Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study A randomized, parallel-group study to evaluate the efficacy of umeclidinium/vilanterol 62.5/25 μg on health-related quality of life in patients with COPD Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial A 4-year trial of tiotropium in chronic obstructive pulmonary disease. One-Year Safety of Olodaterol Once Daily via Respimat® in Patients with GOLD 2–4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison Efficacy and safety of indacaterol 150 μg once-daily in COPD: a double-blind, randomised, 12-week study Cardiovascular outcomes with an inhaled beta2-agonist/corticosteroid in patients with COPD at high cardiovascular risk Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Efficacy of a new once-daily long-acting inhaled β2-agonist indacaterol versus twice-daily formoterol in COPD Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD A randomised trial of fluticasone furoate/vilanterol (50/25 μg; 100/25 μg) on lung function in COPD. Efficacy and safety of once-daily inhaled umeclidinium/vilanterol in Asian patients with COPD: results from a randomized, placebo-controlled study Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study Cardiovascular events in patients with COPD: TORCH Study results Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co‐Suspension Delivery Technology in Patients With COPD FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease. Cardiac safety profile of nebulized formoterol in adults with COPD: a 12-week, multicenter, randomized, double- blind, double-dummy, placebo- and active-controlled trial. Efficacy and tolerability of indacaterol 75 μg once daily in patients aged ≥40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies. A one-year trial of tiotropium Respimat plus usual therapy in COPD patients. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomised trial. Effect of once-daily indacaterol in a predominantly Chinese population with chronic obstructive pulmonary disease: a 26-week Asia-Pacific study. Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial. Effect of long-acting β2-agonists olodaterol and formoterol on heart rate and blood pressure in chronic obstructive pulmonary disease patients. Effect of background long-acting beta2-agonist therapy on the efficacy and safety of a novel, nebulized glycopyrrolate in subjects with moderate-to-very-severe COPD Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: the ENLIGHTEN study. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial
We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium , tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . This was a multicentre , r and omised , double-blind , placebo- and active-controlled , 26-week trial . Patients ( n = 2144 ) were r and omised ( 2:2:2:2:1 ) to receive once-daily QVA149 ( indacaterol 110 & mgr;g/glycopyrronium 50 & mgr;g ) , indacaterol 150 & mgr;g , glycopyrronium 50 & mgr;g , open-label tiotropium 18 & mgr;g or placebo . The primary end-point was trough forced expiratory volume in 1 s ( FEV1 ) at week 26 for QVA149 versus its monocomponents . Secondary end-points included dyspnoea , health status , rescue medication use and safety . Trough FEV1 at week 26 was significantly improved ( p<0.001 ) with QVA149 compared with indacaterol and glycopyrronium ( least squares mean ( LSM ) differences 0.07 L and 0.09 L , respectively ) , tiotropium and placebo ( LSM differences 0.08 L and 0.20 L , respectively ) ; these beneficial effects were sustained throughout the 26-week study . QVA149 significantly improved dyspnoea and health status versus placebo ( p<0.001 and p = 0.002 , respectively ) and tiotropium ( p = 0.007 and p = 0.009 , respectively ) at week 26 . All treatments were well tolerated . Dual bronchodilation with once-daily QVA149 demonstrated superior and clinical ly meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator , with a safety and tolerability profile similar to placebo , supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting & bgr;2-agonist combinations for the treatment of COPD . Dual indacaterol/glycopyrronium therapy was safe and more efficacious than monotherapy in moderate-to-severe COPD Background The combination of the inhaled muscarinic antagonist umeclidinium ( UMEC ) with the long-acting β2-agonist vilanterol ( VI ) has been shown to provide significant improvements in lung function compared with UMEC , VI , or placebo ( PBO ) in patients with chronic obstructive pulmonary disease ( COPD ) . This study was specifically design ed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population . Methods This was a 12-week multicenter , r and omized , double-blind , parallel-group , placebo-controlled study . Eligible patients were r and omized 1:1 to receive once-daily UMEC/VI 62.5/25 μg ( via ELLIPTA ® dry powder inhaler ) or PBO for 12 weeks . The primary endpoint was St George ’s Respiratory Question naire ( SGRQ ) total score at day 84 . Secondary efficacy endpoints included rescue albuterol use ( puffs/day ) over weeks 1–12 and trough forced expiratory volume in 1 second on day 84 . Adverse events were also assessed . Results A total of 496 patients were included in the intent-to-treat population in the UMEC/VI ( n=248 ) and PBO ( n=248 ) treatment groups . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in SGRQ total score at day 84 versus PBO ( difference between treatments in SGRQ total score change from baseline : −4.03 [ 95 % confidence interval { CI } : −6.28 , −1.79 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg result ed in a statistically significant reduction in rescue albuterol use versus PBO ( −0.7 puffs/day [ 95 % CI : −1.1 , −0.4 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO ( 122 mL [ 95 % CI : 71 , 172 ] ; P<0.001 ) . The incidence of adverse events was similar between treatments ( 32 % and 30 % of patients in the UMEC/VI 62.5/25 μg and PBO groups , respectively ) . Conclusion The results of this study demonstrate that treatment with UMEC/VI 62.5/25 μg provides clinical ly important improvements in SGRQ and rescue medication use  versus PBO in patients with moderate-to-very-severe COPD Background NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease ( COPD ) . The glycopyrronium bromide in COPD airways clinical study 1 ( GLOW1 ) evaluated the efficacy , safety and tolerability of NVA237 in patients with moderate-to-severe COPD . Methods Patients with COPD with a smoking history of ≥ 10 pack-years , post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 80 % and ≥ 30 % predicted normal and FEV1/forced vital capacity < 0.70 were enrolled . Patients were r and omized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry . The primary outcome measure was trough FEV1 at Week 12 . Results A total of 822 patients were r and omized to NVA237 ( n = 552 ) or placebo ( n = 270 ) . Least squares mean ( ± st and ard error ) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 ( 1.408 ± 0.0105 L ) , versus placebo ( 1.301 ± 0.0137 L ; treatment difference 108 ± 14.8 mL , p < 0.001 ) . Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26 . FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26 , and at all other visits and timepoints . Transition dyspnoea index focal scores and St. George 's Respiratory Question naire scores were significantly improved with NVA237 versus placebo at Week 26 , with treatment differences of 1.04 ( p < 0.001 ) and -2.81 ( p = 0.004 ) , respectively  . NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31 % ( p = 0.023 ) and use of rescue medication by 0.46 puffs per day ( p = 0.005 ) , versus placebo . NVA237 was well tolerated and had an acceptable safety profile , with a low frequency of cardiac and typical antimuscarinic adverse effects . Conclusions Once-daily NVA237 was safe and well tolerated and provided rapid , sustained improvements in lung function , improvements in dyspnoea , and health-related quality of life , and reduced the risk of exacerbations and the use of rescue medication . Trial registration Clinical Trials.gov : BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . Abstract The novel long-acting β2-agonist olo date rol demonstrated an acceptable safety profile in short-term phase II clinical studies . This analysis of four r and omized , double-blind , placebo-controlled , parallel-group , phase III studies ( 1222.11 , NCT00782210 ; 1222.12 , NCT00782509 ; 1222.13 , NCT00793624 ; 1222.14 , NCT00796653 ) evaluated the long-term safety of olo date rol once daily ( QD ) in a large cohort of patients with moderate to very severe ( Global initiative for chronic Obstructive Lung Disease 2–4 ) chronic obstructive pulmonary disease ( COPD ) . The studies compared olo date rol ( 5 or 10 μg ) QD via Respimat ® , formoterol 12 μg twice daily ( BID ) via Aerolizer ® ( 1222.13 and 1222.14 ) , and placebo for 48 weeks . Patients continued receiving background maintenance therapy , with ∼60 % receiving concomitant cardiovascular therapy and 25 % having a history of concomitant cardiac disease . Pre-specified analyses of pooled data assessed the adverse events ( AEs ) and serious AEs in the whole population , and in subgroups with cardiac disease , along with in-depth electrocardiogram and Holter monitoring . In total , 3104 patients were included in the safety analysis : 876 received olo date rol 5 μg , 883 received olo date rol 10 μg , 885 received placebos , and 460 received formoterol 12 μg BID . Overall incidence of on-treatment AEs ( 71.2 % ) , serious AEs ( 16.1 % ) , and deaths ( 1.7 % ) were balanced across treatment groups . Respiratory and cardiovascular AEs , including major adverse cardiac events , were reported at similar frequencies in placebo and active treatment groups . The safety profiles of both olo date rol 5 μg ( marketed and registered dose ) and 10 μg QD delivered via Respimat ® are comparable to placebo and formoterol BID in this population , with no safety signals identified Background Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease ( COPD ) that are greater than those derived from either treatment alone . The efficacy and safety of a fixed-dose combination ( FDC ) of aclidinium bromide , a long-acting muscarinic antagonist , and formoterol fumarate , a long-acting β2-agonist , in patients with moderate to severe COPD are presented . Methods In this 24-week double-blind study , 1692 patients with stable COPD were equally r and omized to twice-daily treatment with FDC aclidinium 400μg/formoterol 12μg ( ACL400/FOR12 FDC ) , FDC aclidinium 400μg/formoterol 6μg ( ACL400/FOR6 FDC ) , aclidinium 400μg , formoterol 12μg , or placebo administered by a multidose dry powder inhaler (Genuair ® /Pressair ® )*. Co primary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 ( FDCs versus aclidinium ) and change from baseline to week 24 in morning predose ( trough ) FEV1 ( FDCs versus formoterol ) . Secondary endpoints were change from baseline in St. George ’s Respiratory Question naire ( SGRQ ) total score and improvement in Transition Dyspnea Index ( TDI ) focal score at week 24 . Safety and tolerability were also assessed . Results At study end , improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium ( 108 mL and 87 mL , respectively ; p < 0.0001 ) . Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol ( 45 mL ; p = 0.0102 ) , a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC . Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end ( p < 0.0001 ) , with differences over placebo exceeding the minimal clinical ly important difference of ≥4 points and ≥1 unit , respectively . All treatments were well tolerated , with safety profiles of the FDCs similar to those of the monotherapies . Conclusions Treatment with twice-daily aclidinium 400μg/formoterol 12μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy ; clinical ly significant improvements in dyspnea and health status were evident compared with placebo . Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD .Trial registration Clinical trials.gov NCT01437397.*Registered trademarks of Almirall S.A. , Barcelona , Spain ; for use within the US as Pressair ® and Genuair ® within all other licensed territories 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 Indacaterol is a novel , once-daily ( o.d . ) inhaled , long-acting β2-agonist in development for chronic obstructive pulmonary disease ( COPD ) . This 12-week , double-blind study compared the efficacy , safety , and tolerability of indacaterol to that of placebo in patients with moderate-to-severe COPD . Methods Efficacy variables included 24-h trough FEV1 ( mean of 23 h 10 min and 23 h 45 min post-dose ) at Week 12 ( primary endpoint ) and after Day 1 , and the percentage of COPD days with poor control ( i.e. , worsening symptoms ) . Safety was assessed by adverse events ( AEs ) , mean serum potassium and blood glucose , QTc ( Fridericia ) , and vital signs . Results Patients were r and omised ( n = 416 , mean age 63 years ) to receive either indacaterol 150 μg o.d . ( n = 211 ) or placebo ( n = 205 ) via a single-dose dry-powder inhaler ; 87.5 % completed the study . Trough FEV1 ( LSM ± SEM ) at Week 12 was 1.48 ± 0.018 L for indacaterol and 1.35 ± 0.019 L for placebo , a clinical ly relevant difference of 130 ± 24 mL ( p < 0.001 ) . Trough FEV1 after one dose was significantly higher with indacaterol than placebo ( p < 0.001 ) . Indacaterol demonstrated significantly higher peak FEV1 than placebo , both on Day 1 and at Week 12 , with indacaterol-placebo differences ( LSM ± SEM ) of 190 ± 28 ( p < 0.001 ) and 160 ± 28 mL ( p < 0.001 ) , respectively . St and ardised AUC measurements for FEV1 ( between 5 min and 4 h , 5 min and 1 h , and 1 and 4 h post-dose ) at Week 12 were all significantly greater with indacaterol than placebo ( p < 0.001 ) , with LSM ( ± SEM ) differences of 170 ± 24 , 180 ± 24 , and 170 ± 24 mL ,  respectively . Indacaterol significantly reduced the percentage of days of poor control versus placebo by 22.5 % ( p < 0.001 ) and was also associated with significantly reduced use of rescue medication ( p < 0.001 ) . The overall rates of AEs were comparable between the groups ( indacaterol 49.3 % , placebo 46.8 % ) , with the most common AEs being COPD worsening ( indacaterol 8.5 % , placebo 12.2 % ) and cough ( indacaterol 6.2 % , placebo 7.3 % ) . One patient died in the placebo group . Serum potassium and blood glucose levels did not differ significantly between the two groups , and no patient had QTc > 500 ms . Conclusions Indacaterol 150 μg o.d . provided clinical ly significant and sustained bronchodilation , reduced rescue medication use , and had a safety and tolerability profile similar to placebo . Trial registration Objectives Cardiovascular disease ( CVD ) and chronic obstructive pulmonary disease ( COPD ) often coexist . We assessed the effect of inhaled COPD treatments on CVD outcomes and safety in patients with COPD and at heightened CVD risk . Methods The SUMMIT ( Study to Underst and Mortality and MorbidITy ) was a multicentre , r and omised , double-blind , placebo-controlled , event-driven trial in 16 485 patients with moderate COPD who had or were at high risk of CVD . Here , we assessed the prespecified secondary endpoint of time to first on-treatment composite CVD event ( CVD death , myocardial infa rct ion , stroke , unstable angina or transient ischaemic attack ( TIA ) ) by Cox regression and by clinician-reported CVD adverse events across the four groups : once-daily inhaled placebo ( n=4111 ) , long-acting beta2-agonist ( vilanterol ( VI ) 25 µg ; n=4118 ) , corticosteroid ( fluticasone furoate ( FF ) 100 µg ; n=4135 ) and combination therapy ( FF/VI ; n=4121 ) . Results Participants were predominantly middle-aged ( mean 65 ( SD 8) years ) men ( 75 % ) with overt CVD ( 66 % ) .  The composite CVD endpoint occurred in 688 patients ( first event : sudden death ( 35 % ) , acute coronary syndrome ( 37 % ) and stroke or TIA ( 23 % ) , and was not reduced in any treatment group versus placebo : VI ( HR 0.99 , 95 % CI 0.80 to 1.22 ) , FF ( HR 0.90 , 95 % CI 0.72 to 1.11 ) and their combination ( HR 0.93 , 95 % CI 0.75 to 1.14 ) . Outcomes were similar among all subgroups . Adverse events , including palpitations and arrhythmias , did not differ by treatment . Conclusions In patients with COPD with moderate airflow limitation and heightened CVD risk , treatment with inhaled VI , FF or their combination has an excellent safety profile and does not impact CVD outcomes . Trial registration number NCT01313676 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 Clinical manifestations of chronic obstructive pulmonary disease ( COPD ) , including airflow limitation , dyspnea , and activity limitation , ultimately lead to impaired health-related quality of life ( HRQoL ) . This 9-month , r and omized , double-blind , multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL , spirometric parameters , and exacerbations in 554 patients with moderate-to-severe COPD .  HRQoL was assessed using the St. George ’s Respiratory Question naire ( SGRQ ) and the new 8-item Visual Simplified Respiratory Question naire ( VSRQ ) , which is currently being vali date d. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end ( Month 9 ) . Mean ± SD baseline SGRQ total score was 47.4 ± 18.1 . Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score  vs placebo at study end ( 59.1 % vs 48.2 % , respectively ;  p = 0.029 ) . Tiotropium  significantly improved spirometric parameters ( forced expiratory volume in 1 second [ FEV1 ] : 0.11 ± 0.02 L vs 0.01 ± 0.02 L ; between-group difference : 0.10 ± 0.03 L , p = 0.0001 ) and reduced exacerbations vs placebo . Maintenance treatment with tiotropium provided significant and clinical ly relevant improvements in HRQoL , as measured by the SGRQ BACKGROUND Fluticasone furoate (FF)/vilanterol ( VI ) is a novel once-daily inhaled corticosteroid/long-acting β2-agonist combination therapy for COPD . We aim ed to assess the efficacy and safety of two strengths of FF/VI ( 100/25 μg ; 50/25 μg ) vs. individual components ( FF 100 μg , VI 25 μg ) and placebo over 24 weeks . METHODS Multicentre , r and omised , placebo-controlled , double-blind , parallel-group study of patients ( N = 1030 ) with moderate-to-severe COPD . All medication was administered once daily in the morning . Co- primary efficacy endpoints were : ( 1 ) weighted mean ( wm ) FEV1 ( 0 - 4 h post-dose on day 168 ) to assess acute lung function effects ; and ( 2 ) trough FEV1 ( 23 - 24 h post-dose on day 169 ) to assess long-lasting effects . Symptom-related outcomes were analysed and adverse events ( AEs ) assessed . RESULTS Main findings were : ( 1 ) the combination of FF/VI at a strength of 100/25 μg significantly ( p < 0.001 ) improved wm FEV1 ( 173 ml ) and trough FEV1 ( 115 ml ) vs. placebo . Similar effects were observed with FF/VI 50/25 μg ; ( 2 ) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 ( 48 ml , p = 0.082 ) , while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV1 ( 120 ml , p < 0.001 ) ; ( 3 ) VI 25 μg over 24 weeks improved lung function  vs. placebo significantly for wm FEV1 ( 103 ml , p < 0.001 ) and trough FEV1 ( 67 ml , p = 0.017 ) ; and ( 4 ) no safety signal was observed . CONCLUSIONS In subjects with moderate-to-severe COPD , FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks . Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg . All treatments were well tolerated . GSK study number : HZC112206 . Clinical Trials.gov : NCT01053988 Background Combination of the inhaled long-acting muscarinic antagonist umeclidinium ( UMEC ; GSK573719 ) with the long-acting β2-agonist vilanterol ( VI ) is an approved maintenance treatment for COPD in the US and EU . We compared the efficacy and safety of UMEC/VI with placebo in patients with COPD of Asian ancestry . Patients and methods In this 24-week , Phase III , multicenter , r and omized , double-blind , placebo-controlled , parallel-group study , patients were r and omized 1:1:1 to UMEC/VI 125/25 μg , UMEC/VI 62.5/25 μg , or placebo . The primary efficacy end point was trough forced expiratory volume in 1 second ( FEV1 ) on day 169 ; secondary end points were Transition Dyspnea Index ( TDI ) focal score at week 24 and weighted mean ( WM ) FEV1 over 0–6 hours postdose on day 1 . Additional end points and safety were also assessed . Results Both UMEC/VI 125/25 μg and UMEC/VI 62.5/25 μg statistically significantly improved trough FEV1 at day 169 versus placebo ( UMEC/VI 125/25 μg , 0.216 L , [ 95 % confidence interval [ CI ] 0.175–0.257 ] ; UMEC/VI 62.5/25 μg , 0.151 L , 95 % CI 0.110–0.191 ; both P<0.001 ) . Statistically significant improvements in TDI score were observed for both UMEC/VI groups versus placebo ( UMEC/VI 125/25 μg , 0.9 , 95 % CI 0.3–1.4 , P=0.002 ; UMEC/VI 62.5/25 μg , 0.7 , 95 % CI 0.1–1.2 , P=0.016 ) . On day 1 , both UMEC/VI groups improved 0–6-hour WM FEV1  versus placebo ( UMEC/VI 125/25 μg , 0.182 L 95 % CI 0.161–0.203 ; UMEC/VI 62.5/25 μg , 0.160 L , 95 % CI 0.139–0.181 ; both P<0.001 ) . Statistically significant improvements for UMEC/VI groups versus placebo were observed for rescue albuterol use at weeks 1–24 ( puffs/day , both P<0.001 ) . The incidence of adverse events was similar across groups . Conclusion In Asian patients with COPD , once-daily UMEC/VI 125/25 μg and UMEC 62.5/25 μg result ed in clinical ly meaningful and statistically significant improvements in lung-function end points versus placebo . Symptomatic and quality of life measures also improved . The safety profile of UMEC/VI was consistent with previous studies Background Aclidinium/formoterol is a twice-daily ( BID ) fixed-dose combination ( FDC ) in development for chronic obstructive pulmonary disease ( COPD ) . The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed . Methods In this 24-week double-blind , parallel-group , active- and placebo-controlled , multicentre Phase III study , patients ( ≥40 years , post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity < 70 % and FEV1 ≥30 % but < 80 % predicted normal ) were r and omised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg ( n = 385 ) or 400/6 μg ( n = 381 ) , aclidinium 400 μg ( n = 385 ) , formoterol 12 μg ( n = 384 ) or placebo ( n = 194 ) BID via Genuair ® /Pressair ® a . Results At Week 24 , aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1  versus aclidinium ( 125 mL [ 95 % CI : 90 , 160 ; p < 0 · 001 ] and 69 mL [ 95 % CI : 34 , 105 ; p < 0.001 ] , respectively ) and trough FEV1 versus formoterol ( 85 mL [ 95 % CI : 51 , 119 ; p < 0.001 ] and 53 mL [ 95 % CI : 19 , 87 ; p < 0.01 ] , respectively ; co- primary endpoints ) . Additionally , aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index ( TDI ) focal score versus placebo ( 1.29 units [ 95 % CI : 0.73 , 1.86 ; p < 0.001 ] and 1.16 units [ 95 % CI : 0.59 , 1.73 ; p < 0.001 ] , respectively ; secondary endpoint ) . All treatments were well tolerated , with safety profiles of the FDCs similar to those of placebo and monotherapy . Conclusions Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy , and dyspnoea versus placebo , with no increase in safety risk . Aclidinium/formoterol may be an effective treatment for patients with COPD .Trial registration Clinical Trials.gov : NCT01462942 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 Olo date rol is a long-acting β2-agonist with a 24-hour bronchodilator profile . Two replicate , r and omized , double-blind , placebo-controlled , parallel-group , Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olo date rol in patients with moderate to very severe chronic obstructive pulmonary disease ( COPD ) receiving usual-care background therapy . Methods Patients received olo date rol 5 μg or 10 μg or placebo once daily for 48 weeks . Co primary end points were forced expiratory volume in 1 second ( FEV1 ) area under the curve from 0 to 3 hours ( AUC0–3 ) response ( change from baseline ) , and trough FEV1 response at 12 weeks . Secondary end points included additional lung function assessment s , use of rescue medications , FEV1 AUC response from 0 to 12 hours , and Patient Global Rating over 48 weeks . Results Overall , 624 and 642 patients were evaluated in studies 1222.11 and 1222.12 , respectively . In both studies , olo date rol 5 μg and 10 μg significantly improved the FEV1 AUC0–3 response ( P<0.0001 ) and trough FEV1 ( study 1222.11 , P<0.0001 ; study 1222.12 , P<0.05 , post hoc ) at week 12 , with an incidence of adverse events comparable with that of placebo . Secondary end points supported the efficacy of olo date rol . Conclusion These studies demonstrate the long-term efficacy and safety of once-daily olo date rol 5 μg and 10 μg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy RATIONALE Indacaterol is the first once-daily , long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To demonstrate greater efficacy of indacaterol versus placebo on FEV(1 ) at 24 hours post dose ( trough ) after 12 weeks , to compare efficacy with placebo and tiotropium , and to evaluate safety and tolerability over 26 weeks . MEASUREMENTS Patients with moderate-to-severe COPD were r and omized to double-blind indacaterol 150 or 300 microg or placebo , or open-label tiotropium 18 microg , all once daily , for 26 weeks . The primary efficacy outcome was trough FEV(1 ) at 12 weeks . Additional analyses ( not adjusted for multiplicity ) included transition dyspnea index ( TDI ) , health status ( St George 's Respiratory Question naire [ SGRQ ] ) , and exacerbations . Serum potassium , blood glucose , and QTc interval were measured . RESULTS A total of 1,683 patients ( age , 63.3 yr ; post-bronchodilator FEV(1 ) , 56 % predicted ; FEV(1)/FVC , 0.53 ) were r and omized to the four treatment arms . Trough FEV(1 ) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium ( all P < 0.001 vs. placebo ) . At Week 26 , for indacaterol 150/300 microg , respectively , versus placebo , TDI increased ( 1.00/1.18 , P < 0.001 ) and SGRQ total score decreased ( -3.3/-2.4 , P < 0.01 ) ; corresponding results with tiotropium were 0.87 ( P < 0.001 ) for TDI and ( -1.0 , P = not significant ) for SGRQ total score . The incidence of adverse events , low serum potassium , high blood glucose , and prolonged QTc interval was similar across treatments . CONCLUSIONS Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD . Clinical trial registered with clinical trials.gov ( NCT 00463567 ) BACKGROUND The drug development process can be streamlined by combining the traditionally separate stages of dose-finding ( Phase IIb ) and confirmation of efficacy and safety ( Phase III ) using an adaptive seamless design . This approach was used in a clinical study of indacaterol , a novel once-daily ( od ) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD ( chronic obstructive pulmonary disease ) . METHODS The study comprised a dose-finding stage with dose selection after 14 days of treatment , and a second stage evaluating efficacy and safety during 26 weeks of treatment . The dose-finding stage included seven r and omized treatment arms : double-blind indacaterol 75 microg , 150 microg , 300 microg or 600 microg od , the beta(2)-adrenoceptor agonist formoterol 12 microg twice-daily or placebo , or the anticholinergic tiotropium 18 microg od open-label . An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician . The sponsor , investigators and patients remained blinded to the results . The indacaterol doses were selected using pre-set efficacy criteria for trough ( 24-h post-dose ) and early ( 1 - 4 h post-dose ) bronchodilator effect after 14 days , and all safety data . To qualify for selection , the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol , whichever was the highest value . Selected doses were continued into the second , 26-week stage . The two other indacaterol doses not selected , and formoterol , were discontinued following dose selection . RESULTS 801 patients with moderate-to-severe COPD were evaluated . Indacaterol 150 microg was the lowest effective dose , exceeding criteria for trough FEV(1 ) ( reference value 140 mL vs placebo ) and FEV(1 ) AUC(1 - 4 h ) ( reference value 220 mL vs placebo ) . No safety signal was observed with any dose of indacaterol . Thus , indacaterol 150 and 300 microg were selected to continue into the second , 26-week stage . CONCLUSION The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial Background : Long‐acting muscarinic antagonist (LAMA)/long‐acting & bgr;2‐agonist ( LABA ) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone . The Efficacy and Safety of PT003 , PT005 , and PT001 in Subjects with Moderate‐to‐Very Severe COPD ( PINNACLE‐1 ) ( NCT01854645 ) and the Multi‐Center Study to Assess the Efficacy and Safety of PT003 , PT005 , and PT001 in Subjects with Moderate‐to‐Very Severe COPD ( PINNACLE‐2 ) ( NCT01854658 ) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [ FF ] 18/9.6‐&mgr;g ( GFF ) metered dose inhaler ( MDI ) formulated using the Co‐Suspension Delivery Technology in patients with moderate‐to‐very severe COPD . Methods : These two phase III trials took place over 24 weeks and were r and omized , double blind , and placebo controlled ; 2,103 and 1,615 patients ( 40–80 years of age ) , respectively , were r and omized . Patients received GFF MDI , GP MDI 18 & mgr;g , FF MDI 9.6 & mgr;g , or placebo MDI ( all twice daily ) , or tiotropium 18 & mgr;g dry powder inhaler ( once daily in PINNACLE‐1 only [ open‐label active comparator ] ) . Efficacy and safety were assessed . Results : At week 24 , differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI , GP MDI , and FF MDI were 150 mL , 59 mL , and 64 mL in PINNACLE‐1 ( all P < .0001 ) and 103 mL , 54 mL , and 56 mL in PINNACLE‐2 ( all P < .001 ) , respectively . There were no significant safety findings ( incidence of adverse events was similar between treatment arms ) . Conclusions : We conclude that GFF MDI 18/9.6 & mgr;g demonstrated superiority over placebo and monocomponent MDIs and was well tolerated , thus providing an additional treatment option for patients with moderate‐to‐very severe COPD . Trial Registry : Clinical Trials.gov ; No. : NCT01854645 and No. NCT01854658 ; URL : www . clinical trials.gov RATIONALE Current Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease ( COPD ) if symptoms are not adequately controlled by a single bronchodilator . OBJECTIVES The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 ( indacaterol/glycopyrrolate ) , a fixed-dose combination of a long-acting β2-agonist ( indacaterol ) and a long-acting muscarinic antagonist ( glycopyrrolate ) , compared with its monocomponents and placebo in patients with moderate-to-severe COPD . METHODS FLIGHT1 and FLIGHT2 were 12-week , identical , multicenter , r and omized , double-blind , parallel-group , placebo- and active-controlled studies . Patients were r and omized ( 1:1:1:1 ) to indacaterol/glycopyrrolate ( 27.5/15.6 μg twice daily ) , indacaterol ( 27.5 μg twice daily ) , glycopyrrolate ( 15.6 μg twice daily ) , or placebo , all delivered via the Neohaler device . The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for st and ardized area under the curve from 0 - 12 hours for FEV1 at Week 12 . Secondary objectives included St. George 's Respiratory Question naire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo . MEASUREMENTS AND MAIN RESULTS In total , 2,038 patients were included in the pooled analysis . Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0 - 12 hours compared with its monocomponents ( P < 0.001 ) . Statistically and clinical ly meaningful improvements in St. George 's Respiratory Question naire total score , transition dyspnea index total score , and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo ( P < 0.001 ) . The safety profile was comparable across the treatment groups . CONCLUSIONS Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD . Clinical trial registered with www . clinical trials.gov ( NCT 01727141 and NCT 0171251 ) 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 BACKGROUND Indacaterol is the first once-daily , long-acting , inhaled β(2)-agonist bronchodilator for maintenance treatment of chronic obstructive pulmonary disease ( COPD ) . Two studies ( previously reported in a Congress abstract ) were performed in 2010 to provide efficacy and tolerability data to support the application for approval in the United States of indacaterol 75 μg once daily , a dose lower than that previously investigated in most studies . OBJECTIVE The primary objective was to evaluate the efficacy of indacaterol 75 μg once daily in terms of 24-hour post-dose ( " trough " ) forced expiratory volume in the first second of respiration ( FEV(1 ) ) compared with placebo after 12 weeks of treatment . METHODS Patients with moderate to severe COPD were r and omized to receive double-blind treatment with indacaterol 75 μg once daily ( n = 163 and 159 ) or placebo ( n = 160 and 159 ) for 12 weeks . In addition to trough FEV(1 ) after 12 weeks , rescue albuterol use , health status ( St. George 's Respiratory Question naire [ SGRQ ] ) , and tolerability were evaluated . Clinical ly relevant differences between active and placebo treatments were defined as ≥120 mL for trough FEV(1 ) and a decrease of ≥4 units in SGRQ total score . RESULTS Of patients enrolled in the 2 studies , 54 % were men , and 90 % and 94 % were white , with mean age 64 and 61 years . Mean duration of COPD was 7 years ; smoking history was 52 pack-years ; and 45 % and 37 % of patients were receiving inhaled corticosteroid therapy . At week 12 , indacaterol demonstrated clinical ly relevant bronchodilator efficacy , increasing trough FEV(1 ) by ≥120 mL versus placebo ( P < 0.001 ) , with significant bronchodilation maintained at all time points from 5 minutes to 24 hours post-dose . Over 12 weeks , relative to placebo , in patients receiving indacaterol therapy , rescue albuterol use was reduced by 1.2 and 0.7 puffs per day ( P < 0.01 ) , and the percentage of rescue-free days was increased by 13.7 and 8.4 ( P < 0.01 ) . At week 12 , the SGRQ total score differed in the indacaterol group versus the placebo group by -3.8 and -3.6 , respectively ( P ≤ 0.01 ) . Adverse events were reported for 49 % and 45 % of patients receiving indacaterol therapy , and for 46 % and 41 % receiving placebo . CONCLUSIONS Compared with placebo , indacaterol 75 μg once daily provided statistically significant and clinical ly relevant 24-hour bronchodilation and was well tolerated . In patients receiving indacaterol , the reduction in rescue albuterol use was statistically significant . Changes in health status also were statistically significant compared with placebo , although the differences of 3.6 and 3.8 units were below the predefined 4-unit level of clinical relevance . The results of these studies suggest that indacaterol 75 μg once daily is an effective maintenance treatment in patients with moderate to severe COPD . Clinical Trials.gov identifiers : NCT01072448 and NCT01068600 In this r and omised double-blind study , patients > or=40 years old with COPD , a smoking history of > or=10 pack-years , a pre-bronchodilator FEV(1 ) of < or=60 % predicted and an FEV(1)/FVC of < or=70 % received tiotropium 5 microg or placebo via Respimat inhaler once daily for 48 weeks . Other medications were permitted except inhaled anticholinergics . Co- primary endpoints were trough FEV(1 ) and the time to first exacerbation . Adverse events were followed and vital status regularly assessed . In all , 3991 patients ( mean age , 65 years [ SD , 9 years ] ) were evaluable . Mean baseline FEV(1 ) was 1.11 L ( 0.40 L ) or 40 % ( 12 % ) of predicted normal . Adjusted mean differences in trough FEV(1 ) and trough FVC at Week 48 ( tiotropium minus placebo ) were 102 and 168 ml respectively ( p < 0.0001 , both ) . Tiotropium delayed time to first exacerbation relative to placebo ( hazard ratio [ HR ] , 0.69 [ 95 % CI , 0.63 - 0.77 ] ) and time to first hospital-treated exacerbation ( HR , 0.73 [ 0.59 - 0.90 ] ) . SGRQ score at Week 48 was 2.9 units lower with tiotropium ( p < 0.0001 ) . Adverse and serious adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials . The rate ratio for a major adverse cardiovascular event during the treatment period + 30 days was 1.12 ( 0.67 - 1.86 ) . By the end of planned treatment ( Day 337 ) 52 patients on tiotropium ( incidence rate per 100 years , 2.94 ) and 38 on placebo ( 2.13 ) had died ( HR = 1.38 [ 0.91 - 2.10 ] ; p = 0.13 ) . Lung function , exacerbations and quality of life were improved by tiotropium 5 microg Respimat but a numerical imbalance was seen in all-cause mortality . The protocol is registered on the European Clinical Trials Data base as trial number 2006 - 001009 - 27 and in the Clinical Trials.gov data base as NCT00387088 RATIONALE Patients with chronic obstructive pulmonary disease ( COPD ) are afflicted by comorbidities . Few studies have prospect ively evaluated COPD comorbidities and mortality risk . OBJECTIVES To prospect ively evaluate COPD comorbidities and mortality risk . METHODS We followed 1,664 patients with COPD in five centers for a median of 51 months . Systematic ally , 79 comorbidities were recorded . We calculated mortality risk using Cox proportional hazard , and developed a graphic representation of the prevalence and strength of association to mortality in the form of a " comorbidome " . A COPD comorbidity index ( COPD specific comorbidity test [ COTE ] ) was constructed based on the comorbidities that increase mortality risk using a multivariate analysis . We tested the COTE index as predictor of mortality and explored whether the COTE index added predictive information when used with the vali date d BODE index . MEASUREMENTS AND MAIN RESULTS Fifteen of 79 comorbidities differed in prevalence between survivors and nonsurvivors . Of those , 12 predicted mortality and were integrated into the COTE index . Increases in the COTE index were associated with an increased risk of death from COPD -related ( hazard ratio [ HR ] , 1.13 ; 95 % confidence interval , 1.08 - 1.18 ; P < 0.001 ) and non- COPD -related causes ( HR , 1.18 ; 95 % confidence interval , 1.15 - 1.21 ; P < 0.001 ) . Further , increases in the BODE and COTE were independently associated with increased risk of death . A COTE score of greater than or equal to 4 points increased by 2.2-fold the risk of death ( HR , 2.26 - 2.68 ; P < 0.001 ) in all BODE quartile . CONCLUSIONS Comorbidities are frequent in COPD and 12 of them negatively influence survival . A simple disease-specific comorbidities index ( COTE ) helps assess mortality risk in patients with COPD BACKGROUND Once-daily combination treatment is an attractive maintenance therapy for COPD . However , the dose of inhaled corticosteroid to use in a once-daily combination is unknown . We compared two strengths of fluticasone furoate ( FF ) plus vilanterol ( VI ) , the same strengths of the individual components , and placebo . METHODS Multicentre , r and omised , 24-week , double-blind , placebo-controlled , parallel-group study in stable , moderate-to-severe COPD subjects ( N = 1224 ) . Subjects were r and omised to FF/VI ( 200/25 μg ; 100/25 μg ) , FF ( 200 μg ; 100 μg ) , VI 25 μg , or placebo , once daily in the morning . Co- primary efficacy endpoints ; 0 - 4 h weighted mean ( wm ) FEV(1 ) on day 168 , and change from baseline in trough ( 23 - 24 h post-dose ) FEV(1 ) on day 169 . The primary safety objective was adverse events ( AEs ) . RESULTS There was a statistically significant ( p < 0.001 ) increase in wm FEV(1 ) ( 209 ml ) and trough FEV(1 ) ( 131 ml ) for FF/VI 200/25 μg vs. placebo ; similar changes were seen for FF/VI 100/25 μg vs. placebo . Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1 ) ( 32 ml ) was not statistically significant ( p = 0.224 ) , the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1 ) ( 168 ml ) was significantly different ( p < 0.001 ) . VI 25 μg significantly improved wm and trough FEV(1 ) vs. placebo ( 185 ml and 100 ml , [ corrected ] respectively ) . No increase was seen in on-treatment AEs or serious AEs ( SAEs ) , with active therapy vs. placebo . CONCLUSIONS FF/VI provides rapid and significant sustained improvement in FEV(1 ) in subjects with moderate-to-severe COPD , which was not influenced by the dose of FF . These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study . GSK study number : HZC112207 . Clinical Trials.gov : NCT01054885 BACKGROUND AND OBJECTIVE This study , in a predominantly Chinese population , investigated the efficacy and safety of a once-daily ( o.d . ) inhaled ultra-long-acting β2 -agonist indacaterol for the treatment of moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . METHODS This is a 26-week , double-blind study on r and omized patients who received indacaterol 150 μg or 300 μg or placebo o.d .  The primary variable was trough forced expiratory volume in 1 s ( FEV1 , average of 23 h 10 min and 23 h 45 min post-dose values ) at Week 12 . Health status ( St George 's Respiratory Question naire , SGRQ ) , dyspnoea ( transition dyspnoea index , TDI ) and safety were evaluated over 26 weeks . RESULTS Of the 563 patients r and omized , 561 ( 89.8 % Chinese ) received treatment and 482 completed . At Week 12 , trough FEV1 improved significantly for indacaterol 150 and 300 μg versus placebo ( 1.32 , 1.29 vs 1.17 ; P < 0.001 for both comparisons ) , with differences exceeding the pre-specified minimal clinical ly important difference of 0.12 L. At Week 26 , TDI score was superior to placebo for indacaterol 150 and 300 μg ( 0.82 , 1.15 ; P < 0.01 ) , as was the percentage of patients with a clinical ly relevant improvement ( ≥1 point ) ( 74.1 % , 78.6 % vs 55.5 % ; P < 0.05 ) . Both doses provided ≥4-point improvements from baseline in SGRQ score at Week 26 that were numerically greater than placebo ( unadjusted means : -9.6 , -8.8 vs -7.0 ) , with a similar pattern in percentage of patients with clinical ly relevant improvements in SGRQ score ( 65.0 % , 61.5 % vs 60.6 % ) . Incidences of adverse events were comparable across treatment groups . CONCLUSIONS Indacaterol delivered effective bronchodilation with significant improvements in breathlessness and health status in this predominantly Chinese population Context Tiotropium , a new once-daily inhaled anticholinergic bronchodilator , has been shown to improve lung function in patients with chronic obstructive pulmonary disease ( COPD ) . Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients . Contribution This r and omized , parallel-group , double-blind , placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period . Caution s The study period was relatively short , and the beneficial effects were modest . The Editors Exacerbations of chronic obstructive pulmonary disease ( COPD ) can lead to costly and clinical ly significant consequences . Proven treatments for exacerbations are only modestly effective ( 1 , 2 ) . Recovery from even mild exacerbations may be protracted ( 3 ) . Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time ( 4 , 5 ) . Patients with severe exacerbations commonly seek care in emergency departments , and many of these patients are hospitalized . In 2000 , COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States ( 6 ) . Economic analyses suggest that hospitalization alone consumes up to 70 % of all medical expenses for patients with COPD ( 7 , 8) . Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need . An expert panel convened by the National Heart , Lung , and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations ( 9 ) . Tiotropium is a newly developed , once-daily inhaled anticholinergic bronchodilator . Because of its very slow dissociation from muscarinic M3 receptors , 1 inhaled dose produces sustained bronchodilation for at least 24 hours ( 10 ) . In controlled clinical trials , compared with placebo or the short-acting anticholinergic bronchodilator ipratropium , tiotropium improved lung function , dyspnea , and health-related quality of life in patients with COPD ( 11 , 12 ) . An analysis of adverse event reports su bmi tted during those studies suggested that tiotropium might also reduce exacerbation and COPD -related hospitalization rates . Therefore , we design ed a clinical trial to prospect ively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD . Methods Study Design Our study was a parallel-group , r and omized , double-blind , placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States . The sole intervention was tiotropium given by inhalation once daily . The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period . The protocol is consistent with the principles of Helsinki . The institutional review boards of participating medical centers approved the study . All trial participants provided written informed consent . Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants . We enrolled enough participants to ensure a minimum of 1800 r and omly assigned patients . Eligibility criteria included an age of 40 years or older , a cigarette smoking history of 10 pack-years or more , a clinical diagnosis of COPD , and an FEV1 of 60 % predicted or less and 70 % or less of the FVC . Exclusion criteria were a clinical diagnosis of asthma , a myocardial infa rct ion within the previous 6 months , a serious cardiac arrhythmia or hospitalization for heart failure within the previous year , known moderate to severe renal impairment , moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction , narrow-angle glaucoma , current radiation or chemotherapy for a malignant condition , or inability to give informed consent . We also excluded patients who took systemic corticosteroids at unstable doses , or in regular daily doses of 20 mg or more of prednisone ( or equivalent ) , or who had not fully recovered from an exacerbation for at least 30 days before the first study visit . We gathered baseline data on respiratory disease and other relevant medical history by question naire . Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a central ly generated blocked r and omization list . We generated a single r and omization and assigned blocks to centers . We provided r and omly assigned patients with training and detailed instructions on the use of the dry powder inhalation device ( H and iHaler , Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach , Germany ) ( 13 ) . Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites . The double-blind remained in place until all patients were clinical ly complete or until a serious adverse event required unblinding . Each morning during the trial , patients inhaled 1 capsule of tiotropium ( 18 g ) or 1 identical placebo capsule . Participants otherwise received usual medical care , except that they could not take any open-label anticholinergic bronchodilator . They continued taking all other respiratory medications ( including inhaled corticosteroids and long-acting -agonists ) , and primary providers were allowed to prescribe additional medications according to medical need . Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions . For purpose s of recall , patients kept a daily diary throughout the treatment period , recording information about specific respiratory symptoms , medications taken for exacerbations , clinic visits , and hospitalizations . We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits . We assessed study drug adherence by query and by counting returned capsules .  Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits . We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy . However , patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits . All open-label bronchodilators and the study drug were withheld overnight before spirometry . Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations ( 14 , 15 ) . Objectives We aim ed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations . Outcome Measures The co primary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation . We defined an exacerbation as a complex of respiratory symptoms ( increase or new-onset ) of more than 1 of the following : cough , sputum , wheezing , dyspnea , or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids , hospitalization , or both . The study team at each site requested discharge summaries for all hospitalizations , wherever they occurred . We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event result ed in a hospitalization . We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours . Admissions to nursing homes or other extended care facilities were not considered hospitalizations . Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation , the frequencies of exacerbations and of exacerbation-related health care utilization ( hospitalizations , hospitalization days , unscheduled clinic visits , antibiotic treatment days , and systemic corticosteroid treatment days ) , the frequencies of all-cause hospitalizations and hospitalization days , and results of spirometry . Statistical Analysis We analyzed the data by using a modified intention-to-treat principle . Therefore , we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event ( for the time-to-event end points ) or their withdrawal from the trial . For the time-to-event end points , we censored patients without an event at the end of their participation in the trial . Although we intended to follow all patients for the full 6 months , some patients were lost to follow-up . We h and led missing data by using longitudinal data analysis methods ( spirometry ) , analysis of observed data only ( number of events ) , or analysis methods for censored data ( time-to-event data ) . For the percentage of patients with an event , we considered that patients who discontinued the study drug therapy before having an event did not have an event . We analyzed the co primary end points by using a CochranMantelHaenszel test with center as a stratum . We used a stepwise procedure to test the percentage of patients with an exacerbation and , if rejected , to test percentage of patients with a hospitalization due to COPD exacerbation , each at a 2-sided level of 0.05 . Because of the prespecified closed testing procedure , no adjustment for multiplicity was required . We calculated that a sample size of 1800 patients would have 80 % power to 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 Cardiovascular comorbidities are common in chronic obstructive pulmonary disease ( COPD ) , and elevated heart rate reflects increased cardiovascular risk over time , which is associated with unfavourable neurohumoral activation . Long-acting β2-agonists ( LABAs ) are established treatments in COPD , but potentially increase heart rate . We report a post hoc pooled analysis of the effect of olo date rol ( 5 or 10 μg ) or formoterol ( 12 μg ) on heart rate and blood pressure ( BP ) in Global Initiative for Chronic Obstructive Lung Disease Stage 2 - 4 COPD patients . METHODS Four r and omised , double-blind , placebo-controlled , Phase III studies were analysed . Changes in heart rate and systolic/diastolic BP were measured before and after dosing with the study medication at each visit . RESULTS At each study visit , the increase in pre-dose heart rate was numerically lower with both LABAs compared with placebo . Systolic and diastolic BP were decreased with all treatments . Short-term ( pre-dose to 40 min post-dose ) effects of drug administration on heart rate were small and similar for all treatment arms ( between -3 and + 1 beats per minute ) . CONCLUSION Heart rate and BP were not adversely influenced in this study involving long-term administration of olo date rol or formoterol in patients with moderate-to-severe COPD . This supports the cardiovascular safety of LABAs in COPD maintenance treatment Background Phase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution ( GLY ) in subjects with COPD . Secondary analyses were performed to examine the effect of background long-acting beta2-agonist ( LABA ) use on the efficacy and safety of nebulized GLY . Methods In two 12-week placebo-controlled studies ( GOLDEN 3 and GOLDEN 4 ) and one 48-week , open-label active-controlled study ( GOLDEN 5 ) , a total of 2,379 subjects were stratified by background LABA use ( LABA-yes : n=861 ; LABA-no : n=1,518 ) and r and omized to placebo vs GLY 25 or 50 µg twice daily , or GLY 50 µg twice daily vs tiotropium ( TIO ) 18 µg once daily . Lung function , patient-reported outcomes , exacerbations , and safety were assessed . Results Compared with placebo , pooled data from the 12-week studies showed significant improvements from baseline with GLY 25 and 50 µg across LABA subgroups in trough FEV1 ( LABA-yes : 0.101 and 0.110 L ; LABA-no : 0.092 and 0.101 L , respectively ; P<0.001 ) and St George ’s Respiratory Question naire total score ( SGRQ ; LABA-yes : −2.957 and −3.888 ; LABA-no : −3.301 and −2.073 , respectively ; P<0.05 ) . Incidence of treatment-emergent adverse events ( TEAEs ) was similar in LABA subgroups , and lower in GLY 25 µg vs placebo . In the 48-week active-controlled study , GLY and TIO both showed improvement from baseline across LABA subgroups in FEV1 ( LABA-yes : 0.106 and 0.092 L ; LABA-no : 0.096 and 0.096 L , respectively ) and in SGRQ total score ( LABA-yes : −5.190 and −3.094 ; LABA-no : −4.368 and −4.821 , respectively ) . Incidence of TEAEs was similar between GLY and TIO , and across LABA subgroups . Exacerbation rates were similar across treatments and LABA subgroups , and cardiovascular events of special interest were more frequent in the LABA-no subgroup . Nebulized GLY , combined with LABA , did not generate any additional safety signals . Conclusion Nebulized GLY  demonstrated efficacy and was well tolerated up to 48 weeks in subjects with COPD with/without background LABA BACKGROUND QVA149 is an inhaled , once-daily fixed-dose dual bronchodilator combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium ( NVA237 ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . We investigated the safety and efficacy of QVA149 over 52 weeks . METHODS This 52-week , multicenter , double-blind , parallel-group ,  placebo-controlled  study r and omized ( 2:1 ) patients with moderate-to-severe COPD to once-daily  QVA149 ( 110 μg indacaterol/50 μg glycopyrronium ) or placebo delivered via the Breezhaler device . Primary endpoint was safety and tolerability for treatment-emergent adverse events ( AEs ) . Secondary endpoints included safety based on vital signs , electrocardiograms ( ECGs ) , laboratory evaluations , and pre-dose forced expiratory volume in 1 s ( FEV1 ) . RESULTS Of 339 patients r and omized , QVA149 [ n = 226 ] , placebo [ n = 113 ] ; 76.9 % male , mean age : 62.6 years , post-bronchodilator FEV1 : 57.4 % predicted , 83.5 % completed study . A smaller percentage of patients discontinued in the QVA149 group ( 14.2 % ) compared with placebo ( 21.2 % ) . Overall incidence of AEs was similar in the QVA149 ( 57.8 % ) and placebo ( 56.6 % ) groups , with most AEs being mild to moderate in severity . The numerical differences in some AEs observed could be at least in part explained by differences in baseline patient characteristics . No clinical ly relevant differences were observed between treatment groups for vital signs or ECG parameters . The five deaths reported were unrelated to study medication ( QVA149 , n = 4 [ 1.8 % ] ; placebo , n = 1 [ 0.9 % ] ) . QVA149 demonstrated rapid and clinical ly meaningful bronchodilation sustained over 52 weeks versus placebo . CONCLUSION QVA149 demonstrated a good safety and tolerability profile , providing rapid and sustained bronchodilation over 52 weeks in patients with moderate-to-severe COPD . Clinical Trials.gov identifier : NCT01120717 BACKGROUND Chronic obstructive pulmonary disease ( COPD ) often coexists with cardiovascular disease . Treatments for airflow limitation might improve survival and both respiratory and cardiovascular outcomes . The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid , fluticasone furoate , and the long-acting β agonist , vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk . METHODS In this double-blind r and omised controlled trial ( SUMMIT ) done in 1368 centres in 43 countries , eligible patients were aged 40 - 80 years and had a post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) between 50 % and 70 % of the predicted value , a ratio of post-bronchodilator FEV1 to forced vital capacity ( FVC ) of 0·70 or less , a smoking history of at least 10 pack-years , and a score of 2 or greater on the modified Medical Research Council dyspnoea scale . Patients had to have a history , or be at increased risk , of cardiovascular disease . Enrolled patients were r and omly assigned ( 1:1:1:1 ) through a central ised r and omisation service in permuted blocks to receive once daily inhaled placebo , fluticasone furoate ( 100 μg ) , vilanterol ( 25 μg ) , or the combination of fluticasone furoate ( 100 μg ) and vilanterol ( 25 μg ) . The primary outcome was all-cause mortality , and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s ( FEV1 ) and a composite of cardiovascular events . Safety analyses were performed on the safety population ( all patients who took at least one dose of study drug ) and efficacy analyses were performed on the intention-to-treat population ( safety population minus sites excluded with Good Clinical Practice violations ) . This study is registered with Clinical Trials.gov , number NCT01313676 . FINDINGS Between Jan 24 , 2011 , and March 12 , 2014 , 23 835 patients were screened , of whom 16 590 were r and omised . 16 485 patients were included in the intention-to-treat efficacy population ; 4111 in the placebo group , 4135 in the fluticasone furoate group , 4118 in the vilanterol group , and 4121 in the combination group . Compared with  placebo , all-cause mortality was unaffected by combination therapy ( hazard ratio [ HR ] 0·88 [ 95 % CI 0·74 - 1·04 ] ; 12 % relative reduction ; p=0·137 ) or the components ( fluticasone furoate , HR 0·91 [ 0·77 - 1·08 ] ; p=0·284 ; vilanterol , 0·96 [ 0·81 - 1·14 ] ; p=0·655 ) , and therefore secondary outcomes should be interpreted with caution . Rate of decline in FEV1 was reduced by combination therapy ( 38 mL per year [ SE 2·4 ] vs 46 mL per year [ 2·5 ] for placebo , difference 8 mL per year [ 95 % CI 1 - 15 ] ) with similar findings for fluticasone furoate ( difference 8 mL per year [ 95 % CI 1 - 14 ] ) , but not vilanterol ( difference -2 mL per year [ 95 % CI -8 to 5 ] ) . Combination therapy had no effect on composite cardiovascular events ( HR 0·93 [ 95 % CI 0·75 - 1·14 ] ) with similar findings for fluticasone furoate ( 0·90 [ 0·72 - 1·11 ] ) and vilanterol ( 0·99 [ 0·80 - 1·22 ] ) . All treatments reduced the rate of moderate and severe exacerbation . No reported excess risks of pneumonia ( 5 % in the placebo group , 6 % in the combination group , 5 % in the fluticasone furoate group , and 4 % in the vilanterol  group ) or adverse cardiac events ( 17 % in the placebo group , 18 % in the combination group , and 17 % in the fluticasone furoate group , and 17 % in the vilanterol group ) were noted in the treatment groups . INTERPRETATION In patients with moderate COPD and heightened cardiovascular risk , treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes , reduced exacerbations , and was well tolerated . Fluticasone furoate , alone or in combination with vilanterol , seemed to reduce FEV1 decline . FUNDING GlaxoSmithKline
Background : Long-acting muscarinic antagonists ( LAMAs ) and long-acting β2-agonists ( LABAs ) are the mainstay of maintenance therapy for chronic obstructive pulmonary disease ( COPD ) .
Although previous studies have supported inhaled long-acting bronchodilators ( ILABs ) for overall cardiovascular safety , the risk of specific cardiovascular outcomes such as arrhythmia , heart failure and stroke is still unknown .