Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Pooled safety analysis of the fixed-dose combination of indacaterol and glycopyrronium (QVA149), its monocomponents, and tiotropium versus placebo in COPD patients. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial The lung function profile of once-daily tiotropium and olodaterol via Respimat® is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler® (ENERGITO® study) Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4) 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 Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Cardiovascular events in patients with COPD: TORCH Study results Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease. Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. 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 current Global initiative for chronic Obstructive Lung Disease ( GOLD ) treatment strategy recommends the use of one or more bronchodilators according to the patient ’s airflow limitation , their history of exacerbations , and symptoms . The LANTERN study evaluated the effect of the long-acting β2-agonist (LABA)/long-acting muscarinic antagonist ( LAMA ) dual bronchodilator , QVA149 ( indacaterol/glycopyrronium ) , as compared with the LABA/inhaled corticosteroid , salmeterol/fluticasone ( SFC ) , in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year . Methods In this double-blind , double-dummy , parallel-group study , 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were r and omized ( 1:1 ) to QVA149 110/50 μg once daily or SFC 50/500 μg twice daily for 26 weeks . The primary endpoint was noninferiority of QVA149 versus SFC for trough forced expiratory volume in 1 second ( FEV1 ) at week 26 . Results Overall , 676 patients completed the study . The primary objective of noninferiority between QVA149 and SFC in trough FEV1 at week 26 was met . QVA149 demonstrated statistically significant superiority to SFC for trough FEV1 ( treatment difference [Δ]=75 mL ; P<0.001 ) . QVA149 demonstrated a statistically significant improvement in st and ardized area under the curve ( AUC ) from 0 hours to 4 hours for FEV1 ( FEV1 AUC0–4h ) at week 26 versus SFC ( Δ=122 mL ; P<0.001 ) . QVA149 and SFC had similar improvements in transition dyspnea index focal score , St George Respiratory Question naire total score , and rescue medication use . However , QVA149 significantly reduced the rate of moderate or severe exacerbations by 31 % ( P=0.048 ) over SFC . Overall , the incidence of adverse events was comparable between QVA149 ( 40.1 % ) and SFC ( 47.4 % ) . The incidence of pneumonia was threefold lower with QVA149 ( 0.8 % ) versus SFC ( 2.7 % ) . Conclusion These findings support the use of the LABA/LAMA , QVA149 as an alternative treatment , over LABA/inhaled corticosteroid , in the management of moderate-to-severe COPD patients ( GOLD B and GOLD D ) with a history of ≤1 exacerbation in the previous year BACKGROUND Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2 ) agonist is more protective than a once-daily longacting β(2 ) agonist alone against exacerbations of chronic obstructive pulmonary disease ( COPD ) is unknown . We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone . METHODS We did two replicate double-blind parallel-group 1 year trials . Both studies began on Sept 25 , 2009 . Study 1 ended on Oct 31 , 2011 , and study 2 on Oct 17 , 2011 . Eligible patients were aged 40 years or older , had a history of COPD , a smoking history of 10 or more pack-years , a ratio of forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity of 0·70 or less after bronchodilators ( and an FEV(1 ) of 70 % or less of predicted ) , and a documented history of one or more moderate or severe disease exacerbations in the year before screening . Patients were r and omly assigned ( 1:1:1:1 ) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg , 100 μg , or 200 μg fluticasone furoate once daily . Our primary endpoint was the yearly rate of moderate and severe exacerbations . The trials were analysed separately and a pooled analysis was also done . These trials are registered with Clinical Trials.gov ( NCT01009463 and NCT01017952 ) . FINDINGS 1622 patients in study 1 and 1633 patients in study 2 were r and omly assigned . In study 1 , no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group ( mean 0·90 events vs 1·05 events per year ; ratio 0·9 [ 95 % CI 0·7 - 1·0 ] ) . Because of the statistical hierarchy used , we could not infer significance for the 50 μg and 100 μg groups . In study 2 , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( p=0·0398 for the 50 μg group , 0·0244 for the 100 μg group , and 0·0004 for the 200 μg group ) . In the pooled analysis , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( 0·0141 for the 50 μg group , < 0·0001 for the 100 μg group , and 0·0003 for the 200 μg group ) . Nasopharyngitis was the most frequently reported adverse event in both studies . Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone . Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group . INTERPRETATION Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD  in patients with a history of exacerbation , but was also associated with an increased pneumonia risk . FUNDING GlaxoSmithKline BACKGROUND To further assess the safety profile of the fixed-dose combination of indacaterol and glycopyrronium ( QVA149 ) and its monocomponents ; we investigated the impact of individual patient-level factors and time by integrating the patient-level safety data from the QVA149 clinical programme with relevant information from the independent indacaterol and glycopyrronium safety data bases . METHODS Data from 11,404 patients with chronic obstructive pulmonary disease ( COPD ) were pooled from 14 clinical studies of QVA149 , indacaterol and glycopyrronium of ≥3 month 's duration with at least two of the treatment groups :  QVA149 110/50 μg , glycopyrronium 50 μg , indacaterol 150 μg , placebo or tiotropium 18 μg . Overall hazard ratio ( HR ) was assessed between the active treatments and placebo and in various subgroups related to severity of airways obstruction , inhaled corticosteroid use , cardiovascular risk factors , sex , age and body mass index for death , serious cases of cardio- and cerebrovascular ( CCV ) events , major adverse cardiovascular events ( MACEs ) , pneumonia , COPD exacerbations requiring hospitalisation or atrial flutter/fibrillation ( AF/F ) . RESULTS The HR for QVA149 versus placebo showed no significant increase in the overall risk for death ( HR [ 95 % confidence interval ] : 0.93 [ 0.34 - 2.54 ] ) ; CCV events ( 0.60 [ 0.29 - 1.24 ] ) ; MACE ( 1.04 [ 0.45 - 2.42 ] ) ; pneumonia ( 1.10 [ 0.54 - 2.25 ] ) ; COPD exacerbations ( 0.60 [ 0.40 - 0.91 ] ) ; and AF/F ( 1.03 [ 0.49 - 2.18 ] ) . Similar results were observed for indacaterol , glycopyrronium and tiotropium versus placebo for overall risk and in analysed subgroups . CONCLUSIONS There was no increase in the risk for the investigated safety endpoints for the fixed-dose combination QVA149 , and it had a comparable safety profile as its monocomponents and tiotropium versus placebo 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 BACKGROUND Combination long-acting bronchodilator treatment might be more effective than long-acting bronchodilator monotherapy for the treatment of chronic obstructive pulmonary disease ( COPD ) . We aim ed to compare the efficacy and safety of umeclidinium ( UMEC ) plus vilanterol ( VI ) with tiotropium ( TIO ) monotherapy , UMEC monotherapy , or VI monotherapy in patients with moderate to very severe COPD . METHODS In two multicentre , r and omised , blinded , double-dummy , parallel-group , active-controlled trials , eligible patients ( current or former smokers aged 40 years or older with an established clinical history of COPD ) were r and omly assigned in 1:1:1:1 ratio to UMEC 125 μg plus VI 25 μg , UMEC 62·5 μg plus VI 25 μg , TIO 18 μg , and either VI 25 μg ( study 1 ) or UMEC 125 μg ( study 2 ) . All study drugs were used once daily for 24 weeks . TIO was delivered via the H and iHaler inhaler and all other active treatments were delivered via the ELLIPTA dry powder inhaler . R and om assignment ( by a vali date d computer-based system ) was done by centre and was not stratified . All patients and physicians were masked to assigned treatment during the studies . The primary efficacy endpoint of both studies was trough forced expiratory volume in 1 s ( FEV1 ) on day 169 , which was analysed in the intention-to-treat population . Both studies are registered with Clinical Trials.gov , numbers NCT01316900 ( study 1 ) and NCT01316913 ( study 2 ) . FINDINGS 1141 participants were recruited in study 1 , and 1191 in study 2 . For study 1 , after exclusions , 208 , 209 , 214 , and 212 patients were included in the intention-to-treat analyses for TIO monotherapy , VI monotherapy , UMEC 125 μg plus VI 25 μg , and UMEC 62·5 μg plus VI 25 μg , respectively . For study 2 , 215 , 222 , 215 , and 217 patients were included in the intention-to-treat analyses  for TIO monotherapy , UMEC monotherapy , UMEC 125 μg plus VI 25 μg , and UMEC 62·5 μg plus VI 25 μg , respectively . In both studies , we noted improvements in trough FEV1 on day 169 for both doses of UMEC plus VI compared with TIO monotherapy ( study 1 , UMEC 125 μg plus VI 25 μg : 0·088 L [ 95 % CI 0·036 to 0·140 ; p=0·0010 ] ; study 1 , UMEC 62·5 μg plus VI 25 μg : 0·090 L [ 0·039 to 0·141 ; p=0·0006 ] ; study 2 , UMEC 125 μg plus VI 25 μg : 0·074 L [ 0·025 to 0·123 ; p=0·0031 ] ; study 2 , UMEC 62·5 μg plus VI 25 μg : 0·060 L [ 0·010 to 0·109 ; nominal p=0·0182 ] ) . Both doses of UMEC plus VI also improved trough FEV1 compared with VI monotherapy ( UMEC 125 μg plus VI 25 μg : 0·088 L [ 0·036 to 0·140 ; p=0·0010 ] ; UMEC 62·5 μg plus VI 25 μg : 0·090 L [ 0·039 to 0·142 ; p=0·0006 ] , but not compared with UMEC 125 μg monotherapy ( UMEC 125 μg plus VI 25 μg : 0·037 L [ -0·012 to 0·087 ; p=0·14 ] ; UMEC 62·5 μg plus VI 25 μg : 0·022 L [ -0·027 to 0·072 ; p=0·38 ] ) . All treatments produced improvements in dyspnoea and health-related quality of life ; we noted no significant differences in symptoms , health status , or risk of exacerbation between UMEC plus VI and TIO . The most common on-treatment , severe-intensity adverse event in both studies was acute exacerbation of COPD ( 1 - 4 [ < 1 - 2 % ] patients across treatment groups in study 1 and 1 - 6 [ < 1 - 3 % ] patients in study 2 ) . We recorded five to 15 ( 2 - 7 % ) on-treatment serious adverse events across treatment groups in study 1 , and nine to 22 ( 4 - 10 % ) in study 2 . We noted no substantial changes from baseline in vital signs , clinical laboratory findings , or electrocardiography findings in any of the treatment groups . INTERPRETATION Combination treatment with once-daily UMEC plus  VI improved lung function compared with VI monotherapy and TIO monotherapy in patients with COPD . Overall our results suggest that the combination of UMEC plus VI could be beneficial for the treatment of moderate to very severe COPD . FUNDING GlaxoSmithKline Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease ( COPD ) and a history of at least one moderate to severe exacerbation in the previous 12 months . METHODS In this multicentre , r and omised , blinded , double-dummy , parallel group study , we enrolled patients aged 40 years or older with severe COPD and at least one exacerbation within the previous year . We used a computer-generated sequence to r and omly allocate patients ( 1:1 ; stratified by baseline inhaled corticosteroid use , with the balance of treatments maintained at country level ) to receive either indacaterol ( 150 μg ) or tiotropium ( 18 μg ) once-daily for 52 weeks . Our primary and key secondary objectives were to investigate whether indacaterol was non-inferior to tiotropium  for trough forced expiratory volume in 1 s ( FEV1 ) at week 12 ( primary endpoint ) , and for rate of exacerbations at week 52 ( secondary endpoint ) . Analysis population s for the primary and key secondary endpoints were per- protocol sets . The safety set included all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT00845728 . FINDINGS Between March 16 , 2009 , and July 5 , 2012 , we enrolled and r and omly allocated 3444 patients : 1723 to indacaterol and 1721 to tiotropium . At week 12 , the estimated least squares mean trough FEV1 difference between the groups was -0.011 L ( least squares mean with indacaterol [ n=1450 ] 1.134 L [ SE 0.008 ] vs tiotropium [ n=1467 ] 1.145 L [ 0.008 ] ; one-sided 97.5 % CI lower limit -0.026 L ; p<0.0001 ) . The lower limit of the 97.5 % CI was above the prespecified non-inferiority margin of -0.055 L , suggesting that indacaterol was non-inferior to tiotropium . Indacaterol did not show non-inferiority in terms of annualised exacerbation rates : 0.79 ( indacaterol , n=1529 ) versus 0.61 ( tiotropium , n=1543 ) ; ratio 1.29 ( one-sided 97.5 % CI upper limit 1.44 ) . In the safety set , we recorded no between-group difference in the number of patients who had adverse events  ( indacaterol 1119 [ 65 % ] of 1721 patients vs tiotropium 1065 [ 62 % ] of 1718 patients ) or serious adverse events  ( indacaterol , 263 [ 15 % ] of 1721 patients vs tiotropium , 255 [ 15 % ] of 1718 patients ) . Respiratory disorders , particularly worsening of COPD , were the most common adverse events ( COPD : indacaterol , 747 [ 43 % ] of 1721 patients and tiotropium , 665 [ 39 % ] of 1718 patients ) and serious adverse events ( COPD : indacaterol , 147 [ 9 % ] of 1721 patients and tiotropium , 121 [ 7 % ] of 1718 patients ) . INTERPRETATION Indacaterol and tiotropium provided clinical ly relevant improvements in lung function with comparable safety profiles . Tiotropium afforded greater protection from exacerbations , although the absolute number of events was small and the difference between treatments is of uncertain clinical importance . The present data offer evidence consistent with current guidelines . FUNDING Novartis Pharma AG Background Umeclidinium ( UMEC ; long-acting muscarinic antagonist ) plus vilanterol ( VI ; long-acting beta2 agonist [ LABA ] ) and the LABA/inhaled corticosteroid fluticasone propionate/salmeterol ( FP/SAL ) are approved maintenance treatments for chronic obstructive pulmonary disease ( COPD ) . This 12-week , multicentre , double-blind , parallel-group , double-dummy study compared the efficacy and safety of these treatments in symptomatic patients with moderate-to-severe COPD with no exacerbations in the year prior to enrolment . Methods Patients ( n = 717 ) were r and omised 1:1 to once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 500/50 mcg . Endpoints included 0–24 h weighted mean ( wm ) forced expiratory volume in 1 s ( FEV1 ) ( Day 84 ; primary ) , trough FEV1 ( Day 85 ; secondary ) , other lung function endpoints , symptoms , quality of life ( QoL ) and safety . Results Improvements with UMEC/VI versus FP/SAL were 0.080 L ( 95 % confidence interval : 0.046–0.113 ; wmFEV1 ) and 0.090 L ( 0.055–0.125 ; trough FEV1 ) ( both p < 0.001 ) . UMEC/VI statistically significantly improved all other lung function measures versus FP/SAL . Both treatments demonstrated a clinical ly meaningful improvement in symptoms ( Transition Dyspnoea Index ≥1 unit ) and QoL ( St George ’s Respiratory Question naire Total score ≥4 unit decrease from baseline ) over 12 weeks . The incidence of adverse events was 28 % ( UMEC/VI ) and 29 % ( FP/SAL ) ; nasopharyngitis and headache were most common . Conclusions Once-daily UMEC/VI 62.5/25 mcg over 12 weeks result ed in significant and sustained improvements in lung function versus twice-daily FP/SAL 500/50 mcg in patients with moderate-to-severe COPD and with no exacerbations in the year prior to enrolment . Trial Registration NCT01822899 Registration date : March 28 , Background Tiotropium + olo date rol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD . Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation , there is substantial use in individuals at lower risk . This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens . Objective The study aim ed to assess the effect on lung function of once-daily tiotropium + olo date rol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 ( moderate to severe ) COPD . Methods This was a r and omized , double-blind , double-dummy , four-treatment , complete crossover study in which participants received once-daily tiotropium + olo date rol ( 5/5 µg and 2.5/5 µg ) via Respimat ® and twice-daily salmeterol + fluticasone propionate ( 50/500 µg and 50/250 µg ) via Accuhaler ® for 6 weeks . The primary end point was change in forced expiratory volume in 1 second ( FEV1 ) area under the curve from 0 hour to 12 hours ( AUC0–12 ) relative to the baseline after 6 weeks . Results Tiotropium + olo date rol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0–12 compared to salmeterol + fluticasone propionate ( improvements from baseline were 317 mL and 295 mL with tiotropium + olo date rol 5/5 µg and 2.5/5 µg , and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg , respectively ) . Tiotropium + olo date rol was  superior to salmeterol + fluticasone propionate  in lung function secondary end points , including FEV1 area under the curve from 0 hour to 24 hours ( AUC0–24 ) . Conclusion Once-daily tiotropium + olo date rol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate . Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD Efficacy and safety of tiotropium+olo date rol fixed-dose combination ( FDC ) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease ( COPD ) in two replicate , r and omised , double-blind , parallel-group , multicentre , phase III trials . Patients received tiotropium+olo date rol FDC 2.5/5 μg or 5/5 μg , tiotropium 2.5 μg or 5 μg , or olo date rol 5 μg delivered once-daily via Respimat inhaler over 52 weeks . Primary end points were forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 3 h ( AUC0–3 ) response , trough FEV1 response and St George 's Respiratory Question naire ( SGRQ ) total score at 24 weeks . In total , 5162 patients ( 2624 in Study 1237.5 and 2538 in Study 1237.6 ) received treatment . Both FDCs significantly improved FEV1 AUC0–3 and trough FEV1 response versus the mono-components in both studies . Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olo date rol FDC 5/5 μg . Incidence of adverse events was comparable between the FDCs and the mono-components . These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olo date rol FDC versus mono-components over 1 year in patients with moderate to very severe COPD . Lung function/symptomatic benefits of daily tiotropium+olo date rol fixed-dose combination in moderate-very severe COPD 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 Tiotropium + olo date rol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease ( COPD ) . The OTEMTO 1 and 2 studies investigated the effects of tiotropium + olo date rol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD . METHODS In these two replicate , double-blind , parallel-group , placebo-controlled trials , patients were r and omised to receive tiotropium + olo date rol 5/5 μg , 2.5/5 μg , tiotropium 5 μg or placebo for 12 weeks , via the Respimat ( ® ) inhaler . Primary end points were St George 's Respiratory Question naire ( SGRQ ) total score , forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 3 h ( AUC0 - 3 ) response and trough FEV1 response . RESULTS In OTEMTO 1 and 2 , tiotropium + olo date rol 5/5 μg improved SGRQ total score by 4.89 ( 95 % confidence interval [ CI ] -6.90 , -2.88 ) and 4.56 ( 95 % CI -6.50 , -2.63 ) units versus placebo ( both p < 0.0001 ) , and 2.49 ( 95 % CI -4.47 , -0.51 ; p < 0.05 ) and 1.72 ( 95 % CI -3.63 , 0.19 ) units versus tiotropium 5 μg . Tiotropium + olo date rol 2.5/5 μg significantly improved SGRQ score compared to placebo . Both doses significantly improved FEV1 AUC0 - 3 response compared to placebo and tiotropium 5 μg . Tiotropium + olo date rol 5/5 and 2.5/5 μg also significantly improved trough FEV1 response compared to placebo ( both studies ) and separated from tiotropium 5 μg in OTEMTO 2 . Adverse-event incidence was similar between treatment groups . CONCLUSION Tiotropium + olo date rol improved lung function and quality of life compared to placebo and tiotropium 5 μg . TRIAL REGISTRATION Clinical Trials.gov : NCT01964352 and NCT02006732 BACKGROUND We evaluated the effect of dual , longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease ( COPD ) . METHODS In this parallel-group study , 2224 patients ( aged ≥40 years , Global Initiative for Chronic Obstructive Lung Disease stages III-IV , and one or more moderate COPD exacerbation in the past year ) were r and omly assigned ( 1:1:1 ; via interactive voice response or web system ; stratified for smoking status ) to once-daily QVA149 ( fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg ) , glycopyrronium 50 μg , or tiotropium 18 μg for 64 weeks . Assignment to QVA149 and glycopyrronium was double-blind ; tiotropium was open-label . Efficacy was assessed in all patients r and omly assigned to treatment groups who received at least one dose of study drug ; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group . The primary objective was to show superiority  of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations ( defined by worsening symptoms and categorised by treatment requirements ) during treatment . This completed trial is registered at Clinical Trials.gov , NCT01120691 . FINDINGS Between April 27 , 2010 , and July 11 , 2012 , 741 patients were r and omly assigned to receive QVA149 , 741 to receive glycopyrronium , and 742 to receive tiotropium ( 729 , 739 , and 737 patients , respectively , analysed for efficacy ) . QVA149 significantly reduced the rate of moderate to severe exacerbations  versus glycopyrronium by 12 % ( annualised rate of exacerbations 0·84 [ 95 % CI 0·75 - 0·94 ] vs 0·95 [ 0·85 - 1·06 ] ; rate ratio 0·88 , 95 % CI 0·77 - 0·99 , p=0·038 ) . Adverse events ( including exacerbations ) were reported for 678 ( 93 % ) of 729 patients on QVA149 , 694 ( 94 % ) of 740 on glycopyrronium , and 686 ( 93 % ) of 737 on tiotropium . Incidence of serious adverse events was similar between groups ( 167 [ 23 % ] patients on QVA149 , 179 [ 24 % ] on glycopyrronium , and 165 [ 22 % ] on tiotropium ) ; COPD worsening was the most frequent serious adverse event ( 107 [ 15 % ] patients on QVA149 , 116 [ 16 % ] on glycopyrronium , 87 [ 12 % ] on tiotropium ) . INTERPRETATIONS The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium , with concomitant improvements in lung function and health status . These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD . FUNDING Novartis Pharma AG 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 Combinations of inhaled long-acting bronchodilator therapies such as muscarinic antagonists and β2-agonists may be more effective than monotherapy in the treatment of chronic obstructive pulmonary disease ( COPD ) . METHODS This study was a 24-week , Phase III , multicenter , r and omized , blinded , double-dummy , parallel-group study of the once-daily , inhaled , fixed-dose combination of the long-acting muscarinic antagonist umeclidinium bromide and the long-acting β2-agonist vilanterol ( UMEC/VI 62.5/25 mcg ) versus tiotropium ( TIO , 18 mcg ) . The primary endpoint was trough forced expiratory volume in 1 s ( FEV1 ) at Day 169 . The secondary endpoint was weighted mean FEV1 over 0–6 h post-dose at Day 168 . For key endpoints , a step-down closed testing hierarchy was applied to account for multiplicity . Other efficacy and safety endpoints were assessed . RESULTS Statistically significant improvements in trough FEV1 at Day 169 ( 0.112 L , 95 % confidence interval [ CI ] : 0.081 , 0.144 ; p < 0.001 ) and weighted mean FEV1 over 0–6 h post-dose at Day 168 ( 0.105 L , 95 % CI : 0.071 , 0.140 ; p < 0.001 ) were observed for UMEC/VI versus TIO . In addition UMEC/VI improved health-related quality of life , and reduced requirement for the use of rescue medication compared with TIO . The incidence of adverse events was similar between treatment groups . CONCLUSIONS UMEC/VI was associated with statistically significant and clinical ly meaningful improvements in lung function versus TIO . UMEC/VI was well tolerated . UMEC/VI 62.5/25 mcg could provide an effective new treatment option for patients with moderate-to-very severe COPD 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 ) The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable , moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . AFFIRM COPD ( Aclidinium and Formoterol Findings in Respiratory Medicine COPD ) was a 24-week , double-blind , double-dummy , active-controlled study . Patients were  r and omised ( 1:1 ) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler . The primary end-point was peak forced expiratory volume in 1 s ( FEV1 ) at week 24 . Other end-points included Transition Dyspnoea Index ( TDI ) focal score at week 24 , TDI and St George 's Respiratory Question naire ( SGRQ ) responders , COPD Assessment Test and SGRQ scores , assessment of COPD symptoms and exacerbations , use of reliever medication , and device preference . Adverse events were monitored throughout . In total , 933 patients were eligible ( mean age 63.4 years , 65.1 % male ) . Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV1 and noninferior in TDI . Health status and reduction in exacerbation risk were similar in both groups . While both treatments were well tolerated , pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone . In stable COPD , aclidinium/formoterol  significantly improved bronchodilation versus salmeterol/fluticasone , with equivalent benefits in symptom control and reduction in exacerbation risk . Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol . Aclidinium/formoterol achieves significantly greater bronchodilation than salmeterol/fluticasone in stable COPD BACKGROUND QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease ( COPD ) . It combines indacaterol ( a longacting β2-agonist ) with glycopyrronium ( a longacting muscarinic antagonist ) as a dual bronchodilator . We aim ed to compare the efficacy , safety , and tolerability of QVA149 versus salmeterol-fluticasone ( SFC ) over 26 weeks in patients with moderate-to-severe COPD . METHODS In this multicentre double-blind , double-dummy , parallel-group study , 523 patients ( age 40 years or older , Global Initiative for Chronic Obstructive Lung Disease [ GOLD ] stages II-III , without exacerbations in the previous year ) were r and omly assigned ( 1:1 ; via automated , interactive response technology and stratified for smoking status ) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks . Efficacy was assessed in the full analysis set ( r and omised patients who received at least one dose of study drug ) ; safety was assessed in all patients who received at least one dose of study drug . The primary endpoint was to demonstrate the superiority of QVA149 compared with SFC for the st and ardised area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second ( FEV1 AUC0 - 12h ) after 26 weeks of treatment . This trial was registered at Clinical Trial.gov , NCT01315249 . FINDINGS Between March 25 , 2011 , and March 12 , 2012 , 259 patients were r and omly assigned to receive QVA149 and 264 to receive SFC . At week 26 , FEV1 AUC0 - 12h was significantly higher with QVA149 than with SFC ( treatment difference 0·138 L ; 95 % CI 0·100 - 0·176 ; p<0·0001 ) . Overall incidence of adverse events ( including COPD exacerbations ) was 55·4 % ( 143 of 258 ) for the QVA149 group and 60·2 % ( 159 of 264 ) for the SFC group . Incidence of serious adverse events was similar between treatment groups ( QVA149 , 13 of 258 [ 5·0 % ] ; SFC 14 of 264 [ 5·3 % ] ) ; COPD worsening was the most frequent serious adverse event ( one of 13 [ 0·4 % ] and three of 14 [ 1·1 % ] , respectively ) . INTERPRETATION Once-daily QVA149 provides significant , sustained , and clinical ly meaningful improvements in lung function versus twice-daily SFC , with significant symptomatic benefit . These results indicate the potential of dual bronchodilation as a treatment option for non-exacerbating symptomatic COPD patients . FUNDING Novartis Pharma AG STUDY OBJECTIVE To examine the efficacy and safety of the once-daily , inhaled , long-acting muscarinic antagonist/β2-agonist combination umeclidinium/vilanterol ( UMEC/VI ) compared with UMEC and VI monotherapies in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS In this 24-week , double-blind , placebo-controlled , parallel-group study ( Clinical Trials.gov : NCT01313650 ) eligible patients were r and omised 3:3:3:2 to treatment with  UMEC/VI 62.5/25 mcg , UMEC 62.5 mcg , VI 25 mcg or placebo administered once daily via dry powder inhaler ( N = 1532 ; intent-to-treat population ) . Primary endpoint was trough forced expiratory volume in one second ( FEV1 ) on Day 169 ( 23 - 24 h post-dose ) . Additional lung-function , symptomatic , and health-related quality -of-life endpoints were assessed , including 0 - 6 h weighted-mean FEV1 , rescue salbutamol use , Transition Dyspnoea Index ( TDI ) , Shortness Of Breath With Daily Activity ( SOBDA ) and St. George 's Respiratory Question naire ( SGRQ ) scores . Safety evaluations included adverse events ( AEs ) , vital signs , 12-lead/24-h Holter electrocardiography parameters and clinical laboratory/haematology measurements . RESULTS All active treatments produced statistically significant improvements in trough FEV1 compared with placebo on Day 169 ( 0.072 - 0.167 L , all p < 0.001 ) ; increases with UMEC/VI 62.5/25 mcg were significantly greater than monotherapies ( 0.052 - 0.095 L , p ≤ 0.004 ) . Improvements were observed for UMEC/VI 62.5/25 mcg vs placebo for weighted-mean FEV1 on Day 168 ( 0.242 L , p < 0.001 ) , rescue salbutamol use during Weeks 1 - 24 ( -0.8 puffs/day , p = 0.001 ) , TDI ( 1.2 units , p < 0.001 ) , SOBDA ( -0.17 units , p < 0.001 ) and SGRQ ( -5.51 units , p < 0.001 ) scores . No clinical ly-significant changes in vital signs , electrocardiography , or laboratory parameters were observed . CONCLUSION Once-daily UMEC/VI 62.5/25 mcg was well tolerated and provided clinical ly-significant improvements in lung function and symptoms in patients with COPD INTRODUCTION QVA149 is a novel , inhaled , once-daily dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium ( NVA237 ) , for the treatment of chronic obstructive pulmonary disease ( COPD ) . This study evaluated the effects of QVA149 on exercise tolerance , hyperinflation , lung function and lung volumes versus placebo and tiotropium . METHODS Patients with moderate-to-severe COPD were r and omized to QVA149 110/50 μg , placebo or tiotropium 18 μg once daily in a blinded , 3-period crossover study for 3 weeks . The primary endpoint was exercise endurance time at Day 21 for QVA149 versus placebo . RESULTS Eighty-five patients were r and omized ; 86 % completed the study . QVA149 significantly improved exercise endurance time at Day 21 compared with placebo ( least squares mean treatment difference 60 s [ p = 0.006 ] ) . No significant improvements in exercise endurance time at Day 21 between QVA149 and tiotropium were found . Dynamic inspiratory capacity ( IC ) at exercise isotime , trough forced expiratory volume in 1 s , residual volume and functional residual capacity showed significant improvements with QVA149 from Day 1 of treatment that were maintained throughout the study . The safety profiles were similar across groups . CONCLUSIONS In patients with moderate-to-severe COPD , once-daily QVA149 significantly improved exercise endurance time compared with placebo which was associated with sustained reductions of lung hyperinflation as indicated by significant improvement in IC at rest and during exercise . TRIAL REGISTRATION Clinical Trials.gov NCT01294787 . TAKE HOME MESSAGE Dual bronchodilation with QVA149 decreases lung hyperinflation and improves exercise tolerance and lung function in patients with moderate-to-severe COPD BACKGROUND Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease ( COPD ) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent . We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD . METHODS In a 1-year , r and omized , double-blind , double-dummy , parallel-group trial , we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year . RESULTS A total of 7376 patients were r and omly assigned to and treated with tiotropium ( 3707 patients ) or salmeterol ( 3669 patients ) . Tiotropium , as compared with salmeterol , increased the time to the first exacerbation ( 187 days vs. 145 days ) , with a 17 % reduction in risk ( hazard ratio , 0.83 ; 95 % confidence interval [ CI ] , 0.77 to 0.90 ; P<0.001 ) . Tiotropium also increased the time to the first severe exacerbation ( hazard ratio , 0.72 ; 95 % CI , 0.61 to 0.85 ; P<0.001 ) , reduced the annual number of moderate or severe exacerbations ( 0.64 vs. 0.72 ; rate ratio , 0.89 ; 95 % CI , 0.83 to 0.96 ; P=0.002 ) , and reduced the annual number of severe exacerbations ( 0.09 vs. 0.13 ; rate ratio , 0.73 ; 95 % CI , 0.66 to 0.82 ; P<0.001 ) . Overall , the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups . There were 64 deaths ( 1.7 % ) in the tiotropium group and 78 ( 2.1 % ) in the salmeterol group . CONCLUSIONS These results show that , in patients with moderate-to-very-severe COPD  , tiotropium is more effective than salmeterol in preventing exacerbations . ( Funded by Boehringer Ingelheim and Pfizer ; Clinical Trials.gov number , NCT00563381 . ) BACKGROUND Most guidelines recommend either a long-acting beta-agonist ( LABA ) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist ( LAMA ) as the first-choice treatment for patients with chronic obstructive pulmonary disease ( COPD ) who have a high risk of exacerbations . The role of treatment with a LABA-LAMA regimen in these patients is unclear . METHODS We conducted a 52-week , r and omized , double-blind , double-dummy , noninferiority trial . Patients who had COPD with a history of at least one exacerbation during the previous year were r and omly assigned to receive , by inhalation , either the LABA indacaterol ( 110 μg ) plus the LAMA glycopyrronium ( 50 μg ) once daily or the LABA salmeterol ( 50 μg ) plus the inhaled glucocorticoid fluticasone ( 500 μg ) twice daily . The primary outcome was the annual rate of all COPD exacerbations . RESULTS A total of 1680 patients were assigned to the indacaterol-glycopyrronium group , and 1682 to the salmeterol-fluticasone group .  Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations ; the rate was 11 % lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( 3.59 vs. 4.03 ; rate ratio , 0.89 ; 95 % confidence interval [ CI ] , 0.83 to 0.96 ; P=0.003 ) . The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group ( 71 days [ 95 % CI , 60 to 82 ] vs. 51 days [ 95 % CI , 46 to 57 ] ; hazard ratio , 0.84 [ 95 % CI , 0.78 to 0.91 ] , representing a 16 % lower risk ; P<0.001 ) . The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( 0.98 vs. 1.19 ; rate ratio , 0.83 ; 95 % CI , 0.75 to 0.91 ; P<0.001 ) , and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( hazard ratio , 0.78 ; 95 % CI , 0.70 to 0.86 ; P<0.001 ) , as was the time to the first severe exacerbation ( hazard ratio , 0.81 ; 95 % CI , 0.66 to 1.00 ; P=0.046 ) . The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count . The incidence of adverse events and deaths was similar in the two groups . The incidence of pneumonia was 3.2 % in the indacaterol-glycopyrronium group and 4.8 % in the salmeterol-fluticasone group ( P=0.02 ) . CONCLUSIONS Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year . ( Funded by Novartis ; FLAME Clinical Trials.gov number , NCT01782326 . ) 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 R and omized controlled trials ( RCTs ) indicate that long-acting bronchodilator combinations , such as β2-agonist (LABA)/muscarinic antagonist ( LAMA ) , have favorable efficacy compared with commonly used COPD treatments .
The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid ( ICS ) in adults with stable moderate-to-very-severe COPD .