Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee ADRB2 polymorphisms and budesonide/formoterol responses in COPD. The severity of airways obstruction as a determinant of treatment response in COPD An economic assessment of inhaled formoterol dry powder versus ipratropium bromide pressurized metered dose inhaler in the treatment of chronic obstructive pulmonary disease. Efficacy and Tolerability of Budesonide/Formoterol in One Hydrofluoroalkane Pressurized Metered-Dose Inhaler in Patients with Chronic Obstructive Pulmonary Disease Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. The TORCH (TOwards a Revolution in COPD Health) survival study protocol Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison Cardiovascular safety of salmeterol in COPD. 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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 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 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 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 RATIONALE Chronic obstructive pulmonary disease ( COPD ) is characterized by an accelerated decline in lung function . No drug has been shown conclusively to reduce this decline . OBJECTIVES In a post hoc analysis of the Toward a Revolution in COPD Health ( TORCH ) study , we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg , either component alone or placebo , on the rate of post-bronchodilator FEV(1 ) decline in patients with moderate or severe COPD . METHODS A r and omized , double-blind , placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries . Of 6,112 patients from the efficacy population , 5,343 were included in this analysis . MEASUREMENTS AND MAIN RESULTS Spirometry was measured every 24 weeks for 3 years . There were 26,539 on-treatment observations . The adjusted rate of decline in FEV(1 ) was 55 ml/year for placebo , 42 ml/year for salmeterol , 42 ml/year for fluticasone propionate , and 39 ml/year for salmeterol plus fluticasone propionate . Salmeterol plus fluticasone propionate reduced the rate of FEV(1 ) decline by 16 ml/year compared with placebo ( 95 % confidence interval [ CI ] , 7 - 25 ; P < 0.001 ) . The difference was smaller for fluticasone propionate and salmeterol compared with placebo ( 13 ml/year ; 95 % CI , 5 - 22 ; P = 0.003 ) . Rates of decline were similar among the active treatment arms . FEV(1 ) declined faster in current smokers and patients with a lower body mass index , and varied between world regions . Patients who exacerbated more frequently had a faster FEV(1 ) decline . CONCLUSIONS Pharmacotherapy with salmeterol plus fluticasone propionate , or the components , reduces the rate of decline of FEV(1 ) in patients with moderate-to-severe COPD , thus slowing disease progression . Clinical trial ( GSK Study Code SCO30003 ) registered with www . clinical trials.gov ( NCT00268216 ) Only long-term home oxygen therapy has been shown in r and omised controlled trials to increase survival in chronic obstructive pulmonary disease ( COPD ) . There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators , alone or in combination , on mortality in patients with COPD , despite their known benefit in reducing symptoms and exacerbations . The “ TOwards a Revolution in COPD Health ” ( TORCH ) survival study is aim ing to determine the impact of salmeterol/fluticasone propionate ( SFC ) combination and the individual components on the survival of COPD patients . TORCH is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled study . Approximately 6,200 patients with moderate-to-severe COPD were r and omly assigned to b.i.d . treatment with either SFC ( 50/500 µg ) , fluticasone propionate ( 500 µg ) , salmeterol ( 50 µg ) or placebo for 3 yrs . The primary end-point is all-cause mortality ; secondary end-points are COPD morbidity relating to rate of exacerbations and health status , using the St George 's Respiratory Question naire . Other end-points include other mortality and exacerbation end-points , requirement for long-term oxygen therapy , and clinic lung function . Safety end-points include adverse events , with additional information on bone fractures . The first patient was recruited in September 2000 and results should be available in 2006 . This paper describes the “ TOwards a Revolution in COPD Health ” study and explains the rationale behind it 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 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 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 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 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 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 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 objectives of this study were to compare the efficacy and safety of salmeterol xinafoate ( 50 and 100 microg b.i.d . ) with that of placebo , when added to existing therapy , in the treatment of patients with chronic obstructive pulmonary disease ( COPD ) . Six hundred and seventy four patients were r and omized to receive either salmeterol 50 microg b.i.d . , salmeterol 100 microg b.i.d . , or placebo treatment for a period of 16 weeks . The results showed a significant improvement in daily symptom scores noted for patients taking either 50 microg ( p=0.043 ) or 100 microg b.i.d . salmeterol ( p=0.01 ) compared with placebo , with a corresponding decrease in additional daytime salbutamol requirements for both salmeterol groups . The same pattern was reflected for night-time symptoms and additional salbutamol use . During treatment , forced expiratory volume in one second ( FEV1 ) measurements improved significantly in each salmeterol group , with up to a 7 % improvement observed at the end of the study . Although no difference was observed between treatment groups for the distance walked in 6 min , patients treated with salmeterol 50 microg b.i.d . were significantly less breathless than those treated with placebo after their 6 min walk , after 8 weeks ( p=0.024 ) and 16 weeks ( p=0.004 ) of therapy . Adverse events were similar in all three groups except for tremor , which was significantly higher in the 100 microg b.i.d . salmeterol group ( p=0.005 ) compared both with 50 microg b.i.d . salmeterol and placebo . Salmeterol offered further positive improvement to the effect of therapy in patients with chronic obstructive pulmonary disease when added to their existing regimens . This clinical improvement was similar both with 50 and 100 microg b.i.d . dosage , although the group receiving 50 microg b.i.d . tolerated the drug better than those receiving 100 microg b.i.d . salmeterol 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 ) 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 OBJECTIVES To investigate the determinants of patient withdrawal from our study , and the effect of these withdrawals on the outcome of treatment with inhaled corticosteroids in patients with COPD . DESIGN A double-blind , placebo-controlled , r and omized trial . SETTING Eighteen outpatient centers in the United Kingdom . PARTICIPANTS Seven hundred fifty-one patients with stable COPD defined clinical ly and as baseline postbronchodilator FEV(1 ) > or = 0.8 L and < 85 % predicted , FEV(1)/FVC ratio < 70 % , and FEV(1 ) change after albuterol < 10 % of predicted . INTERVENTION R and om assignment of either 500 microg bid of inhaled fluticasone propionate ( FP ) using a spacer device or an identical placebo inhaler . Treatment was continued for 3 years or until patients withdrew from follow-up . MEASUREMENTS AND RESULTS Postbronchodilator FEV(1 ) was measured on three occasions before r and omization and every 3 months thereafter . Health status was assessed by the disease-specific St. George Respiratory Question naire ( SGRQ ) and the modified short-form 36 question naire ( SF-36 ) at baseline and every 6 months . Three hundred thirty-nine patients withdrew , of whom 156 patients received FP .  Prescription of frequent courses of oral prednisolone was the most common reason for withdrawing as specified in the protocol ( 69 patients in the FP group withdrew due to respiratory symptoms , compared with 93 patients in the placebo group ) . This explained the significantly greater dropout of placebo-treated patients that was most evident when FEV(1 ) was < 50 % predicted . Patients withdrawing had a significantly more rapid decline in health status , measured by both the SGRQ and the SF-36 ( p < 0.001 ) . Those withdrawing from the placebo group had a more rapid decline in FEV(1 ) and more exacerbations than the FP-treated groups . Baseline FEV(1 ) was lower in dropouts than in patients completing the study receiving placebo , but there was no difference between the respective groups receiving FP . CONCLUSIONS Patients who withdrew from follow-up were those with the most rapidly deteriorating health status and lung function . Losing these patients from the final analysis can reduce the power of a study to achieve its primary end point The TOwards a Revolution in COPD Health ( TORCH ) study was a 3-yr multicentre trial of 6,112 patients r and omised to salmeterol ( Salm ) , fluticasone propionate ( FP ) , a Salm/FP combination ( SFC ) or placebo ( P ) .  Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed . For four regions , 3-yr all-cause hospitalisation , medication and outpatient care costs were calculated . The sample was restricted to the 21 countries ( n = 4,237 ) in which European quality of life five-dimension ( EQ-5D ) data were collected in order to estimate the number of quality -adjusted life years ( QALYs ) . Regression models were fitted to survival , study medication cost , other medication cost and EQ-5D data in order to estimate total cost , number of QALYs and cost per QALY , adjusted for missing data and region . SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars ( USD ) compared with P ( 95 % confidence interval 21,400–123,500 USD ) . Estimates for Salm versus P ( 197,000 USD ) and FP versus P ( 78,000 USD ) were less favourable . The US estimates were greater than those from other regions ; for SFC versus P , the cost per QALY was 77,100 ( 46,200–241,700 ) USD compared to 24,200 ( 15,200–56,100 ) USD in Western Europe . Compared with P , SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone , and is , therefore , preferred to these monotherapies on the grounds of cost-effectiveness Chronic obstructive pulmonary disease ( COPD ) is associated with a large economic and social burden . Few economic studies have examined the benefits of inhaled therapy for patients with COPD . This 16-week study examined the cost-effectiveness of salmeterol in this patient group . Patients with a history of COPD were r and omised to treatment with salmetrol 50 mcg  ( 229 patients )  or placebo  ( 227 patients ) twice daily administered by metered-dose inhaler in addition to normal therapy . Forced expiratory volume ( FEV1 ) was measured and patients recorded the impact of their symptoms in a daily diary . Health status was assessed using the St Georges Respiratory Question naire . A significantly higher proportion of salmeterol-treated patients had an increase of > 15 % in FEV1 . Salmeterol patients had a higher mean proportion of symptom-free days and nights than those in the placebo group . More salmeterol patients had a clinical ly significant improvement in health status . Total healthcare costs were increased in the salmeterol group , but hospital and GP visit costs and concurrent COPD medication costs were lower . The reduction in hospital costs was sufficient to offset a substantial portion of the acquisition cost of salmeterol . Addition of salmeterol to COPD patients ' current therapy improved lung function , health status at the expense of a modest increase in costs compared with usual therapy 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 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 In the past , the role of long-acting beta(2- ) agonists in chronic obstructive pulmonary disease ( COPD ) relative to other agents has been unclear . OBJECTIVES To compare the effect of adding salmeterol ( 50 microg bid ) or placebo to concurrent anticholinergic therapy on symptom scores , quality of life , prebronchodilator lung function and exacerbations in patients with moderately severe COPD . METHODS This was a double-blind , r and omized , parallel-group study in patients aged 40 years or older receiving anticholinergic medication . Patients were r and omly assigned to treatment with  placebo ( n=207 ) or salmeterol  ( n=201 ) via a Diskus/Accuhaler inhaler for 24 weeks . RESULTS The morning trough ( pre study drug ) forced expiratory volume in 1 s ( FEV(1 ) ) increased significantly above baseline levels among the salmeterol-treated patients . Improvement in FEV(1 ) was greater in the salmeterol group than in the placebo group at four weeks ( difference 0.06 L , P<0.005 ) , eight weeks ( 0.06 L , P<0.005 ) and 16 weeks ( 0.05 L , P<0.05 ) after the start of treatment . There was a nonsignificant trend in favour of salmeterol after 24 weeks of treatment ( P=0.198 ) . Improvements in morning peak flow were significantly greater in the salmeterol group over 24 weeks ( P<0.01 ) . Although symptom scores were numerically higher in the salmeterol group than in the placebo group and there was less requirement for rescue bronchodilator use , these differences were not statistically significant . In the salmeterol group , fewer patients had exacerbations of COPD , and there was a trend toward an improved quality of life . The safety profile of the two groups was similar . CONCLUSIONS Salmeterol has a beneficial effect when added to existing anticholinergic therapy in patients with COPD . The regular use of salmeterol for six months was not associated with worsening of the underlying airflow obstruction ; rather , there was a tendency for the trough FEV1 to improve above the baseline levels over the treatment period 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 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 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 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 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 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 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 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 The Chronic Respiratory Question naire ( CRQ ) and the St George 's Respiratory Question naire ( SGRQ ) are the two most widely used quality of life question naires in chronic obstructive pulmonary disease ( COPD ) . A study was undertaken to compare directly the self-administered version of the CRQ and the SGRQ with respect to feasibility , internal consistency , validity , and sensitivity to changes result ing from bronchodilator therapy . METHODS One hundred and forty four patients with moderate or severe COPD were r and omly assigned to receive three months of treatment with either salmeterol , salmeterol + ipratropium bromide , or placebo .  Quality of life was measured at baseline and after 12 weeks of treatment . RESULTS The proportions of missing values per patient were low for both question naires ( 0.54 % for the CRQ and 2 % for the SGRQ ) . The internal consistency was good for both question naires ( Cronbach 's alpha coefficients > /= 0.84 for the CRQ and > /= 0.76 for the SGRQ ) . Factor analysis confirmed the original domain structure of the CRQ but not of the SGRQ . Correlations with forced expiratory volume in one second ( FEV(1 ) ) % predicted and peak expiratory flow rate ( PEFR ) were low for both question naires but better for the SGRQ than for the CRQ . The ability to discriminate between subjects with different levels of FEV(1 ) was somewhat better for the SGRQ . The correlations with symptom scores were comparable for both question naires . Cross sectionally , the scores of the two question naires were moderately to highly correlated ( coefficients ranged from 0.35 to 0.72 ) . Longitudinally , these correlations were lower ( coefficients ranged from 0.17 to 0.54 ) but were still significant . The CRQ total and emotions score and the SGRQ symptoms score were the most responsive to change . The SGRQ symptoms domain was the only domain where the improvement in patients receiving combination treatment crossed the threshold for clinical relevance . CONCLUSIONS Since this analysis of reliability , validity , and responsiveness to change did not clearly favour one instrument above the other , the choice between the CRQ and the SGRQ can be based on other considerations such as the required sample size or the availability of reference values 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 Inhaled formoterol is a potent selective β2‐agonist with rapid onset and at least 12‐h duration of bronchodilation . The aim of the study was to compare the bronchodilating effect of inhaled formoterol dry powder ‘ dp ) 12 μg b.i.d . with salbutamol dp 400 μg q.i.d . and placebo in patients with reversible obstructive airway disease ‘ ROAD ) . The study design consisted of a closed 12‐week double‐blind , placebo‐controlled , multicenter trial followed by an open noncomparative , multicenter , 12‐month follow‐up trial , in which the tolerability of formoterol dp was assessed . A total of 304 patients ‘ 146 men , 158 women ) aged 18‐79 years , ill during 0.1‐64 years , were r and omized . No demographic or baseline differences were found among the different treatment groups .  The bronchodilating effect of formoterol  , assessed by morning premedication PEFR , was significantly superior to placebo ‘ P < 0.0001 ) and salbutamol ‘ P < 0.0001 ) . Efficacy was maintained during the open follow‐up study with 12 μg b.i.d . in most of the patients . A few patients , however , needed 24 μg b.i.d . to control their ROAD . Formoterol 12 μg b.i.d . significantly reduced morning and evening asthma symptoms and sleep disturbances , and reduced significantly the need for rescue medication . The tolerability of the three treatment groups was comparable . In conclusion , formoterol 12 μg dp b.i.d . was significantly superior to both salbutamol 400 μg dp q.i.d . and placebo  , and reduced asthma symptoms significantly . Overall , formoterol showed a tolerability profile comparable to that of salbutamol , and no tachyphylaxis was observed during 1 year of treatment 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 The prevalence of chronic obstructive pulmonary disease ( COPD ) in women is increasing worldwide . Women may have greater susceptibility to COPD progression than men , and differences in efficacy and safety of respiratory medications by gender are largely unexplored . We aim ed to determine whether the response to treatment in women with COPD differed from men in a large , 1-year double-blind trial ( ' TRISTAN ' ) . In a sensitivity analysis , we compared 539 male and 180 female COPD patients , who were r and omized to the saLmeterol/fluticasone combination 50/500mcg bid or placebo for 12 months .  Combination therapy  improved pre-treatment FEV1 significantly more than placebo in women by 152 ml ( 95 % confidence interval 95 - 208 ) and in men by 127 ml ( 94 - 159 ) . Similarly , a reduction in COPD exacerbation rates of 31 % in women ( 9 - 48 % ) and of 23 % in men ( 8 - 35 % ) was observed . Combination therapy  reduced COPD exacerbations requiring treatment with oral corticosteroids by 36 % in women and by 41 % in men . Finally , combination treatment produced a better improvement in health status than placebo with a decrease in the SGRQ scores in women by -2.3 ( -4.6 - 0.1 ) and in men by -2.1 ( -3.5 to -0.8 ) . No gender interaction was found for any outcome . Treatments were well tolerated with no difference in the frequency of adverse events in women and men . In this trial , therapy with the salmeterol/fluticasone combination produced significant improvements compared to placebo on all main endpoints and the magnitude of these improvements was similar for both men and women BACKGROUND 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 This article is based on a study first published in Allergy . The bronchodilating effect of the long acting beta 2-agonist formoterol dey powder ( dp ) 12 micrograms twice daily was compared to salbutamol 400 micrograms four times daily and placebo in patients with reversible obstructive airway disease . The study design consisted of a closed 12-week double-blind , placebo-controlled , multicentre trial followed by an open noncomparative , multicentre 12-month follow-up trial , in which tolerability of formoterol dp was assessed . A total of 304 patients aged 18 - 79 years were r and omized . The bronchodilating effect of formoterol , assessed by morning premedication peak flow rate , was significantly superior to placebo ( p < 0.0001 ) and salbutamol ( p < 0.001 ) . Efficacy was maintained during the open follow-up study . Formoterol 12 micrograms twice daily significantly reduced morning and evening asthma symptoms and sleep disturbances , and significantly reduced the need for rescue medication . In conclusion , formoterol 12 micrograms dp twice daily was significantly superior to both salbutamol 400 micrograms dp four times daily and placebo , and reduced asthma symptoms significantly . Overall , formoterol showed a tolerability profile comparable to that of salbutamol , and no tachyphylaxis was observed during one year of treatment The efficacy and safety of salmeterol alone was compared with the combination of salmeterol plus ipratropium and with placebo during long-term treatment in patients with stable chronic obstructive pulmonary disease . In addition , the single-dose effect in response to the first dose of treatment was studied over 12 h. The patients ( n=144 ; age 64+/-7 yrs , forced expiratory volume in one second ( FEV1 ) 44+/-11 % pred ) participated in a three-centre double-blind double-placebo parallel group study and were r and omized after a run-in period of 2 weeks to receive either salmeterol 50 microg b.i.d . , salmeterol 5 microg b.i.d . plus ipratropium 40 microg q.i.d . or placebo for a period of 12 weeks . The single-dose study demonstrated that salmeterol produced a significant increase in FEV1 ( peak of 7 % pred ) and specific airway conductance ( sGaw ) ( maximum of 60 % baseline ) for > or = 12 h. The combination of salmeterol plus ipratropium elicited a greater bronchodilator response ( 11 % and 94 % increases respectively ) than salmeterol alone during the first 6 h after inhalation . During treatment there were significant improvements in daytime symptom scores and morning peak expiratory flow in both the salmeterol and the salmeterol plus ipratropium groups ( p<0.001 ) , with an associated decrease in the use of rescue salbutamol . Improvements in FEV1 and sGaw were greater in the salmeterol plus ipratropium group than in the patients receiving only salmeterol . Thirty-five patients had an exacerbation ; 11 ( 23 % ) in the salmeterol group ( versus placebo NS ) , six ( 13 % ) in the salmeterol plus ipratropium group ( versus placebo p<0.01 ) and 18 ( 36 % ) in the placebo group . In conclusion , in patients with severe stable chronic obstructive pulmonary disease , long-term treatment with either salmeterol alone or salmeterol plus ipratropium is safe and effective . There was added benefit from the combination therapy in terms of improvement in airways obstruction , but not for improvement in symptom control or need for rescue salbutamol The need to manage the key symptoms of chronic obstructive pulmonary disease ( COPD ) ( breathlessness , cough and sputum ) is an important treatment objective . Viozan ( sibenadet HCl , AR-C68397AA ) is a novel dual D2 dopamine receptor , beta2-adrenoceptor agonist , which combines conventional bronchodilatory activity with the sensory nerve modulation afforded by dopamine agonism . The efficacy of this agent in relieving patient symptoms has been determined in a series of large-scale clinical studies ; the results of a 3-month , placebo-controlled multi-centre study are reported . Effect on patient symptoms was determined using a novel patient-reported assessment instrument , the Breathlessness , Cough and Sputum Scale ( BCSS ) .  Patients with smoking-related COPD were required to complete a 2-week baseline period before being r and omized to one of three treatment groups ; sibenadet ( 500 microg three times daily ) plus placebo ( twice daily ) ; salmeterol ( 50 microg twice daily ) plus placebo ( three times daily ) ; placebo ( twice daily ) plus a second placebo ( three times daily ) . All treatments were delivered via pressurized metered dose inhaler ( pMDI ) for 12 weeks . From enrolment , patients were required to complete daily diary cards to record symptoms of breathlessness , cough and sputum , medication use and adverse events . The primary outcome measure was the difference between the mean BCSS total score measured over the baseline period and the mean BCSS total score in the final 4 weeks of the treatment period . Secondary measures included assessment of lung function , rescue medication use , exacerbations , health-related quality of life , opinion of efficacy and safety . Although an initial reduction in BCSS total score ( indicating symptom improvement ) was seen with sibenadet therapy , this effect was not maintained for the study duration . Salmeterol therapy , however , result ed in a sustained reduction in BCSS total score . No notable benefit over placebo was seen in lung function , exacerbations or health-related quality of life with either active treatment . While the results of this study failed to demonstrate sustained efficacy with sibenadet therapy , they do indicate the value of symptom assessment in the clinical evaluation of new drugs for the treatment of COPD The TORCH ( Towards a Revolution in COPD Health ) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease . These include collection of off-treatment exacerbation data , analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids ( ICS ) prior to r and omisation . When effective medications are available to patients who withdraw , inclusion of off-treatment data can mask important treatment effects on exacerbation rates . Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments . The negative binomial model is currently the best approach to statistical analysis of exacerbation rates , while analysis of time to exacerbation can supplement this approach . In the TORCH trial , exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments . Retrospective subgroup analysis suggests  ICS reduced exacerbation rates compared with placebo , regardless of prior use of ICS before entry to the study . Factorial analysis provides an alternative analysis for trials with combinations of treatments , but assumes no interaction between treatments , an assumption which can not be verified by a significance test . No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment .  All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) Changes in health-related quality of life ( HRQoL ) were evaluated in patients with chronic obstructive pulmonary disease ( COPD ) following treatment with placebo , salmeterol 50 microg twice a day or 100 microg twice a day by metered-dose inhaler . Patients completed the disease-specific St. George 's Respiratory Question naire ( SGRQ ) and the Medical Outcomes Study Short Form 36 ( SF-36 ) at baseline and after 16 wk of treatment . Data from 283 patients ( 95 patients in the placebo group and 94 in each salmeterol group ) were available for HRQoL analysis . Apart from a small difference in ages , all treatment groups were well matched at baseline in terms of forced expiratory volume in one second ( FEV1 ) and HRQoL scores . Compared with placebo , salmeterol 50 microg twice a day was associated with significant improvements in SGRQ " Total " and " Impacts " scores which exceeded the threshold for a clinical ly significant change . This was not seen with salmeterol 100 microg twice a day . Changes in SGRQ and SF-36 scores correlated . They also showed a weak but significant relationship with FEV1 . This study has shown that a modest change in lung function may be associated with clinical ly significant gain in health and well-being in COPD patients 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 Introduction : R and omised controlled trials ( RCTs ) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published . These usually include drugs with symptomatic benefits and have significant withdrawal rates
BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is a respiratory disease that causes progressive symptoms of breathlessness , cough and mucus build-up .
It is the fourth or fifth most common cause of death worldwide and is associated with significant healthcare costs .
Inhaled long-acting beta2-agonists ( LABAs ) are widely prescribed to manage the symptoms of COPD when short-acting agents alone are no longer sufficient .
Twice-daily treatment with an inhaled LABA is aim ed at relieving symptoms , improving exercise tolerance and quality of life , slowing decline and even improving lung function and preventing and treating exacerbations .
OBJECTIVES To assess the effects of twice-daily long-acting beta2-agonists compared with placebo for patients with COPD on the basis of clinical ly important endpoints , primarily quality of life and COPD exacerbations .