the global initiative for chronic obstructive lung disease ( gold ) strategy document recommends that the pharmacological therapy of chronic obstructive pulmonary disease ( copd ) should be predicated according to the individual patient s level of symptoms , airflow limitation , and history of exacerbations.1 the preferred option for maintenance therapy of copd is long - acting bronchodilators,1,2 either alone or in combination with an inhaled corticosteroid ( ics ) . the gold strategy document1 recommends treatment with at least one long - acting bronchodilator for patients with moderate - to - very severe copd . the strategy of combining short - acting bronchodilators with different mechanisms of action , ie , ipratropium bromide and salbutamol , has previously been shown to provide better symptomatic relief and to be cost - saving in patients with copd.3,4 in line with this , more recent studies have shown that also combining long - acting bronchodilators with different mechanisms of action provides additional benefits over the use of a single long - acting bronchodilator , without significantly increasing the risk of adverse effects.57 previous studies have shown that combining a long - acting 2-agonist with a long - acting anti - muscarinic antagonist leads to significant improvements in symptoms and lung function compared with either type of bronchodilator used alone.5,7 acute exacerbations of copd are associated with a poor prognosis in regard to health status , physical activity , decline in lung function , and mortality.813 prevention of exacerbations is therefore of outmost importance in the management of copd,1 and , in keeping with this , a key objective for new drugs for copd . the aim of this review is to provide an overview of the clinical studies evaluating the safety and clinical efficacy of the once - daily fixed - dose dual bronchodilator combination of indacaterol and glycopyrronium bromide for the treatment of copd . in order to perform this review , the general principles of the preferred reporting items for systematic reviews and meta - analyses ( prisma ) guidelines14,15 were adopted . a planned series of systematic searches was carried out , last updated february 2014 , using the databases pubmed , embase , cochrane central register of controlled trials , and clinicaltrials.gov using the following algorithm of mesh terms :  glycopyrronium bromide  ,  indacaterol  , qva149  ,  long - acting bronchodilators  ,  qab149  ,  nva237  ,  aclidinium bromide  ,  tiotropium bromide  ,  formoterol  ,  salmeterol  , and  copd  . these searches were repeated with these terms in combination with  fev1  ,  dyspnoea  ,  health status  ,  quality of life  ,  day - time symptoms  ,  night - time symptoms  ,  exacerbations  ,  hyperinflation  , and  exercise capacity  , in order to identify published studies . all searches were limited to english - language articles . as the methods and results could not be fully assessed , clinical trials published only in abstract form were excluded from this review . studies were included if they met all of the following criteria : 1 ) published in a peer - reviewed journal ; 2 ) inclusion of adults 40 years of age with stable copd defined according to the gold strategy document1 or the american thoracic society / european respiratory society guideline criteria;2 3 ) comparison of fixed - dose glycopyrronium bromide plus indacaterol with placebo , glycopyrronium bromide , indacaterol , tiotropium bromide , aclidinium bromide , formoterol , or salmeterol ; and 4 ) also reporting at least one of the following outcomes : onset of action ; trough forced expiratory volume in 1 second ( [ fev1 ] 24 hours post - dosing ) at the end of the treatment period ; peak change in fev1 ; health status ( st george s respiratory questionnaire [ sgrq ] ) ; symptom relief transition dyspnea index ( tdi ) ; use of rescue medication ; acute exacerbations ; exercise capacity ; and inspiratory capacity ( ic ) . due primarily to the relatively limited number of published clinical trials fulfilling all inclusion criteria , a meta - analysis was not included in the present review . of the 147 potential relevant citations identified by the series of searches , nine clinical trials fulfilled all inclusion criteria ( 6,166 participants ) . characteristics of the included studies are given in table 1 . all subjects included in the trials were stable but symptomatic at baseline and fulfilled the spirometric criteria for a diagnosis of copd . two studies compared fixed - dose indacaterol / glycopyrronium with indacaterol ( and placebo ) ; one study with indacaterol and glycopyrronium ; two studies with tiotropium ( and placebo ) ; one study with glycopyrronium and tiotropium ; one study with fixed - combination salmeterol / fluticasone ( sfc ) ; one study with indacaterol , glycopyrronium , and tiotropium ( and placebo ) ; and one study with placebo . the cardiovascular safety of fixed - dose indacaterol / glycopyrronium was evaluated by van de maele et al16 in a randomized , double - blind , placebo - controlled , parallel - group study of 257 patients with moderate - to - severe copd . the enrolled patients were randomized to receive fixed - dose indacaterol / glycopyrronium ( 600/100 g , 300/100 g , or 150/100 g ) , indacaterol 300 g , or placebo once daily for 14 days , and the primary endpoint was change from baseline in 24-hour mean heart rate versus placebo on day 14 . no clinical significant difference was observed for the primary endpoint , and once - daily fixed - dose indacaterol / glycopyrronium was , in general , well tolerated among the enrolled copd patients with a cardiovascular safety profile , including qtc interval , and an overall rate of adverse events ( aes ) similar to that of placebo . the safety of fixed - dose indacaterol / glycopyrronium was further investigated in the enlighten study by dahl et al,17 in which 339 patients were randomized to either fixed - dose indacaterol / glycopyrronium or placebo for 52 weeks . no difference between treatment groups was observed for the primary endpoint ; likewise , no clinically relevant differences were observed for vital signs and electrocardiographic parameters . the overall incidence of aes was similar between the two treatment arms ( 57.8% and 56.6% , respectively ) , and the most frequently reported ae was worsening of copd ( 28.5% and 25.7% , respectively , for active and placebo treatment ) . the most common severe ae was exacerbation of copd , and the second most common severe ae was pneumonia , the latter only reported in the indacaterol / glycopyrronium - treated group ( n=8 ) . a post hoc analysis of serious pneumonia aes stratified by copd severity was reported not to provide conclusive evidence that fixed - dose indacaterol / glycopyrronium was associated with a higher incidence of pneumonia than placebo ( rate of events 3.6% , odds ratio 5.11 ; p=0.10 ) . although no statistically significant difference was observed , aes that led to hospitalization or prolonged hospitalization were reported for 15.1% and 8.8% , respectively , of patients treated with fixed - dose indacaterol / glycopyrronium and placebo . in contrast to this , in the illuminate study,18 pneumonia ( confirmed by chest x - ray ) was only reported in patients treated with fixed - combination sfc ( 1.5% ; no cases among patients treated with fixed - dose indacaterol / glycopyrronium ) . the beacon study by dahl et al19 compared fixed - dose indacaterol / glycopyrronium with the concurrent administration of the mono - components indacaterol and glycopyrronium and found that the safety and efficacy profile was similar for the two treatment arms . mahler et al20 investigated the effect of fixed - dose indacaterol / glycopyrronium versus placebo and tiotropium on dyspnea in the blinded , double - dummy , crossover blaze study comprising 247 patients with moderate - to - severe copd ( staging according to the gold 2007 criteria ; mean post - bronchodilator fev1 56% predicted [ pred ] ) . changes in dyspnea were assessed by the self - administered computerized versions of the baseline dyspnea index and the tdi after 6 weeks . the tdi total score was statistically significantly improved with fixed - dose indacaterol / glycopyrronium at 6 weeks compared to both placebo and tiotropium . however , only the improvement with fixed - dose indacaterol / glycopyrronium versus placebo reached the minimal clinically important difference ( mcid ) of 1 point;21 this mcid in total tdi score with fixed - dose indacaterol / glycopyrronium was seen in patients with both moderate ( least squares mean [ lsm ] treatment difference 1.11 ; p<0.001 ) and severe ( lsm treatment difference 1.92 ; p<0.001 ) copd ( defined on spirometric criteria ) compared with placebo . a tdi responder analysis comparing fixed - dose indacaterol / glycopyrronium and tiotropium revealed that the proportion of patients achieving the mcid of at least 1 point was higher with fixed - dose indacaterol / glycopyrronium than with either placebo ( 35.9% and 18.1% , respectively ; p<0.001 ) or tiotropium ( 24.4% ; p=0.012 ) . however , it should be noted that the mcid for comparisons between active treatments has not yet been established . the blaze study20 also showed a significant improvement in percentage of nights with no awakenings , days with no daytime symptoms , and days with usual daily activities compared with placebo , whereas no significant difference in these outcomes was observed between fixed - dose indacaterol / glycopyrronium and tiotropium ; in line with this , no statistically significant differences were observed between the two active treatment arms with regard to mean daily total and individual symptom ( respiratory symptoms , cough , wheeze , and amount of sputum ) scores . however , the patients treated with fixed - dose indacaterol / glycopyrronium used less rescue medication and had a higher percentage of days with no use of rescue medication compared to both placebo ( p<0.001 ) and tiotropium ( p=0.002 and p<0.001 ) . similar findings with regard to symptoms and use of rescue medication were reported in the enlighten study.17 vogelmeier et al18 reported that fixed - dose indacaterol / glycopyrronium significantly increased the tdi focal score after 26 weeks of treatment compared with fixed - combination sfc , with a treatment difference of 0.76 ( p=0.003 ) . although , on average , not reaching the mcid for tdi score , 67.5% of patients treated with fixed - dose indacaterol / glycopyrronium compared with 56.8% of patients on sfc had an increase of at least 1 point in tdi score ( p=0.046 ) . however , no difference in change in total sgrq score was observed between the two treatment groups ; likewise , only modest and , in general , nonsignificant differences were reported with regard to symptoms and use of rescue medication.18 with regard to rescue medication , van noord et al22 found no difference in number of puffs used by patients treated with fixed - dose indacaterol / glycopyrronium and indacaterol , whereas wedzicha et al23 reported a significant decrease in use of rescue medication ( salbutamol ) for patients treated with fixed - dose indacaterol / glycopyrronium compared with glycopyrronium and tiotropium . the shine study24 showed significant improvements in tdi focal score , use of rescue medication , daytime symptoms , nighttime symptoms , and ability to perform usual daily activities for fixed - dose indacaterol / glycopyrronium compared with monotherapy with a long - acting bronchodilator and placebo . furthermore , the shine study also showed a significant improvement in sgrq total score at week 12 and week 26 compared with placebo , whereas no significant improvement was observed for the other active treatments ( indacaterol , glycopyrronium , and tiotropium ) or placebo.24 wedzicha et al23 reported an improvement in sgrq total score from baseline of 89 units with fixed - dose indacaterol / glycopyrronium ; 6 units with glycopyrronium ; and 56 units with tiotropium , and the treatment differences in sgrq total score between fixed - dose indacaterol / glycopyrronium were 1.9 to 2.8 and 1.7 to 3.1 , respectively , compared with glycopyrronium ( p<0.01 ) and tiotropium ( p<0.05 ) . in keeping with this , the percentage of patients achieving the mcid in total sgrq score was significantly higher for fixed - dose indacaterol / glycopyrronium compared with both glycopyrronium and tiotropium up to week 52 . van noord et al,22 in a four - period crossover study ( n=154 ) , compared the efficacy of once - daily fixed - dose indacaterol / glycopyrronium ( 300/50 g ) with indacaterol ( 600 g and 300 g ) and placebo . the lsm trough fev1 on day 7 was significantly higher for fixed - dose indacaterol / glycopyrronium compared with placebo ( treatment difference 0.226 l ; p<0.001 ) and with indacaterol 300 g or 600 g ( treatment difference 0.123 l and 0.117 l , respectively ; p<0.001 ) . furthermore , fixed - dose indacaterol / glycopyrronium had a faster onset of action ( at 5 minutes post - dose on day 1 ) compared with placebo and with indacaterol 300 g or 600 g ( p<0.0001 ) ; the treatment difference between fixed - dose indacaterol / glycopyrronium and placebo was 0.141 l , whereas no exact data were reported for the treatment difference between fixed - dose indacaterol / glycopyrronium and indacaterol . in the shine study , bateman et al24 investigated the efficacy of fixed - dose indacaterol / glycopyrronium versus its mono - components indacaterol and glycopyrronium , tiotropium , and placebo over 26 weeks . patients with moderate - to - severe copd ( defined according to the gold 2007 spirometric criteria ; n=2,144 ) were randomized to once - daily fixed - dose indacaterol / glycopyrronium ( 110/50 g ) , indacaterol ( 150 g ) , glycopyrronium ( 50 g ) , open - label tiotropium ( 18 g ) , or placebo ( table 1 ) . the primary outcome was trough fev1 at week 26 for fixed - dose indacaterol / glycopyrronium versus its mono - components . at week 26 , a significant improvement was seen in trough fev1 for fixed - dose indacaterol / glycopyrronium compared with both indacaterol ( treatment difference 0.07 l ; p<0.001 ) and glycopyrronium ( treatment difference 0.09 l ; p<0.001 ) ; likewise , a significant improvement was observed for fixed - dose indacaterol / glycopyrronium compared with tiotropium and placebo ( treatment difference 0.08 l and 0.20 l , respectively ; p<0.001 ) . the observed statistically significant differences between fixed - dose indacaterol / glycopyrronium versus all active treatments and placebo in trough fev1 were maintained throughout the study period . similar to the findings reported by van noord et al,22 the shine study24 revealed that fixed - dose indacaterol / glycopyrronium provides rapid bronchodilation after administration of the first dose on day 1 , as the fev1 , fev1 4-hour area under the curve , and peak fev1 were higher compared with placebo , glycopyrronium , and tiotropium , whereas data were not given for the comparison with indacaterol . subgroup analysis showed that the improvement in trough fev1 was seen both in patients with moderate and with severe copd ( defined by the spirometric gold criteria ) , although the treatment differences between fixed - dose indacaterol / glycopyrronium and monotherapy with a long - acting bronchodilator ( indacaterol , glycopyrronium , and tiotropium ) was less than 0.10 l. vogelmeier et al,18 in the illuminate study , compared the safety and efficacy of fixed - dose indacaterol / glycopyrronium versus fixed - combination sfc over 26 weeks in patients with moderate - to - severe copd . in this double - blind , double - dummy , parallel - group study , 523 patients ( without exacerbations in the year prior to study entry ) were randomized to either fixed - dose indacaterol / glycopyrronium ( 110/50 g once daily ) or sfc ( 50/500 g twice daily ) . the primary outcome was the standardized area under the fev1 curve from 012 hours post - dose ( fev1auc012 ) at week 26 . thirty - five percent of the enrolled patients were treated with ics at baseline , and the mean post - bronchodilator fev1 was 60.2% pred ( table 1 ) . the fev1auc012 was significantly higher for patients treated with fixed - dose indacaterol / glycopyrronium ( 1.70 l ) than for patients treated with sfc ( 1.56 l ) , with a treatment difference of 0.14 l ( p<0.0001 ) at week 26 ; this treatment difference in fev1auc012 was observed throughout the study period . similar findings were reported for other spirometric parameters , including peak fev1 and forced vital capacity.18 after 6 weeks of treatment in the blaze study,20 a significant and clinically meaningful25 improvement in mean fev1 was seen at every time point from 45 minutes pre - dose to 4 hours post - dose versus both placebo and tiotropium ( p<0.001 ) . the enlighten study17 showed a significant improvement in pre - dose fev1 at week 52 compared with placebo ( treatment difference 0.189 l ; p<0.001 ) , and the treatment difference in pre - dose fev1 from week 3 to week 52 versus placebo was in the range of 0.1520.189 l ( p<0.001 ) . furthermore , the 60-minute post - dose fev1 was significantly higher for patients treated with fixed - dose indacaterol / glycopyrronium compared with placebo ( treatment difference 0.2000.286 l ; p<0.001 ) . trough fev1 in the spark study23 was significantly higher for fixed - dose indacaterol / glycopyrronium at all evaluated time points compared with glycopyrronium ( treatment difference 0.080.09 l ; p<0.0001 ) and tiotropium ( treatment difference 0.060.08 l ; p<0.0001 ) . in the bright study , beeh et al26 investigated the effect of fixed - dose indacaterol / glycopyrronium compared with placebo and tiotropium on exercise tolerance in patients with moderate - to - severe copd ( defined according to the gold 2007 spirometric criteria ; mean fev1 55.9% pred ) ( table 1 ) . a total of 85 patients were randomized to fixed - dose indacaterol / glycopyrronium ( 110/50 g ) , placebo , or tiotropium ( 18 g ) once daily in a blinded , three - period , crossover study for 3 weeks . the primary outcome variable was exercise endurance time at day 21 for fixed - dose indacaterol / glycopyrronium versus placebo . fixed - dose indacaterol / glycopyrronium significantly improved exercise endurance time at day 21 compared with placebo ( lsm treatment difference 60 seconds ) . a similar improvement in exercise endurance time was observed with tiotropium compared with placebo ( lsm treatment difference 66 seconds ) . in line with this , an analysis of data for the subgroup of patients with hyperinflation ( defined as functional residual capacity [ frc ] > 120% pred ) , showed that the mean changes in exercise endurance time from baseline were 85 seconds and 88 seconds , respectively , for indacaterol / glycopyrronium and tiotropium . a significant improvement in ic at peak exercise was observed for fixed - dose indacaterol / glycopyrronium compared with both placebo and tiotropium , and a similar difference was observed for trough ic . in the study by van noord et al,22 changes in ic , although not stated as a secondary outcome variable , were also determined . the authors reported that both lsm ic and trough ic were significantly better for fixed - dose indacaterol / glycopyrronium compared with both indacaterol and placebo ( p=0.02 ) . wedzicha et al , in the spark study,23 investigated the effect of fixed - dose indacaterol / glycopyrronium on exacerbations in patients with severe and very severe copd ( defined according to the gold 2007 spirometric criteria ) . in a parallel - group study , 2,224 patients ( having had at least one exacerbation of copd in the year prior to enrollment ) were randomized to fixed - dose indacaterol / glycopyrronium ( 110/50 g ) , glycopyrronium ( 50 g ) , or open - label tiotropium ( 18 g ) for 64 weeks . the primary outcome variable was to demonstrate superiority of fixed - dose indacaterol / glycopyrronium for the rate of moderate ( defined as worsening of symptoms treated with systemic corticosteroids or antibiotics or both ) and severe ( defined as worsening of symptoms requiring emergency treatment or hospitalization ) exacerbations compared to monotherapy with glycopyrronium . the key secondary outcome variable was to demonstrate superiority of fixed - dose indacaterol / glycopyrronium compared with tiotropium with regard to the rate of moderate and severe exacerbations . twenty - two percent of the patients included in the efficacy analyses had had two or more exacerbations in the previous year , and 88% of the patients had one or more cardiovascular risk factors at baseline , although few patients had a history of cardiovascular disease . furthermore , 75% of the patients in all three treatment arms were treated with icss throughout the study period . the rate of moderate or severe exacerbations was significantly reduced by 12% for the fixed - dose indacaterol / glycopyrronium group compared with the glycopyrronium group ( p=0.038 ) , whereas the 10% reduction in the rate of moderate or severe exacerbations with fixed - dose indacaterol / glycopyrronium compared with tiotropium was nonsignificant . the overall rate of exacerbations ( mild , moderate , and severe ) was significantly reduced with fixed - dose indacaterol / glycopyrronium , by 15% and 14% , respectively , compared with glycopyrronium and tiotropium . the cardiovascular safety of fixed - dose indacaterol / glycopyrronium was evaluated by van de maele et al16 in a randomized , double - blind , placebo - controlled , parallel - group study of 257 patients with moderate - to - severe copd . the enrolled patients were randomized to receive fixed - dose indacaterol / glycopyrronium ( 600/100 g , 300/100 g , or 150/100 g ) , indacaterol 300 g , or placebo once daily for 14 days , and the primary endpoint was change from baseline in 24-hour mean heart rate versus placebo on day 14 . no clinical significant difference was observed for the primary endpoint , and once - daily fixed - dose indacaterol / glycopyrronium was , in general , well tolerated among the enrolled copd patients with a cardiovascular safety profile , including qtc interval , and an overall rate of adverse events ( aes ) similar to that of placebo . the safety of fixed - dose indacaterol / glycopyrronium was further investigated in the enlighten study by dahl et al,17 in which 339 patients were randomized to either fixed - dose indacaterol / glycopyrronium or placebo for 52 weeks . no difference between treatment groups was observed for the primary endpoint ; likewise , no clinically relevant differences were observed for vital signs and electrocardiographic parameters . the overall incidence of aes was similar between the two treatment arms ( 57.8% and 56.6% , respectively ) , and the most frequently reported ae was worsening of copd ( 28.5% and 25.7% , respectively , for active and placebo treatment ) . the most common severe ae was exacerbation of copd , and the second most common severe ae was pneumonia , the latter only reported in the indacaterol / glycopyrronium - treated group ( n=8 ) . a post hoc analysis of serious pneumonia aes stratified by copd severity was reported not to provide conclusive evidence that fixed - dose indacaterol / glycopyrronium was associated with a higher incidence of pneumonia than placebo ( rate of events 3.6% , odds ratio 5.11 ; p=0.10 ) . although no statistically significant difference was observed , aes that led to hospitalization or prolonged hospitalization were reported for 15.1% and 8.8% , respectively , of patients treated with fixed - dose indacaterol / glycopyrronium and placebo . in contrast to this , in the illuminate study,18 pneumonia ( confirmed by chest x - ray ) was only reported in patients treated with fixed - combination sfc ( 1.5% ; no cases among patients treated with fixed - dose indacaterol / glycopyrronium ) . the beacon study by dahl et al19 compared fixed - dose indacaterol / glycopyrronium with the concurrent administration of the mono - components indacaterol and glycopyrronium and found that the safety and efficacy profile was similar for the two treatment arms . mahler et al20 investigated the effect of fixed - dose indacaterol / glycopyrronium versus placebo and tiotropium on dyspnea in the blinded , double - dummy , crossover blaze study comprising 247 patients with moderate - to - severe copd ( staging according to the gold 2007 criteria ; mean post - bronchodilator fev1 56% predicted [ pred ] ) . changes in dyspnea were assessed by the self - administered computerized versions of the baseline dyspnea index and the tdi after 6 weeks . the tdi total score was statistically significantly improved with fixed - dose indacaterol / glycopyrronium at 6 weeks compared to both placebo and tiotropium . however , only the improvement with fixed - dose indacaterol / glycopyrronium versus placebo reached the minimal clinically important difference ( mcid ) of 1 point;21 this mcid in total tdi score with fixed - dose indacaterol / glycopyrronium was seen in patients with both moderate ( least squares mean [ lsm ] treatment difference 1.11 ; p<0.001 ) and severe ( lsm treatment difference 1.92 ; p<0.001 ) copd ( defined on spirometric criteria ) compared with placebo . a tdi responder analysis comparing fixed - dose indacaterol / glycopyrronium and tiotropium revealed that the proportion of patients achieving the mcid of at least 1 point was higher with fixed - dose indacaterol / glycopyrronium than with either placebo ( 35.9% and 18.1% , respectively ; p<0.001 ) or tiotropium ( 24.4% ; p=0.012 ) . however , it should be noted that the mcid for comparisons between active treatments has not yet been established . the blaze study20 also showed a significant improvement in percentage of nights with no awakenings , days with no daytime symptoms , and days with usual daily activities compared with placebo , whereas no significant difference in these outcomes was observed between fixed - dose indacaterol / glycopyrronium and tiotropium ; in line with this , no statistically significant differences were observed between the two active treatment arms with regard to mean daily total and individual symptom ( respiratory symptoms , cough , wheeze , and amount of sputum ) scores . however , the patients treated with fixed - dose indacaterol / glycopyrronium used less rescue medication and had a higher percentage of days with no use of rescue medication compared to both placebo ( p<0.001 ) and tiotropium ( p=0.002 and p<0.001 ) . similar findings with regard to symptoms and use of rescue medication were reported in the enlighten study.17 vogelmeier et al18 reported that fixed - dose indacaterol / glycopyrronium significantly increased the tdi focal score after 26 weeks of treatment compared with fixed - combination sfc , with a treatment difference of 0.76 ( p=0.003 ) . although , on average , not reaching the mcid for tdi score , 67.5% of patients treated with fixed - dose indacaterol / glycopyrronium compared with 56.8% of patients on sfc had an increase of at least 1 point in tdi score ( p=0.046 ) . however , no difference in change in total sgrq score was observed between the two treatment groups ; likewise , only modest and , in general , nonsignificant differences were reported with regard to symptoms and use of rescue medication.18 with regard to rescue medication , van noord et al22 found no difference in number of puffs used by patients treated with fixed - dose indacaterol / glycopyrronium and indacaterol , whereas wedzicha et al23 reported a significant decrease in use of rescue medication ( salbutamol ) for patients treated with fixed - dose indacaterol / glycopyrronium compared with glycopyrronium and tiotropium . the shine study24 showed significant improvements in tdi focal score , use of rescue medication , daytime symptoms , nighttime symptoms , and ability to perform usual daily activities for fixed - dose indacaterol / glycopyrronium compared with monotherapy with a long - acting bronchodilator and placebo . furthermore , the shine study also showed a significant improvement in sgrq total score at week 12 and week 26 compared with placebo , whereas no significant improvement was observed for the other active treatments ( indacaterol , glycopyrronium , and tiotropium ) or placebo.24 wedzicha et al23 reported an improvement in sgrq total score from baseline of 89 units with fixed - dose indacaterol / glycopyrronium ; 6 units with glycopyrronium ; and 56 units with tiotropium , and the treatment differences in sgrq total score between fixed - dose indacaterol / glycopyrronium were 1.9 to 2.8 and 1.7 to 3.1 , respectively , compared with glycopyrronium ( p<0.01 ) and tiotropium ( p<0.05 ) . in keeping with this , the percentage of patients achieving the mcid in total sgrq score was significantly higher for fixed - dose indacaterol / glycopyrronium compared with both glycopyrronium and tiotropium up to week 52 . van noord et al,22 in a four - period crossover study ( n=154 ) , compared the efficacy of once - daily fixed - dose indacaterol / glycopyrronium ( 300/50 g ) with indacaterol ( 600 g and 300 g ) and placebo . the lsm trough fev1 on day 7 was significantly higher for fixed - dose indacaterol / glycopyrronium compared with placebo ( treatment difference 0.226 l ; p<0.001 ) and with indacaterol 300 g or 600 g ( treatment difference 0.123 l and 0.117 l , respectively ; p<0.001 ) . furthermore , fixed - dose indacaterol / glycopyrronium had a faster onset of action ( at 5 minutes post - dose on day 1 ) compared with placebo and with indacaterol 300 g or 600 g ( p<0.0001 ) ; the treatment difference between fixed - dose indacaterol / glycopyrronium and placebo was 0.141 l , whereas no exact data were reported for the treatment difference between fixed - dose indacaterol / glycopyrronium and indacaterol . in the shine study , bateman et al24 investigated the efficacy of fixed - dose indacaterol / glycopyrronium versus its mono - components indacaterol and glycopyrronium , tiotropium , and placebo over 26 weeks . patients with moderate - to - severe copd ( defined according to the gold 2007 spirometric criteria ; n=2,144 ) were randomized to once - daily fixed - dose indacaterol / glycopyrronium ( 110/50 g ) , indacaterol ( 150 g ) , glycopyrronium ( 50 g ) , open - label tiotropium ( 18 g ) , or placebo ( table 1 ) . the primary outcome was trough fev1 at week 26 for fixed - dose indacaterol / glycopyrronium versus its mono - components . at week 26 , a significant improvement was seen in trough fev1 for fixed - dose indacaterol / glycopyrronium compared with both indacaterol ( treatment difference 0.07 l ; p<0.001 ) and glycopyrronium ( treatment difference 0.09 l ; p<0.001 ) ; likewise , a significant improvement was observed for fixed - dose indacaterol / glycopyrronium compared with tiotropium and placebo ( treatment difference 0.08 l and 0.20 l , respectively ; p<0.001 ) . the observed statistically significant differences between fixed - dose indacaterol / glycopyrronium versus all active treatments and placebo in trough fev1 were maintained throughout the study period . similar to the findings reported by van noord et al,22 the shine study24 revealed that fixed - dose indacaterol / glycopyrronium provides rapid bronchodilation after administration of the first dose on day 1 , as the fev1 , fev1 4-hour area under the curve , and peak fev1 were higher compared with placebo , glycopyrronium , and tiotropium , whereas data were not given for the comparison with indacaterol . subgroup analysis showed that the improvement in trough fev1 was seen both in patients with moderate and with severe copd ( defined by the spirometric gold criteria ) , although the treatment differences between fixed - dose indacaterol / glycopyrronium and monotherapy with a long - acting bronchodilator ( indacaterol , glycopyrronium , and tiotropium ) was less than 0.10 l. vogelmeier et al,18 in the illuminate study , compared the safety and efficacy of fixed - dose indacaterol / glycopyrronium versus fixed - combination sfc over 26 weeks in patients with moderate - to - severe copd . in this double - blind , double - dummy , parallel - group study , 523 patients ( without exacerbations in the year prior to study entry ) were randomized to either fixed - dose indacaterol / glycopyrronium ( 110/50 g once daily ) or sfc ( 50/500 g twice daily ) . the primary outcome was the standardized area under the fev1 curve from 012 hours post - dose ( fev1auc012 ) at week 26 . thirty - five percent of the enrolled patients were treated with ics at baseline , and the mean post - bronchodilator fev1 was 60.2% pred ( table 1 ) . the fev1auc012 was significantly higher for patients treated with fixed - dose indacaterol / glycopyrronium ( 1.70 l ) than for patients treated with sfc ( 1.56 l ) , with a treatment difference of 0.14 l ( p<0.0001 ) at week 26 ; this treatment difference in fev1auc012 was observed throughout the study period . similar findings were reported for other spirometric parameters , including peak fev1 and forced vital capacity.18 after 6 weeks of treatment in the blaze study,20 a significant and clinically meaningful25 improvement in mean fev1 was seen at every time point from 45 minutes pre - dose to 4 hours post - dose versus both placebo and tiotropium ( p<0.001 ) . the enlighten study17 showed a significant improvement in pre - dose fev1 at week 52 compared with placebo ( treatment difference 0.189 l ; p<0.001 ) , and the treatment difference in pre - dose fev1 from week 3 to week 52 versus placebo was in the range of 0.1520.189 l ( p<0.001 ) . furthermore , the 60-minute post - dose fev1 was significantly higher for patients treated with fixed - dose indacaterol / glycopyrronium compared with placebo ( treatment difference 0.2000.286 l ; p<0.001 ) . trough fev1 in the spark study23 was significantly higher for fixed - dose indacaterol / glycopyrronium at all evaluated time points compared with glycopyrronium ( treatment difference 0.080.09 l ; p<0.0001 ) and tiotropium ( treatment difference 0.060.08 l ; p<0.0001 ) . in the bright study , beeh et al26 investigated the effect of fixed - dose indacaterol / glycopyrronium compared with placebo and tiotropium on exercise tolerance in patients with moderate - to - severe copd ( defined according to the gold 2007 spirometric criteria ; mean fev1 55.9% pred ) ( table 1 ) . a total of 85 patients were randomized to fixed - dose indacaterol / glycopyrronium ( 110/50 g ) , placebo , or tiotropium ( 18 g ) once daily in a blinded , three - period , crossover study for 3 weeks . the primary outcome variable was exercise endurance time at day 21 for fixed - dose indacaterol / glycopyrronium versus placebo . fixed - dose indacaterol / glycopyrronium significantly improved exercise endurance time at day 21 compared with placebo ( lsm treatment difference 60 seconds ) . a similar improvement in exercise endurance time was observed with tiotropium compared with placebo ( lsm treatment difference 66 seconds ) . in line with this , an analysis of data for the subgroup of patients with hyperinflation ( defined as functional residual capacity [ frc ] > 120% pred ) , showed that the mean changes in exercise endurance time from baseline were 85 seconds and 88 seconds , respectively , for indacaterol / glycopyrronium and tiotropium . a significant improvement in ic at peak exercise was observed for fixed - dose indacaterol / glycopyrronium compared with both placebo and tiotropium , and a similar difference was observed for trough ic . in the study by van noord et al,22 changes in ic , although not stated as a secondary outcome variable , were also determined . the authors reported that both lsm ic and trough ic were significantly better for fixed - dose indacaterol / glycopyrronium compared with both indacaterol and placebo ( p=0.02 ) . wedzicha et al , in the spark study,23 investigated the effect of fixed - dose indacaterol / glycopyrronium on exacerbations in patients with severe and very severe copd ( defined according to the gold 2007 spirometric criteria ) . in a parallel - group study , 2,224 patients ( having had at least one exacerbation of copd in the year prior to enrollment ) were randomized to fixed - dose indacaterol / glycopyrronium ( 110/50 g ) , glycopyrronium ( 50 g ) , or open - label tiotropium ( 18 g ) for 64 weeks . the primary outcome variable was to demonstrate superiority of fixed - dose indacaterol / glycopyrronium for the rate of moderate ( defined as worsening of symptoms treated with systemic corticosteroids or antibiotics or both ) and severe ( defined as worsening of symptoms requiring emergency treatment or hospitalization ) exacerbations compared to monotherapy with glycopyrronium . the key secondary outcome variable was to demonstrate superiority of fixed - dose indacaterol / glycopyrronium compared with tiotropium with regard to the rate of moderate and severe exacerbations . twenty - two percent of the patients included in the efficacy analyses had had two or more exacerbations in the previous year , and 88% of the patients had one or more cardiovascular risk factors at baseline , although few patients had a history of cardiovascular disease . furthermore , 75% of the patients in all three treatment arms were treated with icss throughout the study period . the rate of moderate or severe exacerbations was significantly reduced by 12% for the fixed - dose indacaterol / glycopyrronium group compared with the glycopyrronium group ( p=0.038 ) , whereas the 10% reduction in the rate of moderate or severe exacerbations with fixed - dose indacaterol / glycopyrronium compared with tiotropium was nonsignificant . the overall rate of exacerbations ( mild , moderate , and severe ) was significantly reduced with fixed - dose indacaterol / glycopyrronium , by 15% and 14% , respectively , compared with glycopyrronium and tiotropium . the combination of two long - acting bronchodilators with different mechanisms of action is likely to have the potential to enhance efficacy compared with single long - acting bronchodilators , without a concomitant increase in adverse effects . fixed - dose indacaterol / glycopyrronium is , based on the available evidence , a safe and well - tolerated dual long - acting bronchodilator . in patients with moderate - to - very severe copd ( defined by gold spirometric criteria ) , fixed - dose indacaterol / glycopyrronium has clinically important effects on symptoms , including dyspnea score , health status , level of fev1 , exercise endurance time , and rate of exacerbations . bronchodilation improves airway conductance and airflow and reduces hyperinflation , which subsequently leads to a reduction in dyspnea . sustained bronchodilation is therefore , in accordance with the current gold strategy document,1 recommended as maintenance therapy for patients with symptomatic copd . the published studies show that treatment with once - daily fixed - dose indacaterol / glycopyrronium leads to clinically important improvements , not only in lung function , but also in other important endpoints such as dyspnea index , health status , symptoms , exercise endurance time , and use of rescue medication , although the findings with regard to use of rescue medication were not absolutely consistent . the studies of fixed - dose indacaterol / glycopyrronium are therefore in accordance with several previously published studies that have investigated the efficacy of free combinations of long - acting 2-agonists and long - acting anti - muscarinic agents2730 in patients with copd . furthermore , these studies are also in accordance with a very recently published study by celli et al31 investigating the safety and efficacy of once - daily fixed - dose umeclidinium / vilanterol in patients with copd . sustained bronchodilation is also thought to contribute to the reduction in exacerbations of copd seen with treatment with long - acting bronchodilators , and , although long - acting anti - muscarinic agents are primarily thought to reduce exacerbations by reducing dynamic hyperinflation , both long - acting 2-agonists and long - acting anti - muscarinic agents may have anti - inflammatory effects.3234 the studies published so far investigating the safety and , not least , efficacy of fixed - dose indacaterol / glycopyrronium support the gold 2013 strategy1 alternative - choice recommendation that add - on of a second long - acting bronchodilator in patients with moderate - to - very severe copd ( gold 2013 groups b  d ) may improve symptom control , and , in line with this , that patients classified as being ( group b ) , who remain symptomatic on a single long - acting bronchodilator , may significantly benefit from fixed - dose indacaterol / glycopyrronium . furthermore , the reported findings also support the gold 2013 strategy secondary choice recommendation for  high - risk  patients ( groups c and d based on symptoms and exacerbations ) , as a long - acting 2-agonist plus a long - acting anti - muscarinic agent is recommended as an alternative to a long - acting -agonist plus ics ( group c ) or ics plus long - acting 2-agonist and/or long - acting anti - muscarinic agent ( group d ) . the published studies indicate that once - daily fixed - dose indacaterol / glycopyrronium may become an important therapeutic maintenance option for patients with moderate - to - very severe copd . in years to come , combination therapy with a long - acting antimuscarinic agent and a long - acting 2-agonist , preferably as fixed combination , may become the treatment of choice for maintenance therapy - nave patients with symptomatic copd .
background and aimlong - acting bronchodilators are the preferred option for maintenance therapy of patients with chronic obstructive pulmonary disease ( copd ) . 
 the aim of this review is to provide an overview of the clinical studies evaluating the clinical efficacy of the once - daily fixed - dose dual bronchodilator combination of indacaterol and glycopyrronium bromide in patients suffering from copd.methodsthis study comprised a systematic review of randomized controlled trials identified through systematic searches of different databases of published trials.resultsnine trials ( 6,166 participants ) were included . 
 fixed - dose once - daily indacaterol / glycopyrronium seems to be safe and well tolerated in patients with copd . 
 compared with single therapy with other long - acting bronchodilators ( indacaterol , glycopyrronium , and tiotropium ) and fixed - combination long - acting 2-agonist / inhaled corticosteroid ( salmeterol / fluticasone twice daily ) , once - daily fixed - dose indacaterol / glycopyrronium has clinically important effects on symptoms , including dyspnea score , health status , level of lung function , and rate of moderate or severe exacerbations in patients with moderate - to - very severe copd ( global initiative for chronic obstructive lung disease [ gold ] spirometric criteria ) . 
 furthermore , a very recent study has shown that fixed - dose indacaterol / glycopyrronium improves exercise endurance time compared with placebo , although no significant difference was observed between fixed - dose indacaterol / glycopyrronium and tiotropium.conclusionfixed-dose indacaterol / glycopyrronium has clinically relevant effects on important copd outcome measures and is , in general , superior to therapy with a single long - acting bronchodilator ( with or without inhaled corticosteroid ) indicating long - acting dual bronchodilation as a potential important maintenance therapeutic option for patients with symptomatic copd , possibly also for the treatment of nave patients .