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 UPLIFT ( Underst and ing Potential Long-Term Improvements in Function with Tiotropium ) , a 4-yr trial of tiotropium in chronic obstructive pulmonary disease , allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy . 5,993 patients were r and omised ( tiotropium/placebo )  .  Lung function , St George 's Respiratory Question naire , exacerbations and adverse events were followed . Patients were characterised as  continuing smokers ( CS ) , continuing ex-smokers ( CE ) , or intermittent smokers ( IS ) based on self-reporting smoking behaviour . 60 % , 14 % and 26 % of patients were CE , CS and IS , respectively . The rate of forced expiratory volume in 1 s ( FEV1 ) decline for placebo patients was most rapid in CS ( -51±4 , -36±2 and -23±2 mL·yr−1 in CS , IS , and CE , respectively ) . Tiotropium did not alter FEV1 decline , but was associated with significant improvements in pre- and post-bronchodilator FEV1  over placebo that persisted throughout the 4-yr trial for each smoking status ( pre-bronchodilator : 125 , 55 and 97 mL at 48 months in CS , IS and CE , respectively ; p≤0.0003 ) . Tiotropium  reduced exacerbation risk in CS ( HR ( 95%CI ) 0.81 ( 0.68–0.97 ) ) , in CE ( 0.86 ( 0.79–0.93 ) ) and trended towards significance in IS ( 0.89 ( 0.80–1.01 ) ) . At 4 yrs , St George ’s Respiratory Question naire for tiotropium patients improved the most in CS ( -4.62 units , p = 0.0006 ) and the least in IS ( -0.54 units , p = 0.55 ) , compared with control . Tiotropium provided long-term benefits irrespective of smoking status , although differences among categories were observed BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . Background Exercise training improves exercise tolerance in chronic obstructive pulmonary disease ( COPD ) . Tiotropium 18 μg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation , one of the pathophysiological factors contributing to exertional dyspnea in COPD patients . Aim To determine whether tiotropium enhances the effects of exercise training in patients with COPD . Design Multicenter , 25 week r and omized , double-blind , placebo-controlled , parallel-group study . Setting Twelve Italian Pulmonary Units practicing pulmonary rehabilitation . Patients and intervention Two hundred thirty four COPD patients ( 196 males ; mean age : 67.4 ± 7.6 ; forced expiratory volume at 1 second ( FEV1 ) : 41.4 ± 13.0 % predicted ) were r and omised to tiotropium 18 μg or placebo inhalation capsules  taken once daily . Both groups underwent a 8 week pulmonary rehabilitation program ( PR ) consisting of 3 exercise training session per week . Measurements Baseline , at the end of PR and after 12 weeks , patients completed pulmonary function testing , six minute walking test ( 6MWT ) , the Baseline and Transition Dyspnea Index ( BDI and TDI ) , and the St. George ’s Respiratory Question naire ( SGRQ ) . Results Relative to placebo , tiotropium had larger trough and post- study drug FEV1 responses on all test days . At the end of and 12 weeks following PR , patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo . Compared to the period immediately prior to PR , the mean improvement in 6MWT was only 29.7 meters ( 7.1 % ) for the combined cohort . Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo ( p < 0.01 ) . At 12 weeks after PR , TDI focal scores were 2.71 for tiotropium and 2.11 for placebo ( p = 0.16 ) . Reduction in all four SGRQ component scores , indicating an improvement in health-related quality of life , was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant . During the study period , there were fewer exacerbations and exacerbation days in the tiotropium group . Conclusion Although significant improvements were observed with perceived dyspnea , compared to placebo , the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease ( COPD ) patients , and depends upon the type and dose of bronchodilator and the timing of administration . Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ) trial , a 4-yr r and omised double-blind trial evaluating the efficacy of 18 μg tiotropium daily in reducing the rate of decline in lung function . After wash-out of respiratory medications , patients received 80 μg ipratropium followed by 400 μg salbutamol .  Spirometry was performed before and 90 min following ipratropium administration . The criteria used for forced expiratory volume in one second ( FEV1 ) responsiveness were : ≥12 % increase over baseline and ≥200 mL ; ≥15 % increase over baseline ; and ≥10 % absolute increase in the percentage predicted value . Of the patients , 5,756 had data meeting the criteria for analysis ( age 64.5 yrs ; 75 % male ; baseline FEV1 1.10 L ( 39.3 % predicted ) and forced vital capacity ( FVC ) 2.63 L ) . Compared with baseline , mean improvements were 229 mL in FEV1 and 407 mL in FVC . Of these patients , 53.9 % had ≥12 % and ≥200 mL improvement in FEV1 , 65.6 % had ≥15 % improvement in FEV1 , and 38.6 % had ≥10 % absolute increase in FEV1 % pred . The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators STUDY OBJECTIVES To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease ( COPD ) , and to establish previously reported symptomatic efficacy . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Twelve outpatient investigational centers in the United States . PATIENTS One hundred ninety-six patients with COPD . INTERVENTIONS Patients received either tiotropium 18 mug once/day or placebo , delivered by the H and iHaler device . MEASUREMENTS AND MAIN RESULTS Electrocardiography ( predose and 5 min postdose ) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo . Efficacy measures ( spirometry , global COPD ratings , scores on the EuroQol Health Question naire [ EQ-5D ] , albuterol inhaler as needed ) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies . Mean baseline forced expiratory volume in 1 second ( FEV1 ) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups . No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring . Frequency of premature beats and mean maximal changes in PR , QRS , QT , QTcB , and QTcF intervals were similar in both groups . No patients developed new-onset QT or QTc intervals greater than 500 msec , and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec , 30 - 60 msec , or greater than 60 msec . At 12 weeks , predose and postdose improvements in FEV1 were 184 and 265 ml , respectively , with tiotropium versus placebo ( p<0.001 ) . Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium ( p<0.05 ) ; as-needed albuterol was reduced by 25 % relative to placebo ( p<0.05 ) . CONCLUSION Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate , rhythm , QT intervals , or conduction OBJECTIVE To compare the efficacy and safety between tiotropium capsule and placebo in a 12-week treatment in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS A 
    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 UPLIFT ( Underst and ing Potential Long-Term Improvements in Function with Tiotropium ) , a 4-yr trial of tiotropium in chronic obstructive pulmonary disease , allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy . 5,993 patients were r and omised ( tiotropium/placebo )  .  Lung function , St George 's Respiratory Question naire , exacerbations and adverse events were followed . Patients were characterised as  continuing smokers ( CS ) , continuing ex-smokers ( CE ) , or intermittent smokers ( IS ) based on self-reporting smoking behaviour . 60 % , 14 % and 26 % of patients were CE , CS and IS , respectively . The rate of forced expiratory volume in 1 s ( FEV1 ) decline for placebo patients was most rapid in CS ( -51±4 , -36±2 and -23±2 mL·yr−1 in CS , IS , and CE , respectively ) . Tiotropium did not alter FEV1 decline , but was associated with significant improvements in pre- and post-bronchodilator FEV1  over placebo that persisted throughout the 4-yr trial for each smoking status ( pre-bronchodilator : 125 , 55 and 97 mL at 48 months in CS , IS and CE , respectively ; p≤0.0003 ) . Tiotropium  reduced exacerbation risk in CS ( HR ( 95%CI ) 0.81 ( 0.68–0.97 ) ) , in CE ( 0.86 ( 0.79–0.93 ) ) and trended towards significance in IS ( 0.89 ( 0.80–1.01 ) ) . At 4 yrs , St George ’s Respiratory Question naire for tiotropium patients improved the most in CS ( -4.62 units , p = 0.0006 ) and the least in IS ( -0.54 units , p = 0.55 ) , compared with control . Tiotropium provided long-term benefits irrespective of smoking status , although differences among categories were observed BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . Background Exercise training improves exercise tolerance in chronic obstructive pulmonary disease ( COPD ) . Tiotropium 18 μg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation , one of the pathophysiological factors contributing to exertional dyspnea in COPD patients . Aim To determine whether tiotropium enhances the effects of exercise training in patients with COPD . Design Multicenter , 25 week r and omized , double-blind , placebo-controlled , parallel-group study . Setting Twelve Italian Pulmonary Units practicing pulmonary rehabilitation . Patients and intervention Two hundred thirty four COPD patients ( 196 males ; mean age : 67.4 ± 7.6 ; forced expiratory volume at 1 second ( FEV1 ) : 41.4 ± 13.0 % predicted ) were r and omised to tiotropium 18 μg or placebo inhalation capsules  taken once daily . Both groups underwent a 8 week pulmonary rehabilitation program ( PR ) consisting of 3 exercise training session per week . Measurements Baseline , at the end of PR and after 12 weeks , patients completed pulmonary function testing , six minute walking test ( 6MWT ) , the Baseline and Transition Dyspnea Index ( BDI and TDI ) , and the St. George ’s Respiratory Question naire ( SGRQ ) . Results Relative to placebo , tiotropium had larger trough and post- study drug FEV1 responses on all test days . At the end of and 12 weeks following PR , patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo . Compared to the period immediately prior to PR , the mean improvement in 6MWT was only 29.7 meters ( 7.1 % ) for the combined cohort . Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo ( p < 0.01 ) . At 12 weeks after PR , TDI focal scores were 2.71 for tiotropium and 2.11 for placebo ( p = 0.16 ) . Reduction in all four SGRQ component scores , indicating an improvement in health-related quality of life , was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant . During the study period , there were fewer exacerbations and exacerbation days in the tiotropium group . Conclusion Although significant improvements were observed with perceived dyspnea , compared to placebo , the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease ( COPD ) patients , and depends upon the type and dose of bronchodilator and the timing of administration . Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ) trial , a 4-yr r and omised double-blind trial evaluating the efficacy of 18 μg tiotropium daily in reducing the rate of decline in lung function . After wash-out of respiratory medications , patients received 80 μg ipratropium followed by 400 μg salbutamol .  Spirometry was performed before and 90 min following ipratropium administration . The criteria used for forced expiratory volume in one second ( FEV1 ) responsiveness were : ≥12 % increase over baseline and ≥200 mL ; ≥15 % increase over baseline ; and ≥10 % absolute increase in the percentage predicted value . Of the patients , 5,756 had data meeting the criteria for analysis ( age 64.5 yrs ; 75 % male ; baseline FEV1 1.10 L ( 39.3 % predicted ) and forced vital capacity ( FVC ) 2.63 L ) . Compared with baseline , mean improvements were 229 mL in FEV1 and 407 mL in FVC . Of these patients , 53.9 % had ≥12 % and ≥200 mL improvement in FEV1 , 65.6 % had ≥15 % improvement in FEV1 , and 38.6 % had ≥10 % absolute increase in FEV1 % pred . The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators STUDY OBJECTIVES To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease ( COPD ) , and to establish previously reported symptomatic efficacy . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Twelve outpatient investigational centers in the United States . PATIENTS One hundred ninety-six patients with COPD . INTERVENTIONS Patients received either tiotropium 18 mug once/day or placebo , delivered by the H and iHaler device . MEASUREMENTS AND MAIN RESULTS Electrocardiography ( predose and 5 min postdose ) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo . Efficacy measures ( spirometry , global COPD ratings , scores on the EuroQol Health Question naire [ EQ-5D ] , albuterol inhaler as needed ) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies . Mean baseline forced expiratory volume in 1 second ( FEV1 ) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups . No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring . Frequency of premature beats and mean maximal changes in PR , QRS , QT , QTcB , and QTcF intervals were similar in both groups . No patients developed new-onset QT or QTc intervals greater than 500 msec , and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec , 30 - 60 msec , or greater than 60 msec . At 12 weeks , predose and postdose improvements in FEV1 were 184 and 265 ml , respectively , with tiotropium versus placebo ( p<0.001 ) . Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium ( p<0.05 ) ; as-needed albuterol was reduced by 25 % relative to placebo ( p<0.05 ) . CONCLUSION Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate , rhythm , QT intervals , or conduction OBJECTIVE To compare the efficacy and safety between tiotropium capsule and placebo in a 12-week treatment in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS A 
    Output:
    