow-up was conducted , the factors associated with observed higher mortality ( p<0.05 ) were male gender , older age and more severe COPD . Causes of death were ; 107 ( 52 % ) respiratory , 38 ( 18 % ) cardiac , 29 ( 14 % ) lung cancer , 16 ( 8 % ) other cancer and 16 ( 8 % ) other causes . The percentage of respiratory-related deaths increased during the follow-up period ; from 46 % within the three-year trial , to 48 % after 3 - 6 years , 57 % after 6 - 9 years , and 60 % after 9 - 13 years of follow-up ( p for trend<0.05 ) . We conclude that participants ' survival is poor ( only 44 % in the 13 years after the ISOLDE trial ) , and that respiratory-related illnesses were the most frequent causes of death in patients with moderate to severe COPD Chronic obstructive pulmonary disease ( COPD ) is characterised by a chronic inflammatory process in the large and small airways , as well as in the lung parenchyma . Although the role of oral corticosteroids in the management of acute exacerbations of COPD is well documented , its role in stable COPD is not clear . We examined the anti-inflammatory effect of inhaled budesonide on the percentage of neutrophils and on interleukin-8 ( IL-8 ) levels in bronchoalveolar lavage ( BAL ) and their correlation with spirometry and symptom scores .  Twenty-six patients with stable COPD were r and omised , in a double-blinded , placebo-controlled trial with either 800 microg of inhaled budesonide or placebo for a 6-month period . The budesonide-treated subjects had significant reductions in IL-8 levels in the BAL after therapy ( mean+/-sem , 1.53+/-0.72 at baseline vs. 0.70+/-0.48 ng/ml at 6 months , P=0.004 ) and a reduction in the mean percentages of neutrophils ( 17.16+/-2.67 % vs. 13.25+/-2.28 % P=0.002 ) . The improvement in sputum production was of borderline ( P=0.058 ) significance but there was no improvement in lung function . In stable patients with COPD , treatment with inhaled budesonide for a period of 6 months has a positive effect on markers of lung inflammation , as assessed by reduction in percentage neutrophils and IL-8 concentration in BAL Introduction : Whether smoking-induced lung inflammation subsides after smoking cessation is currently a matter of debate . We used computed tomography ( CT ) to evaluate the effect of smoking cessation on lung density in patients with COPD . Material and methods : Thirty-six patients quit smoking out of 254 current smokers with COPD who were followed with annual CT and lung function tests ( LFT ) for 2–4 years as part of a r and omised placebo-controlled trial of the effect of inhaled budesonide on CT-lung density . Lung density was expressed as the 15th percentile density ( PD15 ) and relative area of emphysema below -910 HU ( RA-910 ) . From the time-trends in the budesonide and placebo groups the expected CT-lung densities at the first visit after smoking cessation were calculated by linear regression and compared to the observed densities . Results : Following smoking cessation RA-910 increased by 2.6 % ( p = 0.003 ) and PD15 decreased by −4.9 HU ( p = 0.0002 ) . Furthermore , changes were larger in the budesonide group than the placebo group ( PD15 : −7.1 vs −2.8 HU . RA-910 3.7 % vs 1.7 % ) . These differences were , however , not statistically significant . The LFT parameters ( FEV1 and diffusion capacity ) were not significantly influenced by smoking cessation . Conclusion : Inflammation partly masks the presence of emphysema on CT and smoking cessation results in a paradoxical fall in lung density , which resembles rapid progression of emphysema . This fall in density is probably due to an anti-inflammatory effect of smoking cessation Abstract Objective : To compare the healthcare costs and effects of budesonide/formoterol in a single inhaler with those of budesonide and formoterol monotherapies , and placebo , in a multinational study in patients with chronic obstructive pulmonary disease ( COPD ) , National Heart , Lung and Blood Institute (NHLBI)/WHO Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stages III or IV . Previous analysis of the clinical data from the study had shown that budesonide/formoterol was associated with better lung function and improved health-related QOL compared with the monocomponents or placebo and lower frequency of exacerbations compared with formoterol and placebo . Method : Patients ( n = 1022 ) were r and omised to twice-daily treatment with two inhalations of budesonide/formoterol ( 160μg/4.5μg ) in a single inhaler , budesonide 200μg , formoterol 4.5μg or placebo for 12 months . Data on medication and healthcare use were combined with Swedish unit cost data to estimate the total annual healthcare cost per patient from the Swedish healthcare payer perspective . Costs were valued in Swedish kronor ( SEK ) [ 2001 values ] and converted to euros ( SEK1 = € 0.11 , 25th April 2003 ) . Results : This evaluation estimated the total annual healthcare costs per patient to be numerically lower for budesonide/formoterol ( € 2518 ) than for budesonide ( € 3194 ) , formoterol ( € 3653 ) or placebo ( € 3213 ) . Cost-effectiveness acceptability curves suggest that budesonide/formoterol may be cost effective compared with formoterol , even if the decision maker is not willing to pay anything for the additional clinical effects , and that budesonide/formoterol  is cost effective  compared with placebo if a decision maker is willing to pay about € 2 per day , per avoided exacerbation . Conclusion : This economic analysis suggests that the clinical benefits of using budesonide/formoterol in a single inhaler are achieved at a numerically lower total healthcare cost  than either monocomponent or placebo . Budesonide/formoterol in patients with severe COPD ( GOLD stages III or IV ) may be cost effective , from the healthcare provider perspective , compared with either monocomponent RATIONALE Exacerbations of chronic obstructive pulmonary disease ( COPD ) greatly contribute to declining health status and the progression of the disease , thereby incurring significant direct and indirect health care costs . The prevention of exacerbations , therefore , is an important treatment goal . OBJECTIVES To assess the impact of combination therapy with salmeterol/fluticasone propionate compared with salmeterol alone on moderate and severe exacerbations in patients with severe COPD and a history of repeated exacerbations . METHODS R and omized , double-blind , parallel-group study . After a 4-wk run-in period , 994 clinical ly stable patients were r and omized to one of two treatment groups : 507 patients received the salmeterol/fluticasone combination 50/500 micro g twice daily and 487 received salmeterol 50 micro g twice daily for 44 wk . MAIN RESULTS The total number of exacerbations was 334 in the combination therapy and 464 in the salmeterol group ( p < 0.0001 ) . The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group , corresponding to a 35 % decrease . In addition , the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group ( 128 vs. 93 d , p < 0.0001 ) . Other endpoints , including health-related quality of life , peak expiratory flow , and use of rescue medication , were significantly improved in the combination therapy group . Both treatments were well tolerated . CONCLUSIONS This study demonstrates that combination therapy with salmeterol/fluticasone compared with salmeterol monotherapy significantly reduces the frequency of moderate/severe exacerbations in patients with severe COPD BACKGROUND Little is known about the long-term efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease ( COPD ) . We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD . METHODS We used a parallel-group , r and omised , double-blind , placebo-controlled design in a singlecentre study , nested in a continuing epidemiological survey ( the Copenhagen City Heart Study ) . Inclusion criteria were as follows : no asthma ; a ratio of forced expiratory volume in 1 s ( FEV1 ) and vital capacity of 0.7 or less ; FEV1 which showed no response ( < 15 % change ) to 1 mg inhaled terbutaline or prednisolone 37.5 mg orally once daily for 10 days . 290 patients were r and omly assigned  budesonide , 800 microg plus 400 microg daily for 6 months followed by 400 microg twice daily for 30 months , or placebo for 36 months . The mean age of the participants was 59 years and the mean FEV1 2.37 L or 86 % of predicted . The main outcome measure was rate of FEV1 decline . Analyses were by intention to treat . FINDINGS The crude rates of FEV1 decline were slightly smaller than expected ( placebo group 41.8 mL per year , budesonide group 45.1 mL per year ) . The estimated rates of decline from the regression model did not differ significantly ( 49.1 mL vs 46.0 mL per year ; difference 3.1 mL per year [ 95 % CI -12.8 to 19.0 ] ; p=0.7 ) . Before the study , the minimum relevant difference was defined as 20 mL per year ; this difference was outside the 95 % CI . No effect of inhaled budesonide was seen on respiratory symptoms . 316 exacerbations occurred during the study period , 155 in the budesonide group and 161 in the placebo group . Treatment was well tolerated . INTERPRETATION Inhaled budesonide was of no clinical benefit in COPD patients recruited from the general population by screening . We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD BACKGROUND Osteoporosis is common in patients with COPD , but its prevalence and progression are not well characterized . Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids ( ICSs ) on bone density in this population . Here , we investigated the long-term effects of therapy with fluticasone propionate ( FP ) alone , salmeterol ( SAL ) alone , and a SAL/FP combination ( SFC ) on bone mineral density ( BMD ) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health ( TORCH ) study . METHODS A r and omized , double-blind , parallel-group , placebo-controlled study conducted at 88 US centers involving 658 patients ( a subset of 6,184 international subjects in TORCH ) . Therapy with placebo , SAL ( 50 microg ) , FP ( 500 microg ) , or SFC ( SAL 50 microg/FP 500 microg ) twice daily was administered for 3 years . Baseline and yearly measurements of BMD at the hip and lumbar spine were performed . The incidence of traumatic and nontraumatic bone fractures was recorded . RESULTS At baseline , 18 % of men and 30 % of women had osteoporosis , and 42 % of men and 41 % of women had osteopenia based on BMD assessment s. Forty-three percent of subjects completed all testing . The changes in BMD at the hip and lumbar spine over 3 years were small . No significant differences were observed between treatment arms ( adjusted mean percent change from baseline at hip was -3.1 % for placebo , -1.7 % for SAL , -2.9 % for FP , and -3.2 % for SFC therapy , respectively ; while , the corresponding changes for the lumbar spine were 0 , 1.5 % , -0.3 % , and -0.3 % for placebo , respectively , SAL , FP , and SFC therapy ) . The incidence of fractures was low and was similar for all treatments ( 5.1 % to 6.3 % ) . CONCLUSIONS Osteoporosis is highly prevalent in patients with COPD , irrespective of gender . In the TORCH study , no significant effect on BMD was detected for ICS therapy compared with placebo . TRIAL REGISTRATION Clinical Trials.gov Identifier : NTC00268216 Treatment of chronic obstructive pulmonary disease ( COPD ) with inhaled and oral corticosteroids is common , although their exact role is unclear . Previous studies suggest these drugs may reduce decline in lung function in this group of patients . We report a study investigating the effect of inhaled beclomethasone diproprionate ( BDP ) on lung function and symptoms in a group of patients with COPD . Treatment was given for 2 years , and the decline in FEV1 in individual patients calculated over this period . Ninety‐eight patients were r and omized for the study , 59 completing 2 years of treatment . Patients withdrawn had more severe airflow obstruction . Decline in FEV1 , measured both prior to and after bronchodilator , was less in patients receiving inhaled BDP , although the differences failed to reach statistical significance except in a subgroup of patients with more severe airflow obstruction . Exacerbation rates were also reduced by inhaled BDP , but again the differences failed to reach conventional levels of statistical significance . The results of this study are consistent with previous published work , but further insight into the long‐term role of corticosteroids in COPD await the publication of large studies which have recently been completed . Although the changes seen in this study and others are numerically small , the rate of decline in FEV1 returned to normal levels expected from age‐related decline , and hence such treatment combined with other strategies may well have a significant role in the long‐term treatment of this condition BACKGROUND Although patients with chronic obstructive pulmonary disease ( COPD ) should stop smoking , some do not . In a double-blind , placebo-controlled study , we evaluated the effect of the inhaled glucocorticoid budesonide in patients with mild COPD who continued smoking . After a six-month run-in period , we r and omly assigned 1277 subjects ( mean age , 52 years ; mean forced expiratory volume in one second [ FEV1 ] , 77 percent of the predicted value ; 73 percent men ) to twice-daily treatment with 400 microg of budesonide or placebo , inhaled from a dry-powder inhaler , for three years . RESULTS Of the 1277 subjects , 912 ( 71 percent ) completed the study . Among these subjects , the median decline in the FEV1 after the use of a bronchodilator over the three-year period was 140 ml in the budesonide group and 180 ml in the placebo group ( P=0.05 ) , or 4.3 percent and 5.3 percent of the predicted value , respectively . During the first six months of the study , the FEV1 improved at the rate of 17 ml per year in the budesonide group , as compared with a decline of 81 ml per year in the placebo group ( P<0.001 ) . From nine months to the end of treatment , the FEV1 declined at similar rates in the two groups ( P=0.39 ) . Ten percent of the subjects in the budesonide group and 4 percent of those in the placebo group had skin bruising ( P<0.001 ) . Newly diagnosed hypertension , bone fractures , postcapsular cataracts , myopathy , and diabetes occurred in less than 5 percent of the subjects , and the diagnoses were equally distributed between the groups . CONCLUSIONS In patients with mild COPD who continue smoking , the use of inhaled budesonide is associated with a small one-time improvement in lung function but does not appreciably affect the long-term progressive decline Inhaled corticosteroids ( ICS ) are effective in the treatment of asthma and markedly reduce the numbers of inflammatory cells in bronchial biopsies . However , the effect of ICS on the inflammatory profile of biopsies in smokers with chronic obstructive pulmonary disease ( COPD ) is unknown . We have performed a double-blind , placebo-controlled , r and omized study to compare fluticasone propionate ( FP ) 500 microg twice daily via a dry powder inhaler and placebo ( P ) over a 3-month period in subjects with COPD .  Fiberoptic bronchoscopy and bronchial biopsy was carried out at baseline and after the 3 months of treatment . Thirty-one subjects completed the trial and 30 paired biopsies were available for analysis . Compared with P ( n = 14 ) , subjects on inhaled FP ( n = 16 ) had no significant reductions in the primary endpoints : CD8 + , CD68 + cells , or neutrophils , considered to be of importance in COPD . However , there was a reduction in the CD8:CD4 ratio in the epithelium and of the numbers of subepithelial mast cells in the FP group . CD4 + cells were significantly raised in the P group in both subepithelium and epithelium . Symptoms significantly improved , and there were significantly fewer exacerbations in subjects on FP , compared to subjects on P. The data indicate that inhaled fluticasone does affect selected aspects of airway inflammation in COPD , and this may explain , in part , the decrease in exacerbations seen in long-term studies with fluticasone propionate BACKGROUND The combination of an inhaled corticosteroid ( ICS ) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations .  Budesonide/formoterol dry powder inhaler ( DPI ) has demonstrated efficacy and tolerability in patients with COPD . OBJECTIVE To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler ( pMDI ) in patients with COPD . METHODS This was a 6-month , r and omized , double-blind , double-dummy , placebo-controlled , parallel-group , multicentre study ( NCT00206154 ) of 1704 patients aged > or = 40 years with moderate to very severe COPD conducted in 194 centres in the US , Czech Republic , the Netherl and s , Pol and and South Africa . After 2 weeks of treatment based on previous therapy ( ICSs and short-acting bronchodilators allowed during the run-in period ) , patients received one of the following treatments administered twice daily : budesonide/formoterol pMDI 160/4.5 microg x two inhalations ( 320/9 microg ) ; budesonide/formoterol pMDI 80/4.5 microg x two inhalations ( 160/9 microg ) ; budesonide pMDI 160 microg x two inhalations ( 320 microg ) plus formoterol DPI 4.5 microg x two inhalations ( 9 microg ) ; budesonide pMDI 160 microg x two inhalations ( 320 microg ) ; formoterol DPI 4.5 microg x two inhalations ( 9 microg ) ; or placebo . MAIN OUTCOME MEASURES The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV(1 ) ) and 1-hour post-dose FEV(1 ) . RESULTS Budesonide/formoterol 320/9 microg demonstrated significantly greater improvements in pre-dose FEV(1 ) versus formoterol ( p = 0.026 ; pre-specified primary comparator ) and 1-hour post-dose FEV(1 ) versus budesonide ( p < 0.001 ; pre-specified primary comparator ) ; budesonide/formoterol 160/9 microg demonstrated significantly greater improvements versus budesonide ( p < 0.001 ) for 1-hour post-dose FEV(1 ) but not versus formoterol for pre-dose FEV(1 ) . Dyspnoea ( measured using the Breathlessness Diary ) and health-related quality -of-life ( HR-QOL ) scores ( based on the St George 's Respiratory Question naire total score ) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide , formoterol and placebo ( p < or = 0.044 for all ) . Although not powered a priori for comparisons , the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and /or hospitalization was numerically ( 20 - 25 % ) lower with the budesonide-containing treatments ( 0.710 - 0.884 ) versus formoterol ( 1.098 ) and placebo ( 1.110 ) . This result was driven by the exacerbations requiring treatment with oral corticosteroids ( 79 - 120 events ) . The number of exacerbations result ing in hospitalization was very low across treatment groups ( 11 - 22 ) ; the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 microg ( 0.158 ) versus other treatment groups ( 0.081 - 0.108 ) except budesonide/formoterol 160/9 microg ( 0.139 ) , and for budesonide/formoterol 160/9 microg versus formoterol ( 0.081 ) [ p < or = 0.05 ] . All treatments were generally well tolerated . The incidence of individual non-fatal serious adverse events was similar across all treatment groups , except COPD , which was highest in the budesonide/formoterol 320/9 microg group ( 6.1 % ) and lowest in the budesonide ( 3.6 % ) and formoterol ( 3.9 % ) groups , with a range of 4.3 - 4.6 % in the budesonide/formoterol 160/9 microg , budesonide plus formoterol and placebo groups . Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo . There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo . CONCLUSIONS Budesonide/formoterol pMDI 320/9 microg demonstrated significantly greater efficacy for pulmonary function on both co- primary endpoints versus the pre-specified comparators ( formoterol DPI 9 microg for pre-dose FEV(1 ) and budesonide pMDI 320 microg for 1-hour post-dose FEV(1 ) ) . Budesonide/formoterol pMDI 160/9 microg demonstrated significantly greater efficacy for 1-hour post-dose FEV(1 ) versus budesonide pMDI 320 microg . Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo . Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo BACKGROUND Increased oxidative stress and bronchial inflammation are important mechanisms in the pathophysiology of COPD . AIM To investigate whether treatment with the inhaled corticosteroid fluticasone propionate ( FP ) or the anti-oxidative agent N-acetylcysteine ( NAC ) are effective in primary care patients . METHODS The study was a 3-year placebo-controlled  r and omised controlled trial preceded by a 3-month washout and 2-week prednisolone pre-treatment . Patients were (ex-)smokers with chronic bronchitis or COPD . Interventions were inhaled FP 500microg b.i.d . , oral NAC 600 mg o.d . , or placebo .  Exacerbation rate and quality of life measured with the Chronic Respiratory Question naire ( CRQ ) were the primary outcomes , FEV(1 ) decline and respiratory symptoms secondary outcomes . RESULTS 286 patients recruited from 44 general practice s were r and omised . Exacerbation rate was 1.35 times higher for NAC ( p=0.054 ) and 1.30 times higher for FP ( p=0.095 ) compared with placebo  . CRQ total scores did not differ between NAC ( p=0.306 ) or FP ( p=0.581 ) treatment compared to  placebo  . Annual postbronchodilator FEV(1 ) decline was 64mL [ SD 5.4 ] for NAC [ p=0.569 versus placebo ] , 59mL [ SD 5.7 ] for FP [ p=0.935 ] , and 60mL [ SD 5.4 ] for placebo . CONCLUSION No beneficial treatment effects for either high-dosed inhaled fluticasone propionate or oral N-acetylcysteine were observed in our study population of patients with COPD or chronic bronchitis OBJECTIVES COPD exacerbations are associated with significant morbidity and mortality . This r and omized , double-blind , parallel-group , multicenter study evaluated the effect of fluticasone propionate/salmeterol 250/50 and salmeterol 50 microg twice daily on moderate to severe exacerbations . METHODS Patients received st and ardized treatment with fluticasone propionate/salmeterol 250/50 during a 1-month run-in , followed by r and omization to fluticasone propionate/salmeterol 250/50 or salmeterol for 12 months . Moderate to severe exacerbations were defined as worsening symptoms of COPD requiring treatment with oral corticosteroids , antibiotics , or hospitalization . RESULTS In 782 patients with COPD ( mean FEV(1)=0.94+/-0.36 L , 33 % predicted normal ) , treatment with fluticasone propionate/salmeterol 250/50 significantly reduced ( 1 ) the annual rate of moderate to severe exacerbations by 30.5 % compared with salmeterol ( 1.06 and 1.53 per subject per year , respectively , p<0.001 ) , ( 2 ) the risk of time to first exacerbation by 25 % ( hazard ratio=0.750 , p=0.003 ) and ( 3 ) the annual rate of exacerbations requiring oral corticosteroids by 40 % ( p<0.001 ) . Clinical improvements observed during run-in treatment with fluticasone propionate/salmeterol 250/50 were better maintained over 12 months with fluticasone propionate/salmeterol 250/50 than salmeterol .  Adverse events were reported for a similar percentage of subjects across groups . A higher reporting of pneumonia was observed with fluticasone propionate/salmeterol 250/50 than salmeterol ( 7 % vs. 4 % ) . CONCLUSIONS We conclude that fluticasone propionate/salmeterol 250/50 is more effective than salmeterol at reducing the rate of moderate to severe exacerbations over 1 year . The benefits of this reduction relative to the risk of a higher incidence of reported pneumonia should be considered . This study supports the use of fluticasone propionate/salmeterol 250/50 for the reduction of COPD exacerbations in patients with COPD There is a need for study ing the effects of long-term inhaled corticosteroid therapy on bone mineral density ( BMD ) and vertebral fracture rates in patients with mild chronic obstructive pulmonary disease ( COPD ) . Patients ( n=912 , mean age 52 yrs ) with mild COPD ( mean forced expiratory volume in one second ( FEV1 ) 77 % of predicted ; mean FEV1/slow vital capacity ratio 62 % ) were r and omized to receive budesonide 400 µg , or placebo twice daily via Turbuhaler ® . BMD was measured at the L2–L4 vertebrae and the femoral neck , trochanter and Ward 's triangle by dual-energy X-ray absorptiometry at baseline and after 6 , 12 , 24 and 36 months ( n=161 ) . Radiographs of the thoracic and lumbar spine were obtained at the beginning and end of treatment ( n=653 ) . Previous fractures were present at baseline in 43 budesonide-treated patients ( 13.4 % ) and 38 placebo-treated patients ( 11.5 % ) . New fractures occurred in five budesonide-treated patients , compared with three in the placebo group ( p=0.50 ) . There were no significant changes in BMD at any site in budesonide-treated patients , compared with the placebo group , during the course of the study . Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin . In the present study , involving a large group of patients with chronic obstructive pulmonary disease , long-term treatment with budesonide 800 µg·day−1 via Turbuhaler ® had no clinical ly significant effects on bone mineral density or fracture rates BACKGROUND Early treatment with inhaled corticosteroids may prevent progression of irreversible obstruction in COPD , especially in patients with bronchial hyperresponsiveness . We investigated the clinical effects of early introduction of inhaled steroids in subjects showing early signs and symptoms of COPD without a prior clinical diagnosis . METHODS Study subjects were detected in a general population screening and monitoring program . Those with a moderately accelerated annual FEV1 decline and persistent respiratory symptoms were invited to participate in a 2-year r and omized controlled trial comparing fluticasone propionate DPI 250 microg b.i.d . with placebo .  Pre- and post-bronchodilator ( BD ) FEV1 , PC20 histamine , functional status ( COOP/WONCA charts ) and occurrence of exacerbations were periodically assessed . Subjects recorded respiratory symptoms . Post-BD FEV1 decline served as the main outcome . Multivariable repeated measurements analysis techniques were applied . RESULTS 48 subjects were r and omized ( 24 fluticasone , 24 placebo ) . After 3 months , the post-BD FEV1 had increased with 125 ml ( SE = 68 , P = 0.075 ) and the pre-BD FEV1 with 174 ml ( SE 90 , P = 0.059 ) in the fluticasone relative to the placebo group . The subsequent post-BD and pre-BD FEV1 decline were not beneficially modified by fluticasone treatment . There were no statistically significant differences in respiratory symptoms , functional status , or exacerbations favoring fluticasone . Subgroup analysis indicated that the presence of bronchial hyperresponsiveness modified the initial FEV1 response on fluticasone , but not the subsequent annual FEV1 decline . CONCLUSION Early initiation of inhaled steroid treatment does not seem to affect the progressive deterioration of lung function or other respiratory health outcomes in subjects with early signs and symptoms of COPD . In subjects at risk for , or in an early stage of COPD , long-term inhaled steroid treatment should not be based on a single spirometric evaluation after 3 months The prevalence of chronic obstructive pulmonary disease ( COPD ) in women is increasing worldwide . Women may have greater susceptibility to COPD progression than men , and differences in efficacy and safety of respiratory medications by gender are largely unexplored . We aim ed to determine whether the response to treatment in women with COPD differed from men in a large , 1-year double-blind trial ( ' TRISTAN ' ) . In a sensitivity analysis , we compared 539 male and 180 female COPD patients , who were r and omized to the saLmeterol/fluticasone combination 50/500mcg bid or placebo for 12 months .  Combination therapy  improved pre-treatment FEV1 significantly more than placebo in women by 152 ml ( 95 % confidence interval 95 - 208 ) and in men by 127 ml ( 94 - 159 ) . Similarly , a reduction in COPD exacerbation rates of 31 % in women ( 9 - 48 % ) and of 23 % in men ( 8 - 35 % ) was observed . Combination therapy  reduced COPD exacerbations requiring treatment with oral corticosteroids by 36 % in women and by 41 % in men . Finally , combination treatment produced a better improvement in health status than placebo with a decrease in the SGRQ scores in women by -2.3 ( -4.6 - 0.1 ) and in men by -2.1 ( -3.5 to -0.8 ) . No gender interaction was found for any outcome . Treatments were well tolerated with no difference in the frequency of adverse events in women and men . In this trial , therapy with the salmeterol/fluticasone combination produced significant improvements compared to placebo on all main endpoints and the magnitude of these improvements was similar for both men and women BACKGROUND Once-daily combination treatment is an attractive maintenance therapy for COPD . However , the dose of inhaled corticosteroid to use in a once-daily combination is unknown . We compared two strengths of fluticasone furoate ( FF ) plus vilanterol ( VI ) , the same strengths of the individual components , and placebo . METHODS Multicentre , r and omised , 24-week , double-blind , placebo-controlled , parallel-group study in stable , moderate-to-severe COPD subjects ( N = 1224 ) . Subjects were r and omised to FF/VI ( 200/25 μg ; 100/25 μg ) , FF ( 200 μg ; 100 μg ) , VI 25 μg , or placebo , once daily in the morning . Co- primary efficacy endpoints ; 0 - 4 h weighted mean ( wm ) FEV(1 ) on day 168 , and change from baseline in trough ( 23 - 24 h post-dose ) FEV(1 ) on day 169 . The primary safety objective was adverse events ( AEs ) . RESULTS There was a statistically significant ( p < 0.001 ) increase in wm FEV(1 ) ( 209 ml ) and trough FEV(1 ) ( 131 ml ) for FF/VI 200/25 μg vs. placebo ; similar changes were seen for FF/VI 100/25 μg vs. placebo . Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1 ) ( 32 ml ) was not statistically significant ( p = 0.224 ) , the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1 ) ( 168 ml ) was significantly different ( p < 0.001 ) . VI 25 μg significantly improved wm and trough FEV(1 ) vs. placebo ( 185 ml and 100 ml , [ corrected ] respectively ) . No increase was seen in on-treatment AEs or serious AEs ( SAEs ) , with active therapy vs. placebo . CONCLUSIONS FF/VI provides rapid and significant sustained improvement in FEV(1 ) in subjects with moderate-to-severe COPD , which was not influenced by the dose of FF . These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study . GSK study number : HZC112207 . Clinical Trials.gov : NCT01054885 OBJECTIVES To explore the cost-effectiveness of fluticasone propionate ( FP ) for the treatment of chronic obstructive pulmonary disease ( COPD ) , we estimated costs and quality -adjusted life-years ( QALYs ) over 3 years , based on an economic appraisal of a previously reported clinical trial ( Inhaled Steroids in Obstructive Lung Disease in Europe [ ISOLDE ] ) . METHODS Seven hundred forty-two patients enrolled in the ISOLDE trial who received either FP or placebo had data available on health-care costs and quality of life over the period of the study . The SF-36-based utility scores for quality of life were used to calculate QALYs . A combined imputation and bootstrapping procedure was employed to h and le missing data and to estimate statistical uncertainty in the estimated cumulative costs and QALYs over the study period . The imputation approach was based on propensity scoring and nesting this approach within the bootstrap ensured that multiple imputations were performed such that statistical estimates included imputation uncertainty . RESULTS Complete data were available on mortality within the follow-up period of the study and a nonsignificant trend toward improved survival of 0.06 ( 95 % confidence interval [CI]-0.01 to 0.15 ) life-years was observed . In an analysis based on a propensity scoring approach to missing data we estimated the incremental costs of FP versus placebo to be 1021 sterling pound(95 % CI 619 - 1338 sterling pound ) with an additional effect of 0.11 QALYs ( CI 0.04 - 0.20 ) . Cost-effectiveness estimates for the within-trial period of 17,700 sterling pound per life-year gained ( 6900 sterling pound to infinity ) and 9500 sterling pound per QALY gained ( CI 4300 - 26,500 sterling pound ) were generated that include uncertainty due to the imputation process . An alternative imputation approach did not material ly affect these estimates . CONCLUSIONS Previous analyses of the ISOLDE study showed significant improvement on disease-specific health status measures and a trend toward a survival advantage for treatment with FP . This analysis shows that joint considerations of quality of life and survival result in a substantial increase in QALYs favoring treatment with FP . Based on these data , the inhaled corticosteroid FP appears cost-effective for the treatment of COPD . Confirmation or refutation of this result may be achieved once the Towards a Revolution in COPD Health ( TORCH ) study reports , a large r and omized controlled trial powered to detect mortality changes associated with the use of FP alone , or in combination with salmeterol , which is also collecting re source use and utility data suitable for estimating cost-effectiveness OBJECTIVES To survey the frequency of use of indirect comparisons in systematic review s and evaluate the methods used in their analysis and interpretation . Also to identify alternative statistical approaches for the analysis of indirect comparisons , to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within review s. DATA SOURCES Electronic data bases . REVIEW METHODS The Data base of Abstract s of Review s of Effects ( DARE ) was search ed for systematic review s involving meta- analysis of r and omised controlled trials ( RCTs ) that reported both direct and indirect comparisons , or indirect comparisons alone . A systematic review of MEDLINE and other data bases was carried out to identify published methods for analysing indirect comparisons . Study design s were created using data from the International Stroke Trial . R and om sample s of patients receiving aspirin , heparin or placebo in 16 centres were used to create meta-analyses , with half of the trials comparing aspirin and placebo and half heparin and placebo . Methods for indirect comparisons were used to estimate the contrast between aspirin  and  heparin . The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results . Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken . RESULTS Of the review s identified through DARE , 31/327 ( 9.5 % ) included indirect comparisons . A further five review s including indirect comparisons were identified through electronic search ing . Few review s carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest . Few method ological papers were identified . Some valid approaches for aggregate data that could be applied using st and ard software were found : the adjusted indirect comparison , meta-regression and , for binary data only , multiple logistic regression ( fixed effect models only ) . Simulation studies showed that the naive method is liable to bias and also produces over-precise answers . Several methods provide correct answers if strong but unverifiable assumptions are fulfilled . Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly r and omised comparisons . Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies , but the direction of such discrepancy is unpredictable . CONCLUSIONS Direct evidence from good- quality RCTs should be used wherever possible . Without this evidence , it may be necessary to look for indirect comparisons from RCTs . However , the results may be susceptible to bias . When making indirect comparisons within a systematic review , an adjusted indirect comparison method should ideally be used employing the r and om effects model . If both direct and indirect comparisons are possible within a review , it is recommended that these be done separately before considering whether to pool data . There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect . Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons . Research into how evidence from indirect comparisons compares to that from non-r and omised studies may also be warranted . Investigations using individual patient data from a meta- analysis of several RCTs using different protocol s and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful The European Respiratory Society 's study on chronic obstructive pulmonary disease ( EUROSCOP ) is a multicentre study performed initially in 12 countries to assess the effect of 3 years ' treatment with inhaled corticosteroids on lung function decline in smokers with chronic obstructive pulmonary disease ( COPD ) . It aim ed at recruiting 50 subjects in 50 European centres . This study discusses the most successful , countrywise , recruitment strategies , an important issue since many multicentre European studies may follow in the future . The total number of recruited subjects was 2147 in 39 participating centres . In total , at least 25,000 screening spirometries were performed , and about 80,000 hospital records were checked . The most effective way of recruiting subjects was to screen subjects by spirometry after mass media campaigns ( eight out of nine countries ) . Others used workplace screenings and different types of population survey , and only a few centres successfully recruited participants by hospital records . Inclusion criteria were slightly changed upon low initial accrual rate . Initial surveys in one country , where 2405 subjects were screened by spirometry  , gave an important indication for the change of the inclusion criteria . Extension of the upper age limit from 60 to 65 yr considerably improved recruitment , as did a change of the upper limit of FEV1 from below 80 % predicted normal to below 100 % predicted normal , while maintaining the FEV1/VC ratio below 70 % . A tremendous effort is needed to recruit individuals with pre clinical COPD , but this is certainly feasible with adequate strategies adjusted to each country The TORCH ( Towards a Revolution in COPD Health ) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease . These include collection of off-treatment exacerbation data , analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids ( ICS ) prior to r and omisation . When effective medications are available to patients who withdraw , inclusion of off-treatment data can mask important treatment effects on exacerbation rates . Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments . The negative binomial model is currently the best approach to statistical analysis of exacerbation rates , while analysis of time to exacerbation can supplement this approach . In the TORCH trial , exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments . Retrospective subgroup analysis suggests  ICS reduced exacerbation rates compared with placebo , regardless of prior use of ICS before entry to the study . Factorial analysis provides an alternative analysis for trials with combinations of treatments , but assumes no interaction between treatments , an assumption which can not be verified by a significance test . No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment .  All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) Chronic obstructive pulmonary disease ( COPD ) is a common disease in industrialised countries and responsible for a considerable morbidity and mortality . Cigarette smoking is the most important aetiological factor . The EUROSCOP trial aims at investigating the hypothesis that airway inflammation plays an important pathogenic role in the development of chronic obstructive airway disease in smokers . In cigarette smokers with poorly reversible airflow obstruction , the effect over 3 yrs of an inhaled glucocorticosteroid , budesonide 400 micrograms b.i.d . , on the decline of lung function , measured as postbronchodilator forced expiratory volume in one second ( FEV1 ) , will be compared with that of placebo . The trial has been design ed to detect a difference in yearly decline of at least 30 ml.year-1 . The study is a parallel group , r and omised , double-blind , multicentre study . Patients will be recruited from 47 centres in 12 countries in Europe . It will start with a run-in consisting of two 3 month periods . During the first 3 months , the patients will be offered a smoking cessation programme . All patients who have not stopped smoking during this period will enter the second half of the run-in where compliance with the dosage regimen will be tested . After these two periods , patients will be r and omised to receive either inhaled budesonide , 400 micrograms b.i.d . , or placebo for a period of 3 yrs OBJECTIVES To evaluate the effect of beclomethasone/formoterol versus budesonide/formoterol ( non-inferiority ) and versus formoterol ( superiority ) in patients with severe stable chronic obstructive pulmonary disease ( COPD ) . METHODS A double-blind , double-dummy , r and omised , active-controlled , parallel-group study . After 4 weeks run-in with ipratropium/salbutamol ( 40/200 μg , three times daily ) patients were r and omised to receive beclomethasone/formoterol ( 200/12 μg pressurised metered dose inhaler ) , budesonide/formoterol ( 400/12 μg dry powder inhaler ) or formoterol ( 12 μg dry powder inhaler ) twice daily for 48 weeks . Co- primary efficacy variables were change from baseline to 48 weeks in pre-dose morning forced expiratory volume in 1 s ( FEV(1 ) ) and mean rate of COPD exacerbations . RESULTS Of 718 patients r and omised , 703 ( 232 beclomethasone/formoterol , 238 budesonide/formoterol , 233 formoterol ) were in the ITT analysis .  Improvement in pre-dose morning FEV(1 ) was 0.077 L , 0.080 L and 0.026 L for beclomethasone/formoterol , budesonide/formoterol and formoterol respectively ( LS mean from the ANCOVA model ) . Beclomethasone/formoterol was not inferior to budesonide/formoterol ( 95 % CI of the difference -0.052 , 0.048 ) and superior to formoterol ( p = 0.046 ) . The overall rate of COPD exacerbations/patient/year was similar and not statistically significantly different among treatments ( beclomethasone/formoterol 0.414 , budesonide/formoterol 0.423 and formoterol 0.431 ) . Quality of life and COPD symptoms improved in all groups and use of rescue medication decreased . Safety profiles were as expected and treatments well-tolerated . CONCLUSIONS Beclomethasone/formoterol ( 400/24 μg ) treatment for 48 weeks improved pulmonary function , reduced symptoms compared to formoterol , was safe and well-tolerated in patients with severe stable COPD . Neither of the long-acting β2-agonist/inhaled corticosteroid combinations affected the low exacerbation rate seen in this population The objective was to evaluate the effect of inhaled corticosteroids on disease progression in smokers with moderate to severe chronic obstructive pulmonary disease ( COPD ) , as assessed by annual computed tomography ( CT ) using lung density ( LD ) measurements . Two hundred and fifty-four current smokers with COPD were r and omised to treatment with either an inhaled corticosteroids ( ICS ) , budesonide 400 μ g bid , or placebo . COPD was defined as FEV1 ≤ 70 % pred , FEV1/FVC ≤ 60 % and no reversibility to β2-agonists and oral corticosteroids . The patients were followed for 2–4 years with biannual spirometry and annual CT and comprehensive lung function tests ( LFT ) . CT images were analysed using Pulmo-CMS software . LD was derived from a pixel-density histogram of the whole lung as the 15thpercentile density ( PD15 ) and the relative area of emphysema at a threshold of −910 Hounsfield units ( RA-910 ) , and both were volume-adjusted to predicted total lung capacity . At baseline , mean age was 64 years and 64 years ; mean number of pack-years was 56 and 56 ;  mean FEV1 was 1.53 L ( 51 % pred ) and 1.53 L ( 53 % pred ) ; mean PD15 was 103 g/L and 104 g/L ; and mean RA-910 was 14 % and 13 % , respectively , for the budesonide and placebo groups . The annual fall in PD15 was −1.12 g/L in the budesonide group and −1.81 g/L in the placebo group ( p = 0.09 ) ; the annual increase in RA–910 was 0.4 % in the budesonide group and 1.1 % in the placebo group ( p = 0.02 ) . There was no difference in annual decline in FEV1 between ICS ( −54 mL ) and placebo ( −56 mL ) ( p = 0.89 ) . Long-term budesonide inhalation shows a non-significant trend towards reducing the progression of emphysema as determined by the CT-derived 15th percentile lung density from annual CT scans in current smokers with moderate to severe COPD BACKGROUND Chronic obstructive pulmonary disease ( COPD ) results from a progressive decline in lung function , which is thought to be the consequence of airway inflammation . We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline . METHODS We enrolled 1116 persons with COPD whose forced expiratory volume in one second ( FEV1 ) was 30 to 90 percent of the predicted value in a 10-center , placebo-controlled , r and omized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily . The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator . The secondary outcome measures included respiratory symptoms , use of health care services , and airway reactivity . In a sub study of 412 participants , we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment . RESULTS The mean duration of follow-up was 40 months . The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group ( 44.2+/-2.9 vs. 47.0+/-3.0 ml per year , P= 0.50 ) . Members of the triamcinolone group had fewer respiratory symptoms during the course of the study ( 21.1 per 100 person-years vs. 28.2 per 100 person-years , P=0.005 ) and had fewer visits to a physician because of a respiratory illness ( 1.2 per 100 person-years vs. 2.1 per 100 person-years , P=0.03 ) . Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months ( P=0.02 for both comparisons ) . After three years , the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group ( P < or = 0.007 ) . CONCLUSIONS Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD , but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems . These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density The aim of this study was evaluate the predictive value of a 2 week course of prednisolone on the effect of 6 months treatment with inhaled budesonide in patients with stable chronic obstructive pulmonary disease ( COPD ) . Forty patients with stable COPD entered the study , and received prednisolone ( 37.5 mg o.d . ) for 2 weeks . They were subsequently divided into steroid-irreversible and steroid-irreversible , using 15 % of baseline as a dividing point . In each group patients were r and omized to receive budesonide 400 micrograms b.i.d . or placebo for 6 months . During treatment with prednisolone , three patients dropped out because of side effects . Of the remaining 37 , only two patients ( 5 % ) were reversible with prednisolone forced expiratory volume in 1s [ ( FEV1 ) > 15 % of baseline ] , and among the steroid-irreversible , 26 patients were evaluated after 6 months treatment with either placebo or budesonide . No significant differences in spirometry values , symptoms , or number of exacerbations were found between these two groups . Reversibility with prednisolone is rarely seen in COPD . In out patients with stable COPD and no signs of asthma or atopy  , 2 weeks treatment with prednisolone seems to be of no value in choosing subsequent long-term therapy Withdrawal of inhaled corticosteroids is known to worsen disease control in bronchial asthma but similar data are lacking in chronic obstructive pulmonary disease ( COPD ) . We hypothesized that clinical exacerbations requiring treatment would occur more often in patients whose inhaled corticosteroids were stopped than in other patients not treated with these agents . We studied 272 patients in mean age 65 ( SD 0.8 ) years , mean FEV1 42.8 ( SD 12.6)% predicted , entering the run-in phase of the Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) trial . All had been clinical ly stable for at least 6 weeks and there were no differences in the degree of bronchodilator reversibility , baseline lung function or pack-years of smoking  between the 160 patients receiving inhaled corticosteroids and those not so treated .  Inhaled corticosteroids were withdrawn in the first week of the study and during the remaining 7 weeks of the study 38 % of those previously treated with these drugs had an exacerbation compared to 6 % of the chronically untreated group . Patients receiving inhaled corticosteroids reported a longer duration of symptoms but neither this or any other recorded variable predicted the risk of exacerbation . These data suggest that abrupt withdrawal of inhaled corticosteroids should be monitored carefully even in patients with apparently irreversible COPD Abstract Objectives : To determine the effect of long term inhaled corticosteroids on lung function , exacerbations , and health status in patients with moderate to severe chronic obstructive pulmonary disease . Design : Double blind , placebo controlled study . Setting : Eighteen UK hospitals . Participants : 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second ( FEV1 ) 50 % of predicted normal . Interventions : Inhaled fluticasone propionate 500 μg twice daily from a metered dose inhaler or identical placebo . Main outcome measures : Efficacy measures : rate of decline in FEV1 after the bronchodilator and in health status , frequency of exacerbations , respiratory withdrawals . Safety measures : morning serum cortisol concentration , incidence of adverse events . Results : There was no significant difference in the annual rate of decline in FEV1 ( P=0.16 ) . Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo ( P<0.001 ) . Median exacerbation rate was reduced by 25 % from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate ( P=0.026 ) . Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate ( P=0.0043 ) . Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group ( 25 % v 19 % , P=0.034 ) . Conclusions : Fluticasone propionate 500 μg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1 . Patients on fluticasone propionate  had fewer exacerbations and a slower decline in health status . These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease Introduction : R and omised 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
BACKGROUND Inhaled corticosteroids ( ICS ) are anti-inflammatory drugs that have proven benefits for people with worsening symptoms of chronic obstructive pulmonary disease ( COPD ) and repeated exacerbations .
They are commonly used as combination inhalers with long-acting beta2-agonists ( LABA ) to reduce exacerbation rates and all-cause mortality , and to improve lung function and quality of life .
The most common combinations of ICS and LABA used in combination inhalers are fluticasone and salmeterol , budesonide and formoterol and a new formulation of fluticasone in combination with vilanterol , which is now available .
ICS have been associated with increased risk of pneumonia , but the magnitude of risk and how this compares with different ICS remain unclear .
Recent review s conducted to address their safety have not compared the relative safety of these two drugs when used alone or in combination with LABA .
OBJECTIVES To assess the risk of pneumonia associated with the use of fluticasone and budesonide for COPD .