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We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium , tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . This was a multicentre , r and omised , double-blind , placebo- and active-controlled , 26-week trial . Patients ( n = 2144 ) were r and omised ( 2:2:2:2:1 ) to receive once-daily QVA149 ( indacaterol 110 & mgr;g/glycopyrronium 50 & mgr;g ) , indacaterol 150 & mgr;g , glycopyrronium 50 & mgr;g , open-label tiotropium 18 & mgr;g or placebo . The primary end-point was trough forced expiratory volume in 1 s ( FEV1 ) at week 26 for QVA149 versus its monocomponents . Secondary end-points included dyspnoea , health status , rescue medication use and safety . Trough FEV1 at week 26 was significantly improved ( p<0.001 ) with QVA149 compared with indacaterol and glycopyrronium ( least squares mean ( LSM ) differences 0.07 L and 0.09 L , respectively ) , tiotropium and placebo ( LSM differences 0.08 L and 0.20 L , respectively ) ; these beneficial effects were sustained throughout the 26-week study . QVA149 significantly improved dyspnoea and health status versus placebo ( p<0.001 and p = 0.002 , respectively ) and tiotropium ( p = 0.007 and p = 0.009 , respectively ) at week 26 . All treatments were well tolerated . Dual bronchodilation with once-daily QVA149 demonstrated superior and clinical ly meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator , with a safety and tolerability profile similar to placebo , supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting & bgr;2-agonist combinations for the treatment of COPD . Dual indacaterol/glycopyrronium therapy was safe and more efficacious than monotherapy in moderate-to-severe COPD 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 UNLABELLED Indacaterol is a novel , inhaled , long-acting β(2)-agonist providing 24-h bronchodilation with once-daily ( o.d . ) dosing in patients with COPD . In this double-blind , incomplete block crossover study , patients with moderate-to-severe COPD were r and omised to receive three treatment cycles from : indacaterol 300 μg o.d . dosed PM or AM , salmeterol 50 μg twice daily or placebo , each for 14 days . Trough FEV(1 ) was measured 24 h after indacaterol , and 12 h after salmeterol . Ninety-six patients ( mean age : 64 years ; post-bronchodilator FEV(1 ) 57 % predicted , FEV(1)/FVC 55 % ) were r and omised ; 83 completed . After 14 days , the difference vs. placebo  in trough FEV(1 ) for PM indacaterol was 200 mL ( p < 0.001 [ primary analysis ] ) and for AM indacaterol was 200 mL ( p < 0.001 ) . Compared with salmeterol , trough FEV(1 ) for PM indacaterol was 110 mL higher ( p < 0.001 ) , and for AM indacaterol was 50 mL higher ( p = NS ) . Over 14 days , vs. placebo , both PM and AM indacaterol improved the % of nights with no awakenings ( by 11.9 and 8.1 points ; p < 0.01 ) ; the % of days with no daytime symptoms ( by 6.7 and 5.5 points ; p < 0.05 ) ; and the % of days able to perform usual activities ( by 6.7 and 7.8 points ; p < 0.05 ) . Indacaterol provided 24-h bronchodilation and improvement in symptoms regardless of whether taken regularly in the morning or evening . CLINICAL TRIAL REGISTRATION Clinical Trials.gov NCT00615030 Background Debate continues as to whether acute bronchodilator responsiveness ( BDR ) predicts long-term outcomes in COPD . Furthermore , there is no consensus on a threshold for BDR . Methods At baseline and during the 4-year Underst and ing Potential Long-term Improvements in Function with Tiotropium ( UPLIFT ® ) trial , patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg . Patients were split according to three BDR thresholds : ≥12 % + ≥200 mL above baseline ( criterion A ) , ≥15 % above baseline ( criterion B ) ; and ≥10 % absolute increase in percent predicted FEV1 values ( criterion C ) . Several outcomes ( pre-dose spirometry , exacerbations , St. George 's Respiratory Question naire [ SGRQ ] total score ) were assessed according to presence or absence of BDR in the treatment groups . Results 5783 of 5993 r and omized patients had evaluable pre- and post-bronchodilator spirometry at baseline . Mean age ( SD ) was 64 ( 8) years , with 75 % men , mean post-bronchodilator FEV1 1.33 ± 0.44 L ( 47.6 ± 12.7 % predicted ) and 30 % current smokers . At baseline , 52 % , 66 % , and 39 % of patients had acute BDR using criterion A , B , and C , respectively . The presence of BDR was variable at follow-up visits . Statistically significant improvements in spirometry and health outcomes  occurred with tiotropium regardless of the baseline BDR or criterion used . Conclusions A large proportion of COPD patients  demonstrate significant acute BDR . BDR in these patients is variable over time and differs according to the criterion used . BDR status at baseline does not predict long-term response to tiotropium . Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD UPLIFT ( Underst and ing Potential Long-Term Improvements in Function with Tiotropium ) , a 4-yr trial of tiotropium in chronic obstructive pulmonary disease , allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy . 5,993 patients were r and omised ( tiotropium/placebo )  .  Lung function , St George 's Respiratory Question naire , exacerbations and adverse events were followed . Patients were characterised as  continuing smokers ( CS ) , continuing ex-smokers ( CE ) , or intermittent smokers ( IS ) based on self-reporting smoking behaviour . 60 % , 14 % and 26 % of patients were CE , CS and IS , respectively . The rate of forced expiratory volume in 1 s ( FEV1 ) decline for placebo patients was most rapid in CS ( -51±4 , -36±2 and -23±2 mL·yr−1 in CS , IS , and CE , respectively ) . Tiotropium did not alter FEV1 decline , but was associated with significant improvements in pre- and post-bronchodilator FEV1  over placebo that persisted throughout the 4-yr trial for each smoking status ( pre-bronchodilator : 125 , 55 and 97 mL at 48 months in CS , IS and CE , respectively ; p≤0.0003 ) . Tiotropium  reduced exacerbation risk in CS ( HR ( 95%CI ) 0.81 ( 0.68–0.97 ) ) , in CE ( 0.86 ( 0.79–0.93 ) ) and trended towards significance in IS ( 0.89 ( 0.80–1.01 ) ) . At 4 yrs , St George ’s Respiratory Question naire for tiotropium patients improved the most in CS ( -4.62 units , p = 0.0006 ) and the least in IS ( -0.54 units , p = 0.55 ) , compared with control . Tiotropium provided long-term benefits irrespective of smoking status , although differences among categories were observed 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 The aim of this study was to perform a 1-yr trial-based cost-effectiveness analysis ( CEA ) of tiotropium versus salmeterol followed by a 5-yr model-based CEA . The within-trial CEA , including 7,250 patients with moderate to very severe chronic obstructive pulmonary disease ( COPD ) , was performed alongside the 1-yr international r and omised controlled Prevention of Exacerbations with Tiotropium (POET)- COPD trial comparing tiotropium with salmeterol regarding the effect on exacerbations . Main end-points of the trial-based analysis were costs , number of exacerbations and exacerbation days . The model-based analysis was conducted to extrapolate results to 5 yrs and to calculate quality -adjusted life years ( QALYs ) . 1-yr costs per patient from the German statutory health insurance ( SHI ) perspective and the societal perspective were € 126 ( 95 % uncertainty interval ( UI ) € 55–195 ) and € 170 ( 95 % UI € 77–260 ) higher for tiotropium , respectively . The annual number of exacerbations was 0.064 ( 95 % UI 0.010–0.118 ) lower for tiotropium , leading to a reduction in exacerbation-related costs of € 87 ( 95 % UI € 19–157 ) . The incremental cost-effectiveness ratio was € 1,961 per exacerbation avoided from the SHI perspective and € 2,647 from the societal perspective . In the model-based analyses , the 5-yr costs per QALY were € 3,488 from the SHI perspective and € 8,141 from the societal perspective . Tiotropium  reduced exacerbations and exacerbation-related costs , but increased total costs . Tiotropium can be considered cost-effective as the result ing cost-effectiveness ratios were below commonly accepted willingness-to-pay thresholds Background NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease ( COPD ) . The glycopyrronium bromide in COPD airways clinical study 1 ( GLOW1 ) evaluated the efficacy , safety and tolerability of NVA237 in patients with moderate-to-severe COPD . Methods Patients with COPD with a smoking history of ≥ 10 pack-years , post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 80 % and ≥ 30 % predicted normal and FEV1/forced vital capacity < 0.70 were enrolled . Patients were r and omized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry . The primary outcome measure was trough FEV1 at Week 12 . Results A total of 822 patients were r and omized to NVA237 ( n = 552 ) or placebo ( n = 270 ) . Least squares mean ( ± st and ard error ) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 ( 1.408 ± 0.0105 L ) , versus placebo ( 1.301 ± 0.0137 L ; treatment difference 108 ± 14.8 mL , p < 0.001 ) . Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26 . FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26 , and at all other visits and timepoints . Transition dyspnoea index focal scores and St. George 's Respiratory Question naire scores were significantly improved with NVA237 versus placebo at Week 26 , with treatment differences of 1.04 ( p < 0.001 ) and -2.81 ( p = 0.004 ) , respectively  . NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31 % ( p = 0.023 ) and use of rescue medication by 0.46 puffs per day ( p = 0.005 ) , versus placebo . NVA237 was well tolerated and had an acceptable safety profile , with a low frequency of cardiac and typical antimuscarinic adverse effects . Conclusions Once-daily NVA237 was safe and well tolerated and provided rapid , sustained improvements in lung function , improvements in dyspnoea , and health-related quality of life , and reduced the risk of exacerbations and the use of rescue medication . Trial registration Clinical Trials.gov : BACKGROUND A significant minority of patients with COPD have favourable response to corticosteroid treatment . In addition , the benefit of corticosteroid treatment may be outweighed by the side-effects . Long-term administration of inhaled steroids is a safe means of treatment . However , only a few studies have addressed the role of inhaled steroids in patients with COPD , with conflicting results . METHODS Forty-four patients with stable COPD were defined as ' responders to bronchodilators ' ( increase in FEV1 > or = 20 % following administration of  beta 2-agonist ) ( group A ) , and 124 as ' non-responders to bronchodilators ' ( group B ) . All patients were r and omized to receive a 6-week course of either a daily dose of 800 micrograms of inhaled budesonide or placebo , separated by 4 weeks when no medication was taken ; were r and omized again to receive a 6-week course of either 1600 micrograms day-1 of inhaled budesonide , or 800 micrograms day-1 of inhaled budesonide plus placebo ; and were r and omized once again to receive a 6-week course of either 40 mg day-1 of prednisone or placebo . All stages were performed in a double-blind cross-over design . RESULTS Following administration of 800 micrograms day-1 of inhaled budesonide , there was an increase in the mean FEV1 from 1.40 + /- 0.20 to 1.92 + /- 0.22 L ( P < 0.001 ) and a significant decrease in inhaled beta 2 agonist consumption in group A. These changes remained almost stable during the increased dose of inhaled budesonide or during prednisone treatment . The mean FEV1 did not change during the placebo period , or in group B in either treatments . CONCLUSIONS Treatment with inhaled steroids improved spirometry data and inhaled beta 2-agonist consumption in about one-quarter of patients with stable COPD , and this rate increased to about three-quarters in patients who responded to beta 2-agonist inhalation . There was no additional benefit in using a higher dose of inhaled budesonide or prednisone Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity ( FEV1 ) to decide when to initiate combination treatment with a long-acting β2-agonist and an inhaled corticosteroid . Assessment of baseline FEV1 as a continuous variable may provide a more reliable prediction of treatment effects . Patients from a 1-year , parallel-group , r and omized controlled trial comparing  50 μg salmeterol ( Sal ) , 500 μg fluticasone propionate ( FP ) , the combination ( Sal/FP ) and placebo , ( bid ) , were categorized post hoc into FEV1 < 50 % and FEV1 ≥50 % predicted subgroups ( n=949/513 respectively ) . Treatment effects on clinical outcomes – lung function , exacerbations , health status , diary card symptoms , and adverse events – were investigated . Treatment responses based on a pre-specified analysis explored treatment differences by severity as a continuous variable . Lung function improved with active treatment irrespective of FEV1 ; Sal/FP had greatest effect . This improvement appeared additive in milder disease ; synergistic in severe disease . Active therapy significantly reduced exacerbation rate in patients with FEV1 < 50 % predicted , not in milder disease . Health status and breathlessness improved with Sal/FP irrespective of baseline FEV1 ; adverse events were similar across subgroups . The spirometric response to Sal/FP varied with baseline FEV1 , and clinical benefits were not restricted to patients with severe disease . These data have implication s for COPD management decisions , suggesting that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . Background Exercise training improves exercise tolerance in chronic obstructive pulmonary disease ( COPD ) . Tiotropium 18 μg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation , one of the pathophysiological factors contributing to exertional dyspnea in COPD patients . Aim To determine whether tiotropium enhances the effects of exercise training in patients with COPD . Design Multicenter , 25 week r and omized , double-blind , placebo-controlled , parallel-group study . Setting Twelve Italian Pulmonary Units practicing pulmonary rehabilitation . Patients and intervention Two hundred thirty four COPD patients ( 196 males ; mean age : 67.4 ± 7.6 ; forced expiratory volume at 1 second ( FEV1 ) : 41.4 ± 13.0 % predicted ) were r and omised to tiotropium 18 μg or placebo inhalation capsules  taken once daily . Both groups underwent a 8 week pulmonary rehabilitation program ( PR ) consisting of 3 exercise training session per week . Measurements Baseline , at the end of PR and after 12 weeks , patients completed pulmonary function testing , six minute walking test ( 6MWT ) , the Baseline and Transition Dyspnea Index ( BDI and TDI ) , and the St. George ’s Respiratory Question naire ( SGRQ ) . Results Relative to placebo , tiotropium had larger trough and post- study drug FEV1 responses on all test days . At the end of and 12 weeks following PR , patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo . Compared to the period immediately prior to PR , the mean improvement in 6MWT was only 29.7 meters ( 7.1 % ) for the combined cohort . Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo ( p < 0.01 ) . At 12 weeks after PR , TDI focal scores were 2.71 for tiotropium and 2.11 for placebo ( p = 0.16 ) . Reduction in all four SGRQ component scores , indicating an improvement in health-related quality of life , was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant . During the study period , there were fewer exacerbations and exacerbation days in the tiotropium group . Conclusion Although significant improvements were observed with perceived dyspnea , compared to placebo , the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is debilitating and costly to manage . A recent clinical trial concluded that formoterol , a long-acting beta(2)-adrenoceptor agonist , was more clinical ly effective than inpratropium bromide in the management of COPD . OBJECTIVE The aim of this study was to perform an economic assessment of the management of COPD with formeterol versus ipratropium bromide . METHODS Assessment were based on the results of a previously published 12-week , multicenter , double-masked , r and omized , parallel-group , placebo-controlled clinical trial comparing inhaled formoterol dry powder 12 and 24 microg BID with ipratropium bromide 40 microg QID pressurized metered dose inhaler and with placebo in 780 COPD patients .  Treatment costs for study drugs and rescue medications were estimated from re source utilization and average wholesale prices . Costs were assessed with respect to forced expiratory lung volume in 1 second ( FEV(1 ) ) and patient-reported quality of life ( QOL ) as assessed via the St. George 's Respiratory Question naire . Cost-effectiveness ratios were calculated for each treatment arm and incremental cost-effectiveness ratios ( ICERs ) were calculated for each treatment relative to the next best alternative . Economic efficiency frontiers were identified . Sensitivity analysis was conducted . RESULTS Cost analysis with respect to FEV(1 ) revealed an economic efficiency frontier formed by placebo , ipratropium bromide 40 microg , and formoterol 12 microg at their respective FEV(1 ) levels , with cost-effectiveness ratios of $ 30.18 , $ 53.50 , and $ 142.04 , respectively , per FEV(1 ) . The ICER for ipratropium over placebo was $ 273.03 ; for formoterol 12 microg over ipratropium , $ 1611.32 . Cost analysis with respect to QOL showed an economic efficiency frontier formed by placebo and formoterol 12 microg at their respective QOL outcomes , with cost-effectiveness ratios of $ 25.96 and $ 32.56 , respectively , per QOL score change . The cost-effectiveness ratio for ipratropium was $ 69.40,which was not on the QOL economic efficiency frontier . The ICER for formoterol 12 microg over placebo was $ 34.51 per QOL score point . CONCLUSIONS Formoterol 12 microg provided greater QOL outcome than ipratropium bromide at an additional cost of $ 554.28 per year . Further research would be necessary to assess whether the differences in outcomes , particularly QOL , observed in the short term with formoterol would lead to favorable long-term health and economic outcomes Abstract Background : This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD . Methods : In this 12-week , double-blind , multicenter trial , patients were r and omized ( 1:1:1 ) to inhaled twice-daily aclidinium 200 μg , aclidinium 400 μg , or placebo . Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12 , respectively . Health status ( St. George 's Respiratory Question naire [ SGRQ ] ) , COPD symptoms ( Transitional Dyspnea Index [ TDI ] , night and early morning symptoms ) , and safety were also assessed . Results : A total of 561 patients ( mean age , 64 ± 9 years ) with a mean baseline FEV1 of 1.36 ± 0.54 L ( 47.2 % of predicted value ) were r and omized . At Week 12 , aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean ( 95 % CI ) trough FEV1 compared with placebo by 86 ( 45 , 127 ) mL and 124 ( 83,164 ) mL , respectively , and in peak FEV1 by 146 ( 101 , 190 ) mL and 192 ( 148 , 236 ) mL , respectively ( p ≤ 0.0001 for all ) . Both aclidinium doses also provided significant improvements in SGRQ , TDI and almost all COPD symptom scores compared with placebo ( p < 0.05 for all ) . Incidences of adverse events ( AEs ) were similar across treatment groups . The incidence of anticholinergic AEs was low and similar across groups ( dry mouth : 0.5%–1.6 % ; constipation : 0%-1.1 % ) . Conclusions : Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation , health status , and COPD symptoms . Both doses were well tolerated and had safety profiles similar to placebo . Trial Registration : This ACCORD I study ( AClidinium in Chronic Obstructive Respiratory Disease I ) was registered on clinical trials.gov ( NCT00891462 ) as “ Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease ( COPD ) ” 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 The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) . In this 24-week , double-blind trial , patients were r and omised to twice-daily aclidinium ( 200 μg or 400 μg ) or placebo . The primary efficacy end-point was change in trough forced expiratory volume in 1 s ( FEV1 ) at week 24 . Other end-points included peak FEV1 , health status ( St George 's Respiratory Question naire ; SGRQ ) and dyspnoea ( Transitional Dyspnoea Index ; TDI ) . Overall , 828 patients were r and omised . At week 24 , significant improvements from baseline were observed with aclidinium 200 μg and 400 μg versus placebo for trough FEV1 ( 99 and 128 mL ; both p<0.0001 ) and peak FEV1 ( 185 and 209 mL ; both p<0.0001 ) . Peak FEV1 improvements on day 1 were comparable with week 24 . Aclidinium 200 μg and 400 μg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score ( -3.8 and -4.6 units ; p<0.001 and p<0.0001 ) and TDI focal score ( 0.6 and 1.0 units ; p<0.05 and p<0.001 ) at week 24 . With both aclidinium doses , the incidence of anticholinergic adverse events was low , and similar to placebo . Twice-daily aclidinium significantly improved bronchodilation , health status and dyspnoea , and was well tolerated in patients with COPD 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 Objective : To estimate the cost-effectiveness of fluticasone propionate – salmeterol combination ( FSC ) compared to salmeterol for maintenance therapy in severe chronic obstructive pulmonary disease ( COPD ) . Study design : Pooled economic analysis . Methods : We performed an economic analysis of pooled data from two r and omized clinical trials ( combined N = 1554 ) that evaluated the effect of maintenance therapy with FSC ( 250/50 μg twice daily ) or salmeterol ( 50 μg twice daily ) on exacerbation rates in patients with severe COPD . We calculated exacerbation rates and applied st and ardized costs to exacerbation-related health care utilization reported in the trials ( office , urgent care , and emergency department visits ; hospitalizations ; and oral corticosteroids and antibiotics ) to determine cost differences between FSC and salmeterol treatment outcomes . Results : Annual rates of any exacerbation and moderate/severe exacerbation were lower in the FSC group than the salmeterol group ( 4.91 vs 5.78 and 1.32 vs 2.00 respectively , both P < 0.05 ) . Total adjusted annual COPD related exacerbation and therapeutic costs were $ 4,842 ( 95 % CI ; $ 4,731–$4,952 ) in the FSC group and $ 5,066 ( 95 % CI ; $ 4,937–$5,195 ) in the salmeterol group . Conclusions : FSC combination therapy is associated with reduced risk of any exacerbation and moderate/severe exacerbation , and incurs lower annual COPD -related health care costs compared to treatment with salmeterol . This analysis demonstrates that FSC therapy may be advantageous from both a clinical and cost-benefit st and point for patients with severe COPD Background Exacerbations affect morbidity in chronic obstructive pulmonary disease ( COPD ) . We sought to evaluate the association between exacerbation frequency and spirometric and health status changes over time using data from a large , long-term trial . Methods This retrospective analysis of data from the 4-year UPLIFT ® ( Underst and ing Potential Long-term Impacts on Function with Tiotropium ) trial compared tiotropium with placebo . Annualized rates of decline and estimated mean differences at each time point were analyzed using a mixed-effects model according to subgroups based on exacerbation frequency ( events per patient-year : 0 , > 0–1 , > 1–2 , and > 2 ) . Spirometry and the St George ’s Respiratory Question naire ( SGRQ ) were performed at baseline and every 6 months ( also at one month for spirometry ) . Results In total , 5992 patients ( mean age 65 years , 75 % male ) were r and omized .  Higher exacerbation frequency was associated with lower baseline postbronchodilator forced expiratory volume in one second ( FEV1 ) ( 1.40 , 1.36 , 1.26 , and 1.14 L ) and worsening SGRQ scores ( 43.7 , 44.1 , 47.8 , and 52.4 units ) . Corresponding rates of decline in postbronchodilator FEV1 ( mL/year ) were 40 , 41 , 43 , and 48 ( control ) , and 34 , 38 , 48 , and 49 ( tiotropium ) . Values for postbronchodilator forced vital capacity decline ( mL/year ) were 45 , 56 , 74 , and 83 ( control ) , and 43 , 57 , 83 , and 95 ( tiotropium ) . The rates of worsening in total SGRQ score ( units/year ) were 0.72 , 1.16 , 1.44 , and 1.99 ( control ) , and 0.38 , 1.29 , 1.68 , and 2.86 ( tiotropium ) . The proportion of patients who died ( intention-to-treat analysis until four years [ 1440 days ] ) for the entire cohort increased with increasing frequency of hospitalized exacerbations . Conclusion Increasing frequency of exacerbations worsens the rate of decline in lung function and health-related quality of life in patients with COPD . Increasing rates of hospitalized exacerbations are associated with increasing risk of death The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease ( COPD ) patients , and depends upon the type and dose of bronchodilator and the timing of administration . Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ) trial , a 4-yr r and omised double-blind trial evaluating the efficacy of 18 μg tiotropium daily in reducing the rate of decline in lung function . After wash-out of respiratory medications , patients received 80 μg ipratropium followed by 400 μg salbutamol .  Spirometry was performed before and 90 min following ipratropium administration . The criteria used for forced expiratory volume in one second ( FEV1 ) responsiveness were : ≥12 % increase over baseline and ≥200 mL ; ≥15 % increase over baseline ; and ≥10 % absolute increase in the percentage predicted value . Of the patients , 5,756 had data meeting the criteria for analysis ( age 64.5 yrs ; 75 % male ; baseline FEV1 1.10 L ( 39.3 % predicted ) and forced vital capacity ( FVC ) 2.63 L ) . Compared with baseline , mean improvements were 229 mL in FEV1 and 407 mL in FVC . Of these patients , 53.9 % had ≥12 % and ≥200 mL improvement in FEV1 , 65.6 % had ≥15 % improvement in FEV1 , and 38.6 % had ≥10 % absolute increase in FEV1 % pred . The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators BACKGROUND --Despite effective treatments , the morbidity and mortality of obstructive airways disease ( asthma and COPD ) remains high . Home monitoring of peak expiratory flow ( PEF ) is increasingly being advocated as an aid to better management of obstructive airways disease . The few available studies describing effects of treatment on the level and variation of PEF have involved relatively small numbers of subjects and did not use control groups . METHODS -- Patients aged 18 - 60 years were selected with PC20 < or = 8 mg/ml and FEV1 < 95 % confidence interval of predicted normal . They were r and omised to receive , in addition to a beta 2 agonist , either an inhaled corticosteroid ( BA+CS ) , an anticholinergic ( BA+AC ) , or a placebo ( BA+PL ) .  One hundred and forty one of these subjects with moderately severe obstructive airways disease completed seven periods of two weeks of morning and afternoon PEF measurements at home during 18 months of blind follow up . RESULTS --Improvements in PEF occurred within the first three months of treatment with BA+CS and was subsequently maintained : the mean ( SE ) increase in morning PEF was 51 ( 8) l/min in the BA+CS group compared with no change in the other two groups . Similarly , afternoon PEF increased by 22 ( 7 ) l/min . Diurnal variation in PEF ( amplitude % mean ) decreased from 18.0 % to 10.2 % in the first three months of treatment with BA+CS . Within-subject relations between changes in diurnal variation in PEF and changes in PC20 were found to be predominantly negative ( median rho-0.40 ) but with a large scatter . Relations between diurnal variation in PEF and changes in symptom scores , FEV1 , and bronchodilator response were even weaker . CONCLUSIONS --In patients with moderately severe obstructive airways disease , PEF rates and variation are greatly improved by inhaled corticosteroids . Since the relation of diurnal PEF variation with PC20 , symptoms , FEV1 , and bronchodilator response were all weak , these markers of disease severity may all provide different information on the actual disease state . PEF measurements should be used in addition to the other markers but not instead of them STUDY OBJECTIVES To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease ( COPD ) , and to establish previously reported symptomatic efficacy . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Twelve outpatient investigational centers in the United States . PATIENTS One hundred ninety-six patients with COPD . INTERVENTIONS Patients received either tiotropium 18 mug once/day or placebo , delivered by the H and iHaler device . MEASUREMENTS AND MAIN RESULTS Electrocardiography ( predose and 5 min postdose ) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo . Efficacy measures ( spirometry , global COPD ratings , scores on the EuroQol Health Question naire [ EQ-5D ] , albuterol inhaler as needed ) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies . Mean baseline forced expiratory volume in 1 second ( FEV1 ) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups . No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring . Frequency of premature beats and mean maximal changes in PR , QRS , QT , QTcB , and QTcF intervals were similar in both groups . No patients developed new-onset QT or QTc intervals greater than 500 msec , and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec , 30 - 60 msec , or greater than 60 msec . At 12 weeks , predose and postdose improvements in FEV1 were 184 and 265 ml , respectively , with tiotropium versus placebo ( p<0.001 ) . Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium ( p<0.05 ) ; as-needed albuterol was reduced by 25 % relative to placebo ( p<0.05 ) . CONCLUSION Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate , rhythm , QT intervals , or conduction Chronic bronchitis is associated with airways obstruction and inflammation . In order to determine whether aerosolized beclomethasone can modulate airway inflammation and diminish airway obstruction , subjects with chronic bronchitis performed spirometry and underwent bronchoalveolar lavage ( BAL ) before and after receiving 6 wk of therapy ( five puffs four times a day ) with either aerosolized beclomethasone ( n = 20 ) or placebo ( n = 10 ) in a double-blinded , r and omized fashion . All subjects received aerosolized albuterol before each use of the study medications . Before BAL , the airways were visually assessed for the appearance of inflammation and assigned a score , the bronchitis index . BAL was performed by instilling five 20-ml aliquots of saline into each of three sites and pooling and separately analyzing the returns from the first aliquots to yield a " bronchial sample . " The bronchial lavages were repeated in an additional three sites to increase the volume of fluid available for analysis . The fluid was prepared for cytologic examination by cytocentrifugation . Albumin ( as a measure of epithelium permeability ) and lactoferrin and lysozyme ( as measures of serous cell activity ) were measured in unconcentrated BAL fluid by enzyme-linked immunosorbent assay , and concentrations in epithelial lining fluid were estimated using urea as an internal marker for dilution . After treatment , the beclomethasone group , but not the placebo group , showed improvement in FVC ( p = 0.02 ) , FEV1 ( p = 0.002 ) , and 25 to 75 % forced expiratory flow ( p = 0.006 ) . Associated with the improvement in spirometry , the bronchitis index fell ( 13.5 + /- 1.0 versus 10.75 + /- 1.1 , p = 0.02 ) in the beclomethasone-treated group , but not the placebo-treated group . ( ABSTRACT TRUNCATED AT 250 WORDS 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 RATIONALE Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination ( salmeterol/fluticasone propionate ) 50/500 microg twice daily and the long-acting bronchodilator ( tiotropium ) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD . METHODS A total of 1,323 patients ( mean age , 64 yr , post-bronchodilator FEV1 , 39 % predicted ) were r and omized in this 2-year , double-blind , double-dummy parallel study . MEASUREMENTS AND MAIN RESULTS Primary endpoint was health care utilization exacerbation rate . Other endpoints included health status measured by St. George 's Respiratory Question naire ( SGRQ ) , mortality , adverse events , and study withdrawal . Probability of withdrawing from the study was 29 % greater with tiotropium than salmeterol/fluticasone propionate ( P = 0.005 ) . The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group ( rate ratio , 0.967 ; 95 % confidence interval [ CI ] , 0.836 - 1.119 ] ; P = 0.656 ) . The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium ( difference 2.1 units ; 95 % CI , 0.1 - 4.0 ; P = 0.038 ) . Mortality was significantly lower in the salmeterol/fluticasone propionate group ; 21 ( 3 % ) of patients in this group died compared with 38 ( 6 % ) in the tiotropium group ( P = 0.032 ) . More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium ( P = 0.008 ) . CONCLUSIONS We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium . More patients failed to complete the study while receiving tiotropium . A small statistically significant beneficial effect was found on health status , with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients . Clinical trial registered with www . clinical trials.gov ( NCT 00361959 ) 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 , Background The long-term efficacy and safety of aclidinium bromide , a novel , long-acting muscarinic antagonist , were investigated in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) . Methods In two double-blind , 52-week studies , ACCL AIM / COPD I ( n = 843 ) and II ( n = 804 ) , patients were r and omised to inhaled aclidinium 200 μg or placebo once-daily . Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70 % and FEV1 < 80 % of the predicted value . The primary endpoint was trough FEV1 at 12 and 28 weeks . Secondary endpoints were health status measured by St George 's Respiratory Question naire ( SGRQ ) and time to first moderate or severe COPD exacerbation . Results At 12 and 28 weeks , aclidinium  improved trough FEV1 versus placebo in ACCL AIM / COPD I ( by 61 and 67 mL ; both p < 0.001 ) and ACCL AIM / COPD II ( by 63 and 59 mL ; both p < 0.001 ) . More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCL AIM / COPD I ( 48.1 % versus 39.5 % ; p = 0.025 ) and ACCL AIM / COPD II ( 39.0 % versus 32.8 % ; p = 0.074 ) . The time to first exacerbation was significantly delayed by aclidinium in ACCL AIM / COPD II ( hazard ratio [ HR ] 0.7 ; 95 % confidence interval [ CI ] 0.55 to 0.92 ; p = 0.01 ) , but not ACCL AIM / COPD I ( HR 1.0 ; 95 % CI 0.72 to 1.33 ; p = 0.9 ) . Adverse events were minor in both studies . Conclusion Aclidinium is effective and well tolerated in patients with moderate to severe COPD .Trial registration Clinical Trials.gov : NCT00363896 ( ACCL AIM / COPD I ) and NCT00358436 ( ACCL AIM / COPD II ) Although most patients with obstructive airways disease show some amelioration with long-term inhaled corticosteroid therapy , the extent of improvement may vary considerably between patients . Patients with mild to moderately severe obstructive airways disease ( asthma and COPD ) were selected if provocative concentration producing a 20 % fall in forced expiratory volume in one second ( PC20 ) < or = 8 mg.ml-1 , and forced expiratory volume in one second ( FEV1 ) < 95 % confidence intervals ( CI ) of predicted normal . The independent influences of baseline PC20FEV1 , inspiratory vital capacity ( IVC ) , bronchodilator response , smoking habits , and allergy both on the " immediate " ( within 3 months ) response in FEV1 and the change in long-term ( from 3 months onwards ) slope of FEV1 with inhaled corticosteroids were analysed . Patients had a larger " immediate " improvement in their FEV1 with inhaled corticosteroids with each doubling doses lower PC20 , with each ten-fold higher immunoglobulin E ( IgE ) , and if they did not smoke . Total IgE proved a better independent predictor of " immediate " response than specific IgE for house dust mite , skin tests , or blood eosinophils . A more favourable long-term slope of FEV1 was predicted by a larger baseline bronchodilator response , but not by smoking . In conclusion , PC20 , total IgE , and smoking habits are independent predictors of immediate treatment response to inhaled corticosteroids .  Bronchodilator response is the single independent predictor of changes in long-term slope of FEV1 with corticosteroid treatment 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 ) Introduction Obesity is a growing health problem in Europe and it causes many diseases . Many weight-reducing methods are reported in medical literature , but none of them proved to be effective in maintaining the results achieved over time . Self-empowerment can be an important innovative method , but an effectiveness study is necessary . In order to st and ardise the procedures for a r and omised controlled study , a pilot study will be run to observe , measure and evaluate the effects of a period of  self-empowerment group treatment on overweight/obese patients . Methods and analysis Non-controlled , experimental , pilot study . A selected group of patients with body mass index > 25 , with no severe psychiatric disorders , with no aesthetic or therapeutic motivation will be included in the study . A set of quantitative and qualitative measures will be utilised to evaluate the effects of a self-empowerment course in a 12 month time . Group therapy and medical examinations will also complete this observational phase . At the end of this pilot study , a set of appropriate measures and procedures to determine the effectiveness of individual empowerment will be identified and agreed among the different professional figures . Results will be recorded and analysed to start a r and omised controlled trial to evaluate the effectiveness of the proposed methodology . Ethics and dissemination This protocol was approved by the local Ethics Committee of Udine in March 2012 . The findings of the trial will be disseminated through peer- review ed journals , national and international conference presentations and public events involving the local administrations of the towns where the trial participants are resident . Trial Registration http://www . clinical strials.gov identifier NCT01644708 Inhaled corticosteroids ( ICS ) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease ( COPD ) . However , little is known about the risk of associated infections . In a post hoc analysis of the TOwards a Revolution in COPD Health ( TORCH ) study , we analysed and identified potential risk factors for adverse event reports of pneumonia in this r and omised , double-blind trial comparing twice-daily inhaled salmeterol ( SAL ) 50 μg , fluticasone propionate ( FP ) 500 μg , and the combination ( SFC ) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs . Despite a higher withdrawal rate in the placebo arm , after adjusting for time on treatment , a greater rate of pneumonia was reported in the FP and SFC treatment arms ( 84 and 88 per 1,000 treatment-yrs , respectively ) compared with SAL and placebo ( 52 and 52 per 1,000 treatment-yrs , respectively ) . Risk factors for pneumonia were age ≥55 yrs , forced expiratory volume in 1 s < 50 % predicted , COPD exacerbations in the year prior to the study , worse Medical Research Council dyspnoea scores and body mass index < 25 kg·m−2 . No increase in pneumonia deaths with SFC was observed ; this could not be concluded for FP . Despite the benefits of ICS-containing regimens in COPD management , healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies 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 Indacaterol is a novel , inhaled , once-daily , ultra-long-acting & bgr;2-agonist bronchodilator recently approved in Europe for the treatment of chronic obstructive pulmonary disease ( COPD ) . The aim of the present study was to investigate the efficacy and safety of indacaterol compared with placebo and the twice-daily & bgr;2-agonist , salmeterol , as an active control . Patients with moderate-to-severe COPD were r and omised to 6 months double-blind treatment with indacaterol ( 150 & mgr;g once daily ) , salmeterol ( 50 & mgr;g twice daily ) or placebo . The primary efficacy end-point was trough ( 24 h post-dose ) forced expiratory volume in 1 s ( FEV1 ) after 12 weeks . 1,002 patients were r and omised and 838 ( 84 % ) completed the study .  Indacaterol increased trough FEV1 at week 12 by 170 mL over placebo ( p<0.001 ) and by 60 mL over salmeterol ( p<0.001 ) . Both active treatments improved health status ( St George 's Respiratory Question naire ) and dyspnoea ( transition dyspnoea index ) compared with placebo , with differences between them favouring indacaterol .  Safety profiles were similar across the treatment groups , and both indacaterol and salmeterol were well tolerated . Once-daily treatment with 150 & mgr;g indacaterol had a significant and clinical ly relevant bronchodilator effect over 24 h post-dose and improved health status and dyspnoea to a greater extent than twice-daily 50 & mgr;g salmeterol . Indacaterol should prove a useful additional treatment for patients with COPD 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 Currently available long-acting inhaled bronchodilators ( tiotropium , salmeterol , formoterol ) have demonstrated beneficial effects on exacerbations in placebo-controlled trials . However , there have been no direct comparisons of these drugs with exacerbations as the primary outcome and consequently COPD treatment guidelines do not indicate a preference for either bronchodilator . Therefore , an international , r and omized , double-blind , double-dummy , parallel-group clinical trial has been design ed to investigate the comparative efficacy of 2 long-acting bronchodilators tiotropium 18 μg daily and salmeterol 50 μg bid on exacerbations . The trial will include at least 6800 r and omized patients with diagnosis of COPD , ≥ 10 pack-year history of smoking , post-bronchodilator FEV1 ≤ 70 % predicted , and a history of exacerbations in the previous year . The primary endpoint is time to first COPD exacerbation . Secondary endpoints include number of exacerbations and time to premature discontinuation of trial medication . The trial has been design ed to address several of the challenges in study ing exacerbations in a controlled trial by a symptom and event-based definition of exacerbations , frequent follow-up contacts , selection of time to first event as the primary endpoint and using exposure adjusted analysis when examining number of events . Other challenges in design ing exacerbation trials such as differential discontinuation and follow-up of discontinued patients are discussed 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 Chronic obstructive pulmonary disease ( COPD ) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation . Tiotropium has been shown to reduce exacerbation frequency , but its effect on airway inflammation is unknown . The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency .  Patients ( n = 142 ) were r and omised to receive tiotropium or placebo in addition to their usual medication for 1 yr . Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary . There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups , but sputum IL-8 level was increased in the tiotropium arm . There was no difference between start and end of study in serum IL-6 or C-reactive protein level .  Tiotropium was associated with a 52 % reduction in exacerbation frequency ( 1.17 versus 2.46 exacerbations·yr−1 ) . Of patients on tiotropium , 43 % experienced at least one exacerbation , compared with 64 % on placebo  . The total number of exacerbation days was reduced compared with placebo ( 17.3 versus 34.5 days ) . Tiotropium  reduces exacerbation frequency in chronic obstructive pulmonary disease , but this effect does not appear to be due to a reduction in airway or systemic inflammation 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 Premature discontinuation from clinical trials may bias results against effective therapies . In the present study mortality rates were retrospectively review ed in a 6-month , r and omised , placebo-controlled trial in which tiotropium 18 μg daily was shown to decrease chronic obstructive pulmonary disease exacerbations . Patients participated for 6 months even if trial medication was prematurely discontinued . Exposure-adjusted incidence rates ( IRs ) were calculated for r and omisation – end trial , r and omisation – end trial drug ( 0–ED ) and end trial drug – end trial ( ED – ET ) . Of 1,829 patients ( forced expiratory volume in one second 1.04 L ( 36 % predicted ) , mean age 68 yrs , 99 % male ) , 16  % tiotropium  and 27 % placebo patients prematurely stopped trial medication . The number of fatal events for the entire cohort was : 62 all cause , including 16 cardiac and 16 lower respiratory . IRs for fatal events per 100 patient-yrs were higher in the discontinued period : 1.9 ( 0–ED ) versus 23.0 ( ED – ET ) in the tiotropium group and 1.8 versus 19.0 in the placebo group . Respective IRs for fatal cardiac events were 0.7 versus 2.8 ( tiotropium ) and 0.5 versus 6.2 ( placebo ) ; for fatal lower respiratory events were 0.7 versus 2.8 ( tiotropium ) and 0.8 versus 5.4 (  placebo ) . Rate ratios ( tiotropium/placebo ) for fatal events were lower in the discontinued period : 1.4 versus 0.5 for cardiac and 0.9 versus 0.5 for lower respiratory . Higher incidence rates of fatal events occurred following premature discontinuation of study medication . Incomplete information from rate ratios occurs as a result of failure to consider outcomes of patients who discontinue early from clinical trials 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 Patients with COPD have an increased risk of cardiovascular disease . Despite the clinical benefits of long-acting beta-agonist agents in the treatment of COPD , patients may be at an increased risk of cardiovascular toxicity , including tachyarrhythmia due to beta-adrenergic stimulation . OBJECTIVE To evaluate the cardiovascular safety of salmeterol in COPD patients by conducting a pooled analysis of cardiovascular safety data . DESIGN R and omized , double-blind , parallel group , multiple-dose studies , which included salmeterol , 50 micro g bid , and placebo arms . STUDY SELECTION Seven of a total of 17 studies met the predefined inclusion requirements and were pooled . A total of 1,443 patients received placebo , while 1,410 patients received salmeterol , 50 micro g bid . The median duration of treatment was 24 weeks ( range , 12 to 52 weeks ) . RESULTS Treatment with salmeterol , 50 micro g bid , showed no increased risk of cardiovascular adverse events ( AEs ) compared with placebo ( relative risk , 1.03 ; 95 % confidence interval , 0.8 to 1.3 ; p = 0.838 ) . Both groups had a similar incidence of cardiovascular events ( 8 % ) , including cardiovascular deaths . The incidence of cardiovascular AEs increased with age , concurrent cardiovascular conditions , and treatment with antiarrhythmic/bradycardic agents , although increases were comparable in both treatment groups . There were no episodes of sustained ventricular tachycardia , and no clinical ly significant differences were observed in 24-h heart rate , ventricular and supraventricular ectopic events , qualitative ECGs , QT intervals , or vital signs between the salmeterol , 50 micro g bid , group and the placebo group . Similar findings were observed when patients were stratified for age of > 65 years or the known presence of cardiovascular disease . CONCLUSIONS Treatment with salmeterol , 50 micro g bid , does not increase the risk of cardiovascular AEs in this population of COPD patients compared with placebo STUDY OBJECTIVE To examine the effect of fluticasone propionate , 250 microg/salmeterol , 50 microg combination ( FSC 250/50 ) twice daily on lung hyperinflation and associated measures of exercise performance in patients with COPD . DESIGN This was a r and omized , double-blind , parallel-group study . PATIENTS Eligible patients were > or = 40 years old with a diagnosis of COPD , prealbuterol FEV(1 ) < 70 % of predicted , FEV1/FVC ratio > or = 0.70 , and functional residual capacity ( FRC ) > or = 120 % of predicted normal . INTERVENTIONS Patients were r and omized to FSC 250/50 ; salmeterol , 50 microg ; or placebo twice daily for 8 weeks . Predose and postdose spirometry , plethysmography , and constant-load cycle cardiopulmonary exercise test evaluations were compared . The primary comparison was FSC 250/50 with placebo . The salmeterol group was included for exploratory comparisons with FSC 250/50 . RESULTS A total of 185 patients ( mean baseline FEV1 of 41 % predicted ) were enrolled . At rest , FSC 250/50 significantly reduced postdose FRC and increased inspiratory capacity ( IC ) compared with placebo ( differences of - 0.35 + /- 0.12 L and 0.33 + /- 0.06 L [ mean + /- SE ] , respectively , at week 8 ; p > or = 0.003 ) and increased exercise endurance time ( difference , 132 + /- 45 s ; p = 0.004 ) . At a st and ardized time during exercise ( isotime ) , FSC 250/50 increased postdose IC by 0.20 + /- 0.05 L over placebo with associated improvements in tidal volume and minute ventilation ( p < 0.05 vs placebo at week 8) . Improvement in exercise time was significantly correlated with the increase in IC ( r = 0.45 , p < 0.001 ) but not FEV1 ( r = 0.23 , p = 0.08 ) . Predose comparisons of FSC 250/50 with salmeterol and placebo favored FSC 250/50 . CONCLUSION We conclude that FSC 250/50 decreases lung hyperinflation at rest and during exercise with an associated increase in exercise endurance time when compared with placebo We compared the effectiveness of inhaled formoterol with that of ipratropium in the treatment of chronic obstructive pulmonary disease ( COPD ) . After a 2-wk run-in period , 780 patients with COPD were r and omized to receive for 12 wk formoterol dry powder 12 or 24 microg twice daily , ipratropium bromide 40 microg four times daily , or placebo in a multicenter , double-blind , parallel-group study . The primary efficacy variable was the area under the curve for forced expiratory volume in 1 s ( FEV(1 ) ) measured over 12 h after 12 wk of treatment . Secondary variables included diary symptoms and quality of life . Both doses of formoterol and ipratropium significantly increased the area under the curve for FEV(1 ) in comparison with placebo ( all p < 0.001 ) . Both doses of formoterol were also significantly superior to ipratropium ( all p < 0.025 ) . Compared with placebo , both doses of formoterol significantly improved symptoms ( all p < or = 0.007 ) and quality of life ( p < 0.01 for total scores ) whereas ipratropium did not show significant effects ( all p > or = 0.3 ) . All study treatments exhibited a similar safety profile . We conclude that formoterol is more effective than ipratropium bromide in the treatment of COPD , as the efficacy of ipratropium on airflow obstruction does not translate into a clinical benefit that patients can perceive 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 This study evaluated whether the effect of tiotropium on the change in trough forced expiratory volume in 1s ( FEV1 ) , vs. placebo , is affected by smoking status . In a 3-month , double-blind study in 31 centres in Portugal , 311 ( 289 completed ) patients were r and omised to tiotropium 18 microg once daily or placebo .  Baseline mean ( st and ard deviation ( SD ) ) FEV1 was 1.11 ( 0.39 ) l in the tiotropium group and 1.13 ( 0.39 ) l in the placebo group . Patients had an average smoking history of 55 ( 25.7 ) pack-years ; 80 ( 26 % ) were smokers and 224 ( 74 % ) were ex-smokers . The primary end-point was change in morning pre-dose ( i.e. trough ) FEV1 after 12 weeks . Trough FEV1 at 12 weeks was significantly improved with tiotropium vs. placebo : the difference in means was 102 ml , P=0.0011 , 95 % confidence interval ( CI ) ( 41 , 164 ) . The difference in means in smokers was 138 ml , P=0.0105 , CI ( 32 , 244 ) ; in ex-smokers it was 66 ml , P=0.0375 , CI ( 3 , 129 ) . The difference between smokers and ex-smokers was not statistically significant ( P=0.6982 ) and may be due to greater variability and differences in disease severity . The significant improvement in lung function in patients treated with tiotropium vs. placebo in both smokers and ex-smokers suggests that tiotropium is an effective and well-tolerated therapy in chronic obstructive pulmonary disease ( COPD ) , regardless of smoking status BACKGROUND In 2003 , chronic obstructive pulmonary disease ( COPD ) accounted for 46 % of the burden of chronic respiratory disease in the Australian community . In the 65 - 74-year-old age group , COPD was the sixth leading cause of disability for men and the seventh for women . AIMS To measure the influence of disease severity , COPD phenotype and comorbidities on acute health service utilization and direct acute care costs in patients admitted with COPD . METHODS Prospect i ve cohort study of 80 patients admitted to the Royal Melbourne Hospital in 2001 - 2002 for an exacerbation of COPD . Patients were followed for 12 months and data were collected on acute care utilization . Direct hospital costs were derived using Transition II , an activity-based costing system .  Individual patient costs were then modelled to ascertain which patient factors influenced total direct hospital costs . RESULTS Direct costs were calculated for 225 episodes of care , the median cost per admission was AU$3124 ( interquartile range $ 1393 to $ 5045 ) . The median direct cost of acute care management per patient per year was AU$7273 ( interquartile range $ 3957 to $ 14 448 ) . In a multivariate analysis using linear regression modelling , factors predictive of higher annual costs were increasing age ( P= 0.041 ) , use of domiciliary oxygen ( P= 0.008 ) and the presence of chronic heart failure ( P= 0.006 ) . CONCLUSION This model has identified a number of patient factors that predict higher acute care costs and awareness of these can be used for service planning to meet the needs of patients admitted with COPD BACKGROUND Gender differences may occur in many chronic diseases . We have examined the influence of gender in chronic obstructive pulmonary disease ( COPD ) on long-term responses to tiotropium . METHODS Subgroup analysis of data from the Underst and ing the Potential Long-term Impact of Tiotropium ( UPLIFT ) trial ( 4-year , r and omized , double-blind , placebo-controlled trial of tiotropium in patients with COPD ) . RESULTS Of 5992 patients , 75 % were men and 25 % women . Mean age was 65 and 63 years , respectively . Baseline post-bronchodilator forced expiratory volume in 1s ( FEV(1))=47 % predicted(men ) and 49 % predicted(women ) . St George 's Respiratory Question naire ( SGRQ ) total score was 44.9 and 48.7units , respectively . At 48 months , improvement in trough FEV(1 ) over control was 92mL(men ) and 77mL(women ) ( p<0.001 for both ) , with no differences in the rate of decline ( trial primary endpoint ) . Hazard ratio ( HR ) ( 95 % confidence interval [ CI ] ) for first exacerbation ( tiotropium/placebo ) was 0.87(0.81 , 0.93)(men ) and 0.83(0.74 , 0.94)(women ) . Number of exacerbations ( per patient-year ) was reduced with tiotropium in men ( from 0.82 to 0.71 ) and women ( from 0.92 to 0.77 ) ( p<0.005 for both ) . HR ( 95 % CI ) for a hospitalized exacerbation was 0.89(0.79 , 0.99 ) and 0.77(0.62 , 0.94 ) , respectively . HR ( 95 % CI ) for mortality during treatment was 0.85(0.72 , 0.99)(men ) and 0.85(0.62 , 1.18)(women ) . Improvements in SGRQ total score ( tiotropium-control ) at 1 , 2 , 3 and 4 years were : -2.8 , -2.3 , -3.6 , -2.4(men ) and -2.7 , -2.6 , -2.6 , -2.1(women ) ( p<0.05 for all ) . CONCLUSION Long-term treatment of COPD with tiotropium improves lung function , exacerbations and health status in men and women , with similar magnitudes of benefit . Boehringer Ingelheim trial 205.235 ; Clinical Trials.gov : NCT00144339 One hundred and twenty seven adults considered on clinical grounds to have non-asthmatic chronic airflow obstruction entered a r and omised , double blind , placebo controlled , crossover trial comparing the physiological response to inhaled beclomethasone dipropionate 500 micrograms thrice daily with oral prednisolone 40 mg a day , both given for two weeks . One hundred and seven patients completed the study . Response was assessed as change in FEV1 and FVC measured on the last treatment day , and as change in mean peak expiratory flow ( PEF ) over the final seven days of treatment from home PEF recordings performed five times daily . A full response to treatment was defined as an increase in FEV or FVC , or an increase in mean daily PEF over the final seven days of treatment , of at least 20 % from baseline values . An improvement in one measurement of at least 15 % , or of 10 % in any two measurements , was defined as a partial treatment response . Response to placebo showed a significant order effect , suggesting a carry over effect of active treatment of at least three weeks . Response to active treatment was therefore related to initial baseline values , and compared with placebo by considering responses in the first treatment phase only . A full response to oral prednisolone ( 16/38 ) was significantly more common than to placebo ( 3/35 ) . The number of full responses to inhaled beclomethasone ( 8/34 ) did not differ significantly from the number responding to oral prednisolone or placebo in the first treatment phase , though full and partial responses to inhaled beclomethasone ( 12/34 ) were significantly more common than those to placebo ( 4/35 ) . When all three treatment phases were considered 44/107 patients showed a full response to one or both forms of corticosteroid treatment , a response to prednisolone ( 39 ) occurring more frequently than to inhaled beclomethasone ( 26 ) . Only 21 of the 44 responders showed a response to both forms of treatment . Inhaled beclomethasone dipropionate 500 micrograms thrice daily was inferior to oral prednisolone 40 mg per day , but better than placebo , in producing improvement in physiological measurements in patients thought to have nonasthmatic chronic airflow obstruction . It was , however , an effective alternative in over half of those showing a response to prednisolone 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 Combined use of β2-agonists and anticholinergic bronchodilators may have complementary benefits in patients with chronic obstructive pulmonary disease ( COPD ) . The objective of this study was to compare combination treatment with formoterol ( FORM ) plus tiotropium ( TIO ) versus treatment with TIO alone in patients with COPD . In this active-controlled , double-blind , multicenter trial , a total of 255 subjects with diagnosed COPD were r and omized to 12 weeks of either a combination of FORM 12 μ g twice-daily plus TIO 18 μ g once-daily in the morning ( QD AM ) or monotherapy with TIO 18 μ g QD AM . The primary efficacy variable was the area under the curve for forced expiratory volume in 1 second measured 0 to 4 hours after AM dosing ( FEV1 AUC0−4h ) . Significantly greater improvements in the FEV1 AUC0−4h were seen with FORM + TIO ( n = 116 ) versus TIO ( n = 124 ) at all time points . The increase in FEV1 5 minutes after the first dose was 180 mL with FORM + TIO versus 40 mL with TIO ( p < 0.001 ) . At endpoint , FEV1 AUC0−4h increased 340 mL with FORM + TIO versus 170 mL with TIO ( p < 0.001 ) . Improvements in trough FEV1 with FORM + TIO versus TIO were 180 mL and 100 mL , respectively ( p < 0.01 ) . Significantly greater reductions from baseline in symptom scores ( p < 0.05 ) and daytime albuterol use ( p < 0.04 ) were seen at endpoint with combination FORM + TIO versus TIO monotherapy . Both treatments were well tolerated . This study demonstrated that concurrent treatment with FORM + TIO results in greater therapeutic benefits than TIO alone Airways hyperresponsiveness ( AHR ) is an important feature of patients with chronic obstructive pulmonary disease ( COPD ) . Little is known about factors that modulate AHR in COPD 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 STUDY OBJECTIVE To compare the efficacy , tolerability , and safety of therapy with formoterol and oral slow-release theophylline ( THEO ) in patients with COPD . DESIGN A r and omized , parallel-group study , with double-blind arms for formoterol and placebo ( PL ) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations . SETTING Eighty-one centers worldwide . PATIENTS Eight hundred fifty-four patients with symptomatic COPD . INTERVENTION Comparison of twice-daily inhaled formoterol dry powder ( 12 or 24 microg ) , PL , and THEO ( individualized doses ) over 12 months . MEASUREMENTS AND RESULTS Compared to PL , doses of formoterol and THEO both significantly improved the area under the curve for FEV(1 ) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months ( p < 0.001 for all comparisons ) . Therapy with formoterol , 12 microg , was significantly more effective than that with THEO ( p < or = 0.026 ) . Formoterol significantly reduced the percentage of " bad days " ( i.e. , days with at least two individual symptom scores > or = 2 and /or a reduction in peak expiratory flow from a baseline of > 20 % ; p < or = 0.035 vs. PL and THEO ) , and the use of salbutamol rescue medication ( p < or = 0.003 vs PL ) over the whole treatment period , while the effect of THEO was similar to that of PL . Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months ( p < or = 0.030 ) . Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol . CONCLUSIONS Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD Inhaled corticosteroids are known to reduce respiratory symptoms and airway responsiveness in allergic patients with asthma . The aim of the present r and omised , double blind study was to assess the effect of eight weeks ' treatment with inhaled budesonide in non-allergic smokers with chronic obstructive lung disease . Twenty four subjects ( 23 male ) entered the study . Their ages ranged from 40 to 70 ( mean 57 ) years , with a mean of 35 ( range 9 - 80 ) pack years of smoking ; the mean FEV1 was 53 % ( range 32 - 74 % ) predicted and geometric mean PC20 ( histamine concentration causing a 20 % fall in FEV1 ) 0.96 ( range 0.07 - 7.82 ) mg/ml . After a two week washout , single blind , placebo period , 12 patients were allocated to treatment with budesonide 1600 microgram/day and 12 to placebo for eight weeks . The only additional drug to be taken was ipratropium bromide " if needed . " Twenty one patients completed the study , 10 in the budesonide group and 11 in the placebo group . The st and ard deviation of the difference between duplicate measurements of PC20 histamine and citric acid cough threshold made two weeks apart was below one doubling dose step . There was a significant reduction in dyspnoea in the budesonide group , but otherwise no change in symptom scores or use of ipratropium bromide over the eight weeks of treatment within or between the two groups . No significant differences in spirometric values , peak expiratory flow , PC20 histamine , or citric acid cough threshold were found between the groups . Although differences were not significant , some of the changes showed a trend in favour of budesonide . Whether a longer observation period would show a significant influence of inhaled corticosteroids in patients with chronic obstructive lung disease remains to be determined 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 Indacaterol is a long-acting inhaled β2-agonist ( LABA ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . In previous studies , indacaterol provided 24 h bronchodilation on once-daily dosing with a fast onset of action . This study compared the efficacy and safety of indacaterol with the twice-daily LABA formoterol and placebo over 1 year . Methods Patients with moderate to severe COPD were r and omised to receive once-daily indacaterol 300 μg ( n=437 ) or 600 μg ( n=428 ) , twice-daily formoterol 12 μg ( n=435 ) or placebo ( n=432 ) for 52 weeks in a double-blind double-dummy parallel group study . The primary efficacy variable was forced expiratory volume in 1 s ( FEV1 ) measured 24 h postdose after 12 weeks ( indacaterol vs placebo ) . Other outcomes included dyspnoea ( transition dyspnoea index , TDI ) , use of as-needed salbutamol , symptom-based measures recorded on diary cards , exacerbations , health status ( St George 's Respiratory Question naire ) , BODE index ( body mass index , obstruction , dyspnoea , exercise ) , safety and tolerability . Results Indacaterol  increased 24 h postdose FEV1 after 12 weeks by 170 ml ( both doses ) versus placebo and by 100 ml versus formoterol ( all p<0.001 ) . These significant differences were maintained at 52 weeks . Symptomatic outcomes were improved compared with placebo with all active treatments , and indacaterol was more effective than formoterol in improving TDI score and reducing the need for as-needed salbutamol . Indacaterol was well tolerated and had a good overall safety profile , including minimal impact on QTc interval and systemic β2-mediated events . Conclusions Once-daily indacaterol is an effective 24 h bronchodilator that improves symptoms and health status and confers clinical improvements over a twice-daily 12 h LABA as a treatment for patients with moderate to severe COPD . Trial registration number NCT 00393458 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 Airways hyperresponsiveness is a hallmark of asthma , and many patients with COPD also demonstrate hyperresponsiveness . Inhaled corticosteroids improve hyperresponsiveness , but the extent of improvement may vary considerably between patients . This study was design ed to determine which patient characteristics predict these differences in response . Patients with mild to moderately severe obstructive airways disease ( asthma and COPD ) were selected if PC20 < or = 8 mg/ml and FEV1 < 95 % confidence interval of predicted normal . They were followed for 2.5 yr , during which one-third received  inhaled corticosteroids . The independent influences of baseline FEV1/IVC , bronchodilator response , PC20 , smoking habits , allergy , age , and sex on the improvement in airways hyperresponsiveness with inhaled corticosteroids were analyzed . Total serum IgE was taken as a parameter of allergy , next to specific IgE for house dust mite , skin tests , and blood eosinophils . Total serum IgE was found to be the most important and single independent predictor of change in PC20 with inhaled corticosteroids : patients with a higher IgE had a greater increase in PC20 when administered inhaled corticosteroids than those with lower IgE levels . Alternatively , patients with a higher IgE who did not receive corticosteroids had a decrease in PC20 compared with patients with a lower IgE. This effect was most prominent in asthma but was inconsistent in asthmatic bronchitis and COPD . The level of IgE can not be used to predict the response to inhaled corticosteroids in individuals accurately . Total serum IgE is the single most important predictor of change in PC20 with and without inhaled corticosteroids . ( ABSTRACT TRUNCATED AT 250 WORDS STUDY OBJECTIVE Inhaled corticosteroids ( ICS ) are widely used in the treatment of COPD . One of the potential adverse effects of their use is the development of adrenal suppression . Our study aim ed to determine the effects of ICS on adrenal function over 3 years of use in patients with COPD . METHODS Two hundred twenty-one subjects were recruited from the 1,116 patients already enrolled in Lung Health Study II and were r and omized to receive either triamcinolone , 1,200 microg , or placebo daily . Basal cortisol levels and cortisol levels at 30 min and 60 min following cosyntropin injection were measured at study entry and after 1 year and 3 years of participation . RESULTS Basal cortisol levels in the placebo group were higher than in those receiving active drug at all time points and rose through the study period . There was no suppression of cortisol levels after cosyntropin stimulation at any study point in any subgroup . CONCLUSION Use of inhaled triamcinolone , 1,200 microg/d , over 3 years does not suppress baseline adrenal function or diminish adrenal responsiveness to cosyntropin stimulation Background : Little is known about adherence to inhaled medication in chronic obstructive pulmonary disease ( COPD ) and the impact on mortality and morbidity . Methods : Data on drug adherence from a r and omised double-blind trial comparing inhaled salmeterol 50 μg + fluticasone propionate 500 μg twice daily with placebo and each drug individually in 6112 patients with moderate to severe COPD over 3 years in the TORCH study were used  . All-cause mortality and exacerbations leading to hospital admission were primary and secondary end points . The study of adherence was not specified a priori as an ancillary study . Results : Of the 4880 patients ( 79.8 % ) with good adherence defined as > 80 % use of study medication  , 11.3 % died compared with 26.4 % of the 1232 patients ( 20.2 % ) with poor adherence .  The annual rates of hospital admission for exacerbations were 0.15 and 0.27 , respectively . The association between adherence and mortality remained unchanged and statistically significant after adjusting for other factors related to prognosis ( hazard ratio 0.40 ( 95 % CI 0.35 to 0.46 ) , p<0.001 ) . The association was even stronger when analysing on-treatment deaths only . Similarly , the association between adherence and hospital admission remained unchanged and significant in a multivariate analysis ( rate ratio 0.58 ( 95 % CI 0.44 to 0.73 , p<0.001 ) . The association between increased adherence and improved mortality and reduction in hospital admission was independent of study treatment . The effect of treatment was more pronounced in patients with good adherence than in those with poor adherence . Conclusion : Adherence to inhaled medication is significantly associated with reduced risk of death and admission to hospital due to exacerbations in COPD . Further research is needed to underst and these strong associations Clinical manifestations of chronic obstructive pulmonary disease ( COPD ) , including airflow limitation , dyspnea , and activity limitation , ultimately lead to impaired health-related quality of life ( HRQoL ) . This 9-month , r and omized , double-blind , multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL , spirometric parameters , and exacerbations in 554 patients with moderate-to-severe COPD .  HRQoL was assessed using the St. George ’s Respiratory Question naire ( SGRQ ) and the new 8-item Visual Simplified Respiratory Question naire ( VSRQ ) , which is currently being vali date d. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end ( Month 9 ) . Mean ± SD baseline SGRQ total score was 47.4 ± 18.1 . Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score  vs placebo at study end ( 59.1 % vs 48.2 % , respectively ;  p = 0.029 ) . Tiotropium  significantly improved spirometric parameters ( forced expiratory volume in 1 second [ FEV1 ] : 0.11 ± 0.02 L vs 0.01 ± 0.02 L ; between-group difference : 0.10 ± 0.03 L , p = 0.0001 ) and reduced exacerbations vs placebo . Maintenance treatment with tiotropium provided significant and clinical ly relevant improvements in HRQoL , as measured by the SGRQ The role of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease ( COPD ) is unclear . We investigated the effects of budesonide on airway hyperresponsiveness ( AHR ) to methacholine ( MCh ) and adenosine 5'-monophosphate ( AMP ) , to which we hypothesized the existence of greater sensitivity . Additionally , we studied the effects of budesonide on terfenadine  and ipratropium bromide  and on serum levels of interleukin-8 ( IL-8 ) and histamine .  Forty-four hyperresponsive smokers with moderate to severe COPD participated in the study .  MCh and AMP challenges were given on three study days , after pretreatment with single doses of ipratropium bromide , terfenadine , or placebo . Thereafter , subjects were r and omized to 6 wk treatment with either 1,600 microg budesonide or placebo , and the same three study days were repeated . Budesonide , as compared with placebo , did not significantly change PC20AMP , PC20MCh , or FEV1 after placebo pretreatment . Budesonide increased PC20MCh after ipratropium bromide  pretreatment , from 5.05 to 10.20 mg/ml ( p = 0.036 ) . Budesonide decreased serum IL-8 from 9.2 + /- 3.7 to 6.2 + /- 2.1 pg/ml ( p < 0.001 ) . We conclude that AMP did not elicit greater sensitivity than MCh in assessing short-term effects of budesonide on AHR in smokers with COPD . We suggest that long-term treatment with inhaled corticosteroids might be beneficial , by reducing neutrophil load in the airways and improving the action of anticholinergic drugs Inhaled corticosteroids are widely prescribed for the treatment of stable chronic obstructive pulmonary disease ( COPD ) , despite lack of proven efficacy . Because COPD involves airway inflammation and probable protease-antiprotease imbalance , we examined the effect of high dose fluticasone propionate on markers of activity of both pathogenetic mechanisms . Thirteen patients with COPD were treated with fluticasone propionate ( 500 microg twice a day ) for 4 wk , delivered via MDI and spacer , in a double-blind crossover study . There was no clinical benefit in terms of lung function or symptom scores , and induced sputum inflammatory cells , percentage neutrophils , and IL-8 levels were unchanged . Sputum supernatant elastase activity , matrix metalloproteinase (MMP)-1 , MMP-9 , and the antiproteases secretory leukoprotease inhibitor ( SLPI ) and tissue inhibitor of metalloproteinase (TIMP)-1 were similarly unaffected by treatment . These results add to previous evidence that inhaled steroids have no anti-inflammatory action in stable COPD . Furthermore , inhaled steroids do not appear to redress the protease-antiprotease imbalance that is thought to be important in the pathogenesis of airway obstruction Background The rate of decline in forced expiratory volume in 1 second ( FEV1 ) is representative of the natural history of COPD . Sparse information exists regarding the associations between the magnitude of annualised loss of FEV1 with other endpoints . Methods Retrospective analysis of UPLIFT ® trial ( four-year , r and omized , double-blind , placebo-controlled trial of tiotropium 18 μg daily in chronic obstructive pulmonary disease [ COPD ] , n = 5993 ) . Decline of FEV1 was analysed with r and om co-efficient regression . Patients were categorised according to quartiles based on the rate of decline ( RoD ) in  post-bronchodilator FEV1  . The St George 's Respiratory Question naire ( SGRQ ) total score , exacerbations and mortality were assessed within each quartile . Results Mean ( st and ard error [ SE ] ) post-bronchodilator FEV1 increased in the first quartile ( Q1 ) by 37 ( 1 ) mL/year . The other quartiles showed annualised declines in FEV1 ( mL/year ) as follows : Q2 = 24 ( 1 ) , Q3 = 59 ( 1 ) and Q4 = 125 ( 2 ) . Age , gender , respiratory medication use at baseline and SGRQ did not distinguish groups . The patient subgroup with the largest RoD had less severe lung disease at baseline and contained a higher proportion of current smokers . The percentage of patients with ≥ 1 exacerbation showed a minimal difference from the lowest to the largest RoD , but exacerbation rates increased with increasing RoD. The highest proportion of patients with ≥ 1 hospitalised exacerbation was in Q4 ( Q1 = 19.5 % [ tiotropium ] , 26 % [ control ] ; Q4 = 33.8 % [ tiotropium ] and 33.1 % [ control ] ) . Time to first exacerbation and hospitalised exacerbation was shorter with increasing RoD. Rate of decline in SGRQ increased in direct proportion to each quartile . The group with the largest RoD had the highest mortality . Conclusion Patients can be grouped into different RoD quartiles with the observation of different clinical outcomes indicating that specific ( or more aggressive ) approaches to management may be needed . Trial Registration Clinical Trials.gov number , 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 Clinical trials of tiotropium have principally recruited patients from secondary care with more severe chronic obstructive pulmonary disease ( COPD ) , and typically had included limitation of concomitant medication . In primary care , which is the most common setting for COPD management , many patients may have milder disease , and also may take a broad range of concomitant medication . Methods This r and omised , placebo-controlled , parallel-group , 12-week , 44-centre study investigated the efficacy ( trough forced expiratory volume in 1 second [ FEV1 ] response ) and safety of additional treatment with once-daily tiotropium 18 μg via the H and iHaler ® in a primary care COPD population ( tiotropium : N = 191 , FEV1 = 1.25 L [ 47.91 % predicted ] ; placebo : N = 183 , FEV1 = 1.32 L [ 49.86 % predicted ] ) . Secondary endpoints included : trough forced vital capacity ( FVC ) response , weekly use of rescue short-acting β-agonist , and exacerbation of COPD ( complex of respiratory symptoms/events of > 3 days in duration requiring a change in treatment ) . Treatment effects were determined using non-parametric analysis . Results At Week 12 , median improvement in trough FEV1 response  with tiotropium versus placebo was 0.06 L ( p = 0.0102 ) . The improvement was consistent across baseline treatment and COPD severity . Median improvement in FVC at 2 , 6 and 12 weeks was 0.12 L ( p < 0.001 ) . The percentage of patients with ≥1 exacerbation was reduced ( tiotropium 9.5 % ; placebo 17.9 % ; p = 0.0147 ) , independent of disease severity . Rescue medication usage was significantly reduced in the tiotropium  group compared with  placebo . Adverse event profile was consistent with previous studies . Conclusion Tiotropium provides additional benefits to usual primary care management in a representative COPD population .Trial registration The identifier is : NCT00274079 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 Background This study compared the effect of inhaled fluticasone propionate ( FP ) with the combination of salmeterol/fluticasone propionate ( SFC ) on lung function parameters in patients with mild asthma . Methods Adult patients with mild persistent asthma ( ≥ 80 % predicted FEV1 ) receiving 200–500 μg of BDP or equivalent were r and omised to receive either FP 100 μg or SFC 50/100 μg twice daily from a Diskus ® inhaler for four weeks . The primary outcome was the change from baseline in airway resistance ( sRaw ) at 12 hrs post dose measured by whole body plethysmography . Impulse oscillometry and spirometry were also performed . Results A comparison of the geometric mean sRaw at 12 hrs post dose in the SFC group to the FP group gave a ratio of 0.76 ( 0.66 – 0.89 , p < 0.001 ) at week 2 and 0.81 ( 0.71 – 0.94 , p = 0.006 ) at week 4 . Similarly , significant results in favour of SFC for oscillometry measurements of resistance and reactance were observed . FEV1 was also significantly superior at week 2 in the SFC group ( mean difference 0.16L , 95 % CI ; 0.03 – 0.28 , p = 0.015 ) , but not at week 4 ( mean difference 0.17L , 95 % CI -0.01 – 0.34 , p = 0.060 ) . ConclusionS FC is superior to  FP in reducing airway resistance in mild asthmatics with near normal FEV1 values . This study provides evidence that changes in pulmonary function in patients with mild asthma are detected more sensitively by plethysmography compared to spirometryTrial registration numberNCT00370591 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 The aim of this study was to investigate formoterol , an inhaled long-acting β2-agonist , in patients with chronic obstructive pulmonary disease ( COPD ) . Six-hundred and ninety-two COPD patients , mean baseline forced expiratory volume in one second ( FEV1 ) 54 % , FEV1/forced vital capacity 75 % of predicted , reversibility 6.4 % pred , were treated with formoterol ( 4.5 , 9 or 18 µg b.i.d . ) or placebo via Turbuhaler ® for 12 weeks . Symptoms were recorded daily . Spirometry and the incremental shuttle walking test ( SWT ) were performed at clinic visits . Compared with placebo , 18 µg b.i.d . formoterol reduced the mean total symptom score by 13 % and increased the percentage of nights without awakenings by 15 % . Formoterol ( 9 and 18 µg b.i.d . ) significantly reduced symptom scores for breathlessness ( −7 % and −9 % , respectively ) and chest tightness ( −11 % and −8 % , respectively ) , reduced the need for rescue medication ( −25 % and −18 % , respectively ) , and increased symptom-free days ( 71 % and 86 % , respectively ) . FEV1 improved significantly after all three doses of formoterol ( versus placebo ) . No differences were found between groups in SWT walking distance . No unexpected adverse events were seen . In conclusion , 9 and 18 µg b.i.d . formoterol reduced symptoms and increased the number of symptom-free days in a dose-dependent manner in chronic obstructive pulmonary disease patients .  Formoterol improved lung function at a dose of 4.5 µg b.i.d . and higher 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 Background This study evaluated the efficacy and safety of the long-acting β2-agonist formoterol in patients with moderate-to-severe COPD . Methods This double-blind , placebo-controlled , parallel-group , multinational phase III study r and omized patients ≥ 40 years of age with moderate-to-severe COPD to inhaled formoterol 4.5 or 9 μg twice daily ( bid ) via Turbuhaler ® or placebo for 12 weeks . Salbutamol 100 μg/actuation via pMDI was permitted as reliever medication . The primary outcome variable was change ( ratio ) from baseline to treatment period in FEV1 60-min post-dose . Results 613 patients received treatment ( formoterol 4.5 μg n = 206 ; 9 μg n = 199  ; placebo n = 208 ) ; 539 ( 87.9 % ) male ; 324 ( 52.9 % ) Japanese and 289 ( 47.1 % ) European . End of study increases in FEV1 60-min post-dose were significantly greater ( p < 0.001 for both ) with formoterol 4.5 and 9 μg bid ( 113 % of baseline for both ) than with placebo , as were all secondary outcome measures . The proportion of patients with an improvement in St George 's Respiratory Question naire score of ≥ 4 was 50.2 % for formoterol 4.5 μg ( p = 0.0682 vs. placebo ) , 59.2 % ( p = 0.0004 ) for 9 μg , and 41.3 % for  placebo . Reduction in reliever medication use was significantly greater with formoterol vs. placebo ( 9 μg : -0.548 , p < 0.001 ; 4.5 μg : -0.274 , p = 0.027 ) , with 9 μg being significantly superior to 4.5 μg ( -0.274 ,  p = 0.029 ) . Formoterol was well tolerated with the incidence and type of adverse events not being different for the three groups . Conclusions Formoterol 4.5 μg and 9 μg bid was effective and well tolerated in patients with COPD ; there was no difference between formoterol doses for the primary endpoint ; however , an added value of formoterol 9 μg over 4.5 μg bid was observed for some secondary endpoints . Trial registration NCT00628862 ( Clinical Trials.gov ) ; D5122C00001 ( AstraZeneca Study code ) A significant minority of patients with COPD have favorable response to corticosteroid treatment . In addition , the benefit of corticosteroid treatment may be outweighed by the side effects . Long-term administration of inhaled steroids is a safe means of treatment . We hypothesized that treatment with high-dose inhaled budesonide would improve clinical symptoms and pulmonary function in subjects with COPD , and that the response to inhaled beta 2-agonist will serve to individualize steroid responders . We compared a 6-week course of 800 micrograms/d inhaled budesonide with placebo , separated by 4 weeks when no medication was taken , in a double-blind crossover trial , in 8 patients responding to inhaled beta 2-agonist , and in 22 nonresponders with stable COPD . In six of eight " responders to beta 2-agonist , " there was a significant improvement in the FEV1 ( defined as > or = 20 % ) following inhaled budesonide , as compared with placebo . In the 22 " nonresponders to beta 2-agonist , " there was no significant improvement in the mean FEV1 ( 1.41 + /- 0.1 L before , and 1.61 + /- 0.1 L after treatment ) with inhaled budesonide or placebo . Over the 6-week course of treatment by either budesonide or placebo , the nonresponders reported similar beta 2-agonist consumption ( 4.8 + /- 0.2 and 5.0 + /- 0.1 puffs per patient per day , respectively ) . However , there was a significant difference between the two periods of treatment in the responders as for the mean daily number of beta 2-agonist inhalations ( 2.4 + /- 0.1 in the budesonide period as compared with 5.3 + /- 0.1 in the placebo period ; p < 0.005 ) . We conclude that treatment with inhaled steroids improved spirometry data and inhaled beta 2-agonist consumption in about 25 % of patients with stable COPD , and this rate is increased to about 75 % in patients who respond to beta 2-agonist inhalation Two , once daily ( q.d . ) inhaled bronchodilators are available for the treatment of chronic obstructive pulmonary disease ( COPD ): the & bgr;2-agonist indacaterol and the anticholinergic tiotropium . This blinded study compared the efficacy of these two agents and assessed their safety and tolerability . Patients with moderate-to-severe COPD were r and omised to treatment with indacaterol 150 μg q.d . ( n=797 ) or tiotropium 18 μg q.d . ( n=801 ) for 12 weeks . After 12 weeks , the two treatments had similar overall effects on “ trough ” ( 24 h post-dose ) forced expiratory volume in 1 s.  Indacaterol-treated patients had greater improvements in transition dyspnoea index ( TDI ) total score ( least squares means 2.01 versus 1.43 ; p<0.001 ) and St George ’s Respiratory Question naire ( SGRQ ) total score ( least squares means 37.1 versus 39.2 ; p<0.001 ; raw mean change from baseline -5.1 versus -3.0 ) , and were significantly more likely to achieve clinical ly relevant improvements in these end-points ( indacaterol versus tiotropium odds ratios of 1.49 for TDI and 1.43 for SGRQ , both p<0.001 ) . Adverse events were recorded for 39.7 % and 37.2 % of patients in the indacaterol and tiotropium treatment groups , respectively . The most frequent adverse events were COPD worsening , cough and nasopharyngitis . Both bronchodilators demonstrated spirometric efficacy . The two treatments were well tolerated with similar adverse event profiles . Compared with tiotropium , indacaterol provided significantly greater improvements in clinical outcomes The aim of the present study was investigate the long-term effect of tiotropium as first maintenance respiratory medication in chronic obstructive pulmonary disease ( COPD ) . A 4-yr , r and omised , multicentre , double-blind , parallel-group , placebo-controlled trial ( Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ® ) ) was conducted . Analysis focused on the effect of tiotropium versus matching placebo in the 810 ( 13.5 % ) COPD patients not on other maintenance treatment ( long-acting & bgr;-agonists , inhaled corticosteroids , theophyllines or anticholinergics ) at r and omisation .  Spirometry , health-related quality of life ( St George ’s Respiratory Question naire ( SGRQ ) score ) , exacerbations of COPD and mortality were also analysed . 403 patients ( mean±sd age 63±8 yrs , post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) 53±12 % predicted )  received tiotropium and 407 ( 64±8 yrs of age , post-bronchodilator FEV1 51±12 % pred ) received placebo . Post-bronchodilator FEV1 decline was 42±4 mL·yr−1 in the tiotropium group and 53±4 mL·yr−1 in the placebo group ( p = 0.026 ) . At 48 months , the morning pre-dose FEV1 was 134 mL higher in the tiotropium group compared to the placebo group ( p<0.001 ) . SGRQ total score declined more slowly in the tiotropium group ( difference of 1.05±0.34 units·yr−1 ; p = 0.002 ) . This was particularly significant for the impact ( difference of 1.08±0.37 units·yr−1 ; p = 0.004 ) and activity ( 1.44±0.40 units·yr−1 ; p<0.001 ) domains , but not for symptoms ( 0.26±0.50 units·yr−1 ; p = 0.6 ) . At 48 months , the difference in total score was 4.6 units ( p<0.001 ) with tiotropium compared to placebo . In patients with COPD who are not on maintenance therapy , tiotropium is associated with significant benefits in disease progression STUDY OBJECTIVES To examine and compare the efficacy and safety of salmeterol xinafoate , a long-acting inhaled beta2-adrenergic agonist , with inhaled ipratropium bromide and inhaled placebo in patients with COPD . DESIGN A stratified , r and omized , double-blind , double-dummy , placebo-controlled , parallel group clinical trial . SETTING Multiple sites at clinics and university medical centers throughout the United States . PATIENTS Four hundred eleven symptomatic patients with COPD with FEV1 < or = 65 % predicted and no clinical ly significant concurrent disease . INTERVENTIONS Comparison of inhaled salmeterol ( 42 microg twice daily ) , inhaled ipratropium bromide ( 36 microg four times a day ) , and inhaled placebo ( 2 puffs four times a day ) over 12 weeks . RESULTS Salmeterol xinafoate was significantly ( p < 0.0001 ) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial . Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo ; this improvement was associated with reduced use of supplemental albuterol . Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium ( p < 0.05 ) . Adverse effects were similar among the three treatments . CONCLUSIONS These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD The aim of this study was to compare the effects of formoterol , ipratropium bromide and a placebo on walking distance , lung function , symptoms and quality of life ( QoL ) in chronic obstructive pulmonary disease ( COPD ) patients . A total of 183 patients ( mean age 64 yrs , 86 female ) with moderate-to-severe nonreversible COPD participated in this r and omised , double-blind , parallel-group study . After a 2-week placebo run-in , patients were r and omised to formoterol Turbuhaler ® 18 μg b.i.d . ( delivered dose ) , ipratropium bromide 80 μg t.i.d . via a pressurised metered dose inhaler , or placebo for 12 weeks . Inhaled short-acting β2-agonists were allowed as relief medication and inhaled glucocorticosteroids were allowed at a constant dose . The primary variable was walking distance in the shuttle walking test ( SWT ) . Baseline mean SWT distance was 325 m , mean forced expiratory volume in one second ( FEV1 ) was 40 % predicted . Clinical ly significant improvements in SWT ( > 30 m ) were seen in 41 , 38 and 30 % of formoterol , ipratropium and placebo patients , respectively ( not significant ) . Mean increases from run-in were 19 , 17 and 5 m in the formoterol , ipratropium and placebo groups , respectively . Both active treatments significantly improved FEV1 , forced vital capacity , peak expiratory flow and daytime dyspnoea score compared with  placebo . Formoterol reduced relief medication use compared with placebo . Neither active treatment improved QoL. Formoterol and ipratropium improved airway function and symptoms , without significant improvements in the shuttle walking test Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease ( COPD ) necessitate multiple daily dosing . The present study evaluates the long-term safety and efficacy of tiotropium , a new once-daily anticholinergic in COPD . Patients with stable COPD ( age 65.2±8.7 yrs ( mean±sd ) , n=921 ) were enrolled in two identical r and omized double-blind placebo-controlled 1-yr studies . Patients inhaled tiotropium 18 µg or placebo ( mean screening forced expiratory volume in one second ( FEV1 ) 1.01 versus 0.99 L , 39.1 and 38.1 % of the predicted value ) once daily as a dry powder . The primary spirometric outcome was trough FEV1 ( i.e. FEV1 prior to dosing ) . Changes in dyspnoea were measured using the Transition Dyspnea Index , and health status with the disease-specific St. George 's Respiratory Question naire and the generic Short Form 36 . Medication use and adverse events were recorded . Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response ( ∼12 % over baseline ) ( p<0.01 ) and mean response during the 3 h following dosing ( ∼22 % over baseline ) ( p<0.001 ) over the 12-month period . Tiotropium recipients showed less dyspnoea ( p<0.001 ) , superior health status scores , and fewer COPD exacerbations and hospitalizations ( p<0.05 ) . Adverse events were comparable with placebo , except for dry mouth incidence ( tiotropium 16.0 % versus placebo 2.7 % , p<0.05 ) . Tiotropium is an effective , once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status . This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy 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 Introduction The BEACON study evaluated the efficacy and safety of QVA149 , a once-daily dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist ( LABA ) indacaterol and long-acting muscarinic antagonist ( LAMA ) glycopyrronium ( NVA237 ) , in development for the treatment of patients with chronic obstructive pulmonary disease ( COPD ) , compared with the free-dose concurrent administration of indacaterol plus glycopyrronium ( IND+GLY ) . Methods In this multicenter , double-blind , parallel group study , patients with stage II or stage III COPD ( Global initiative for chronic Obstructive Lung Disease [ GOLD ] 2010 ) were r and omized ( 1:1 ) to once-daily QVA149  ( 110 μg indacaterol/50 μg glycopyrronium ) or concurrent administration of indacaterol ( 150 μg ) and glycopyrronium ( 50 μg ) via the Breezhaler ® device ( Novartis AG , Basel , Switzerl and ) for 4 weeks . The primary endpoint was to evaluate the noninferiority of QVA149  as compared with concurrent administration of IND+GLY , for trough forced expiratory volume in 1 second ( FEV1 ) after 4 weeks of treatment . The other assessment s included FEV1 area under the curve from 0 to 4 hours ( AUC0–4 hours ) at day 1 and week 4 , symptom scores , rescue medication use , safety , and tolerability over the 4-week study period . Results Of 193 patients r and omized , 187 ( 96.9 % ) completed the study . Trough FEV1 at week 4 for QVA149 and IND+GLY was 1.46 L ± 0.02 and 1.46 L ± 0.18 , respectively . The FEV1 AUC0–4 hours at day 1 and week 4 were similar between the two treatment groups . Both treatment groups had a similar reduction in symptom scores and rescue medication use for the 4-week treatment period . Overall , 25.6 % of patients in QVA149 group and 25.2 % in the IND+GLY group experienced an adverse event , with the majority being mild-to-moderate in severity . No deaths were reported during the study or during the 30 days follow-up period . Conclusion The BEACON study demonstrated that once-daily QVA149 provides an efficacy and safety profile similar to the concurrent administration of its monocomponents indacaterol and glycopyrronium 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 We evaluated the effect of dual , longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease ( COPD ) . METHODS In this parallel-group study , 2224 patients ( aged ≥40 years , Global Initiative for Chronic Obstructive Lung Disease stages III-IV , and one or more moderate COPD exacerbation in the past year ) were r and omly assigned ( 1:1:1 ; via interactive voice response or web system ; stratified for smoking status ) to once-daily QVA149 ( fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg ) , glycopyrronium 50 μg , or tiotropium 18 μg for 64 weeks . Assignment to QVA149 and glycopyrronium was double-blind ; tiotropium was open-label . Efficacy was assessed in all patients r and omly assigned to treatment groups who received at least one dose of study drug ; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group . The primary objective was to show superiority  of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations ( defined by worsening symptoms and categorised by treatment requirements ) during treatment . This completed trial is registered at Clinical Trials.gov , NCT01120691 . FINDINGS Between April 27 , 2010 , and July 11 , 2012 , 741 patients were r and omly assigned to receive QVA149 , 741 to receive glycopyrronium , and 742 to receive tiotropium ( 729 , 739 , and 737 patients , respectively , analysed for efficacy ) . QVA149 significantly reduced the rate of moderate to severe exacerbations  versus glycopyrronium by 12 % ( annualised rate of exacerbations 0·84 [ 95 % CI 0·75 - 0·94 ] vs 0·95 [ 0·85 - 1·06 ] ; rate ratio 0·88 , 95 % CI 0·77 - 0·99 , p=0·038 ) . Adverse events ( including exacerbations ) were reported for 678 ( 93 % ) of 729 patients on QVA149 , 694 ( 94 % ) of 740 on glycopyrronium , and 686 ( 93 % ) of 737 on tiotropium . Incidence of serious adverse events was similar between groups ( 167 [ 23 % ] patients on QVA149 , 179 [ 24 % ] on glycopyrronium , and 165 [ 22 % ] on tiotropium ) ; COPD worsening was the most frequent serious adverse event ( 107 [ 15 % ] patients on QVA149 , 116 [ 16 % ] on glycopyrronium , 87 [ 12 % ] on tiotropium ) . INTERPRETATIONS The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium , with concomitant improvements in lung function and health status . These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD . FUNDING Novartis Pharma AG A double-blind cross-over trial was carried out on 83 sequential out- patients presenting with adult onset chronic airflow obstruction who were not clearly asthmatic . The study consisted of three treatment phases each lasting two weeks with a two week interval between each phase . The treatment phases were prednisolone 40 mg daily , beclomethasone dipropionate 500 ug three times a day and placebo , administered in a r and om order . FEV1 and FVC were measured at the end of each of the treatment phases and peak expiratory flow rate five times a day throughout . Over the study period 25 ( 30 % ) patients responded with an improvement of greater than or equal to 20 % in at least one of the parameters measured as compared with the best of either baseline or placebo measurements . A further eight patients were classified as partial responders with an improvement of greater than 15 % in any single parameter or greater than 10 % in any two parameters . A similar number responded to  beclomethasone  [ 15 ] as responded to prednisolone [ 16 ] . Only six patients , however , responded fully to both forms of steroid therapy . A number of patients responded to one form of steroid treatment only which was also comparable between the two groups ( prednisolone 10 , beclomethasone 9 ) . For full and partial responders mean improvement in FEV1 , FVC and PEFR was greater during the prednisolone phase than during the beclomethasone phase , however , the difference did not achieve statistical significance The effects of fluticasone propionate ( FP ) on sputum chemotactic activity , elastase inhibitory potential , albumin concentrations , and peripheral neutrophil function were studied in a group of patients with clinical ly stable , smoking-related chronic bronchitis and emphysema . Seventeen patients ( 50 to 75 yr of age ) were entered into a double-blind , placebo-controlled study of 1.5 mg inhaled FP/d for 8 wk . Following treatment with FP the chemotactic activity of the sputum sol phase was lower than the corresponding values for the placebo group ( p < 0.01 ) . Values fell from a mean of 21.75 ( + /- 1.58 ) during the run-in period to 18.37 ( + /- 1.46 ; p < 0.01 ) after 4 wk and 17.63 ( + /- 1.86 ; p < 0.05 ) after 8 wk treatment returning to 22.08 ( + /- 1.26 ) cell/field after the washout period . The neutrophil elastase inhibitory capacity of the sputum sol phase increased ( p < 0.025 ) with treatment from a mean of 0.177 microM elastase inhibited/L ( + /- 0.05 ) pretreatment to 0.413 microM ( + /- 0.054 ) after 4 wk and 0.415 microM ( + /- 0.054 ) after 8 wk returning to 0.270 microM ( + /- 0.07 ) after the washout period . Treatment with FP did not result in a change in the peripheral neutrophil functions studied or sputum albumin and myeloperoxidase concentrations . The results suggest that FP may play a protective role in these patients through a reduction in the chemotactic activity of lung secretions and potentially a reduction in the recruitment of neutrophils to the lung , and also by directly affecting the proteinase/antiproteinase balance , in favor of antiproteinases , within lung secretions BACKGROUND Indacaterol is a novel , inhaled , ultra-long-acting β(2)-agonist bronchodilator for maintenance use in patients with COPD . The aim of this paper is to assess the effect of indacaterol on dyspnoea and health status , using pooled study data to evaluate the relative efficacy of indacaterol and existing bronchodilators . METHODS Individual patient data were pooled from three r and omized , placebo-controlled studies ( NCT00393458 ; NCT00567996 ; NCT00463567 ) , conducted in patients with moderate-to-severe COPD . Treatments were double-blind indacaterol 150 μg ( n = 746 ) or 300 μg ( n = 853 ) once-daily , formoterol 12 μg twice-daily ( n = 556 ) , salmeterol 50 μg twice-daily ( n = 333 ) and placebo ( n = 1185 ) ; and open-label tiotropium 18 μg once-daily ( n = 415 ) . Evaluation after 6 months ' treatment was by transition dyspnoea index ( TDI ; minimum clinical ly important difference [ MCID ] ≥1 point ) , and St George 's Respiratory Question naire ( SGRQ ; MCID ≥4 units ) . RESULTS Differences from placebo in TDI total score were 1.01 ( indacaterol 150 μg ) 1.28 ( indacaterol 300 μg ) , 0.74 ( formoterol ) , 0.92 ( salmeterol ) and 0.88 ( tiotropium ) ( all p < 0.05 ) , with corresponding odds ratios versus placebo for exceeding the MCID from baseline of 1.91 , 2.69 , 2.02 , 1.79 and 1.49 ( all p < 0.05 ) . Differences versus placebo in SGRQ total score were -4.4 ( indacaterol 150 μg ) , -3.4 ( indacaterol 300 μg ) , -2.8 ( formoterol ) , -4.0 ( salmeterol ) and -1.7 ( tiotropium ) ( all p < 0.05 ) , with corresponding odds ratios versus placebo for exceeding the MCID of 1.95 , 1.63 , 1.54 , 1.82 and 1.29 ( all p < 0.05 apart from tiotropium ) . CONCLUSIONS Indacaterol provided clinical ly important improvements in dyspnoea and health status that were at least as good as and often better than those observed with existing bronchodilator treatments for COPD 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 OBJECTIVE To observe the efficacy of combination therapy with inhaled salmeterol/fluticasone and tiotropium in reducing the frequency of acute episodes of symptom exacerbation and improving lung function and health status in chronic obstructive pulmonary disease ( COPD ) . METHODS One hundred and twenty-six patients ( M/F : 92/34 ) with COPD were treated in a r and omised , parallel-group , controlled study with salmeterol/fluticasone ( 50/250 microg ) twice daily and tiotropium 18 microg once daily ( n = 33 , M/F : 23/10 ) ; salmeterol/fluticasone ( 50/250 microg ) twice daily ( n = 32 , M/F : 24/8 ) ; or tiotropium 18 microg once daily ( n = 32 , M/F : 23/9 ) for 12 months . Patients in the blank control group ( n = 29 , M/F : 22/7 ) did not receive any inhaled anticholinergic drugs , long-acting beta(2 ) agonists or glucocorticoid therapy . Intention-to-treat analysis ( n = 161 ) and per- protocol analysis ( n = 126 , age 45 - 71 years ) were performed . RESULTS Three active treatments significantly improved symptoms and health status . The use of rescue medication in the combination group [ 1 ( 0 - 7 ) time , 95 % CI ] was significantly decreased compared with those in the blank group [ 2 ( 0 - 29 ) times ] , salmeterol/fluticasone alone [ 2 ( 0 - 13 ) times ] , tiotropium alone [ 1 ( 0 - 11 ) time ] , F = 4.914 , P < 0.01 . The frequency of exacerbations in the combination group was ( 0.7 + /- 0.5 ) time , significantly lower than that in the blank group [ ( 1.5 + /- 0.9 ) times ] , salmeterol/fluticasone alone [ ( 1.2 + /- 0.6 ) times ] , and tiotropium alone [ ( 1.1 + /- 0.5 ) times ] , F = 8.513 , P < 0.01 . The FEV(1 ) in the combination group after the trial was ( 1.19 + /- 0.03 ) L , significantly improved compared to that before treatment ( 1.09 + /- 0.04 ) L , a 9.5 % increase , which was greater than the blank ( 0.9 % ) , tiotropium alone ( 8.2 % ) and salmeterol/fluticasone alone ( 6.3 % ) , t = -5.024 to -15.58 , P < 0.01 . CONCLUSION Combination therapy with salmeterol/fluticasone and tiotropium leads to better control of symptoms and improved lung function , with no greater risk of side-effects , as compared to salmeterol/fluticasone or tiotropium alone in the treatment of COPD The aim of these studies was to compare the efficacy and the safety of tiotropium , delivered via Respimat Soft Mist Inhaler ( SMI ) , a novel multi-dose , propellant-free inhaler , with ipratropium pressurized metered-dose inhaler ( pMDI ) in chronic obstructive pulmonary disease ( COPD ) patients . Two identical , 12-week , multi-national , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled studies were performed . COPD patients were r and omized to treatment with either inhaled tiotropium ( 5 or 10 microg ) via Respimat SMI administered once daily , ipratropium ( 36 microg ) pMDI QID or placebo . The primary endpoint was the mean trough forced expiratory volume in 1s ( FEV(1 ) ) response after 12 weeks of treatment . Secondary endpoints included other spirometry measures and rescue medication use .  A total of 719 patients were r and omized ; the majority were male ( 69 % ) with a mean pre-bronchodilator FEV(1 ) ( % predicted ) of 40.7 % . The mean treatment differences between tiotropium 5 and 10 microg and placebo for the primary endpoint ( mean trough FEV(1 ) response at week 12 ) were 0.118 and 0.149L , respectively ( both P<0.0001 ) . Treatment differences between tiotropium 5 and 10 microg and ipratropium were 0.064L ( P=0.006 ) and 0.095L ( P<0.0001 ) . The increases in peak FEV(1 ) , FEV(1 ) AUC((0 - 6h ) ) and FVC for both tiotropium doses were statistically superior to placebo ( P<0.01 ) and higher than ipratropium . All active treatments significantly reduced the rescue medication use compared with placebo , but only tiotropium 10 microg was statistically superior to ipratropium ( P=0.04 ) . The incidence of adverse events was comparable across groups . In conclusion , tiotropium 5 and 10 microg daily , delivered via Respimat SMI , significantly improved lung function compared with ipratropium pMDI and placebo 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 STUDY OBJECTIVES To compare the efficacy and safety of the inhaled corticosteroid fluticasone propionate ( FP ) and the inhaled long-acting beta(2)-agonist salmeterol ( SM ) , when administered together in a single device ( Diskus ; GlaxoSmithKline , Inc ; Research Triangle Park , NC ) , with that of placebo and the individual agents alone in patients with COPD . DESIGN R and omized , double-blind , multicenter , placebo-controlled study . SETTING Seventy-six investigative sites in the United States . PATIENTS Seven hundred twenty-three patients > or = 40 years of age with COPD and a mean baseline FEV(1 ) of 42 % predicted . INTERVENTIONS FP ( 250 microg ) , SM ( 50 microg ) , FP plus SM combined in a single inhaler ( FSC ) , or placebo administered twice daily through the Diskus device for 24 weeks . MEASUREMENTS Primary efficacy measures were morning predose ( ie , trough FEV(1 ) ) for FSC compared with SM and 2-h postdose FEV(1 ) for FSC compared with FP . Other efficacy measures were as follows : morning peak expiratory flow rate ( PEF ) ; transition dyspnea index ; chronic respiratory disease question naire ; chronic bronchitis symptom question naire ; exacerbations ; and other symptomatic measures . RESULTS At Endpoint ( ie , the last on-treatment , post-baseline assessment ) , treatment with FSC significantly ( p < or = 0.012 ) increased the morning predose FEV(1 ) ( 165 mL ) compared with SM ( 91 mL ) and placebo ( 1 mL ) , and significantly ( p < or = 0.001 ) increased the 2-h postdose FEV(1 ) ( 281 mL ) compared with FP ( 147 mL ) and placebo ( 58 mL ) . Improvements in lung function with FSC compared with FP and SM , and with FP and SM compared with placebo , as measured by the average daily morning PEF , was observed within approximately 24 h after the initiation of treatment , indicating an early onset of effect ( p < or = 0.034 ) . Compared with placebo , FSC significantly improved dyspnea , quality of life , and symptoms of chronic bronchitis . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and FP ) were similar among the treatment groups . CONCLUSIONS Treatment with FSC ( FP , 250 microg , and SM , 50 microg ) twice daily substantially improved morning lung function and sustained these improvements for over a period of 24 weeks compared with FP or SM treatment alone in patients with COPD , with no additional safety concerns for the combination treatment vs that with the individual components Beta-adrenergic stimulation may increase heart rate and the potential for cardiac arrhythmias . The effect of inhaled long-acting beta2-agonists ( LABAs ) on these outcomes was evaluated in patients with chronic obstructive pulmonary disease ( COPD ) in 2 double-blind r and omized clinical trials . The pretreatment arrhythmia occurrence frequency in these patients was also described . In this analysis , 24-hour Holter monitoring data were pooled from 2 identically design ed Phase III trials . Patients were r and omized to LABA treatment or placebo for 12 weeks : a ) nebulized arformoterol 15 & mgr;g BID , b ) 25 & mgr;g BID , or c ) 50 & mgr;g QD ; d ) salmeterol metered dose inhaler 42 & mgr;g BID ; or e ) placebo . The 24-hour Holter monitoring was performed pretreatment and at Weeks 0 ( first day of dosing ) , 6 , and 12 . We assessed the proportion of patients with each of 4 arrhythmias : atrial tachycardia , atrial fibrillation/flutter , and " nonsustained " ; ( 4 - 10 beats ) and " sustained " ; ( > 10 beats ) ventricular tachycardia . There were 5226 Holter recordings in 1429 treated patients . At baseline , there was a low frequency of occurrence of atrial fibrillation/flutter ( 0.1 % ) , nonsustained ventricular tachycardia ( 3.1 % ) , and > 10 beat ventricular tachycardia ( 0.3 % ) . Atrial tachycardia occurred frequently ( 41.8 % ) . The proportion of patients with treatment-emergent atrial tachycardia ranged from 27 % to 32 % and was non-significantly higher , by ∼2%-5 % ( p = 0.70 ) , in the LABA groups compared with the placebo group . The rates of the other more serious arrhythmias did not increase with LABA treatment and were similar to placebo . All treatment groups ( LABA and placebo ) had consistent small decreases from baseline in mean 24-hour and maximum hourly heart rate . In conclusion , in this large cohort of COPD patients with no or stable cardiac comorbidities , a high proportion ( ∼40 % ) of patients were observed to have atrial tachycardia before treatment , which increased by 2%-5 % with LABA treatment . More serious arrhythmias were infrequent and did not increase with inhaled LABA therapy . LABA administration did not increase mean heart rate . Abbreviations : bpm = beats per minute , CI = confidence interval , COPD = chronic obstructive pulmonary disease , FEV1 = forced expiratory volume in 1 second , FVC = forced vital capacity , ITT = intent-to-treat , LABA = long-acting beta2-agonist , MedDRA = Medical Dictionary for Regulatory BACKGROUND Indacaterol is an inhaled , long-acting β(2)-agonist providing 24-h bronchodilation with once-daily dosing in patients with COPD . METHODS Subjects with moderate to severe COPD who completed a 26-week , r and omized , double-blind study were eligible for enrollment in an extension , during which treatment with double-blind indacaterol , 150 or 300 μg once daily , or placebo was continued for a further 26 weeks . The primary objective was to evaluate the long-term safety of indacaterol  . Efficacy end points included trough ( 24 h postdose ) FEV(1 ) at 52 weeks , exacerbations , and health status ( St. George Respiratory Question naire [ SGRQ ] ) . RESULTS Four hundred fifteen subjects participated in the extension . Adverse events , mostly mild or moderate , occurred in 76 % , 77 % , and 68 % of subjects receiving indacaterol , 150 μg ; indacaterol , 300 μg ; and placebo , respectively . Serious adverse events occurred in 10.4 % , 12.3 % , and 10.5 % , respectively . Indacaterol had no clinical ly significant effects on ECG findings ( corrected QT interval ) or on serum potassium or plasma glucose levels  . Indacaterol  increased trough FEV(1 ) relative to placebo throughout the study ( difference of ≥ 170 mL at week 52 ) . No tolerance to its bronchodilator effect was detected . Indacaterol treatment was accompanied by significant reductions in COPD exacerbations ( rate ratios compared with placebo , 0.62 - 0.64 ; P < .05 ) and as-needed albuterol use ( 1.2 - 1.4 puffs/d decrease , P < .001 compared with placebo ) . Health status improved with indacaterol treatment , with decreases from baseline in mean total SGRQ score generally > 4 units . CONCLUSIONS During 1 year of treatment , indacaterol was well tolerated and provided significant and well-maintained bronchodilation that was accompanied by improved clinical outcomes . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00677807 ; URL : www . clinical trials.gov RATIONALE Indacaterol is the first once-daily , long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To demonstrate greater efficacy of indacaterol versus placebo on FEV(1 ) at 24 hours post dose ( trough ) after 12 weeks , to compare efficacy with placebo and tiotropium , and to evaluate safety and tolerability over 26 weeks . MEASUREMENTS Patients with moderate-to-severe COPD were r and omized to double-blind indacaterol 150 or 300 microg or placebo , or open-label tiotropium 18 microg , all once daily , for 26 weeks . The primary efficacy outcome was trough FEV(1 ) at 12 weeks . Additional analyses ( not adjusted for multiplicity ) included transition dyspnea index ( TDI ) , health status ( St George 's Respiratory Question naire [ SGRQ ] ) , and exacerbations . Serum potassium , blood glucose , and QTc interval were measured . RESULTS A total of 1,683 patients ( age , 63.3 yr ; post-bronchodilator FEV(1 ) , 56 % predicted ; FEV(1)/FVC , 0.53 ) were r and omized to the four treatment arms . Trough FEV(1 ) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium ( all P < 0.001 vs. placebo ) . At Week 26 , for indacaterol 150/300 microg , respectively , versus placebo , TDI increased ( 1.00/1.18 , P < 0.001 ) and SGRQ total score decreased ( -3.3/-2.4 , P < 0.01 ) ; corresponding results with tiotropium were 0.87 ( P < 0.001 ) for TDI and ( -1.0 , P = not significant ) for SGRQ total score . The incidence of adverse events , low serum potassium , high blood glucose , and prolonged QTc interval was similar across treatments . CONCLUSIONS Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD . Clinical trial registered with clinical trials.gov ( NCT 00463567 ) Although guidelines recommend combining long-acting bronchodilators in COPD , data are limited . We examined the clinical efficacy and safety of formoterol , tiotropium and the combination in patients with COPD . Eight hundred and forty-seven patients with COPD ( mean FEV(1 ) 52 % predicted ; FEV(1)/FVC 53 % ) were r and omized to receive one of the following four treatments for 24 weeks : formoterol 10 microg b.i.d . plus tiotropium 18 microg o.d . ; formoterol 10 microg b.i.d . ; tiotropium 18 microg o.d . , or placebo . The study was partially blinded ( formoterol and placebo ) . For the primary endpoint , FEV(1 ) 2h post-dose after 24 weeks , there were small differences in favour of the combination therapy versus formoterol ( 0.07 L , p=0.044 ) or tiotropium ( 0.06 L , p=0.066 ) . All three treatments were superior to placebo ( p<0.001 ) . The combination was statistically superior to monotherapy for : the primary endpoint ( p=0.044 vs. formoterol ) ; FEV(1 ) 5 min after the first dose ( p<0.001 ) and at 12 weeks ( p<0.05 vs. tiotropium ) ; and peak expiratory flow averaged over the first 6 weeks ( p<0.001 vs. both ) . The three active treatments were significantly more effective than placebo for secondary endpoints : COPD -related ' bad days ' , symptoms , use of rescue medication and peak expiratory flow , and aspects of health-related quality of life . The overall incidence of adverse events was similar with all active treatments , although COPD -related adverse events were more common with tiotropium . Combined bronchodilator therapy may be a valuable treatment option for patients with COPD 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 BACKGROUND There is still a lack of data on the seasonality of exacerbations of COPD based on large r and omized studies using COPD exacerbations as primary end points . The objective of this study was to assess the seasonal pattern of moderate and severe exacerbations and analyze the influence of associated baseline factors . We also determined the timing of second exacerbations and the potential impact of the 2009 influenza A(H1N1 ) p and emic on exacerbations . METHODS Analyses of exacerbation rates across treatment groups were adjusted for differing times on treatment by means of descriptive statistics based on the 1-year Prevention of Exacerbations with Tiotropium in COPD ( POET- COPD ) trial , in which exacerbations were the primary end point . RESULTS Of the 7,376 patients who were r and omized , a total of 4,411 exacerbations were reported in 2,691 patients .  Mean monthly exacerbation rates during winter were 2.16-fold higher than during summer , regardless of baseline characteristics ( age , sex , COPD severity , smoking status , BMI , inhaled corticosteroid use , cardiovascular comorbidity , concomitant cardiovascular medication ) . Second exacerbations after a previous event in October to March occurred 1 month earlier than during the warmer half of the season . The portion of exacerbation-related hospitalizations remained constant throughout the year . Most exacerbations were treated with antibiotics and reached a peak in the colder season . All-cause mortality showed a seasonal pattern similar to exacerbations . The 2009 A(H1N1 ) p and emic was not associated with an increase in exacerbation rates or deaths . CONCLUSIONS This analysis presented a marked impact of season on exacerbation outcomes , antibiotic treatment , timing of second exacerbations , and all-cause mortality We compared the effect of inhaled budesonide with placebo on decline in lung function and respiratory symptoms in a three-year study of patients with chronic obstructive pulmonary disease ( COPD ) . We used a parallel-group , r and omized , double-blind , placebo-controlled design , nested in an ongoing epidemiological survey . Patients were non-asthmatic subjects with a decreased ratio between forced expiratory volume in one second ( FEV1 ) and vital capacity ( VC ) ; i.e. , FEV1/VC < or = 0.7 . All included patients had an FEV1 which was irreversible to both inhaled terbutaline and prednisolone .  Two hundred and ninety patients were r and omized to receive either budesonide , 1200 mcg . daily for six months followed by 800 mcg . daily for 30 months , or placebo for 36 months . Patients had a mean age of 59 years and their mean FEV1 was 2.37 liters or 86 % of predicted .  Crude FEV1 declines were 41.8 ml/year in the placebo group and 45.1 ml/year in the budesonide group . Using a regression model in the intention-to-treat population , patients in the placebo group had an FEV1 decline of 49.1 ml/year in contrast to 46.0 ml/year in the budesonide group ; the estimated difference 3.1 ml/year ( 95 % confidence interval--12.8 - 19.0 ) was statistically insignificant , p = 0.70 . No effect of inhaled budesonide was seen on respiratory symptoms or number of exacerbations . These findings question the role of longterm inhaled corticosteroids in the treatment of mild-moderate COPD 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 . BACKGROUND The drug development process can be streamlined by combining the traditionally separate stages of dose-finding ( Phase IIb ) and confirmation of efficacy and safety ( Phase III ) using an adaptive seamless design . This approach was used in a clinical study of indacaterol , a novel once-daily ( od ) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD ( chronic obstructive pulmonary disease ) . METHODS The study comprised a dose-finding stage with dose selection after 14 days of treatment , and a second stage evaluating efficacy and safety during 26 weeks of treatment . The dose-finding stage included seven r and omized treatment arms : double-blind indacaterol 75 microg , 150 microg , 300 microg or 600 microg od , the beta(2)-adrenoceptor agonist formoterol 12 microg twice-daily or placebo , or the anticholinergic tiotropium 18 microg od open-label . An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician . The sponsor , investigators and patients remained blinded to the results . The indacaterol doses were selected using pre-set efficacy criteria for trough ( 24-h post-dose ) and early ( 1 - 4 h post-dose ) bronchodilator effect after 14 days , and all safety data . To qualify for selection , the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol , whichever was the highest value . Selected doses were continued into the second , 26-week stage . The two other indacaterol doses not selected , and formoterol , were discontinued following dose selection . RESULTS 801 patients with moderate-to-severe COPD were evaluated . Indacaterol 150 microg was the lowest effective dose , exceeding criteria for trough FEV(1 ) ( reference value 140 mL vs placebo ) and FEV(1 ) AUC(1 - 4 h ) ( reference value 220 mL vs placebo ) . No safety signal was observed with any dose of indacaterol . Thus , indacaterol 150 and 300 microg were selected to continue into the second , 26-week stage . CONCLUSION The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial 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 Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications . Initially , tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties . However , generally such observations have been reported in asthma . A 6-month r and omized , double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD .  Spirometry was measured over 12h at baseline and at days 15 , 57 , 116 and 169 . Changes over time from baseline were compared relative to changes observed with placebo .  A total of 623 patients participated ( tiotropium = 209 , salmeterol = 213 , placebo = 201 ) . The groups were similar in age ( mean = 65 years ) , gender ( 75 % men ) , and baseline FEV1 ( mean = 1.08 + /- 0.37l [ 40 + /- 12 % predicted ] ) . Relative to placebo , both active drugs improved morning pre-drug , peak and average FEV1 and FVC throughout the trial . However , from day 1 to 169 , salmeterol was associated with a higher decline in average FEV1 and FVC ( 0 - 12h ) ( difference from placebo : -36 and -115 ml , P < 0.05 ) , which was most prominent over the 8 - 12 h period ( difference from placebo : -45 and -138 ml , P < 0.01 ) . Significant declines in peak FVC relative to placebo ( -83 ml , P < 0.05 ) but not FEV1 ( -12ml ) were observed with salmeterol . Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial . In conclusion , tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics INTRODUCTION Use of maintenance bronchodilator therapy is currently recommended in symptomatic patients with Chronic obstructive pulmonary disease ( COPD ) and in those with Stage II or greater COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) . Because no prospect i ve data describe when rescue therapy alone is insufficient or the optimal time to start maintenance therapy , it is unclear whether maintenance therapy has benefits in milder disease . To explore potential benefits we asked : Does once-daily tiotropium improve lung function , health status , and /or symptoms in " undertreated " COPD patients ( i.e. , those who are not receiving maintenance bronchodilator therapy ) or patients considered by their health care providers as having milder disease ? METHODS A post-hoc analysis of data from COPD patients participating in two , 1-year , placebo-controlled trials with tiotropium  was performed . Patients were defined as " undertreated " if they received no respiratory medication or only as-needed short-acting beta-agonists prior to enrollment . Measures included serial spirometry , Transition Dyspnea Index ( TDI ) , and St. George 's Respiratory Question naire ( SGRQ ) . RESULTS Of 921 patients enrolled , 218 ( 23.7 % ) were " undertreated " : 130 received tiotropium ; 88 received placebo .  Demographics for the two treatment groups were comparable . Tiotropium-treated patients had significantly improved forced expiratory volume in 1s ( FEV1 ) and forced vital capacity ( FVC ) compared with patients using placebo on all study days . Additionally , TDI and SGRQ scores significantly improved with tiotropium compared with placebo . CONCLUSIONS Once-daily tiotropium provides significant improvement in lung function , health status , and dyspnea when used as maintenance therapy in undertreated COPD patients who were not previously receiving maintenance bronchodilator therapy BACKGROUND AND OBJECTIVE Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions . We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial . METHODS Subgroup analysis from a r and omized , double-blinded , placebo-controlled trial of tiotropium 18 µg daily in COPD . Primary end-point was rate of decline in FEV(1 ) . Secondary end-points included spirometry at individual time points , health-related quality of life ( St George 's Respiratory Question naire ) , exacerbations and mortality . RESULTS Of 5992 patients , 362 were from Asian centres ( 100 from Japan ) . Mean age 66 years , 95 % men , 13 % current smokers , BMI : 21 kg/m(2 ) ; post-bronchodilator FEV(1 ) : 44 % predicted ; St George 's Respiratory Question naire total score : 44 units . No treatment effect was observed for rate of decline in FEV(1 ) although annual decline was less in Asian patients . Morning pre-bronchodilator FEV(1 ) and forced vital capacity improved in Asian patients ( P < 0.05 ) . Tiotropium  reduced number of exacerbations ( rate ratio ( 95 % confidence interval ( CI ) ) : 0.73 ( 0.57 - 0.94 ) ) . Hazard ratios ( 95%CI ) for exacerbations and hospitalized exacerbations  ( tiotropium/control ) were 0.81 ( 0.62 - 1.05 ) and 0.85 ( 0.61 - 1.19 ) , respectively . St George 's Respiratory Question naire total score improved by 1.5 - 6.1 units ( P < 0.05 for months 18 , 24 , 30 and 36 ) with tiotropium . Fatal events occurred in 34 tiotropium ( 18.5 % ) and 42 control ( 23.6 % ) patients . CONCLUSIONS In COPD patients from Asia  , tiotropium  improves lung function , improves health-related quality of life and reduces exacerbations over 4 years of treatment 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 Rationale : Arformoterol , a single isomer long-acting β2-agonist , was developed as an inhalation solution for the maintenance treatment of bronchoconstriction in COPD . Methods : The pulmonary function efficacy of nebulized arformoterol ( 15 μ g BID , 25 μ g BID , 50 μ g QD ) and salmeterol MDI ( 42 μ g BID ) versus placebo was assessed in 1456 subjects ( mean FEV1 1.2L , mean predicted 41 % ) . Data were pooled from 2 identical , 12-week , double-blind , r and omized trials . The percent change in trough FEV1 , percent change in FEV1 average AUC(0 - 12 hrs ) and peak percent change FEV1 from predose were analyzed . Results : Improvement in trough FEV1 averaged over 12 weeks was greater for arformoterol and salmeterol versus placebo ( mean differences from placebo [ 95 % CI ] arformoterol–15 μ g BID : 11.4 % [ 8.4 , 14.3 ] ; 25 μ g BID : 15.4 % [ 12.2 , 18.6 ] ; 50 μ g QD : 10.9 % [ 7.9 , 13.9 ] ) ; salmeterol : ( 11.6 % [ 8.8 , 14.4 ] ) . Greater improvements versus placebo occurred after the first dose ( mean differences between arformoterol and placebo for trough FEV1 : 13–19 % ; FEV1 AUC(0 - 12 hrs ) : 19–24 % ; peak percent change : 20–25 % ) and at week 12 ( trough FEV1 : 10–13 % ; FEV1 AUC(0 - 12 hrs ) : 6–13 % ; peak percent change : 7–14 % ) ; all 95 % CIs excluded zero . Increases in FEV1 AUC(0 - 12 hrs ) and peak percent change were greater for arformoterol than for salmeterol ( 95 % CIs excluded zero ) . After 12 weeks , 78–87 % of arformoterol subjects had ≥ 10 % increases in FEV1 from pre-dose ( 56 % salmeterol , 44 % placebo ) ; the median time to response was 3–13 minutes ( 142 minutes salmeterol ) . Conclusions : In these trials , COPD subjects administered nebulized arformoterol demonstrated significant and sustained improvement in lung function over 12 weeks The objective of this study was to determine the costs and effects of combined bronchodilator and anti-inflammatory therapy . In a 2.5-yr r and omized controlled study , combined beta 2-agonist/corticosteroid therapy ( BA + CS ) and combined beta 2-agonist/anticholinergic therapy ( BA + AC ) were compared with beta 2-agonist/placebo therapy ( BA + PL ) . Included in the study were 274 patients 18 to 60 yr of age with moderately severe obstructive airways disease . The main clinical endpoints were lung function , hyperresponsiveness , restricted activity days , and symptom-free days . The economic endpoints were the costs of health care utilization . Compared with BA + PL , BA + CS led to significant improvements in FEV1 , PC20 , and symptom-free days . BA + AC did not differ from BA + PL in this respect . The respective annual acquisition costs of BA + CS , BA + AC , and BA + PL were 532 US$ , 277 US$ , and 156 US$ . Thus , BA + CS costs 376 US$ more than BA + PL . However , compared with BA + PL therapy , BA + CS led to statistically significant savings in other health care costs of about 175 US$ ( 95 % CI from 46 to 303 US$ ) . Thus , more than half of the additional costs of adding the inhaled corticosteroid are compensated for by a reduction in the costs of other health care services . Overall , inhaled corticosteroids lead to a small but net increase in health care costs of 201 US$ per patient per year . ( ABSTRACT TRUNCATED AT 250 WORDS RATIONALE Combination therapy with corticosteroid and long-acting β(2)-agonists ( LABA ) in a single inhaler is associated with superior effects on airway function and exercise performance in COPD compared with LABA monotherapy . The physiological effects of adding inhaled corticosteroid monotherapy to maintenance bronchodilator therapy ( long-acting anticholinergics and LABA singly or in combination ) in COPD are unknown . METHODS This was a r and omized , double-blind , placebo-controlled , crossover study ( NCT00387036 ) to compare the effects of inhaled fluticasone propionate 500 μg ( FP500 ) twice-daily and placebo ( PLA ) on airway function during rest and exercise , measured during constant work rate cycle exercise at 75 % of maximum incremental cycle work rate , in 17 patients with COPD ( FEV(1 ) ≤ 70 % predicted ) . RESULTS After treatment with FP500 compared to PLA , there were significant increases in post-dose measurements of FEV(1 ) ( + 115 mL , P = 0.006 ) and the FEV(1)/FVC ratio ( + 2.5 % , P = 0.017 ) , along with decreases in plethysmographic residual volume ( -0.32L ; P = 0.031 ) , functional residual capacity ( -0.30L , P = 0.033 ) , and total lung capacity ( -0.30L , P = 0.027 ) but no changes in vital capacity or inspiratory capacity ( IC ) . Post-treatment comparisons demonstrated a significant improvement in endurance time by 188 ± 362 s with FP500 ( P = 0.047 ) with no concomitant increase in dyspnea intensity . End-inspiratory and end-expiratory lung volumes were reduced at rest and throughout exercise with FP500 compared with PLA ( P < 0.05 ) . CONCLUSION Inhaled FP500 monotherapy was associated with consistent and clinical ly important improvements in FEV(1 ) , static lung volumes , dynamic operating lung volumes , and exercise endurance when added to established maintenance long-acting bronchodilator therapy in patients with moderate to severe COPD Inhaled corticosteroids are often used in the treatment of stable chronic obstructive pulmonary disease ( COPD ) , however , studies of these agents have had mixed results . Previous trials have often excluded subjects with bronchodilator response , have failed to evaluate effect on gas exchange , and have usually looked at only post- rather than prebronchodilator forced expiratory volume ( FEV ) . Our objective was to better assess the efficacy of topical corticosteroids in the treatment of COPD . We used a prospect i ve , r and omized , double-blinded , placebo-controlled , crossover study at the Outpatient Department , Department of Veterans Affairs Medical Center . Thirty-six COPD patients with a mean ( ± SD ) FEV1 of 1.10 ± 0.43 L , with or without significant bronchodilator response participated in the study . Subjects received a 3-month course of inhaled fluticasone propionate ( 220 mg/puff ) or identical-appearing placebo by metered-dose inhaler at 2 puffs twice daily , followed by crossover to the alternative inhaler for an additional 3 months . Fluticasone treatment result ed in a higher prebronchodilator FEV1 ( 1.17 ± 0.08 L [ mean ± SEM ] versus 1.07 ± 0.08 L , p = 0.001 ) , a higher PaO2 ( 66.6 ± 1.4 mmHg versus 63.6 ± 1 .6 mmHg , p = 0.002 ) , and a better dyspnea score on the chronic respiratory question naire ( 3.70 ± 0.18 versus 3.47 ± 0.19 , p = 0.03 ) . A trend towards fewer exacerbations  with fluticasone did not quite meet statistical significance ( p = 0.11 ) . Inhaled fluticasone over 3 months improved prebronchodilator airflow obstruction and oxygenation while decreasing dyspnea in moderate to severe COPD . Postbronchodilator FEV1 was not significantly changed Abstract GOLD stage II COPD encompasses patients with FEV1 50–80 % predicted . A published trials review suggested that benefits of maintenance therapy are limited to patients with FEV1 < 60 % predicted . We previously reported data demonstrating the efficacy of tiotropium in GOLD stage II disease in the 4-year UPLIFT ® trial , and present here a further analysis of a sub-category of GOLD stage II patients with post-bronchodilator FEV1 ≥60 % predicted from UPLIFT ® . Outcomes included pre- and post-bronchodilator spirometry , exacerbations , SGRQ and mortality . Of the 5,992 UPLIFT ® cohort , 1,210 ( 632 tiotropium , 578 control ) had baseline post-bronchodilator FEV1 ≥60 % predicted ( range 60–78 % ) , mean age was 64 years , 70 % were men , and mean SGRQ total score was 39.9 units .  Mean annual rate of post-bronchodilator FEV1 decline was 41 ( tiotropium ) and 49 ( control ) mL/year ( P = 0.07 ) ; corresponding pre-bronchodilator values were 32 and 37 mL/year ( P = 0.24 ) . Morning pre-drug FEV1 and FVC improvements for tiotropium versus control were 87–127 mL and 139–186 ml , respectively ( P < 0.001 , all time-points ) . SGRQ total score improvements ( tiotropium – control ) were 2.0–3.4 units ( P < 0.05 for all ) ; a higher percentage of patients had an improvement of ≥4 units with tiotropium ( P < 0.05 ) . Tiotropium reduced risk for an exacerbation ( HR [ 95 % CI ] = 0.83 [ 0.71 , 0.96 ] ) and mortality for the 4-year protocol -defined treatment period ( HR [ 95 % CI ] = 0.66 [ 0.45 , 0.96 ] ) . Tiotropium treatment provides clinical efficacy in patients with GOLD stage II disease with an FEV1 ≥60 % predicted , supporting current GOLD guidelines for COPD treatment . ( Clinical Trials.gov number NCT00144339 ) 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 BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) who smoke have a greater annual rate of decline in forced expiratory volume in 1 s ( FEV(1 ) ) than those patients who have stopped smoking . OBJECTIVES To assess the effect of tiotropium on pre-dose ( trough ) FEV(1 ) in patients with COPD followed in Canada . METHODS A total of 913 patients were r and omly assigned to receive either tiotropium 18 mug once daily ( n=608 ) or placebo ( usual care minus inhaled anticholinergics ) ( n=305 ) for 48 weeks in the present r and omized , double-blind , parallel-group study . The effect of tiotropium on measurements of lung function ( FEV(1 ) , FEV(6 ) and forced vital capacity ) , symptoms , health-related quality of life ( St George 's Respiratory Question naire ) and exacerbations were examined . RESULTS Tiotropium improved trough FEV(1 ) in both current and ex-smokers compared with placebo .  Baseline FEV(1 ) in smokers and ex-smokers was 1.03 L and 0.93 L , respectively ( P<0.001 ) . At week 48 , the mean difference between the tiotropium and placebo groups was 0.14+/-0.04 L ( P<0.001 ) in the smoker group and 0.08+/-0.02 L ( P<0.0001 ) in the ex-smoker group . Tiotropium also significantly improved trough forced vital capacity and FEV(6 ) compared with placebo throughout the treatment period ( P<0.05 , for all ) . Furthermore , tiotropium significantly improved the St George 's Respiratory Question naire total score compared with placebo at week 48 ( 40.9 versus 43.7 units , P<0.005 ) . CONCLUSIONS Compared with the placebo group , tiotropium provides sustained improvements in lung function in patients with COPD , with improvements for smokers and ex-smokers Formoterol is a long-acting beta2-agonist with a rapid onset of effect in patients with chronic obstructive pulmonary disease ( COPD ) , making it potentially suitable for both maintenance and as-needed bronchodilator treatment . To evaluate the efficacy and tolerability of maintenance formoterol in patients with COPD and to compare the effects of additional formoterol as needed with terbutaline . In this 6-month , double-blind study , 657 patients with COPD ( 40 years , forced expiratory volume in 1s [ FEV1 ] 40 - 70 % predicted normal ) were r and omized to formoterol 9 microg twice daily ( bid ) plus terbutaline 0.5 mg as needed ( FORM bid ) , formoterol 9 microg bid plus formoterol 4.5 microg as needed ( FORM bid+prn ) , or placebo bid plus terbutaline 0.5 mg as needed ( placebo ) , all administered via Turbuhaler . Primary efficacy variables were FEV1 and the sum of breathlessness and chest tightness scores combined symptom score . Formoterol significantly ( P<0.01 ) increased FEV(1 ) compared with placebo : FORM bid 6.5 % ( 95 % CI : 2.5 , 10.7 % ) ; FORM bid+prn 11.8 % ( 95 % CI : 7.7 , 16.2 % ) . Combined symptom score decreased significantly in both formoterol groups compared with placebo : FORM bid -0.27 ( 95 % CI : -0.49 , -0.06 ; P=0.012 ) ; FORM bid+prn -0.32 ( 95 % CI : -0.53 , -0.11 ; P=0.0026 ) . Similar significant ( P<0.05 ) improvements were seen in both formoterol groups for morning peak expiratory flow , cough and sleep scores , and reliever use . In this study , formoterol 9 microg bid via Turbuhaler as maintenance therapy , with either formoterol or terbutaline as rescue medication , provided sustained improvements in lung function and COPD symptoms . Both formoterol regimens were well tolerated with no differences in adverse events or electrocardiogram profiles BACKGROUND Pneumonia is an important complication of COPD and is reported more often in patients receiving inhaled corticosteroids ( ICSs ) . Little is known about the clinical course and factors predisposing to pneumonia in patients with COPD . We investigated patient characteristics and symptoms occurring before pneumonia reports in the Investigating New St and ards for Prophylaxis in Reduction of Exacerbations ( INSPIRE ) study . METHODS This was a 2-year , double-blind , double-dummy parallel study of 1,323 patients r and omized to salmeterol/fluticasone propionate 50/500 μg bid ( SFC ) or tiotropium 18 μg once daily ( Tio ) . Baseline demographics , including serum C-reactive protein ( CRP ) levels , were measured , and daily record cards ( DRCs ) were completed . RESULTS We identified 87 pneumonia reports from adverse event records ( SFC=62 ; Tio=25 ) in 74 patients ( SFC=50 ; Tio=24 ) , compared with 2,255 exacerbations ( SFC=1,185 ; Tio=1,070 ) . Pneumonia was more common in patients with severe dyspnea and in those with a baseline CRP level>10 mg/L. Numbers of de novo pneumonias ( events that were not preceded by symptoms of an exacerbation ) were similar between treatment groups , but pneumonia was more likely after either a treated or untreated unresolved exacerbation in patients receiving ICSs ( SFC=32 ; Tio=7 ) . Similar results were seen when analysis was confined to radiologically confirmed events . CONCLUSIONS Pneumonia is much less frequent than exacerbation in COPD . The excess of events with ICS treatment appears to be associated with protracted symptomatic exacerbations . Earlier identification and treatment of these events to prevent pneumonia merits further investigation . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00361959 ; Study No. : SC040036 ; URL : clinical trials.gov 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 BACKGROUND The Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) recommends long-acting bronchodilators as first-line maintenance treatment for patients with chronic obstructive pulmonary disease ( COPD ) . A study was conducted comparing the long-acting anticholinergic tiotropium with the long-acting beta-agonist salmeterol to confirm the significant improvements in daytime bronchodilator efficacy seen with tiotropium in previous studies . METHODS R and omized , double-blind , double-dummy , parallel-group study , comparing daytime bronchodilator efficacy of tiotropium 18 mcg once daily with salmeterol 50 mcg twice daily in patients with COPD . Serial spirometry was performed over 12 h after 12 weeks of treatment . Co- primary endpoints were average ( over 12 h ) and peak FEV1 at 12 weeks . RESULTS 653 patients were r and omized ( 328 tiotropium , 325 salmeterol ) : mean age 64 years ; 66 % male ; mean baseline FEV1 1.05 l ( 37.7 % predicted ) . After 12 weeks , the average post-dose FEV1 over 12 h was significantly higher with tiotropium compared with salmeterol ( 167 vs. 130 mL , respectively , p=0.03 ) , as was peak FEV1 ( 262 vs. 216 ml , respectively , p=0.01 ) . The average FEV1 responses from 0 - 6 h and 6 - 12 h were higher in the tiotropium group compared with salmeterol ( p<0.05 ) . Peak and average FVC were significantly higher with tiotropium compared with salmeterol ( p<0.01 ) . Morning pre-dose FEV1 responses were not significantly different ; however , tiotropium demonstrated a significantly higher pre-dose FVC than salmeterol ( p<0.05 ) . CONCLUSION Tiotropium demonstrated significantly greater post-dose improvements in spirometric parameters compared with salmeterol . These improvements were sustained over 12 Bronchodilators , including long-acting β2-adrenoceptor agonists and anticholinergic bronchodilators , are effective in the treatment of chronic obstructive pulmonary disease . Evidence suggests that the addition of a long-acting β2-agonist to an inhaled corticosteroid is associated with a reduced rate of exacerbations compared with either treatment alone or placebo . However , it is not known whether a long-acting β2-agonist/inhaled corticosteroid combination is more effective than an anticholinergic bronchodilator alone in reducing exacerbations . The Investigating New St and ards for Prophylaxis In Reduction of Exacerbations ( INSPIRE ) trial will study salmeterol ( a long-acting β2-agonist ) in combination with fluticasone propionate ( an inhaled corticosteroid ) compared with tiotropium bromide ( an anticholinergic bronchodilator ) in patients with moderate-to-severe chronic obstructive pulmonary disease . The INSPIRE study is a multicentre , r and omised , double-blind , double dummy , parallel group study conducted over 104 weeks . This is the first study to use two parallel definitions of an exacerbation ; an event-based exacerbation is defined as one that requires use of healthcare re sources , including additional treatment and hospitalization , whereas a symptom-based exacerbation is defined as one that satisfies the 1987 Anthonisen criteria . It is also the first study to compare the long-term effects of salmeterol/fluticasone propionate with tiotropium bromide on the rate of event-based exacerbations . Endpoints include rate of exacerbations ( primary endpoint ) , time to first exacerbation , and duration of exacerbations . Health outcomes will be assessed via the St George 's Respiratory Question naire . If the innovative methodology of utilizing 2 definitions of exacerbation proves successful , it will set the benchmark for future studies in chronic obstructive pulmonary disease 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 Systemic inflammation is present in chronic obstructive pulmonary disease ( COPD ) , which has been linked to cardiovascular morbidity and mortality . We determined the effects of oral and inhaled corticosteroids on serum markers of inflammation in patients with stable COPD . We recruited 41 patients with mild to moderate COPD . After 4 weeks during which inhaled corticosteroids were discontinued , patients were assigned to fluticasone ( 500 mcg twice a day ) , oral prednisone ( 30 mg/day ) , or placebo over 2 weeks , followed by 8 weeks of fluticasone at 500 mcg twice a day and another 8 weeks at 1,000 mcg twice a day . Withdrawal of inhaled corticosteroids increased baseline C-reactive protein ( CRP ) levels by 71 % ( 95 % confidence interval [ CI ] , 16 - 152 % ) . Two weeks with inhaled fluticasone reduced CRP levels by 50 % ( 95 % CI , 9 - 73 % ) ; prednisone reduced it by 63 % ( 95 % CI , 29 - 81 % ) . No significant changes were observed with the placebo . An additional 8 weeks of fluticasone were associated with CRP levels that were lower than those at baseline ( a 29 % reduction ; 95 % CI , 7 - 46 % ) . Inhaled and oral corticosteroids are effective in reducing serum CRP levels in patients with COPD and suggest their potential use for improving cardiovascular outcomes in 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 BACKGROUND : Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease . We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide . METHODS : Ten non-allergic subjects with stable disease were investigated ; eight completed the r and omised , double blind , three period cross over study . Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks , 40 mg oral prednisone a day for eight days , and placebo . After each period cumulative doubling doses of salbutamol , ipratropium , a combination of salbutamol and ipratropium , and placebo were administered on separate days until a plateau in FEV1 was reached . A histamine challenge was then performed . RESULTS : At the end of placebo treatment mean FEV1 was 55.5 % predicted after inhaled placebo , 67.9 % predicted after salbutamol and 64.0 % predicted after ipratropium . Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7 % predicted after treatment with budesonide and by 0.7 % predicted after treatment with prednisone ; the FEV1 with ipratropium  increased by 0.7 % predicted after budesonide and by 4.8 % predicted after prednisone ; none of these changes was significant . After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo , 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium . Compared with the placebo period the PC20 with  salbutamol  was increased by 0.86 doubling concentrations after treatment with budesonide , and by 0.67 doubling concentrations after prednisone ; the PC20 with ipratropium  increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo ; none of these changes was significant . CONCLUSIONS : In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine . Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery , particularly for COPD patients unable to use h and -held devices easily or correctly . The long-acting beta2-agonist , formoterol fumarate , is differentiated by its onset of significant bronchodilation within 5 min of administration . In a r and omized , double-blind , double-dummy trial , COPD subjects ( n=351 , mean forced expiratory volume FEV1=1.3 L , 44 % predicted ) received nebulized formoterol fumarate ( Perforomist inhalation solution ; FFIS 20 microg ) or DPI ( Foradil Aerolizer ; FA 12 microg ) , or placebo twice daily for 12 weeks . Efficacy was assessed with 12-h pulmonary function tests , and quality of life was assessed before and after treatment with the St. George 's Respiratory Question naire ( SGRQ ) . At the 12-week endpoint , FFIS significantly increased FEV1 AUC0 - 12h relative to placebo ( p<0.0001 ) . No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment . FFIS also significantly increased peak FEV1 , trough FEV1 , and st and ardized FVC AUC0 - 12h compared with placebo . SGRQ assessment at Week 12 demonstrated significant and clinical ly meaningful improvements in total score ( FFIS vs placebo , -4.9 , p=0.0067 ) , symptom , and impact scores . No significant differences in efficacy were observed between the two active treatments . Drug related AEs in the FFIS arm with a frequency > or = 1 % and exceeding placebo were dry mouth , nausea , and insomnia . Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated . The efficacy and safety profile of FFIS was comparable to FA DPI 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 Abstract Objective : To evaluate the efficacy and safety of budesonide (BUD)/formoterol ( FORM ) compared with BUD , both administered by way of a dry powder inhaler ( Turbuhaler * ) . * Turbuhaler is a registered trade name of AstraZeneca , Södertälje , Sweden . Methods : This was a 6-month , multicenter , r and omized , parallel-group , double-blind , double-dummy design study ( NCT 00421122 ) . Patients were r and omized to either BUD/FORM 160/4.5 μg , two inhalations twice daily , or BUD 200 μg , two inhalations twice daily .  Improvement of lung function , daily symptoms , reliever use and health-related quality -of-life ( St George ’s Respiratory Question naire [ SGRQ ] score ) were compared between the two treatment groups . Results : A total of 308 patients with moderate to very severe COPD from 12 centers in China were r and omized to BUD/FORM ( n = 156 ) or BUD ( n = 152 ) . The primary endpoint , 1-hour post-dose forced expiratory volume in 1 second ( FEV1 ) , in the BUD/FORM group improved by 0.18 L ( from 0.83 L at baseline to 1.01 L ) and this was significantly better ( p < 0.001 ) than the small increase ( 0.03 L ) observed in the BUD group after 24 weeks ’ treatment . Increases in pre-dose and 15-min post-dose FEV1 together with 1-hour post-dose forced vital capacity were also significantly larger with BUD/FORM than BUD ( p < 0.001 for all ) . Compared with BUD alone , BUD/FORM improved COPD total symptom scores ( −1.04 ± 0.16 vs. −0.55 ± 0.17 ; p = 0.03 ) , reduced reliever use ( −0.85 ± 0.16 puffs/day vs. −0.31 ± 0.16 puffs/day ; p = 0.012 ) and improved health-related quality -of-life ( mean change of total SGRQ score −4.5 points ( p = 0.0182 ) . Overall , both treatments were well tolerated . Conclusions : In Chinese patients with moderate to very severe COPD , fixed combination treatment with BUD/FORM result ed in clinical ly meaningful improvements in lung function , health-related quality -of-life , COPD symptoms and a reduction in  reliever use , compared with BUD alone and both treatments were well tolerated . Treatment of BUD/FORM for milder patients with COPD and head to head comparison of Chinese and Caucasians in future studies will be helpful to exp and upon the findings of the current clinical trial The objective of this study was to investigate the effect of tiotropium compared with salmeterol on exacerbations in patients with moderate ( Global Initiative for Chronic Obstructive Lung Disease [ GOLD ] stage II ) chronic obstructive pulmonary disease ( COPD ) and those naïve to maintenance respiratory therapy  in the 1-year Prevention Of Exacerbations with Tiotropium in COPD ( POET- COPD ( ® ) ) trial ( NCT00563381 ) . Time to first exacerbation ( primary endpoint ) and rates of exacerbations were analyzed using exploratory Cox and Poisson regression ( adjusting for time on treatment ) . Of 7376 r and omized patients , 3614 were GOLD stage II ( tiotropium n = 1781 ;  salmeterol n = 1833 ) and 1343 were maintenance therapy naïve ( tiotropium  n = 672 ; salmeterol n = 671 )  . Tiotropium significantly increased time to first exacerbation vs. salmeterol in GOLD stage II patients ( hazard ratio [ HR ] , 0.88 ; 95 % confidence interval [ CI ] : 0.79 - 0.99 ; p = 0.028 ) and maintenance therapy naïve patients ( HR , 0.79 ; 95 % CI , 0.65 - 0.97 ; p = 0.028 ) . Annual exacerbation rates were also significantly lower with tiotropium in the maintenance naïve subgroup compared with salmeterol ( rate ratio [ RR ] , 0.77 ; 95 % CI , 0.63 - 0.94 ; p = 0.012 ) . In the GOLD stage II subgroup , the rate of hospitalized exacerbations per year was significantly lower with tiotropium than with salmeterol ( RR , 0.70 ; 95 % CI , 0.57 - 0.85 ; p < 0.001 ) ; tiotropium also significantly prolonged time to first hospitalized exacerbation  versus salmeterol in this subgroup ( HR , 0.66 ; 95 % CI , 0.48 - 0.91 ; p = 0.012 ) . In conclusion , results from this prespecified subgroup analysis support the selection of tiotropium as first-choice maintenance therapy for patients with GOLD stage II COPD This dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol , a novel once-daily inhaled beta2-agonist , in subjects clinical ly diagnosed with COPD . Comparative data with tiotropium were collected . In the double-blind , core period of the study , 635 subjects with COPD ( prebronchodilator FEV(1)40 % of predicted and > or = 1.0L ; FEV1/FVC < 70 % ) were r and omized to receive indacaterol 50 , 100 , 200 or 400microg or placebo via multi-dose dry powder inhaler , or indacaterol 400microg via single-dose dry powder inhaler , once daily for 7 days . After completing double-blind treatment and washout , a subset of subjects from each treatment group entered an open-label extension and received tiotropium 18microg once daily for 8 days . The primary efficacy variable was the trough bronchodilator effect : st and ardized area under the FEV1 curve between 22 and 24h post-dose ( FEV1 AUC(22 - 24h ) ) on Day 1 . Clinical ly relevant improvements versus placebo in FEV1 AUC(22 - 24h ) were seen for 400 and 200microg doses on Day 1 and all doses on Day 7 . All indacaterol doses significantly ( P<0.05 ) increased FEV1 from 5min to 24h post-dose ; the 400 and 200microg doses were most effective . All doses were well tolerated . Indacaterol trough FEV1 levels compared favorably with the improvement seen by Day 8 in subjects treated with tiotropium in the open-label extension . The results confirm that indacaterol has a 24-h duration of bronchodilator effect and a fast onset of action in COPD and suggest that indacaterol could be an effective once-daily inhaled beta2-agonist bronchodilator . Indacaterol demonstrated a good overall safety and tolerability profile Inhaled glucocorticosteroids ( ICS ) are commonly prescribed for chronic obstructive pulmonary disease . No adverse effect on bone mineral density ( BMD ) has been proven . In a r and omized double-blind , placebo-controlled trial at seven centers in North America , we recruited 412 current smokers or recent quitters with mild to moderate chronic obstructive pulmonary disease . They used inhaled triamcinolone acetonide , 600 mcg , or placebo , twice daily . We measured femoral neck and lumbar spine BMD at baseline and after 1 and 3 years , and serum osteocalcin at baseline , 3 months , 1 year , and 3 years . After 3 years , BMD at the femoral neck decreased 1.78 % more with ICS than with placebo ( p < 0.001 ) . More participants in the ICS group experienced 6 % or more loss of femoral neck BMD ( p = 0.002 ) . Lumbar spine BMD increased in the placebo group by 0.98 % but decreased by 0.35 % in the ICS group ( a difference of 1.33 % , p = 0.007 ) . Changes in osteocalcin did not correlate with changes in BMD . Fractures , lost height , or osteoporosis diagnoses were not increased among ICS users compared with placebo users . In summary , the use of inhaled triamcinolone acetonide was associated with loss of BMD at the femoral neck and lumbar spine after 3 years of treatment 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 The r and omized , double-blind trial UPLIFT ® demonstrated in 5,993 patients with moderate to very severe COPD that 4 years of tiotropium bromide therapy were associated with improvements in lung function , exacerbations , quality of life , and mortality compared with placebo . The pharmacoeconomic evaluation was performed through a probabilistic , patient-level simulation Markov model . Routine COPD care ( RC ) was compared with the inclusion of tiotropium bromide on it . The analysis was conducted over a lifetime horizon , with 1 year cycles and a 3.5 % annual discount rate . Patients were characterized by gender , age , height , smoking status , and forced expiratory volume in 1 s ( FEV1 ) . FEV1 time trend was modeled according to the annual decline recorded in UPLIFT ® . Mortality derived from that of the general Italian population was adjusted by smoking status and FEV1 . Health utilities derived from published Italian observational studies and were varied in time according to UPLIFT ® data . Exacerbation rates were derived from a published Italian observational prospect i ve study . The cost perspective was that of the Italian National Health Service . Healthcare re source consumption for RC and exacerbations derived from Italian observational studies were valued according to current price and tariffs . Simulated patients in the tiotropium arm gained an average ( 95 % CI ) 0.50 ( −1.63 to 6.27 ) Life Years ( LYs ) and 0.42 ( −0.25 to 3.05 ) Quality -Adjusted Life Years ( QALYs ) . The incremental lifetime cost result ed € 3,357 ( −€10,669 to € 29,820 ) . The incremental cost-effectiveness ratio ( ICER ) was € 6,698/LY and € 7,916/QALY . In the cost-effectiveness acceptability curve ( CEAC )  , tiotropium had a 90 % probability of being cost-effective for a willingness to pay ( WTP ) threshold of € 10,000/QALY Background : Chronic obstructive pulmonary disease ( COPD ) is characterized by airflow limitation , which results in the progressive development of dyspnea and exercise limitation . Objective and Methods : To compare the effect of tiotropium with placebo on forced vital capacity ( FVC ) in patients with moderate-to-severe COPD and lung hyperinflation , using exercise endurance , dyspnea and health-related quality of life ( HRQoL ) as secondary endpoints . One hundred patients were r and omized to receive either tiotropium 18 µg once daily or placebo for 12 weeks . Results : Trough ( predose ) FVC was significantly improved with tiotropium compared to placebo on day 42 ( 0.27 ± 0.08 liters ) and 84 ( 0.20 ± 0.08 liters ; p < 0.05 for both ) . Trough inspiratory capacity ( IC ) was also significantly improved with tiotropium compared to placebo on day 42 ( 0.16 ± 0.07 liters ) and 84 ( 0.15 ± 0.07 liters ; p < 0.05 for both ) . Tiotropium increased the mean distance walked during the shuttle walking test by 33 ± 12 ( day 42 ) and 36 ± 14 m ( day 84 ) compared to placebo ( p < 0.05 for both ) . On day 84 , 59 % of the patients in the tiotropium group and 35 % of the patients in the placebo group had significant and clinical ly meaningful improvements in the St. George ’s Respiratory Question naire total score ( p < 0.05 ) . Numerical decreases in the focal score in the Transition Dyspnea Index in patients receiving tiotropium versus placebo suggest that tiotropium also improved dyspnea during activities of daily living . Conclusion : Tiotropium 18 µg once daily reduced hyperinflation with consequent improvements in walking distance and HRQoL in patients with COPD and lung hyperinflation There is controversy about the role of inhaled corticosteroids in chronic obstructive pulmonary disease ( COPD ) . Although they appear to have little impact on airways obstruction or its progression , their use may reduce the frequency and /or severity of exacerbations in a subset of patients . We undertook the following study to determine the impact of inhaled corticosteroid on two noninvasive markers of airways inflammation . We assigned 20 stable nonsmoking patients with COPD in r and om , double-blind crossover fashion to two 2-wk treatment periods with inhaled beclomethasone 500 microg twice daily or matching placebo , followed by a 2-wk washout period . We measured exhaled nitric oxide ( ENO ) , breath condensate H(2)O(2 ) , and flow volume spirometry at weekly intervals . Median baseline ENO was 26.2 ( 19.3 to 54.8 ) ppb and fell significantly following 1 and 2 wk of beclomethasone ( -10.6 ppb , p = 0.002 , and -6.3 ppb , p = 0.013 , respectively ) but was unchanged by placebo inhalation . Breath condensate H(2)O(2 ) levels did not change significantly with inhaled beclomethasone or placebo . Although there were no significant changes in FEV(1 ) with BDP therapy , there was a moderate inverse correlation between changes in ENO and changes in FEV(1 ) ( r -0.50 ) . We conclude that inhaled beclomethasone reduces ENO levels in stable nonsmoking patients with COPD , a finding compatible with an antiinflammatory mechanism of action BACKGROUND Aim of this study was to evaluate the efficacy of inhaled Tiotropium bromide in COPD patients of different severities in pneumological practice s during a three months clinical trial . METHODS A r and omized , double blind , placebo controlled study including COPD - patients ( FEV1/FVC < 70 % , FEV1 < or = 70 % predicted ; age > or = 40 years ; > or = 10 pack years ) of different severities was performed . The efficacy of 18 microg Tiotropium bromide once daily on lung function and exacerbations over 12 weeks was evaluated by respective pulmonary function tests ( spirometry ) before ( trough value ) and 2 hours after inhalation of study medication . RESULTS 1639 patients ( 1236 Tiotropium bromide , 403 placebo ;  FEV1 reversibility after 200 microg Ipratropium bromide + 200 microg Fenoterol : 7.9 + /- 7.5 % predicted [ mean + /- sd ] ) were r and omized . After 12 weeks of treatment Tiotropium bromide led to significant increases of trough FEV1 ( 23 - 24 h after last inhalation ; + 79 + /- 17 ml ) , and 2 h after Tiotropium bromide inhalation ( + 128 + /- 19 ml ) ( all values vs. placebo , adjusted mean + /- se , p < 0.0001 ) . FVC and IVC were also improved significantly . In mild COPD ( FEV1 > or = 50 - 70 % ) improvements were most pronounced ( trough FEV1 + 113 + /- 29 ml , 2 h post-inhalation + 181 + /- 33 ml ; all values vs. placebo . , p < 0.0001 ) . 14.6 % of patients treated with Tiotropium bromide had a COPD exacerbation vs. 19.9 % of patients treated with placebo ( p = 0.0151 ) . The time to first exacerbation was prolonged ( p = 0.0092 vs. placebo ) . CONCLUSION Tiotropium bromide 18 microg once daily led to a persistent improvement of lung function and a reduction of exacerbations in patients with COPD of different severities RATIONALE In the 4-year UPLIFT trial , tiotropium improved lung function and health-related quality of life and decreased exacerbations compared with usual respiratory medications except inhaled anticholinergics in patients with chronic obstructive pulmonary disease ( COPD ) . Mortality and its causes was a secondary endpoint in UPLIFT . OBJECTIVES We describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow-up of discontinued patients . METHODS This study involved a r and omized , double-blind trial comparing tiotropium with placebo in patients with COPD ( > or=40 yr of age ; postbronchodilator FEV(1 ) < or=70 % ; FEV(1)/FVC < or=70 % ) .  Mortality was evaluated during treatment and with follow-up of discontinued patients . Cause of death was adjudicated by an endpoint committee . MEASUREMENTS AND MAIN RESULTS A total of 5,993 patients were r and omized , 3,006 to placebo and 2,987 to tiotropium .  While patients were receiving treatment , there were 792 deaths , with a lower risk in the tiotropium group ( hazard ratio , 0.84 ; 95 % confidence interval [ CI ] , 0.73 - 0.97 ) . Statistical significance was observed at the end of the protocol -defined treatment period ( P = 0.034 ) but not 30 days thereafter ( P = 0.086 ) . Adjustment by GOLD stage , sex , age , baseline smoking behavior , and baseline respiratory medications subgroups did not alter the results of the analysis . The most common causes of death adjudicated by an independent end-point committee were lower respiratory , cancer , general disorders , and cardiac disorders . The hazard ratios for lower respiratory and cardiac mortality during treatment were 0.86 ( 95 % CI , 0.68 - 1.09 ) and 0.86 ( 95 % CI , 0.75 - 0.99 ) , respectively . CONCLUSIONS Treatment with tiotropium over 4 years is associated with decreased mortality , with the effect being most prominent in the cardiac and respiratory systems RATIONALE Small studies have suggested that inhaled corticosteroids can suppress systemic inflammation in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To determine the effect of inhaled corticosteroids with or without long-acting beta(2)-adrenergic agonist on systemic biomarkers of inflammation . METHODS We conducted a double-blind r and omized placebo-controlled trial across 11 centers ( n = 289 patients with FEV(1 ) of 47.8 + /- 16.2 % of predicted ) to compare the effects of inhaled fluticasone alone or in combination with salmeterol against placebo on circulating biomarkers of systemic inflammation over 4 weeks . The primary endpoint was C-reactive protein ( CRP ) level . Secondary molecules of interest were IL-6 and surfactant protein D ( SP-D ) . MEASUREMENTS AND MAIN RESULTS Neither fluticasone nor the combination of fluticasone/salmeterol had a significant effect on CRP or IL-6 levels . There was , however , a significant reduction in SP-D levels with fluticasone and fluticasone/salmeterol compared with placebo ( P = 0.002 ) . Health status also improved significantly in both the fluticasone and fluticasone/salmeterol groups compared with placebo , driven mostly by improvements in the symptom scores . Changes in the circulating SP-D levels were related to changes in health status scores . FEV(1 ) improved significantly only in the fluticasone/salmeterol group compared with placebo . CONCLUSIONS ICS in conjunction with long-acting beta(2)-adrenergic agonist do not reduce CRP or IL-6 levels in serum of patients with COPD over 4 weeks . They do , however , significantly reduce serum SP-D levels . These data suggest that these drugs reduce lung-specific but not generalized biomarkers of systemic inflammation in COPD One hundred and twenty one patients considered on clinical grounds to have non-asthmatic chronic airflow obstruction completed a double blind , crossover trial comparing oral prednisolone 40 mg per day with inhaled beclomethasone dipropionate 500 micrograms thrice daily , each given for 14 days , with a 14 day washout period between treatments . The time course of response was analysed for the 57 occasions where there was a significant increase in mean daily peak expiratory flow ( PEF ) over the treatment period . Mean daily PEF was still rising at day 14 on 12 occasions . After withdrawal of treatment mean daily PEF remained above pretreatments levels for more than two weeks in half the responses analysed . The peak response occurred earlier with inhaled beclomethasone ( median 9.5 ( range 3 - 14 ) days ) than with oral prednisolone ( median 12 ( range 1 - 14 ) days ) , though both treatments produced a response that was sustained for a similar period . The results suggest that a trial of treatment with corticosteroids in this group of patients should last more than 14 days , and that in a study with a crossover design the washout period should be longer than two weeks 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 BACKGROUND This study explores spirometry quality and reproducibility in the Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ( ® ) ) trial . METHODS Four-year , r and omized , double-blind , placebo-controlled , multicenter trial in 5993 patients with chronic obstructive pulmonary disease . Within-test variability of pre- and post-bronchodilator forced expiratory volume in 1 s ( FEV(1 ) ) was compared across study visits . Between-test variability of best pre- or post-FEV(1 ) values between two visits 6 months apart was compared at the start , middle and end of the trial . RESULTS Three or more acceptable maneuvers were obtained in 93 % of visits . Within-test variability of pre- and post-FEV(1 ) ( mean st and ard deviation : 0.092 and 0.098 L ) decreased during the trial . Between-test variability also decreased : pre-FEV(1 ) ( visit 3 - 5 = 0.141 ± 0.138 L ; visit 9 - 11 = 0.129 ± 0.121 L ; visit 17 - 19 = 0.121 ± 0.122 L ) ; post-FEV(1 ) ( 0.139 ± 0.140 , 0.126 ± 0.123 , 0.121 ± 0.122 L , respectively ) , and was dependent on age , sex , smoking status and disease stage , but not on bronchodilator response or study treatment . CONCLUSION Spirometry quality in UPLIFT ( ® ) was good and improved during the trial . Between-test variability across patient subgroups suggests that relevant cut-offs for individual disease monitoring are difficult to establish . TRIAL REGISTRATION NUMBER NCT00144339 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 AIMS Evaluation of tiotropium  efficacy in patients with mild chronic obstructive pulmonary disease ( COPD ) defined by the 2003 Swedish Society of Respiratory Medicine guidelines ( post-bronchodilator FEV1/FVC < 70 % ; FEV1 > 60 % predicted ) . METHODS In this 12-week , r and omised , double-blind , placebo-controlled study of tiotropium 18 mcg once daily versus placebo , respiratory function was assessed on Days 1 , 15 and 85 ( baseline : pre-dose Day 1 ) . RESULTS Mean+/-SD baseline FEV1 ( % predicted ) was 73.4+/-12.5 ( tiotropium , n=107 ; placebo , n=117 ) . Tiotropium significantly improved change from baseline in area under the curve from pre-dose to 2 hours post-dose ( AUC0 - 2 h ) FEV1 versus placebo , by 166+/-26 mL ( mean+/-SE ) at study end ( p<0.0001 ) . With tiotropium , there were significant increases in the change in AUC0 - 2 h FVC versus baseline , and trough FEV1 and FVC , versus placebo , on all test days ( p<0.01 ) . Adverse event rates were similar . CONCLUSION Compared with placebo , tiotropium improved lung function in patients with mild COPD OBJECTIVE To define the relationship between skin bruising ( as well as other cutaneous manifestations ) and inhaled corticosteroid ( ICS ) therapy vs placebo in subjects with COPD who were participating in a clinical trial . To explore the relationship between easy skin bruising and other systemic effects of ICS therapy , including adrenal suppression and loss of bone mineral density ( BMD ) . DESIGN Double-blind , r and omized , placebo-controlled clinical trial of triamcinolone acetonide ( 1200 microg daily ) vs placebo in participants with mild-to-moderate COPD . SETTING Lung Health Study II , a clinical trial to assess the effect of ICS compared to placebo in 1,116 participants in 10 centers over > 3.5 to 4.5 years . PARTICIPANTS A total of 1,116 smokers or recent ex-smokers with mild-to-moderate COPD ( age range , 40 to 69 years ; mean age , 56.3 years ; 37.2 % female ) . MEASUREMENTS AND RESULTS Every 6 months , a structured question naire was administered to elicit reports of any bruising and /or skin rashes , slow healing of cuts or sores , or other skin changes . Compliance with inhaler use was assessed by canister weighing . A significantly higher proportion of ICS than placebo participants who complied with using their inhaler reported easy bruising ( 11.2 % vs 3.5 % , respectively ) and the slow healing of skin cuts or sores ( 2.4 % vs 0.5 % , respectively ) . Older men in the ICS group with good inhaler compliance appeared to be at the greatest risk of bruising . In those participants undergoing serial measurements of adrenal function and BMD , no association was noted between skin bruising and either the suppression of adrenal function or the loss of BMD as systemic complications of ICS use . CONCLUSION These findings indicate that moderate-to-high doses of ICSs result in an increased incidence of easy bruising and impairment in skin healing in middle-aged to elderly persons with COPD . No association was noted between skin bruising and other markers of systemic toxicity from the use of ICSs 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 Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the H and iHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease ( COPD ) . Although tiotropium H and iHaler was associated with reduced mortality , as compared with placebo , more deaths were reported with tiotropium Respimat than with placebo . METHODS In this r and omized , double-blind , parallel-group trial involving 17,135 patients with COPD , we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 μg or 5 μg , as compared with tiotropium H and iHaler at a once-daily dose of 18 μg . Primary end points were the risk of death ( noninferiority study , Respimat at a dose of 5 μg or 2.5 μg vs. H and iHaler ) and the risk of the first COPD exacerbation ( superiority study , Respimat at a dose of 5 μg vs. H and iHaler ) . We also assessed cardiovascular safety , including safety in patients with stable cardiac disease . RESULTS During a mean follow-up of 2.3 years , Respimat was noninferior to H and iHaler with respect to the risk of death ( Respimat at a dose of 5 μg vs. H and iHaler : hazard ratio , 0.96 ; 95 % confidence interval [ CI ] , 0.84 to 1.09 ; Respimat at a dose of 2.5 μg vs. H and iHaler : hazard ratio , 1.00 ; 95 % CI , 0.87 to 1.14 ) and not superior to H and iHaler with respect to the risk of the first exacerbation ( Respimat at a dose of 5 μg vs. H and iHaler : hazard ratio , 0.98 ; 95 % CI , 0.93 to 1.03 ) . Causes of death and incidences of major cardiovascular adverse events were similar in the three groups . CONCLUSIONS Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium H and iHaler at a dose of 18 μg in patients with COPD . ( Funded by Boehringer Ingelheim ; TIOSPIR Clinical Trials.gov number , NCT01126437 . ) BACKGROUND --In the day to day care of obstructive airways diseases ( asthma and chronic obstructive pulmonary disease ) important decisions such as disease classification and choice of therapy are based on assessment of the bronchodilator response . However , surprisingly little is known of the long term course of the bronchodilator response in patients with obstructive airways disease . METHODS -- Data from a multicentre trial were used in which 274 patients aged 18 - 60 years with airways obstruction were selected with PC20 < 8 mg/ml and FEV1 < 95 % CI of predicted . FEV1 was measured before and 20 minutes after 1000 micrograms terbutaline and 40 minutes after an additional 80 micrograms ipratropium bromide . Data were analysed from 185 patients who were followed up for 21 months ( five measurements ) . Four different expressions of bronchodilator response ( BDR ) were examined for change under long term therapy , long term variability , and prognostic value in predicting response to inhaled corticosteroids . RESULTS --There was a significant reduction in BDR of 117 ml after three months of treatment with a beta 2 agonist plus a corticosteroid ( BA + CS ) , but not after bronchodilators only . Significant reductions with BA + CS were also found in BDR as a percentage of initial FEV1 , and in BDR as a percentage of predicted FEV1 . Bronchodilator tests were quite variable ( SD 186 ml or 11 % of initial value ) and less than half of the patients could consistently be classified as " irreversible " with recommended cutoff levels . The bronchodilator response at the start of the study proved to be a poor predictor of improvement in FEV1 under BA + CS treatment ( correct prediction 60 % ) . CONCLUSIONS --Bronchodilator responses decrease substantially with inhaled corticosteroid therapy , and within subject variability is considerable both in asthma and chronic obstructive pulmonary disease . Dichotomous decisions on whether patients are " irreversible " according to any single bronchodilator measurement should therefore be made with great caution . The bronchodilator response can not be used accurately as a predictor of response to inhaled corticosteroids in obstructive airways disease BACKGROUND Recently , there have been concerns about the tolerability of long-acting (2)-agonists , including possible adverse cardiovascular effects-a particular concern in patients with chronic obstructive pulmonary disease ( COPD ) , who are at elevated risk for cardiovascular disease . OBJECTIVE The aim of this study was to assess the cardiac safety profile of nebulized formoterol fumarate inhalation solution . METHODS Cardiac safety was assessed as part of a 12-week , r and omized , double-blind , double-dummy , placebo- and active-controlled trial that was conducted at 38 centers across the United States . Male and female patients aged > /=40 years with COPD and without other significant disease were enrolled . After a 4- to 14-day , single-blind placebo run-in period , patients with COPD were r and omly assigned to receive formoterol fumarate inhalation solution 20 microg BID via nebulizer ( FFIS group ) , formoterol fumarate 12 microg BID via dry powder inhaler ( FA group ) , or placebo .  Cardiac effects-measured by changes in heart rate ( HR ) and ventricular premature beats ; incidence of proarrhythmic events ; change in corrected QT ( QTc ) interval ; and incidence of maximum mean change in QTc > /=60 ms-were assessed using 24-hour Holter monitoring at baseline and 12 weeks ; 12-lead electrocardiography at screening and weeks 4 , 8 , and 12 ; and patient diary cards . RESULTS A total of 351 patients with COPD were r and omized ( mean age , 62.8 years ; 56.1 % male ; mean postbronchodilator forced expiratory volume in 1 second , 1.5 L ) . Holter monitoring found no clinical ly meaningful effects of FFIS or FA treatment on mean or maximum HR , ventricular premature beats , or inci dence of arrhythmic events compared with placebo . At week 12 , mean ( SD ) changes from baseline in mean HR were -0.6 ( 10.9 ) , + 0.1 ( 11.6 ) , and -1.4 ( 9.4 ) bpm in the FFIS , FA , and placebo groups , respectively . The incidence of mean maximum changes in QTc > /=60 ms at any time during the 12-week treatment period were 1.6 % , 1.8 % , and 1.8 % with FFIS , FA , and placebo , respectively . Treatment-emergent cardiac adverse events ( AEs ) occurred in 4.1 % , 3.5 % , and 4.4 % of patients in the FFIS , FA , and placebo groups ; withdrawals due to possible cardiac AEs occurred in 1 patient per treatment group . No deaths or serious cardiac AEs occurred during the treatment period . CONCLUSION In this COPD population , no clinical ly significant cardiac effects were found with twicedaily treatment with nebulized formoterol fumarate inhalation solution RATIONALE No currently available treatment is reported to reduce the exaggerated airway wall inflammation of chronic obstructive pulmonary disease . OBJECTIVES We tested the hypothesis that inhaled combined long-acting beta2-agonist ( salmeterol ) and corticosteroid ( fluticasone propionate ) will reduce inflammation . METHODS Bronchial biopsies and induced sputum were taken from 140 current and former smokers ( mean age , 64 yr ) with moderate to severe disease , r and omized in a 13-wk double-blind study to placebo  ( n = 73 ) or  salmeterol/fluticasone propionate 50/500 microg ( n = 67 ) twice daily . Biopsies were repeated at 12 wk and sputa at 8 and 13 wk . After adjustment for multiplicity , comparisons between active and placebo were made for median change from baseline in the numbers of biopsy CD8 + and CD68 + cells/mm2 and sputum neutrophils . MEASUREMENTS AND MAIN RESULTS Combination therapy was associated with a reduction in biopsy CD8 + cells of -118 cells/mm2 ( 95 % confidence interval [ CI ] , -209 to -42 ; p = 0.02 ) , a reduction of 36 % over placebo ( p = 0.001 ) . CD68 + cells were unaffected by combination treatment . Sputum differential ( but not total ) neutrophils reduced progressively and , at Week 13 , significantly with combination treatment ( median treatment difference , 8.5 % ; 95 % CI , 1.75%-15.25 % ; p = 0.04 ) . The combination also significantly reduced biopsy CD45 + and CD4 + cells and cells expressing genes for tumor necrosis factor-alpha and IFN-gamma and sputum total eosinophils ( all p < or = 0.03 ) . These antiinflammatory effects were accompanied by a 173-ml ( 95 % CI , 104 - 242 ; p < 0.001 ) improvement in prebronchodilator FEV1 . CONCLUSIONS The combination of salmeterol and fluticasone propionate has a broad spectrum of antiinflammatory effects in both current and former smokers with chronic obstructive pulmonary disease , which may contribute to clinical efficacy The UPLIFT study ( Underst and ing Potential Long-term Impacts on Function with Tiotropium ) was a double-blind , r and omised , international , multicentric , placebo-controlled clinical trial , investigating with tiotropium ( Spiriva ) the change in the annual rate of decline in FEV1 in chronic obstructive pulmonary disease ( COPD ) . Secondary end points included COPD exacerbation rate with or without hospitalisation , lung function , quality of life and mortality .  5.993 patients were r and omized . In this article , we briefly describe the most important results of the study . While tiotropium did not alter the annual rate of decline in FEV1 ( pre and postbronchodilatation ) , it improved lung function and quality of life , and reduced exacerbations and hospitalisations by comparison with control for up to 4 years . Tiotropium also reduced respiratory and cardiac morbidity 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 In this r and omised double-blind study , patients > or=40 years old with COPD , a smoking history of > or=10 pack-years , a pre-bronchodilator FEV(1 ) of < or=60 % predicted and an FEV(1)/FVC of < or=70 % received tiotropium 5 microg or placebo via Respimat inhaler once daily for 48 weeks . Other medications were permitted except inhaled anticholinergics . Co- primary endpoints were trough FEV(1 ) and the time to first exacerbation . Adverse events were followed and vital status regularly assessed . In all , 3991 patients ( mean age , 65 years [ SD , 9 years ] ) were evaluable . Mean baseline FEV(1 ) was 1.11 L ( 0.40 L ) or 40 % ( 12 % ) of predicted normal . Adjusted mean differences in trough FEV(1 ) and trough FVC at Week 48 ( tiotropium minus placebo ) were 102 and 168 ml respectively ( p < 0.0001 , both ) . Tiotropium delayed time to first exacerbation relative to placebo ( hazard ratio [ HR ] , 0.69 [ 95 % CI , 0.63 - 0.77 ] ) and time to first hospital-treated exacerbation ( HR , 0.73 [ 0.59 - 0.90 ] ) . SGRQ score at Week 48 was 2.9 units lower with tiotropium ( p < 0.0001 ) . Adverse and serious adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials . The rate ratio for a major adverse cardiovascular event during the treatment period + 30 days was 1.12 ( 0.67 - 1.86 ) . By the end of planned treatment ( Day 337 ) 52 patients on tiotropium ( incidence rate per 100 years , 2.94 ) and 38 on placebo ( 2.13 ) had died ( HR = 1.38 [ 0.91 - 2.10 ] ; p = 0.13 ) . Lung function , exacerbations and quality of life were improved by tiotropium 5 microg Respimat but a numerical imbalance was seen in all-cause mortality . The protocol is registered on the European Clinical Trials Data base as trial number 2006 - 001009 - 27 and in the Clinical Trials.gov data base as NCT00387088 OBJECTIVE To evaluate the cost-utility of adding tiotropium to usual care versus usual care alone for patients with moderate to very severe chronic obstructive pulmonary disease ( COPD ) in the UK and Belgium . METHODS A four-state Markov model was developed with three disease severity states ( moderate , severe , very severe ) and death . Severity was based on post-bronchodilator FEV₁ and transitions were based on outcomes of the Underst and ing Potential Long Term Impacts on Function with Tiotropium ( UPLIFT ® ) trial . Utilities were derived from EQ-5D scores for a subset of UPLIFT ® patients . UK costs were evaluated separately for Engl and ( E ) , and for Scotl and , Wales and Northern Irel and ( SWNI ) . Belgian ( B ) costs were obtained from local sources . Uncertainty was assessed by deterministic and probabilistic sensitivity analysis ( PSA ) . RESULTS Adding tiotropium to usual care result ed in an incremental cost per patient of € 969 ( B ) , £ 796 ( E ) , and £ 812 ( SWNI ) , and incremental QALYs of 0.052 ( B ) , and 0.051 ( E , SWNI ) . The four-year incremental cost-effectiveness ratios ( ICER ) were € 18,617 ( B ) , £ 15,567 ( E ) and £ 15,890 ( SWNI ) per QALY .  Probability of tiotropium  being cost-effective at £ 30,000 ( € 50,000 ) per QALY gained was greater than 60 % . CONCLUSIONS At willingness to pay thresholds of £ ( € ) 30,000 per QALY gained , adding tiotropium to usual care  is cost-effective 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 BACKGROUND The institution of inhaled corticosteroids is generally advocated for effective treatment of patients with asthma . It is yet unknown what is the best time to start inhaled corticosteroid therapy and especially whether delayed introduction is harmful . PHASE 1 : In a previous study in patients with asthma and COPD , we found that 2.5 years of treatment with a beta 2-agonist plus inhaled corticosteroid ( BA + CS ) was more effective in improving the FEV1 and the provocative concentration of histamine causing a 20 % reduction in FEV1 ( PC20 ) than treatment with a beta 2-agonist plus anticholinergic ( BA + AC ) or placebo ( BA + PL ) . PHASE 2 : We extended this study with 6 months to investigate whether delayed introduction of inhaled CS therapy ( 800 micrograms beclomethasone dipropionate ) in the groups previously not treated with inhaled CS ( BA + /- AC ) could also improve FEV1 and PC20 to the same degree . A distinction was made between patients with predominantly asthma ( high baseline reversibility , delta FEV1 > or = 9 % of predicted ) , and predominantly COPD ( low baseline reversibility , delta FEV1 < 9 % of predicted ) . RESULTS Improvement of FEV1 percent predicted by inhaled CS  was comparable both in the asthmatics between phase 1 ( 13.8 % predicted ) and phase 2 ( 8.5 % predicted ; p = 0.31 ) as well as in the patients with COPD ( 2.5 % and 1.5 % predicted , respectively ) . PC20 , however , increased significantly more in the asthmatics in phase 1 ( 1.77 doubling concentration [ DC ] ) than in phase 2 ( 0.79 DC ; p = 0.03 ) . Improvement of PC20 in the patients with COPD was not significantly higher in phase 1 ( 0.74 DC ) than in phase 2 ( 0.00 DC ; p = 0.19 ) . CONCLUSIONS Our study indicates that although delayed introduction of inhaled CS in asthmatics leads to similar improvements in FEV1 , improvements in PC20 are significantly less . These findings in patients with longer-existing asthma concur with other findings in newly detected asthma . We suggest that institution of inhaled CS therapy should not be postponed in asthmatics with documented airways obstruction and reversibility BACKGROUND Tiotropium , a once-daily anticholinergic , and salmeterol represent two inhaled , long-acting bronchodilators from different pharmacologic classes . A trial was design ed to examine the efficacy and safety of both compounds with multiple outcome measures , including lung function , dyspnea , and health-related quality of life ( HRQoL ) in patients with COPD . METHODS A 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group study of tiotropium , 18 microg once daily via dry-powder inhaler , compared with salmeterol , 50 microg bid via metered-dose inhaler , was conducted in patients with COPD .  Efficacy was assessed by 12-h monitoring of spirometry , transition dyspnea index ( TDI ) , and the St. George 's Respiratory Question naire ( SGRQ ) . RESULTS A total of 623 patients participated ( tiotropium , n= 209 ; salmeterol , n = 213 ; and  placebo , n = 201 ) . The groups were similar in age ( mean , 65 years ) , gender ( 75 % men ) , and baseline FEV(1 ) ( mean , 1.08 + /- 0.37 L ; percent predicted , 40 + /- 12 % [ + /- SD ] ) . Compared with placebo treatment , the mean predose morning FEV(1 ) following 6 months of therapy increased significantly more for the tiotropium group ( 0.14 L ) than the salmeterol group ( 0.09 L ; p < 0.01 ) . The average FEV(1 ) ( 0 to 12 h ) for tiotropium was statistically superior to salmeterol ( difference , 0.08 L ; p < 0.001 ) . Tiotropium improved TDI focal score by 1.02 U compared with placebo ( p = 0.01 ) , whereas there was no significant change in TDI focal score with salmeterol ( 0.24 U ) . Tiotropium was superior to salmeterol in improving TDI focal score ( p < 0.05 ) . At 6 months , the mean improvement in SGRQ total score vs baseline was tiotropium , - 5.14 U ( p < 0.05 vs placebo ) ; salmeterol , - 3.54 U ( p = 0.4 vs placebo ) ; and placebo , - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo . Both active drugs reduced the need for rescue albuterol ( p < 0.0001 ) . CONCLUSIONS Tiotropium once daily produces superior bronchodilation , improvements in dyspnea , and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD We have studied the relationship between emphysema and airways collapse , and response to corticosteroids in patients with chronic airflow obstruction . One hundred and seven patients completed a placebo-controlled trial comparing 2 wks treatment with oral prednisolone 40 mg.day-1 to inhaled beclomethasone dipropionate 500 micrograms t.d.s . Response to corticosteroids was defined on the basis of changes in forced expiratory volume in one second ( FEV1 ) , and /or forced vital capacity ( FVC ) , and /or mean peak expiratory flow ( PEF ) after treatment . Patients were categorized as those with physiologically defined emphysema ( carbon monoxide transfer coefficient ( KCO ) less than 70 % predicted and total lung capacity greater than 120 % predicted ) , and those with pressure dependent airways collapse on the flow-volume loop ( ratio of inspiratory to expiratory flow at 50 % vital capacity [ I : E50 ] greater than 10 ) . The response to placebo showed a significant order effect , probably due to a carry-over effect of active treatment of at least 3 wks . Hence , the efficacy of active treatment over placebo in the subgroups defined was assessed by analysis of data generated from the first treatment phase of the trial . The presence or absence of physiologically defined emphysema did not affect the response to  oral prednisolone . Inhaled beclomethasone dipropionate  , however , was less effective in the emphysema group . Pressure dependent airways collapse did not affect the response to either prednisolone or beclomethasone . However , when data from all three treatment phases were analysed there was no significant difference in the response to either drug in any of the subgroups defined . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND Chronic obstructive pulmonary disease ( COPD ) and asthma have different diagnostic criteria and treatment paradigms . Both are common and can occur in the same patient . We sought to determine the spirometric effects of tiotropium in COPD patients with concomitant asthma . METHODS A 12-week r and omized , double-blind , placebo-controlled , parallel group trial with tiotropium 18 mcg daily was performed . Patients continued usual respiratory medications except for inhaled anticholinergics . INCLUSION CRITERIA Physician diagnosis of COPD and asthma , age > or= 40 years , smoking > 10 pack years , post-bronchodilator forced expiratory volume in 1s ( FEV(1))<80 % predicted , FEV(1)/forced vital capacity (FVC)<70 % , > or= 12 % , and > or= 200 ml increase in FEV(1 ) following inhaled bronchodilator , treatment with inhaled steroids > or= 1 year . Spirometry was measured serially for 6h on days 1 , 29 and 85 . RESULTS Four hundred and seventy-two patients were r and omized . Baseline characteristics were balanced . Mean age=59.6 years , 61.4 % were men , and FEV(1)=1.55l ( 53.0 % predicted ) . Improvements at 12 weeks with tiotropium were observed for the primary endpoint FEV(1 ) area under the curve ( AUC ) from 0 to 6h ( difference=186+/-24 ml , p<0.001 ) and for morning pre-dose FEV(1 ) ( difference=98+/-23 ml , p<0.001 ) . Significant differences in favor of tiotropium were observed for pre-dose FVC ( difference=128+/-34 ml , p<0.001 ) and FVC AUC 0 - 6h ( difference=232+/-35 ml , p<0.001 ) . Compared to baseline , the mean weekly number of daily puffs of prn salbutamol was reduced by 0.05+/-0.12 puffs/day in the placebo group and by 0.50+/-0.12 puffs/day in the tiotropium group at week 12 ( p<0.05 ) . CONCLUSIONS Patients with COPD and concomitant asthma achieve spirometric improvements with tiotropium along with symptomatic benefit as seen by reduced need for rescue medication 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 aim of this pilot study was to explore the relative efficacy in terms of improvement in symptoms and lung function of combining fluticasone propionate/salmeterol combination ( FSC ) and tiotropium in patients with severe-to-very severe stable COPD . Ninety patients were r and omized to receive 3 months of treatment in one of three treatment groups : ( 1 ) FSC 500/50 microg Diskus , 1 inhalation twice daily+placebo H and ihaler 1 inhalation once-daily daily ; ( 2 ) tiotropium 18 microg H and ihaler , 1 inhalation once daily+placebo Diskus , 1 inhalation twice daily ; ( 3 ) FSC 500/50 microg Diskus , 1 inhalation twice daily+tiotropium 18 microg H and ihaler , 1 inhalation once-daily daily . Patients attended the clinic before and after 1 month , 2 months , and 3 months of treatment for evaluations of pulmonary function , and dyspnea , which was assessed using a visual analog scale ( VAS ) . Also the supplemental salbutamol use was measured . Eighty-one patients completed the 3-month treatment period : 26 patients receiving FSC , 26 patients receiving tiotropium , and 29 patients receiving FSC+tiotropium .  Patients were withdrawn for COPD exacerbation . Improvements in trough FEV(1 ) with all treatments medications were observed by the first month when trough FEV(1 ) had improved significantly above baseline by 74 mL ( p<0.05 ) in the tiotropium group , by 117 mL ( p<0.05 ) in the FSC group and by 115 mL ( p<0.05 ) in FSC+tiotropium group . At the end of the study , trough FEV(1 ) had improved significantly above baseline by 141 mL ( p<0.05 ) in the tiotropium group , by 140 mL ( p<0.05 ) in the FSC group and by 186 mL ( p<0.05 ) in FSC+tiotropium group . The difference between FSC and tiotropium appeared to decrease , that between FSC and FSC+tiotropium appeared to increase and that between tiotropium and FSC+tiotropium remained almost similar with study duration . Our results suggest that adding FSC and tiotropium may provide benefits in symptomatic patients with severe-to-very severe stable COPD BACKGROUND To determine the safety and efficacy of BEA2180 , an anticholinergic agent in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS Smokers or ex-smokers ≥40 years with COPD and a postbronchodilator forced expiratory volume in 1 s ( FEV1 ) < 80 % predicted and FEV1/forced vital capacity ≤70 % participated in this multinational , r and omised , double-blind , parallel study . Patients received BEA2180 ( 50 , 100 or 200 μg ) , tiotropium ( 5 μg ) or placebo once daily via Respimat Soft Mist ™ . The primary endpoint was trough FEV1 after 24 weeks . Secondary endpoints included Transition Dyspnoea Index ( TDI ) focal score , St George 's Respiratory Question naire ( SGRQ ) total score , exacerbations and adverse events . RESULTS Patients ( n = 2080 , 64.5 % male ) had a mean age of 64.2 years and a baseline FEV1 of 1.2 L.  Trough FEV1 at 24 weeks with all BEA2180 doses ( 0.044 - 0.087 L ) and tiotropium 5 μg ( 0.092 L ) was significantly higher ( p < 0.0001 ) than placebo ( -0.034 L ) and BEA2180 ( 200 μg ) was noninferior to tiotropium . Mean TDI focal scores were higher with BEA2180 ( 1.43 - 1.48 ) or tiotropium ( 1.46 ) versus placebo ( 0.94 ; p ≤ 0.01 for all ) . Mean SGRQ total scores also improved with BEA2180 ( 40.1 - 40.7 ) or tiotropium ( 39.5 ) compared with placebo ( 43.0 , p < 0.01 for all ) . COPD exacerbation rates were reduced for all active treatments , reaching statistical significance for BEA2180 ( 50 and 200 μg ) ( p < 0.05 , for both ) . CONCLUSION All study doses of BEA2180 improved lung function , reduced symptoms and exacerbations , and improved health status in COPD ; all treatments were well tolerated . Clinical trial identifier : NCT00528996 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 The benefits of inhaled corticosteroids in the management of COPD are less apparent than they are in asthma therapy , and the potential for adverse systemic effects of high-dose inhaled corticosteroids has been recognized recently . It is therefore essential to know the maximal obtainable benefits in order to assess the risk/benefit ratio of this treatment . PURPOSE The aim of this study was to investigate the maximal obtainable benefits of high-dose inhaled corticosteroids , 3 mg/d of beclomethasone dipropionate ( BDP ) , when used in combination with adequate doses of regular bronchodilators in patients with stable COPD . STUDY DESIGN Thirty patients with stable COPD completed a r and omized , double-blind , placebo-controlled cross-over trial with either 3 mg/d of BDP or with a matching placebo using a metered-dose inhaler with a spacer device for 4 weeks during each treatment period . All of the patients continued to inhale both 400 microg of salbutamol qid and 80 microg of ipratropium bromide qid . RESULTS The mean prebronchodilator FEV1 was 0.97+/-0.35 L during the placebo period and 1.08+/-0.38 L during the BDP period ( p < 0.001 ) . While on BDP , five patients demonstrated a response in their FEV1 of more than 8.5 % of the predicted value , which was above the range that covered 95 % of the distribution of the placebo response . The mean absolute improvement in the FEV1 in these 5 objective responders was 0.34+/-0.10 L , compared to 0.06+/-0.09 L in the 25 objective nonresponders . Symptom scores for wheezing and dyspnea were significantly better with BDP than with placebo .  Hoarseness and sore throat were associated more with BDP treatment . CONCLUSION Although a considerable minority of patients benefited substantially from this treatment , the overall outcome does not seem to justify the widespread use of this treatment in the light of increasing recognition of the potential adverse systemic effects of high-dose inhaled corticosteroids Systemic corticosteroids have been recommended as a therapeutic option in patients with moderate to severe COPD . In an early stage of the disease , i.e. chronic bronchitis with mild or no airflow obstruction , a trial with inhaled steroids could reveal potential benefits , particularly in terms of a modulation of airway inflammation . We therefore investigated the effect of inhaled fluticasone ( 1000 microg day(-1 ) ) on markers of airway inflammation in 19 patients with chronic bronchitis ( mean+/-SEM FEV1 , 83.4+/-3.0 % predicted ; FEV1/VC , 67.5+/-2.4 % ) in a double-blind , cross-over , placebo-controlled manner . Visits were performed before and after two 4-week treatment periods . separated by a 4-week washout period . Lung function , the concentration of exhaled nitric oxide , differential cell counts in induced sputum and the number of cells positive for iNOS , as well as the levels of LDH , ECP , neutrophil elastase and IL-8 in sputum supernatants were determined . Although the total cell number decreased significantly after fluticasone ( geometric mean 12.3 vs. 7.7 x 10(6)/ml ; P<0.05 ) it was not significantly different from the change observed after placebo ( 14.2 vs. 10.6 x 10(6)/ml ; n.s . ) . None of the other parameters showed statistically significant changes after fluticasone or placebo and the results did not depend on the presence of airway hyperresponsiveness . We conclude that in patients with chronic bronchitis short-term treatment with inhaled corticosterids did not improve lung function or inflammatory parameters to an extent which was statistically significant as compared to spontaneous variability Whilst recent large-scale studies have provided much evidence on the natural history and therapeutic response in patients with chronic obstructive pulmonary disease ( COPD ) , relatively little is known about the effect in younger patients . We report a pre-specified post-hoc analysis of 356 patients with COPD ≤ 50 years old from the four year r and omised , double blind placebo controlled Underst and ing Potential Long Term Impact on Function with Tiotropium ( UPLIFT ) trial . Inclusion criteria included a post-bronchodilator forced expiratory volume in 1 s ( FEV(1 ) ) of ≤70 % , FEV(1)/FVC < 0.70 , age ≥40 years , and smoking history of ≥10 pack years . Younger patients had a mean FEV(1 ) of 1.24 L ( 39 % predicted ) and an impaired health-related quality of life ( St. George 's Respiratory Question naire ( SGRQ ) ) compared to the entire UPLIFT population . There were 40.2 % women and 51.1 % current smokers in the younger age group . Tiotropium was associated with a sustained improvement in spirometry and SGRQ . Mean decline in post-bronchodilator FEV(1 ) was 58 ml/year ( placebo ) vs. 38 ml/year ( tiotropium ) ( p = 0.01 ) . Corresponding values for pre-bronchodilator FEV(1 ) were 41 ml/year ( placebo ) compared with 34 ml/year ( tiotropium ) ( p = 0.34 ) . The hazard ratio ( 95%CI ) for an exacerbation in the younger age group was 0.87(0.68 , 1.13 ) ) . The rate of exacerbations was reduced by tiotropium ( rate ratio ( 95%CI ) = 0.73(0.56 , 0.95 ) ) . Tiotropium result ed in sustained bronchodilation , improved quality of life , and a decreased exacerbation rate in younger  patients . Tiotropium also result ed in a significant reduction in the decline in post-bronchodilator FEV(1 ) , suggesting possible disease modification by tiotropium in younger patients with COPD 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 Context Tiotropium , a new once-daily inhaled anticholinergic bronchodilator , has been shown to improve lung function in patients with chronic obstructive pulmonary disease ( COPD ) . Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients . Contribution This r and omized , parallel-group , double-blind , placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period . Caution s The study period was relatively short , and the beneficial effects were modest . The Editors Exacerbations of chronic obstructive pulmonary disease ( COPD ) can lead to costly and clinical ly significant consequences . Proven treatments for exacerbations are only modestly effective ( 1 , 2 ) . Recovery from even mild exacerbations may be protracted ( 3 ) . Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time ( 4 , 5 ) . Patients with severe exacerbations commonly seek care in emergency departments , and many of these patients are hospitalized . In 2000 , COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States ( 6 ) . Economic analyses suggest that hospitalization alone consumes up to 70 % of all medical expenses for patients with COPD ( 7 , 8) . Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need . An expert panel convened by the National Heart , Lung , and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations ( 9 ) . Tiotropium is a newly developed , once-daily inhaled anticholinergic bronchodilator . Because of its very slow dissociation from muscarinic M3 receptors , 1 inhaled dose produces sustained bronchodilation for at least 24 hours ( 10 ) . In controlled clinical trials , compared with placebo or the short-acting anticholinergic bronchodilator ipratropium , tiotropium improved lung function , dyspnea , and health-related quality of life in patients with COPD ( 11 , 12 ) . An analysis of adverse event reports su bmi tted during those studies suggested that tiotropium might also reduce exacerbation and COPD -related hospitalization rates . Therefore , we design ed a clinical trial to prospect ively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD . Methods Study Design Our study was a parallel-group , r and omized , double-blind , placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States . The sole intervention was tiotropium given by inhalation once daily . The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period . The protocol is consistent with the principles of Helsinki . The institutional review boards of participating medical centers approved the study . All trial participants provided written informed consent . Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants . We enrolled enough participants to ensure a minimum of 1800 r and omly assigned patients . Eligibility criteria included an age of 40 years or older , a cigarette smoking history of 10 pack-years or more , a clinical diagnosis of COPD , and an FEV1 of 60 % predicted or less and 70 % or less of the FVC . Exclusion criteria were a clinical diagnosis of asthma , a myocardial infa rct ion within the previous 6 months , a serious cardiac arrhythmia or hospitalization for heart failure within the previous year , known moderate to severe renal impairment , moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction , narrow-angle glaucoma , current radiation or chemotherapy for a malignant condition , or inability to give informed consent . We also excluded patients who took systemic corticosteroids at unstable doses , or in regular daily doses of 20 mg or more of prednisone ( or equivalent ) , or who had not fully recovered from an exacerbation for at least 30 days before the first study visit . We gathered baseline data on respiratory disease and other relevant medical history by question naire . Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a central ly generated blocked r and omization list . We generated a single r and omization and assigned blocks to centers . We provided r and omly assigned patients with training and detailed instructions on the use of the dry powder inhalation device ( H and iHaler , Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach , Germany ) ( 13 ) . Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites . The double-blind remained in place until all patients were clinical ly complete or until a serious adverse event required unblinding . Each morning during the trial , patients inhaled 1 capsule of tiotropium ( 18 g ) or 1 identical placebo capsule . Participants otherwise received usual medical care , except that they could not take any open-label anticholinergic bronchodilator . They continued taking all other respiratory medications ( including inhaled corticosteroids and long-acting -agonists ) , and primary providers were allowed to prescribe additional medications according to medical need . Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions . For purpose s of recall , patients kept a daily diary throughout the treatment period , recording information about specific respiratory symptoms , medications taken for exacerbations , clinic visits , and hospitalizations . We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits . We assessed study drug adherence by query and by counting returned capsules .  Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits . We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy . However , patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits . All open-label bronchodilators and the study drug were withheld overnight before spirometry . Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations ( 14 , 15 ) . Objectives We aim ed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations . Outcome Measures The co primary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation . We defined an exacerbation as a complex of respiratory symptoms ( increase or new-onset ) of more than 1 of the following : cough , sputum , wheezing , dyspnea , or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids , hospitalization , or both . The study team at each site requested discharge summaries for all hospitalizations , wherever they occurred . We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event result ed in a hospitalization . We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours . Admissions to nursing homes or other extended care facilities were not considered hospitalizations . Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation , the frequencies of exacerbations and of exacerbation-related health care utilization ( hospitalizations , hospitalization days , unscheduled clinic visits , antibiotic treatment days , and systemic corticosteroid treatment days ) , the frequencies of all-cause hospitalizations and hospitalization days , and results of spirometry . Statistical Analysis We analyzed the data by using a modified intention-to-treat principle . Therefore , we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event ( for the time-to-event end points ) or their withdrawal from the trial . For the time-to-event end points , we censored patients without an event at the end of their participation in the trial . Although we intended to follow all patients for the full 6 months , some patients were lost to follow-up . We h and led missing data by using longitudinal data analysis methods ( spirometry ) , analysis of observed data only ( number of events ) , or analysis methods for censored data ( time-to-event data ) . For the percentage of patients with an event , we considered that patients who discontinued the study drug therapy before having an event did not have an event . We analyzed the co primary end points by using a CochranMantelHaenszel test with center as a stratum . We used a stepwise procedure to test the percentage of patients with an exacerbation and , if rejected , to test percentage of patients with a hospitalization due to COPD exacerbation , each at a 2-sided level of 0.05 . Because of the prespecified closed testing procedure , no adjustment for multiplicity was required . We calculated that a sample size of 1800 patients would have 80 % power to 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 UNLABELLED Bronchodilator agents are central to the symptomatic management of Chronic Obstructive Pulmonary Disease ( COPD ) , and long-acting inhaled bronchodilators are regarded as more convenient . The role of inhaled corticosteroids still remains controversial , but there is increasing evidence that they may improve FEV(1 ) and symptoms in the long-term . AIM of the present small pilot study was to compare Salmeterol & Fluticasone ( SM&FP ) 50/250 microg bid via a single Diskus inhaler with SM 50 microg bid alone , and with placebo ( P ) in the treatment of moderate COPD . METHODS Eighteen moderate COPD patients ( 53 - 77 yr , mean basal FEV(1)=49.1 % pred.+/-5.0 s.d . ; mean FEV(1 ) reversibility=3.6 % bsln+/-3.8 s.d . ) treated with theophylline 400 mg/day and beta(2 ) short acting prn , were divided into three matched groups of six subjects according to a double-blind design , and treated with SM&FP 50/250 microcg , or SM 50 microcg alone , or P via Diskus inhaler bid for 52 weeks . In bsln , after 4 , 12 , 24 , 36 and 52 weeks , FEV(1 ) ( % pred ) , morning PEF ( l/s ) , the daily symptom score , and the number of exacerbations ( compared with the previous year ) were considered . Statistics . t-test , anova in each treatment group , and anova among basal values and among the 52 week values were used , being p<0.05 accepted . Also changes ( DeltaFEV(1 ) ) from baseline were compared at different control times . RESULTS The mean number of exacerbations/yr decreased from 3.5+/-0.8 to 1.16+/-0.75 s.d . exacerbation/yr in the SM&FP group ( t-test p<0.001 ) ; from 3.0+/-0.89 to 2.3+/-0.81 s.d . in the SM group ( t-test p = ns ) ; and from 3.16+/-1.16 to 4.16+/-0.75 s.d . in the P group ( t-test p = ns ) . Patients receiving SM&FP showed the highest mean improvement in FEV(1 ) ( + 7.3%+/-3.3 s.d . ) over the baseline pre-treatment value after 36 weeks of treatment ( anova p<0.001 ) , being FEV(1 ) unchanged after 52 weeks of treatment in SM group ( + 0.33%+/-2.4 s.d . ) and with a substantial decrease following P ( -2.6%+/-1.2 s.d . ) ( anova p<0.001 ) . Morning PEF ( l/min ) increased in subjects treated with SM&FP ( anova p<0.001 ) , while it remained unchanged in SM and P group ( in both , anova p = ns ) . After 52 weeks of treatment , only subjects treated with SM&FP showed a reduction of the daily symptoms score from 3.6+/-0.7 to 2.0+/-0.2 s.d . ( anova p=0.008 ) . Daily beta(2 ) short acting prn consumption was reduced only in SM&FP group from 4.2+/-0.81 to 2.2+/-1.2 s.d . after 52 weeks ( anova p<0.001 ) . CONCLUSIONS SM&FP 50/250 microcg regularly assumed in combination via a single Diskus inhaler for a 52 week period improves respiratory function ( such as FEV(1 ) , morning PEF ) , and and symptom score significantly in moderate COPD previously treated with theophylline , and at an higher extent than SM alone or P. The use of beta(2 ) short acting prn is also reduced , together with the number of exacerbations BACKGROUND The morbidity from obstructive airways disease ( asthma and chronic obstructive pulmonary disease ) is considerable , and the mortality rate is rising in several countries . It has been hypothesized that long-term improvement in prognosis might result from vigorous bronchodilator or antiinflammatory therapy . METHODS In a multicenter trial we compared three inhalation regimens in which a beta 2-agonist ( terbutaline , 2000 micrograms daily ) was combined with a corticosteroid ( beclomethasone , 800 micrograms daily ) , an anticholinergic bronchodilator ( ipratropium bromide , 160 micrograms daily ) , or placebo .  Patients with airways hyperresponsiveness and obstruction who were 18 to 60 years old were followed for 2 1/2 years . RESULTS Of the 274 patients enrolled , 56 percent had allergies . The mean forced expiratory volume in one second ( FEV1 ) was 64 percent of the predicted value . The mean PC20 ( the concentration of inhaled histamine causing a 20 percent decrease in FEV1 , a measure of hyperresponsiveness ) was 0.26 mg per milliliter . Withdrawal from the study , due mainly to pulmonary symptoms , was less frequent in the corticosteroid group ( 12 of 91 patients ) than in the anticholinergic-drug group ( 45 of 92 patients ) or the placebo group ( 44 of 91 patients ; P < 0.001 ) . The mean FEV1 ( + /- SE ) increased by 10.3 + /- 1.3 percent of the predicted value in the corticosteroid group within three months and remained stable thereafter , whereas it did not change in the other two groups ( P < 0.001 ) . The PC20 increased by 2.0 doubling concentrations in the corticosteroid group but did not change in the other groups ( P < 0.001 ) . In the corticosteroid group , patients who did not smoke , who had allergies , or who were less than 40 years old benefited more from their treatment than did those who smoked , did not have allergies , or were over 40 , but all subgroups of the corticosteroid group had improvement as compared with the anticholinergic-drug or placebo group . CONCLUSIONS The addition of an inhaled corticosteroid -- but not an inhaled anticholinergic agent -- to maintenance treatment with a beta 2-agonist ( terbutaline ) substantially reduced morbidity , hyperresponsiveness , and airways obstruction in patients with a spectrum of obstructive airways disease OBJECTIVE The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate ( a selective , long-acting beta(2)-adrenergic agonist that is the [ R , R ] isomer of formoterol ) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS This 12-week , multicenter , r and omized , double-blind , double-dummy , placebo- and active-controlled trial was conducted at 60 centers across the United States . Male and female patients aged > or=35 years with physician-diagnosed COPD received arformoterol ( 15 microg BID , 25 microg BID , or 50 microg QD via nebulizer ) , salmeterol ( 42 microg BID via metered dose inhaler ) , or placebo .  Pulmonary function was assessed by spirometry ; dyspnea , by the Transitional Dyspnea Index ( TDI ) ; and health status , by the St. George 's Respiratory Question naire ( SGRQ ) . Adverse events ( AEs ) were assessed by site personnel at all clinic visits ( screening , first dose at week 0 , and at weeks 3 , 6 , 9 , 12 , and follow-up ) . COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit . RESULTS A total of 717 patients received study medication . The demographic composition of all treatment arms was similar . The mean age was 62.9 years , 58 % were men , and mean baseline forced expiratory volume in 1 second ( FEV(1 ) ) was 1.2 L ( 41 % predicted ) . Mean improvement in trough FEV(1 ) over 12 weeks was significantly greater with all 3 arformoterol doses ( 15 microg BID , + 16.9 % ; 25 microg BID , + 18.9 % ; 50 microg QD , + 14.9 % ) and for salmeterol ( + 17.4 % ) relative to placebo ( + 6.0 % ; P < 0.001 ) . There were significantly greater improvements in the mean percentage change in FEV(1 ) AUC(0 - 12h ) from the predose value over 12 weeks ( 15 microg BID , 12.7 % , 25 microg BID , 13.9 % , 50 microg QD , 18.9 % ; salmeterol , 9.8 % ) versus placebo ( 2.7 % ; P < or= 0.001 ) ; all doses of arformoterol were statistically different from salmeterol for this end point ( P < or= 0.024 ) . At week 12 , TDI focal scores were significantly greater with all arformoterol doses compared with placebo ( mean [ 95 % CI ] : 15 microg BID , 0.97 [ 0.25 - 1.69 ] ; 25 microg BID , 1.08 [ 0.3 - 1.86 ] ; 50 microg QD , 1.04 [ 0.32 - 1.771 ) , suggesting treatment-associated improvement in dyspnea , however , the difference between salmeterol and placebo was not statistically significant ( 0.36 [ -0.40 to 1.12 ] ) . Improvements in health status , as measured using SGRQ total scores , were -2.6 to -3.6 U in the arformoterol groups , -4.4 U for salmeterol , and -1.2 U for placebo ; 95 % CI of differences versus placebo suggested significant improvement for the arformoterol 25 microg BID and salmeterol groups . There was a similar frequency of AEs and COPD exacerbations across all groups , including placebo . CONCLUSIONS In this trial , patients with moderate to severe COPD administered nebulized arformoterol over 12 weeks were observed to have significant and sustained improvements in airway function and dyspnea compared with placebo . The results also suggest that all doses of arformoterol , including the lowest dose ( 15 microg BID ) , were effective . Overall , nebulized arformoterol was well tolerated BACKGROUND Chronic obstructive pulmonary disease ( COPD ) patients are thought to have limited bronchodilator response , determined by changes in forced expiratory volume in 1s ( FEV(1 ) ) . In this study , we assessed bronchodilator response in patients with COPD using not only FEV(1 ) but also changes in lung volume expressed as forced vital capacity ( FVC ) and inspiratory capacity ( IC ) . We also evaluated the speed of onset of bronchodilation . METHODS Data were from 2 r and omized , double-blind , placebo-controlled studies ( 6-months [ NCT00206154 ] ; 12-months [ NCT00206167 ] ) in patients with moderate to very severe COPD . TREATMENTS twice daily budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9μg , budesonide/formoterol pMDI 160/9μg , formoterol dry powder inhaler ( DPI ) 9μg , placebo . RESULTS The percentage of patients with FEV(1 ) improvement ( ≥12 % and ≥200mL ; American Thoracic Society [ ATS ] criterion ) was 34 - 39 % post-albuterol ( screening ) . On day of r and omization ( DOR ) , a larger proportion receiving formoterol-containing treatment exhibited reversibility within 60min : FEV(1 ) ( 57 - 59 % ) . Similar results were seen for IC ( 50 - 61 % ) and FVC ( 57 - 67 % ) using the same improvement criteria . The time to ≥15 % FEV(1 ) improvement on DOR was 5.0 , 4.8 , and 7.3min for budesonide/formoterol 320/9 , budesonide/formoterol 160/9 , and formoterol , respectively . Time to ≥15 % FEV(1 ) improvement was better maintained with budesonide/formoterol than formoterol at treatment end ( 6 and 12 months ) . CONCLUSIONS Most patients with moderate to very severe COPD exhibit ATS-defined bronchodilator reversibility based on flow and lung volume measures after budesonide/formoterol pMDI or formoterol treatment . Budesonide/formoterol pMDI also has a rapid ( within 5min ) onset of bronchodilation that is maintained over time compared with formoterol alone 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 BACKGROUND Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease ( COPD ) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent . We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD . METHODS In a 1-year , r and omized , double-blind , double-dummy , parallel-group trial , we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year . RESULTS A total of 7376 patients were r and omly assigned to and treated with tiotropium ( 3707 patients ) or salmeterol ( 3669 patients ) . Tiotropium , as compared with salmeterol , increased the time to the first exacerbation ( 187 days vs. 145 days ) , with a 17 % reduction in risk ( hazard ratio , 0.83 ; 95 % confidence interval [ CI ] , 0.77 to 0.90 ; P<0.001 ) . Tiotropium also increased the time to the first severe exacerbation ( hazard ratio , 0.72 ; 95 % CI , 0.61 to 0.85 ; P<0.001 ) , reduced the annual number of moderate or severe exacerbations ( 0.64 vs. 0.72 ; rate ratio , 0.89 ; 95 % CI , 0.83 to 0.96 ; P=0.002 ) , and reduced the annual number of severe exacerbations ( 0.09 vs. 0.13 ; rate ratio , 0.73 ; 95 % CI , 0.66 to 0.82 ; P<0.001 ) . Overall , the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups . There were 64 deaths ( 1.7 % ) in the tiotropium group and 78 ( 2.1 % ) in the salmeterol group . CONCLUSIONS These results show that , in patients with moderate-to-very-severe COPD  , tiotropium is more effective than salmeterol in preventing exacerbations . ( Funded by Boehringer Ingelheim and Pfizer ; Clinical Trials.gov number , NCT00563381 . ) 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 RATIONALE Budesonide/formoterol and tiotropium are commonly used maintenance treatments for patients with chronic obstructive pulmonary disease . Combining these medications may provide additional benefits . OBJECTIVES To assess the efficacy and tolerability of budesonide/formoterol added to tiotropium in patients eligible for inhaled corticosteroid/long-acting beta(2)-agonist combination therapy . METHODS In this 12-week , r and omized , double-blind , parallel-group , multicenter study , after a 2-week run-in , 660 subjects ( 75 % male ; mean age , 62 yr ; FEV(1 ) , 1.1 L ; 38 % predicted normal ) , 40 years of age or older , received tiotropium ( 18 microg once daily )  plus either budesonide/formoterol ( 320/9 microg ) ( n = 329 ) or placebo ( n = 331 ) twice daily . MEASUREMENTS AND MAIN RESULTS Clinic predose ( primary outcome ) and postdose FEV(1 ) , predose and postdose forced vital capacity and inspiratory capacity , and health status were measured . Other outcomes included daily measurements taken at home ( pre- and postdose morning FEV(1 ) and peak expiratory flow , morning symptoms and activities , and morning reliever use ) , severe exacerbations , and tolerability . Over the treatment period , budesonide/formoterol plus tiotropium significantly increased predose FEV(1 ) by 6 % ( 65 ml ) and postdose by 11 % ( 123 and 131 ml at 5 and 60 min postdose , respectively ) versus tiotropium alone ( both P < 0.001 ) . Other outcomes all significantly improved with budesonide/formoterol plus tiotropium versus tiotropium alone . The number of severe exacerbations decreased by 62 % ( rate ratio , 0.38 ; 95 % confidence interval , 0.25 - 0.57 ; P < 0.001 ) . Both treatments were well tolerated . CONCLUSIONS In patients with chronic obstructive pulmonary disease , budesonide/formoterol added to tiotropium versus tiotropium alone provides rapid and sustained improvements in lung function , health status , morning symptoms and activities , and reduces severe exacerbations . Clinical trial registered with www . clinical trials.gov ( NCT00496470 )
BACKGROUND Pharmacological therapy for chronic obstructive pulmonary disease ( COPD ) is aim ed at relieving symptoms , improving quality of life and preventing or treating exacerbations .
Treatment tends to begin with one inhaler , and additional therapies are introduced as necessary .
For persistent or worsening symptoms , long-acting inhaled therapies taken once or twice daily are preferred over short-acting inhalers .
Several Cochrane review s have looked at the risks and benefits of specific long-acting inhaled therapies compared with placebo or other treatments .
However for patients and clinicians , it is important to underst and the merits of these treatments relative to each other , and whether a particular class of inhaled therapies is more beneficial than the others .
OBJECTIVES To assess the efficacy of treatment options for patients whose chronic obstructive pulmonary disease can not be controlled by short-acting therapies alone .
The review will not look at combination therapies usually considered later in the course of the disease .
How does long-term efficacy compare between different pharmacological treatments for COPD ?
2 .
Are there limitations in the current evidence base that may compromise the conclusions drawn by this network meta- analysis ?
If so , what are the implication s for future research ?
AUTHORS ' CONCLUSIONS This network meta- analysis compares four different classes of long-acting inhalers for people with COPD who need more than short-acting bronchodilators .