human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background Debate continues as to whether acute bronchodilator responsiveness ( BDR ) predicts long-term outcomes in COPD . Furthermore , there is no consensus on a threshold for BDR . Methods At baseline and during the 4-year Underst and ing Potential Long-term Improvements in Function with Tiotropium ( UPLIFT ® ) trial , patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg . Patients were split according to three BDR thresholds : ≥12 % + ≥200 mL above baseline ( criterion A ) , ≥15 % above baseline ( criterion B ) ; and ≥10 % absolute increase in percent predicted FEV1 values ( criterion C ) . Several outcomes ( pre-dose spirometry , exacerbations , St. George 's Respiratory Question naire [ SGRQ ] total score ) were assessed according to presence or absence of BDR in the treatment groups . Results 5783 of 5993 r and omized patients had evaluable pre- and post-bronchodilator spirometry at baseline . Mean age ( SD ) was 64 ( 8) years , with 75 % men , mean post-bronchodilator FEV1 1.33 ± 0.44 L ( 47.6 ± 12.7 % predicted ) and 30 % current smokers . At baseline , 52 % , 66 % , and 39 % of patients had acute BDR using criterion A , B , and C , respectively . The presence of BDR was variable at follow-up visits . Statistically significant improvements in spirometry and health outcomes  occurred with tiotropium regardless of the baseline BDR or criterion used . Conclusions A large proportion of COPD patients  demonstrate significant acute BDR . BDR in these patients is variable over time and differs according to the criterion used . BDR status at baseline does not predict long-term response to tiotropium . Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD RATIONALE Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination ( salmeterol/fluticasone propionate ) 50/500 microg twice daily and the long-acting bronchodilator ( tiotropium ) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD . METHODS A total of 1,323 patients ( mean age , 64 yr , post-bronchodilator FEV1 , 39 % predicted ) were r and omized in this 2-year , double-blind , double-dummy parallel study . MEASUREMENTS AND MAIN RESULTS Primary endpoint was health care utilization exacerbation rate . Other endpoints included health status measured by St. George 's Respiratory Question naire ( SGRQ ) , mortality , adverse events , and study withdrawal . Probability of withdrawing from the study was 29 % greater with tiotropium than salmeterol/fluticasone propionate ( P = 0.005 ) . The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group ( rate ratio , 0.967 ; 95 % confidence interval [ CI ] , 0.836 - 1.119 ] ; P = 0.656 ) . The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium ( difference 2.1 units ; 95 % CI , 0.1 - 4.0 ; P = 0.038 ) . Mortality was significantly lower in the salmeterol/fluticasone propionate group ; 21 ( 3 % ) of patients in this group died compared with 38 ( 6 % ) in the tiotropium group ( P = 0.032 ) . More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium ( P = 0.008 ) . CONCLUSIONS We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium . More patients failed to complete the study while receiving tiotropium . A small statistically significant beneficial effect was found on health status , with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients . Clinical trial registered with www . clinical trials.gov ( NCT 00361959 ) BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) often present with severe acute exacerbations requiring hospital treatment . However , little is known about the prognostic consequences of these exacerbations . A study was undertaken to investigate whether severe acute exacerbations of COPD exert a direct effect on mortality . METHODS Multivariate techniques were used to analyse the prognostic influence of acute exacerbations of COPD treated in hospital ( visits to the emergency service and admissions ) , patient age , smoking , body mass index , co-morbidity , long term oxygen therapy , forced spirometric parameters , and arterial blood gas tensions in a prospect i ve cohort of 304 men with COPD followed up for 5 years . The mean ( SD ) age of the patients was 71 ( 9 ) years and forced expiratory volume in 1 second was 46 (17)% . RESULTS Only older age ( hazard ratio ( HR ) 5.28 , 95 % CI 1.75 to 15.93 ) , arterial carbon dioxide tension ( HR 1.07 , 95 % CI 1.02 to 1.12 ) , and acute exacerbations of COPD were found to be independent indicators of a poor prognosis . The patients with the greatest mortality risk were those with three or more acute COPD exacerbations ( HR 4.13 , 95 % CI 1.80 to 9.41 ) . CONCLUSIONS This study shows for the first time that severe acute exacerbations of COPD have an independent negative impact on patient prognosis . Mortality increases with the frequency of severe exacerbations , particularly if these require admission to hospital This r and omised , double-blind , parallel-group , 1-yr study compared the effect of tiotropium 18 microg once daily ( n=500 ) and placebo  ( n=510 ) on exacerbations , associated health re source use ( HRU ) and  airflow limitation in chronic obstructive pulmonary disease ( COPD ) patients . The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40 , the mean weekly morning peak expiratory flow ( PEF ) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second ( FEV1 ) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days , reduced the proportion of patients experiencing more than one exacerbation by 17 % , and decreased the number of exacerbations by 35 % and exacerbation days by 37 % versus placebo . Tiotropium also decreased HRU versus placebo , as indicated by the significant reductions in the use of concomitant respiratory medications , antibiotics and oral steroids , and the number of unscheduled physician contacts . Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study . At the end of the study , tiotropium significantly improved trough ( pre-dose ) FEV1 , forced vital capacity , slow vital capacity and inspiratory capacity versus placebo . In conclusion , tiotropium reduced exacerbations and associated health re source use , and improved airflow over 1 yr in chronic obstructive pulmonary disease patients BACKGROUND Gender differences may occur in many chronic diseases . We have examined the influence of gender in chronic obstructive pulmonary disease ( COPD ) on long-term responses to tiotropium . METHODS Subgroup analysis of data from the Underst and ing the Potential Long-term Impact of Tiotropium ( UPLIFT ) trial ( 4-year , r and omized , double-blind , placebo-controlled trial of tiotropium in patients with COPD ) . RESULTS Of 5992 patients , 75 % were men and 25 % women . Mean age was 65 and 63 years , respectively . Baseline post-bronchodilator forced expiratory volume in 1s ( FEV(1))=47 % predicted(men ) and 49 % predicted(women ) . St George 's Respiratory Question naire ( SGRQ ) total score was 44.9 and 48.7units , respectively . At 48 months , improvement in trough FEV(1 ) over control was 92mL(men ) and 77mL(women ) ( p<0.001 for both ) , with no differences in the rate of decline ( trial primary endpoint ) . Hazard ratio ( HR ) ( 95 % confidence interval [ CI ] ) for first exacerbation ( tiotropium/placebo ) was 0.87(0.81 , 0.93)(men ) and 0.83(0.74 , 0.94)(women ) . Number of exacerbations ( per patient-year ) was reduced with tiotropium in men ( from 0.82 to 0.71 ) and women ( from 0.92 to 0.77 ) ( p<0.005 for both ) . HR ( 95 % CI ) for a hospitalized exacerbation was 0.89(0.79 , 0.99 ) and 0.77(0.62 , 0.94 ) , respectively . HR ( 95 % CI ) for mortality during treatment was 0.85(0.72 , 0.99)(men ) and 0.85(0.62 , 1.18)(women ) . Improvements in SGRQ total score ( tiotropium-control ) at 1 , 2 , 3 and 4 years were : -2.8 , -2.3 , -3.6 , -2.4(men ) and -2.7 , -2.6 , -2.6 , -2.1(women ) ( p<0.05 for all ) . CONCLUSION Long-term treatment of COPD with tiotropium improves lung function , exacerbations and health status in men and women , with similar magnitudes of benefit . Boehringer Ingelheim trial 205.235 ; Clinical Trials.gov : NCT00144339 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 % ] 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background Debate continues as to whether acute bronchodilator responsiveness ( BDR ) predicts long-term outcomes in COPD . Furthermore , there is no consensus on a threshold for BDR . Methods At baseline and during the 4-year Underst and ing Potential Long-term Improvements in Function with Tiotropium ( UPLIFT ® ) trial , patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg . Patients were split according to three BDR thresholds : ≥12 % + ≥200 mL above baseline ( criterion A ) , ≥15 % above baseline ( criterion B ) ; and ≥10 % absolute increase in percent predicted FEV1 values ( criterion C ) . Several outcomes ( pre-dose spirometry , exacerbations , St. George 's Respiratory Question naire [ SGRQ ] total score ) were assessed according to presence or absence of BDR in the treatment groups . Results 5783 of 5993 r and omized patients had evaluable pre- and post-bronchodilator spirometry at baseline . Mean age ( SD ) was 64 ( 8) years , with 75 % men , mean post-bronchodilator FEV1 1.33 ± 0.44 L ( 47.6 ± 12.7 % predicted ) and 30 % current smokers . At baseline , 52 % , 66 % , and 39 % of patients had acute BDR using criterion A , B , and C , respectively . The presence of BDR was variable at follow-up visits . Statistically significant improvements in spirometry and health outcomes  occurred with tiotropium regardless of the baseline BDR or criterion used . Conclusions A large proportion of COPD patients  demonstrate significant acute BDR . BDR in these patients is variable over time and differs according to the criterion used . BDR status at baseline does not predict long-term response to tiotropium . Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD RATIONALE Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination ( salmeterol/fluticasone propionate ) 50/500 microg twice daily and the long-acting bronchodilator ( tiotropium ) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD . METHODS A total of 1,323 patients ( mean age , 64 yr , post-bronchodilator FEV1 , 39 % predicted ) were r and omized in this 2-year , double-blind , double-dummy parallel study . MEASUREMENTS AND MAIN RESULTS Primary endpoint was health care utilization exacerbation rate . Other endpoints included health status measured by St. George 's Respiratory Question naire ( SGRQ ) , mortality , adverse events , and study withdrawal . Probability of withdrawing from the study was 29 % greater with tiotropium than salmeterol/fluticasone propionate ( P = 0.005 ) . The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group ( rate ratio , 0.967 ; 95 % confidence interval [ CI ] , 0.836 - 1.119 ] ; P = 0.656 ) . The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium ( difference 2.1 units ; 95 % CI , 0.1 - 4.0 ; P = 0.038 ) . Mortality was significantly lower in the salmeterol/fluticasone propionate group ; 21 ( 3 % ) of patients in this group died compared with 38 ( 6 % ) in the tiotropium group ( P = 0.032 ) . More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium ( P = 0.008 ) . CONCLUSIONS We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium . More patients failed to complete the study while receiving tiotropium . A small statistically significant beneficial effect was found on health status , with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients . Clinical trial registered with www . clinical trials.gov ( NCT 00361959 ) BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) often present with severe acute exacerbations requiring hospital treatment . However , little is known about the prognostic consequences of these exacerbations . A study was undertaken to investigate whether severe acute exacerbations of COPD exert a direct effect on mortality . METHODS Multivariate techniques were used to analyse the prognostic influence of acute exacerbations of COPD treated in hospital ( visits to the emergency service and admissions ) , patient age , smoking , body mass index , co-morbidity , long term oxygen therapy , forced spirometric parameters , and arterial blood gas tensions in a prospect i ve cohort of 304 men with COPD followed up for 5 years . The mean ( SD ) age of the patients was 71 ( 9 ) years and forced expiratory volume in 1 second was 46 (17)% . RESULTS Only older age ( hazard ratio ( HR ) 5.28 , 95 % CI 1.75 to 15.93 ) , arterial carbon dioxide tension ( HR 1.07 , 95 % CI 1.02 to 1.12 ) , and acute exacerbations of COPD were found to be independent indicators of a poor prognosis . The patients with the greatest mortality risk were those with three or more acute COPD exacerbations ( HR 4.13 , 95 % CI 1.80 to 9.41 ) . CONCLUSIONS This study shows for the first time that severe acute exacerbations of COPD have an independent negative impact on patient prognosis . Mortality increases with the frequency of severe exacerbations , particularly if these require admission to hospital This r and omised , double-blind , parallel-group , 1-yr study compared the effect of tiotropium 18 microg once daily ( n=500 ) and placebo  ( n=510 ) on exacerbations , associated health re source use ( HRU ) and  airflow limitation in chronic obstructive pulmonary disease ( COPD ) patients . The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40 , the mean weekly morning peak expiratory flow ( PEF ) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second ( FEV1 ) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days , reduced the proportion of patients experiencing more than one exacerbation by 17 % , and decreased the number of exacerbations by 35 % and exacerbation days by 37 % versus placebo . Tiotropium also decreased HRU versus placebo , as indicated by the significant reductions in the use of concomitant respiratory medications , antibiotics and oral steroids , and the number of unscheduled physician contacts . Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study . At the end of the study , tiotropium significantly improved trough ( pre-dose ) FEV1 , forced vital capacity , slow vital capacity and inspiratory capacity versus placebo . In conclusion , tiotropium reduced exacerbations and associated health re source use , and improved airflow over 1 yr in chronic obstructive pulmonary disease patients BACKGROUND Gender differences may occur in many chronic diseases . We have examined the influence of gender in chronic obstructive pulmonary disease ( COPD ) on long-term responses to tiotropium . METHODS Subgroup analysis of data from the Underst and ing the Potential Long-term Impact of Tiotropium ( UPLIFT ) trial ( 4-year , r and omized , double-blind , placebo-controlled trial of tiotropium in patients with COPD ) . RESULTS Of 5992 patients , 75 % were men and 25 % women . Mean age was 65 and 63 years , respectively . Baseline post-bronchodilator forced expiratory volume in 1s ( FEV(1))=47 % predicted(men ) and 49 % predicted(women ) . St George 's Respiratory Question naire ( SGRQ ) total score was 44.9 and 48.7units , respectively . At 48 months , improvement in trough FEV(1 ) over control was 92mL(men ) and 77mL(women ) ( p<0.001 for both ) , with no differences in the rate of decline ( trial primary endpoint ) . Hazard ratio ( HR ) ( 95 % confidence interval [ CI ] ) for first exacerbation ( tiotropium/placebo ) was 0.87(0.81 , 0.93)(men ) and 0.83(0.74 , 0.94)(women ) . Number of exacerbations ( per patient-year ) was reduced with tiotropium in men ( from 0.82 to 0.71 ) and women ( from 0.92 to 0.77 ) ( p<0.005 for both ) . HR ( 95 % CI ) for a hospitalized exacerbation was 0.89(0.79 , 0.99 ) and 0.77(0.62 , 0.94 ) , respectively . HR ( 95 % CI ) for mortality during treatment was 0.85(0.72 , 0.99)(men ) and 0.85(0.62 , 1.18)(women ) . Improvements in SGRQ total score ( tiotropium-control ) at 1 , 2 , 3 and 4 years were : -2.8 , -2.3 , -3.6 , -2.4(men ) and -2.7 , -2.6 , -2.6 , -2.1(women ) ( p<0.05 for all ) . CONCLUSION Long-term treatment of COPD with tiotropium improves lung function , exacerbations and health status in men and women , with similar magnitudes of benefit . Boehringer Ingelheim trial 205.235 ; Clinical Trials.gov : NCT00144339 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 % ] 
    Output:
    