Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial Long-term efficacy of tiotropium in relation to smoking status in the UPLIFT trial A 4-year trial of tiotropium in chronic obstructive pulmonary disease. Tiotropium and exercise training in COPD patients: Effects on dyspnea and exercise tolerance Bronchodilator responsiveness in patients with COPD Absence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary disease. [A randomized, double-blind, placebo-control study of once-daily inhaled tiotropium in chronic obstructive pulmonary disease]. Outcomes in COPD patients receiving tiotropium or salmeterol plus treatment with inhaled corticosteroids Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD Premature discontinuation of patients: a potential bias in COPD clinical trials Tiotropium improves FEV1 in patients with COPD irrespective of smoking status. Acute care costs of patients admitted for management of chronic obstructive pulmonary disease exacerbations: contribution of disease severity, infection and chronic heart failure. Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD Adverse health consequences in COPD patients with rapid decline in FEV1 - evidence from the UPLIFT trial Efficacy and safety of tiotropium in COPD patients in primary care – the SPiRiva Usual CarE (SPRUCE) study Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT® trial A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease A randomized study of tiotropium Respimat Soft Mist inhaler vs. ipratropium pMDI in COPD. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group. Healthcare Costs with Tiotropium Plus Usual Care versus Usual Care Alone Following 1 Year of Treatment in Patients with Chronic Obstructive Pulmonary Disorder (COPD) Improved respiratory system conductance following bronchodilator predicts reduced exertional dyspnoea. Tolerance to bronchodilating effects of salmeterol in COPD. Tiotropium in COPD patients not previously receiving maintenance respiratory medications. Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial. Cardiovascular safety of tiotropium in patients with COPD. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Lack of protective effect of tiotropium vs induced dynamic hyperinflation in moderate COPD. The Effect of Tiotropium on Hyperinflation and Exercise Capacity in Chronic Obstructive Pulmonary Disease Improvement in self-reported exercise participation with the combination of tiotropium and rehabilitative exercise training in COPD patients [Efficacy of tiotropium bromide (Spiriva) in patients with chronic-obstructive pulmonary disease (COPD) of different severities]. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Meaningful effect size and patterns of response of the transition dyspnea index. Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD. [The UPLIFT study (Understanding Potential Long-term Impacts on Function with Tiotropium)]. A one-year trial of tiotropium Respimat plus usual therapy in COPD patients. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Improvements with tiotropium in COPD patients with concomitant asthma. COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT). Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator
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 multi-center , r and omized , double-blind , and placebo-control clinical trial was conducted in 205 patients with stable COPD . They were r and omized into inhaled tiotropium 18 µg once daily or placebo , lasting for 12 weeks . The spirometry was conducted at baseline , 6 and 12 weeks after treatment . RESULTS A total of 205 patients with stable stage I or II COPD were r and omized to tiotropium and placebo groups . The improvement rate of clinical symptom in the tiotropium group was 25.2 % ( 26/103 ) after a 12 week treatment , but that of the control group was 4.9 % ( 5/102 ) . The forced expiratory volume in one second ( FEV₁ ) and forced vital capacity ( FVC ) in the tiotropium group increased ( 0.2 ± 0.3 ) L and ( 19.2 ± 29.1)% after the 12 week therapy , but only ( 0.0 ± 0.2 ) L and ( 0.8 ± 18.2)% in the placebo group . The rate of adverse reaction in the tiotropium group was 7.8 % ( 8/103 ) , but in the placebo group was 12.8 % ( 13/102 ) . The difference between the 2 groups was not significant . All adverse reactions were mild , including dry mouth and sore throat . CONCLUSIONS This trial confirmed that tiotropium powder 18 µg once daily relieved dyspnea , prevented aggravation and improved pulmonary function , clinical symptoms and life quality . Tiotropium was a safe and effective once-daily anticholinergic bronchodilator as first-line maintenance therapy in COPD Patients with COPD are frequently prescribed inhaled corticosteroids ( ICS ) ; however , it is unclear whether the treatment with ICS might modify responses to inhaled bronchodilators . Two 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group studies of tiotropium 18 μg once daily , compared with salmeterol , 50 μg bid , had been conducted in patients with moderate-to-severe COPD . Efficacy was assessed by spirometry , transition dyspnea index ( TDI ) , St. George ’s Respiratory Question naire ( SGRQ ) , and exacerbations . Data from both studies were combined to form subgroups with regard to concurrent use of ICS .  796 patients receiving ICS were separately analyzed from 390 patients not receiving ICS . Mean age was 64 years , and pre-bronchodilator FEV1 was 1.06 L ( ICS group ) and 1.13 L ( non-ICS group ) . Both bronchodilators increased morning mean ± SE pre-dose FEV1 compared with placebo ( ICS groups : tiotropium 110 ± 20 mL , salmeterol 80 ± 20 mL ; non-ICS groups : tiotropium 150 ± 30 mL , salmeterol 110 ± 30 mL ; p > 0.05 for tiotropium vs salmeterol ) . Improvements in TDI and SGRQ and frequency of exacerbations also tended to be more profound for tiotropium . Treatment with tiotropium in patients with moderate-to-severe COPD was superior to salmeterol in lung function , irrespective of concurrent use of ICS Chronic obstructive pulmonary disease ( COPD ) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation . Tiotropium has been shown to reduce exacerbation frequency , but its effect on airway inflammation is unknown . The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency .  Patients ( n = 142 ) were r and omised to receive tiotropium or placebo in addition to their usual medication for 1 yr . Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary . There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups , but sputum IL-8 level was increased in the tiotropium arm . There was no difference between start and end of study in serum IL-6 or C-reactive protein level .  Tiotropium was associated with a 52 % reduction in exacerbation frequency ( 1.17 versus 2.46 exacerbations·yr−1 ) . Of patients on tiotropium , 43 % experienced at least one exacerbation , compared with 64 % on placebo  . The total number of exacerbation days was reduced compared with placebo ( 17.3 versus 34.5 days ) . Tiotropium  reduces exacerbation frequency in chronic obstructive pulmonary disease , but this effect does not appear to be due to a reduction in airway or systemic inflammation Premature discontinuation from clinical trials may bias results against effective therapies . In the present study mortality rates were retrospectively review ed in a 6-month , r and omised , placebo-controlled trial in which tiotropium 18 μg daily was shown to decrease chronic obstructive pulmonary disease exacerbations . Patients participated for 6 months even if trial medication was prematurely discontinued . Exposure-adjusted incidence rates ( IRs ) were calculated for r and omisation – end trial , r and omisation – end trial drug ( 0–ED ) and end trial drug – end trial ( ED – ET ) . Of 1,829 patients ( forced expiratory volume in one second 1.04 L ( 36 % predicted ) , mean age 68 yrs , 99 % male ) , 16  % tiotropium  and 27 % placebo patients prematurely stopped trial medication . The number of fatal events for the entire cohort was : 62 all cause , including 16 cardiac and 16 lower respiratory . IRs for fatal events per 100 patient-yrs were higher in the discontinued period : 1.9 ( 0–ED ) versus 23.0 ( ED – ET ) in the tiotropium group and 1.8 versus 19.0 in the placebo group . Respective IRs for fatal cardiac events were 0.7 versus 2.8 ( tiotropium ) and 0.5 versus 6.2 ( placebo ) ; for fatal lower respiratory events were 0.7 versus 2.8 ( tiotropium ) and 0.8 versus 5.4 (  placebo ) . Rate ratios ( tiotropium/placebo ) for fatal events were lower in the discontinued period : 1.4 versus 0.5 for cardiac and 0.9 versus 0.5 for lower respiratory . Higher incidence rates of fatal events occurred following premature discontinuation of study medication . Incomplete information from rate ratios occurs as a result of failure to consider outcomes of patients who discontinue early from clinical trials This study evaluated whether the effect of tiotropium on the change in trough forced expiratory volume in 1s ( FEV1 ) , vs. placebo , is affected by smoking status . In a 3-month , double-blind study in 31 centres in Portugal , 311 ( 289 completed ) patients were r and omised to tiotropium 18 microg once daily or placebo .  Baseline mean ( st and ard deviation ( SD ) ) FEV1 was 1.11 ( 0.39 ) l in the tiotropium group and 1.13 ( 0.39 ) l in the placebo group . Patients had an average smoking history of 55 ( 25.7 ) pack-years ; 80 ( 26 % ) were smokers and 224 ( 74 % ) were ex-smokers . The primary end-point was change in morning pre-dose ( i.e. trough ) FEV1 after 12 weeks . Trough FEV1 at 12 weeks was significantly improved with tiotropium vs. placebo : the difference in means was 102 ml , P=0.0011 , 95 % confidence interval ( CI ) ( 41 , 164 ) . The difference in means in smokers was 138 ml , P=0.0105 , CI ( 32 , 244 ) ; in ex-smokers it was 66 ml , P=0.0375 , CI ( 3 , 129 ) . The difference between smokers and ex-smokers was not statistically significant ( P=0.6982 ) and may be due to greater variability and differences in disease severity . The significant improvement in lung function in patients treated with tiotropium vs. placebo in both smokers and ex-smokers suggests that tiotropium is an effective and well-tolerated therapy in chronic obstructive pulmonary disease ( COPD ) , regardless of smoking status BACKGROUND In 2003 , chronic obstructive pulmonary disease ( COPD ) accounted for 46 % of the burden of chronic respiratory disease in the Australian community . In the 65 - 74-year-old age group , COPD was the sixth leading cause of disability for men and the seventh for women . AIMS To measure the influence of disease severity , COPD phenotype and comorbidities on acute health service utilization and direct acute care costs in patients admitted with COPD . METHODS Prospect i ve cohort study of 80 patients admitted to the Royal Melbourne Hospital in 2001 - 2002 for an exacerbation of COPD . Patients were followed for 12 months and data were collected on acute care utilization . Direct hospital costs were derived using Transition II , an activity-based costing system .  Individual patient costs were then modelled to ascertain which patient factors influenced total direct hospital costs . RESULTS Direct costs were calculated for 225 episodes of care , the median cost per admission was AU$3124 ( interquartile range $ 1393 to $ 5045 ) . The median direct cost of acute care management per patient per year was AU$7273 ( interquartile range $ 3957 to $ 14 448 ) . In a multivariate analysis using linear regression modelling , factors predictive of higher annual costs were increasing age ( P= 0.041 ) , use of domiciliary oxygen ( P= 0.008 ) and the presence of chronic heart failure ( P= 0.006 ) . CONCLUSION This model has identified a number of patient factors that predict higher acute care costs and awareness of these can be used for service planning to meet the needs of patients admitted with COPD 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 Clinical manifestations of chronic obstructive pulmonary disease ( COPD ) , including airflow limitation , dyspnea , and activity limitation , ultimately lead to impaired health-related quality of life ( HRQoL ) . This 9-month , r and omized , double-blind , multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL , spirometric parameters , and exacerbations in 554 patients with moderate-to-severe COPD .  HRQoL was assessed using the St. George ’s Respiratory Question naire ( SGRQ ) and the new 8-item Visual Simplified Respiratory Question naire ( VSRQ ) , which is currently being vali date d. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end ( Month 9 ) . Mean ± SD baseline SGRQ total score was 47.4 ± 18.1 . Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score  vs placebo at study end ( 59.1 % vs 48.2 % , respectively ;  p = 0.029 ) . Tiotropium  significantly improved spirometric parameters ( forced expiratory volume in 1 second [ FEV1 ] : 0.11 ± 0.02 L vs 0.01 ± 0.02 L ; between-group difference : 0.10 ± 0.03 L , p = 0.0001 ) and reduced exacerbations vs placebo . Maintenance treatment with tiotropium provided significant and clinical ly relevant improvements in HRQoL , as measured by the SGRQ Background The rate of decline in forced expiratory volume in 1 second ( FEV1 ) is representative of the natural history of COPD . Sparse information exists regarding the associations between the magnitude of annualised loss of FEV1 with other endpoints . Methods Retrospective analysis of UPLIFT ® trial ( four-year , r and omized , double-blind , placebo-controlled trial of tiotropium 18 μg daily in chronic obstructive pulmonary disease [ COPD ] , n = 5993 ) . Decline of FEV1 was analysed with r and om co-efficient regression . Patients were categorised according to quartiles based on the rate of decline ( RoD ) in  post-bronchodilator FEV1  . The St George 's Respiratory Question naire ( SGRQ ) total score , exacerbations and mortality were assessed within each quartile . Results Mean ( st and ard error [ SE ] ) post-bronchodilator FEV1 increased in the first quartile ( Q1 ) by 37 ( 1 ) mL/year . The other quartiles showed annualised declines in FEV1 ( mL/year ) as follows : Q2 = 24 ( 1 ) , Q3 = 59 ( 1 ) and Q4 = 125 ( 2 ) . Age , gender , respiratory medication use at baseline and SGRQ did not distinguish groups . The patient subgroup with the largest RoD had less severe lung disease at baseline and contained a higher proportion of current smokers . The percentage of patients with ≥ 1 exacerbation showed a minimal difference from the lowest to the largest RoD , but exacerbation rates increased with increasing RoD. The highest proportion of patients with ≥ 1 hospitalised exacerbation was in Q4 ( Q1 = 19.5 % [ tiotropium ] , 26 % [ control ] ; Q4 = 33.8 % [ tiotropium ] and 33.1 % [ control ] ) . Time to first exacerbation and hospitalised exacerbation was shorter with increasing RoD. Rate of decline in SGRQ increased in direct proportion to each quartile . The group with the largest RoD had the highest mortality . Conclusion Patients can be grouped into different RoD quartiles with the observation of different clinical outcomes indicating that specific ( or more aggressive ) approaches to management may be needed . Trial Registration Clinical Trials.gov number , Background Clinical trials of tiotropium have principally recruited patients from secondary care with more severe chronic obstructive pulmonary disease ( COPD ) , and typically had included limitation of concomitant medication . In primary care , which is the most common setting for COPD management , many patients may have milder disease , and also may take a broad range of concomitant medication . Methods This r and omised , placebo-controlled , parallel-group , 12-week , 44-centre study investigated the efficacy ( trough forced expiratory volume in 1 second [ FEV1 ] response ) and safety of additional treatment with once-daily tiotropium 18 μg via the H and iHaler ® in a primary care COPD population ( tiotropium : N = 191 , FEV1 = 1.25 L [ 47.91 % predicted ] ; placebo : N = 183 , FEV1 = 1.32 L [ 49.86 % predicted ] ) . Secondary endpoints included : trough forced vital capacity ( FVC ) response , weekly use of rescue short-acting β-agonist , and exacerbation of COPD ( complex of respiratory symptoms/events of > 3 days in duration requiring a change in treatment ) . Treatment effects were determined using non-parametric analysis . Results At Week 12 , median improvement in trough FEV1 response  with tiotropium versus placebo was 0.06 L ( p = 0.0102 ) . The improvement was consistent across baseline treatment and COPD severity . Median improvement in FVC at 2 , 6 and 12 weeks was 0.12 L ( p < 0.001 ) . The percentage of patients with ≥1 exacerbation was reduced ( tiotropium 9.5 % ; placebo 17.9 % ; p = 0.0147 ) , independent of disease severity . Rescue medication usage was significantly reduced in the tiotropium  group compared with  placebo . Adverse event profile was consistent with previous studies . Conclusion Tiotropium provides additional benefits to usual primary care management in a representative COPD population .Trial registration The identifier is : NCT00274079 STUDY OBJECTIVES Pulmonary rehabilitation ( PR ) improves exercise tolerance in COPD patients .  Tiotropium is a once-daily , inhaled anticholinergic bronchodilator that provides sustained 24-h improvements in airflow and lung hyperinflation reduction . We hypothesized that ventilatory mechanics improvements from tiotropium would permit enhanced ability to train muscles of ambulation and therefore augment exercise tolerance benefits of PR . DESIGN In a r and omized , double-blind , placebo-controlled trial  ( tiotropium , n = 47 ; placebo , n = 44 ) ,  tiotropium  ( 18 microg qd ) was administered to COPD patients participating in 8 weeks of PR ( treadmill training three times a week ; > /= 30 min per session ) at 17 sites . Study drug was administered 5 weeks prior to , 8 weeks during , and 12 weeks following PR . The primary end point was treadmill walking ( 0 % incline ) endurance time at 80 % of maximum speed attained in an initial incremental test . The transition dyspnea index ( TDI ) , St. George 's respiratory question naire ( SGRQ ) , and rescue albuterol use were secondary end points . PARTICIPANTS Mean age of the 93 participants was 67 years , 57 % were men , and mean FEV(1 ) was 0.88 L ( 34 % predicted ) . RESULTS Mean endurance time differences  ( tiotropium minus placebo ) prior to PR , at the end of PR , and 12 weeks after PR were 1.65 min ( p = 0.183 ) , 5.35 min ( p = 0.025 ) , and 6.60 min ( p = 0.018 ) , respectively . Mean TDI focal scores at the end of PR were 1.75 for tiotropium and 0.91 for placebo ( p > 0.05 ) . At 12 weeks after PR , TDI focal scores were 1.75 for tiotropium and 0.08 for placebo ( p < 0.05 ) . Relative to placebo , tiotropium improved SGRQ total scores by 3.86 at the end of PR and 4.44 at 12 weeks after PR ( p > 0.05 ) . Mean albuterol use declined following PR plus tiotropium , compared to PR alone ( p < /= 0.05 for 17 of 25 weeks ) . CONCLUSIONS Tiotropium in combination with PR improved endurance of a constant work rate treadmill task and produced clinical ly meaningful improvements in dyspnea and health status compared to PR alone . Improvements with tiotropium were sustained for 3 months following PR completion The aim of the present study was investigate the long-term effect of tiotropium as first maintenance respiratory medication in chronic obstructive pulmonary disease ( COPD ) . A 4-yr , r and omised , multicentre , double-blind , parallel-group , placebo-controlled trial ( Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ® ) ) was conducted . Analysis focused on the effect of tiotropium versus matching placebo in the 810 ( 13.5 % ) COPD patients not on other maintenance treatment ( long-acting & bgr;-agonists , inhaled corticosteroids , theophyllines or anticholinergics ) at r and omisation .  Spirometry , health-related quality of life ( St George ’s Respiratory Question naire ( SGRQ ) score ) , exacerbations of COPD and mortality were also analysed . 403 patients ( mean±sd age 63±8 yrs , post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) 53±12 % predicted )  received tiotropium and 407 ( 64±8 yrs of age , post-bronchodilator FEV1 51±12 % pred ) received placebo . Post-bronchodilator FEV1 decline was 42±4 mL·yr−1 in the tiotropium group and 53±4 mL·yr−1 in the placebo group ( p = 0.026 ) . At 48 months , the morning pre-dose FEV1 was 134 mL higher in the tiotropium group compared to the placebo group ( p<0.001 ) . SGRQ total score declined more slowly in the tiotropium group ( difference of 1.05±0.34 units·yr−1 ; p = 0.002 ) . This was particularly significant for the impact ( difference of 1.08±0.37 units·yr−1 ; p = 0.004 ) and activity ( 1.44±0.40 units·yr−1 ; p<0.001 ) domains , but not for symptoms ( 0.26±0.50 units·yr−1 ; p = 0.6 ) . At 48 months , the difference in total score was 4.6 units ( p<0.001 ) with tiotropium compared to placebo . In patients with COPD who are not on maintenance therapy , tiotropium is associated with significant benefits in disease progression Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease ( COPD ) necessitate multiple daily dosing . The present study evaluates the long-term safety and efficacy of tiotropium , a new once-daily anticholinergic in COPD . Patients with stable COPD ( age 65.2±8.7 yrs ( mean±sd ) , n=921 ) were enrolled in two identical r and omized double-blind placebo-controlled 1-yr studies . Patients inhaled tiotropium 18 µg or placebo ( mean screening forced expiratory volume in one second ( FEV1 ) 1.01 versus 0.99 L , 39.1 and 38.1 % of the predicted value ) once daily as a dry powder . The primary spirometric outcome was trough FEV1 ( i.e. FEV1 prior to dosing ) . Changes in dyspnoea were measured using the Transition Dyspnea Index , and health status with the disease-specific St. George 's Respiratory Question naire and the generic Short Form 36 . Medication use and adverse events were recorded . Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response ( ∼12 % over baseline ) ( p<0.01 ) and mean response during the 3 h following dosing ( ∼22 % over baseline ) ( p<0.001 ) over the 12-month period . Tiotropium recipients showed less dyspnoea ( p<0.001 ) , superior health status scores , and fewer COPD exacerbations and hospitalizations ( p<0.05 ) . Adverse events were comparable with placebo , except for dry mouth incidence ( tiotropium 16.0 % versus placebo 2.7 % , p<0.05 ) . Tiotropium is an effective , once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status . This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy The aim of these studies was to compare the efficacy and the safety of tiotropium , delivered via Respimat Soft Mist Inhaler ( SMI ) , a novel multi-dose , propellant-free inhaler , with ipratropium pressurized metered-dose inhaler ( pMDI ) in chronic obstructive pulmonary disease ( COPD ) patients . Two identical , 12-week , multi-national , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled studies were performed . COPD patients were r and omized to treatment with either inhaled tiotropium ( 5 or 10 microg ) via Respimat SMI administered once daily , ipratropium ( 36 microg ) pMDI QID or placebo . The primary endpoint was the mean trough forced expiratory volume in 1s ( FEV(1 ) ) response after 12 weeks of treatment . Secondary endpoints included other spirometry measures and rescue medication use .  A total of 719 patients were r and omized ; the majority were male ( 69 % ) with a mean pre-bronchodilator FEV(1 ) ( % predicted ) of 40.7 % . The mean treatment differences between tiotropium 5 and 10 microg and placebo for the primary endpoint ( mean trough FEV(1 ) response at week 12 ) were 0.118 and 0.149L , respectively ( both P<0.0001 ) . Treatment differences between tiotropium 5 and 10 microg and ipratropium were 0.064L ( P=0.006 ) and 0.095L ( P<0.0001 ) . The increases in peak FEV(1 ) , FEV(1 ) AUC((0 - 6h ) ) and FVC for both tiotropium doses were statistically superior to placebo ( P<0.01 ) and higher than ipratropium . All active treatments significantly reduced the rescue medication use compared with placebo , but only tiotropium 10 microg was statistically superior to ipratropium ( P=0.04 ) . The incidence of adverse events was comparable across groups . In conclusion , tiotropium 5 and 10 microg daily , delivered via Respimat SMI , significantly improved lung function compared with ipratropium pMDI and placebo STUDY OBJECTIVE To compare the bronchodilator efficacy and safety of tiotropium and placebo . DESIGN A 3-month , r and omized , double-blind , placebo-controlled , multicenter trial . SETTING Outpatient . PATIENTS Four hundred seventy patients with stable COPD ( mean FEV(1 ) = 38.6 % predicted ) . INTERVENTIONS Tiotropium 18 microg ( N = 279 ) or placebo ( N = 191 ) given once daily via a lactose-based dry-powder inhaler device . MEASUREMENTS AND RESULTS Spirometry was evaluated on days 1 , 8 , 50 , and 92 . Data were expressed as the mean trough ( ie , before morning dose ; 23 to 24 h after previous dose ) and average response observed in the 3 h after the dose was received . Tiotropium produced significant improvement in trough FEV(1 ) and FVC , averaging 12 % greater than baseline on day 8 ; these improvements were maintained on days 50 and 92 . The average postdose FEV(1 ) was 16 % greater than baseline on day 1 and 20 % greater than baseline on day 92 ; FVC was 17 % greater than baseline on day 1 and 19 % greater than baseline on day 92 . Tiotropium was significantly more effective than placebo in both trough and average FEV(1 ) and FVC response ( p < 0.001 ) . These spirometric effects were corroborated by significant improvements in daily morning and evening peak expiratory flow rate , as well as a reduction in " as-needed " albuterol use . Symptoms of wheezing and shortness of breath were significantly less in patients receiving tiotropium , and the physician global assessment noted overall improvements with those treated with tiotropium relative to placebo . The most common reported adverse event after tiotropium was dry mouth ( 9.3 % vs 1.6 % relative to placebo ; p < 0.05 ) . CONCLUSIONS These data demonstrate that tiotropium is a safe and effective once-daily anticholinergic bronchodilator and should prove useful as first-line maintenance therapy in COPD Abstract Background : Healthcare costs for chronic obstructive pulmonary disease ( COPD ) have continued to increase with the increasing prevalence of the disease . New interventions that can reduce the medical costs of COPD are needed . Tiotropium bromide , a once-daily inhaled anticholinergic , has been evaluated in patients with COPD enrolled in two 1-year r and omised , double-blind , placebo-controlled ( usual care ) trials which showed the drug reduced exacerbations and improved spirometry , dyspnoea , and health status . Objective : To retrospectively assess the direct costs of medical care for COPD in a US healthcare setting for patients treated with tiotropium in addition to usual care compared with usual care alone over a 1-year timeframe . The study was based on re source utilisation in the two previously described trials . Methods : Re source utilisation and clinical data were prospect ively collected for the two 1-year , r and omised , double-blind trials of tiotropium plus usual care versus usual care alone ( placebo ) in 921 patients with COPD . Usual care was defined as any medication for COPD used prior to the trial except anticholinergics and long-acting β-adrenoceptor agonists . Medical care re source utilisation was recorded at every scheduled visit in each trial . Mean total costs were calculated retrospectively by combining the re sources utilised with the appropriate unit costs ( 1999 US dollars ) , excluding study drug ( tiotropium ) costs . Results : Compared with usual care , patients receiving tiotropium in addition to usual care had significantly fewer COPD exacerbations ( 20 % decrease ) , hospitalisations ( 44 % reduction ) and hospital days ( 50 % reduction ) . Utilisation of re sources other than hospitalisation did not differ between study groups . As a consequence , patients receiving tiotropium had significantly lower mean per- patient costs of hospitalisation compared with patients receiving usual care alone ( tiotropium $ US1738 ± $ US259 ; placebo $ US2793 ± $ US453 ) . The mean difference in the cost of hospitalisation ( result ing from all causes , including COPD ) between treatment groups was -$US1056 ( 95 % CI -$US2078 , -$US34 ) , and the difference in total healthcare costs ( excluding study drug acquisition cost ) was -$US1043 ( 95 % CI -$US2136 , $ US48 ) in favour of tiotropium  . The cost of hospital admissions accounted for 48 % of the total direct medical costs in this trial . Conclusions : As hospitalisation is a large contributor to the cost of COPD , the addition of tiotropium to usual care therapy may have the potential to reduce the economic burden of COPD in a US healthcare setting . However , as our study did not consider the acquisition cost of tiotropium , further economic evaluation including this cost is needed to address whether tiotropium is cost saving compared with usual care ( placebo ) BACKGROUND In COPD , improvements in lung mechanics following bronchodilator , measured using the forced oscillation technique ( FOT ) , are more sensitive than spirometry at detecting improvement in lung function following bronchodilator . The relationship between these improvements in lung mechanics and improvements in functional outcomes , such as exertional dyspnoea , following bronchodilator , in COPD is unknown . METHODS 17 COPD subjects were recruited into a double blind placebo controlled r and omised cross over study . Dyspnoea was induced using a st and ardised six-minute walk test ( 6 MWT ) , and measured by borg score throughout the test . Measurement of respiratory system conductance ( Grs ) , respiratory system reactance ( Xrs ) , inspiratory capacity ( IC ) and spirometry were made at baseline and 1 h after a single dose of either 18 μg of tiotropium bromide plus 200 μg salbutamol , or placebo . RESULTS Subjects had a mean baseline FEV(1 ) of 45.5 ± 11.0 % predicted . The bronchodilator induced reduction in exertional dyspnoea correlated significantly with the increase in Grs ( r(s ) = 0.59 , p = 0.01 ) and approached significance with FEV(1 ) ( r(s ) = 0.45 , p = 0.07 ) but not with FVC ( r(s ) = 0.30 , p = 0.24 ) , Xrs ( r(s ) = 0.19 , p = 0.47 ) or IC ( r(s ) = -0.08 , p = 0.78 ) . Increase in Grs was the best and sole predictor of reduction in exertional dyspnoea , explaining 41 % of the variance . There was no additional contribution to the model from the increase in FEV(1 ) or IC . CONCLUSION Bronchodilator induced improvements in exertional dyspnoea in moderate to severe COPD are predicted by improvements in Grs , measured by FOT , independent of improvements in spirometry or hyperinflation . The findings suggest that FOT may be useful for measuring response to bronchodilator in COPD Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications . Initially , tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties . However , generally such observations have been reported in asthma . A 6-month r and omized , double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD .  Spirometry was measured over 12h at baseline and at days 15 , 57 , 116 and 169 . Changes over time from baseline were compared relative to changes observed with placebo .  A total of 623 patients participated ( tiotropium = 209 , salmeterol = 213 , placebo = 201 ) . The groups were similar in age ( mean = 65 years ) , gender ( 75 % men ) , and baseline FEV1 ( mean = 1.08 + /- 0.37l [ 40 + /- 12 % predicted ] ) . Relative to placebo , both active drugs improved morning pre-drug , peak and average FEV1 and FVC throughout the trial . However , from day 1 to 169 , salmeterol was associated with a higher decline in average FEV1 and FVC ( 0 - 12h ) ( difference from placebo : -36 and -115 ml , P < 0.05 ) , which was most prominent over the 8 - 12 h period ( difference from placebo : -45 and -138 ml , P < 0.01 ) . Significant declines in peak FVC relative to placebo ( -83 ml , P < 0.05 ) but not FEV1 ( -12ml ) were observed with salmeterol . Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial . In conclusion , tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics INTRODUCTION Use of maintenance bronchodilator therapy is currently recommended in symptomatic patients with Chronic obstructive pulmonary disease ( COPD ) and in those with Stage II or greater COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) . Because no prospect i ve data describe when rescue therapy alone is insufficient or the optimal time to start maintenance therapy , it is unclear whether maintenance therapy has benefits in milder disease . To explore potential benefits we asked : Does once-daily tiotropium improve lung function , health status , and /or symptoms in " undertreated " COPD patients ( i.e. , those who are not receiving maintenance bronchodilator therapy ) or patients considered by their health care providers as having milder disease ? METHODS A post-hoc analysis of data from COPD patients participating in two , 1-year , placebo-controlled trials with tiotropium  was performed . Patients were defined as " undertreated " if they received no respiratory medication or only as-needed short-acting beta-agonists prior to enrollment . Measures included serial spirometry , Transition Dyspnea Index ( TDI ) , and St. George 's Respiratory Question naire ( SGRQ ) . RESULTS Of 921 patients enrolled , 218 ( 23.7 % ) were " undertreated " : 130 received tiotropium ; 88 received placebo .  Demographics for the two treatment groups were comparable . Tiotropium-treated patients had significantly improved forced expiratory volume in 1s ( FEV1 ) and forced vital capacity ( FVC ) compared with patients using placebo on all study days . Additionally , TDI and SGRQ scores significantly improved with tiotropium compared with placebo . CONCLUSIONS Once-daily tiotropium provides significant improvement in lung function , health status , and dyspnea when used as maintenance therapy in undertreated COPD patients who were not previously receiving maintenance bronchodilator therapy BACKGROUND AND OBJECTIVE Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions . We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial . METHODS Subgroup analysis from a r and omized , double-blinded , placebo-controlled trial of tiotropium 18 µg daily in COPD . Primary end-point was rate of decline in FEV(1 ) . Secondary end-points included spirometry at individual time points , health-related quality of life ( St George 's Respiratory Question naire ) , exacerbations and mortality . RESULTS Of 5992 patients , 362 were from Asian centres ( 100 from Japan ) . Mean age 66 years , 95 % men , 13 % current smokers , BMI : 21 kg/m(2 ) ; post-bronchodilator FEV(1 ) : 44 % predicted ; St George 's Respiratory Question naire total score : 44 units . No treatment effect was observed for rate of decline in FEV(1 ) although annual decline was less in Asian patients . Morning pre-bronchodilator FEV(1 ) and forced vital capacity improved in Asian patients ( P < 0.05 ) . Tiotropium  reduced number of exacerbations ( rate ratio ( 95 % confidence interval ( CI ) ) : 0.73 ( 0.57 - 0.94 ) ) . Hazard ratios ( 95%CI ) for exacerbations and hospitalized exacerbations  ( tiotropium/control ) were 0.81 ( 0.62 - 1.05 ) and 0.85 ( 0.61 - 1.19 ) , respectively . St George 's Respiratory Question naire total score improved by 1.5 - 6.1 units ( P < 0.05 for months 18 , 24 , 30 and 36 ) with tiotropium . Fatal events occurred in 34 tiotropium ( 18.5 % ) and 42 control ( 23.6 % ) patients . CONCLUSIONS In COPD patients from Asia  , tiotropium  improves lung function , improves health-related quality of life and reduces exacerbations over 4 years of treatment BACKGROUND The clinical trial safety data base for tiotropium has been augmented with a 4-year trial in patients with COPD , which provides an opportunity to better evaluate the cardiovascular ( CV ) profile of tiotropium . METHODS Trials with the following criteria were considered : > or = 4 weeks , r and omized , double-blind , parallel-group , placebo-controlled . Inclusion /exclusion criteria were similar , including spirometry-confirmed COPD , > or = 10 pack-year smoking , and age > or = 40 years .  Adverse events were collected throughout each trial using st and ardized case report forms . Incidence rates ( IRs ) were determined from the total number of patients with an event divided by total time at risk . Rate ratios ( RRs ) and 95 % CI for  tiotropium/placebo  were calculated . IRs were determined for all-cause mortality and selected CV events , including a composite CV end point encompassing CV deaths , nonfatal myocardial infa rct ion ( MI ) , nonfatal stroke , and the terms sudden death , sudden cardiac death , and cardiac death . RESULTS There were 19,545 patients r and omized : 10,846 ( tiotropium ) and 8,699 ( placebo ) from 30 trials . Mean FEV(1 ) = 1.15 + /- 0.46 L ( 41 + /- 14 % predicted ) , 76 % men , mean age = 65 + /- 9 years .  Cumulative exposure to study drug was 13,146 ( tiotropium ) and 11,095 ( placebo ) patient-years . For all-cause mortality , the IR was 3.44 ( tiotropium ) and 4.10 ( placebo ) per 100 patient-years ( RR [ 95 % CI ] = 0.88 [ 0.77 - 0.999 ] ) . IR for the CV end point was 2.15 ( tiotropium ) and 2.67 ( placebo ) per 100 patient-years ( RR [ 95 % CI ] = 0.83 ( 0.71 - 0.98 ] ) . The IR for the CV mortality excluding nonfatal MI and stroke was 0.91 ( tiotropium ) and 1.24 ( placebo ) per 100 patient-years ( RR [ 95 % CI ] = 0.77 [ 0.60 - 0.98 ] ) . For total MI , cardiac failure , and stroke the RRs ( 95 % CI ) were 0.78 ( 0.59 - 1.02 ) , 0.82 ( 0.69 - 0.98 ) , and 1.03 ( 0.79 - 1.35 ) , respectively . CONCLUSION Tiotropium was associated with a reduction in the risk of all-cause mortality , CV mortality , and CV events BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) who smoke have a greater annual rate of decline in forced expiratory volume in 1 s ( FEV(1 ) ) than those patients who have stopped smoking . OBJECTIVES To assess the effect of tiotropium on pre-dose ( trough ) FEV(1 ) in patients with COPD followed in Canada . METHODS A total of 913 patients were r and omly assigned to receive either tiotropium 18 mug once daily ( n=608 ) or placebo ( usual care minus inhaled anticholinergics ) ( n=305 ) for 48 weeks in the present r and omized , double-blind , parallel-group study . The effect of tiotropium on measurements of lung function ( FEV(1 ) , FEV(6 ) and forced vital capacity ) , symptoms , health-related quality of life ( St George 's Respiratory Question naire ) and exacerbations were examined . RESULTS Tiotropium improved trough FEV(1 ) in both current and ex-smokers compared with placebo .  Baseline FEV(1 ) in smokers and ex-smokers was 1.03 L and 0.93 L , respectively ( P<0.001 ) . At week 48 , the mean difference between the tiotropium and placebo groups was 0.14+/-0.04 L ( P<0.001 ) in the smoker group and 0.08+/-0.02 L ( P<0.0001 ) in the ex-smoker group . Tiotropium also significantly improved trough forced vital capacity and FEV(6 ) compared with placebo throughout the treatment period ( P<0.05 , for all ) . Furthermore , tiotropium significantly improved the St George 's Respiratory Question naire total score compared with placebo at week 48 ( 40.9 versus 43.7 units , P<0.005 ) . CONCLUSIONS Compared with the placebo group , tiotropium provides sustained improvements in lung function in patients with COPD , with improvements for smokers and ex-smokers STUDY OBJECTIVE Novel evaluation of protective effect of tiotropium against induced dynamic hyperinflation ( DH ) during metronome paced hyperventilation ( MPH ) in moderate COPD . METHODS Prospect i ve , r and omized , double-blind , placebo control , crossover study . Lung function measured pre/post MPH at 30 breaths/min for 20 s in 29 ( 18 M ) COPD patients ( GOLD Stage 2 ) age 70±9 yr ( mean ± SD ) before and after 30 days of 18 μg tiotropium bromide vs placebo .  Lung CT scored for emphysema ( ES ) . RESULTS At baseline post 180 μg aerosolized albuterol sulfate , FEV(1 ) : 1.8±0.6 L ( 69±6 % pred ) and ≥60 % predicted in all , and 14 of 29 had FEV(1 ) ( L ) ≥70 % predicted with FEV(1)/FVC 58±8 % . After 29 days + 23 h post tiotropium ( trough ) there was significant decrease only in FRC/TLC% ( p=0.04 ) ; after 30 days + 2 h post tiotropium ( peak ) significant increase only in FEV(1 ) ( L ) ( p=0.03 ) compared to placebo . Results post MPH  induced DH at baseline and after 30 days and 2 h post placebo or tiotropium were similar with decrease in IC 0.44±0.06 L ( p<0.001 ) . Correlation between ES and increased FEV(1 ) ( L ) at peak tiotropium : r=0.19 , p=0.96 and decreased FRC/TLC% at trough tiotropium : r=-0.26 , p=0.36 . CONCLUSION In moderate COPD , tiotropium did not reduce MPH induced DH and reduction in IC . However , at peak tiotropium , there was significant bronchodilation in FEV(1 ) ( L ) and at trough a decrease in FRC/TLC% compared to placebo despite varying emphysema Background : Chronic obstructive pulmonary disease ( COPD ) is characterized by airflow limitation , which results in the progressive development of dyspnea and exercise limitation . Objective and Methods : To compare the effect of tiotropium with placebo on forced vital capacity ( FVC ) in patients with moderate-to-severe COPD and lung hyperinflation , using exercise endurance , dyspnea and health-related quality of life ( HRQoL ) as secondary endpoints . One hundred patients were r and omized to receive either tiotropium 18 µg once daily or placebo for 12 weeks . Results : Trough ( predose ) FVC was significantly improved with tiotropium compared to placebo on day 42 ( 0.27 ± 0.08 liters ) and 84 ( 0.20 ± 0.08 liters ; p < 0.05 for both ) . Trough inspiratory capacity ( IC ) was also significantly improved with tiotropium compared to placebo on day 42 ( 0.16 ± 0.07 liters ) and 84 ( 0.15 ± 0.07 liters ; p < 0.05 for both ) . Tiotropium increased the mean distance walked during the shuttle walking test by 33 ± 12 ( day 42 ) and 36 ± 14 m ( day 84 ) compared to placebo ( p < 0.05 for both ) . On day 84 , 59 % of the patients in the tiotropium group and 35 % of the patients in the placebo group had significant and clinical ly meaningful improvements in the St. George ’s Respiratory Question naire total score ( p < 0.05 ) . Numerical decreases in the focal score in the Transition Dyspnea Index in patients receiving tiotropium versus placebo suggest that tiotropium also improved dyspnea during activities of daily living . Conclusion : Tiotropium 18 µg once daily reduced hyperinflation with consequent improvements in walking distance and HRQoL in patients with COPD and lung hyperinflation Background Improvements in ventilatory mechanics with tiotropium increases exercise tolerance during pulmonary rehabilitation . We wondered whether tiotropium also increased physical activities outside of pulmonary rehabilitation . Methods COPD patients participating in 8 weeks of pulmonary rehabilitation were studied in a r and omized , double-blind , placebo-controlled trial of tiotropium 18 μg daily ( tiotropium = 47 , placebo = 44 ) . Study drug was administered for 5 weeks prior to , 8 weeks during , and 12 weeks following pulmonary rehabilitation . Patients completed a question naire documenting participation in pre-defined activities outside of pulmonary rehabilitation during the 2 weeks prior to each visit . Patients who su bmi tted an activity question naire at week 4 and on at least one subsequent visit were included in the analysis . For each patient , the number of sessions was multiplied with the duration of each activity and then summed to give overall activity duration . Results Patients ( n = 46 ) had mean age of 67 years , mean baseline FEV1 of 0.84 L ( 33 % predicted ) . Mean ( SE ) increase in duration of activities ( minutes during 2 weeks prior to each visit ) from week 4 ( prior to PR ) to week 13 ( end of PR ) was 145 ( 84 ) minutes with tiotropium and 66 ( 96 ) minutes with placebo . The increase from week 4 to week 25 ( end of follow-up ) was 262 ( 96 ) and 60 ( 93 ) minutes for the respective groups . Increases in activity duration from week 4 to weeks 17 , 21 , and 25 were statistically significant with tiotropium . No statistical differences over time were observed within the placebo-treated group and differences between groups were not significant . Conclusions Tiotropium appears to amplify the effectiveness of pulmonary rehabilitation as seen by increases in patient self-reported participation in physical activities BACKGROUND Aim of this study was to evaluate the efficacy of inhaled Tiotropium bromide in COPD patients of different severities in pneumological practice s during a three months clinical trial . METHODS A r and omized , double blind , placebo controlled study including COPD - patients ( FEV1/FVC < 70 % , FEV1 < or = 70 % predicted ; age > or = 40 years ; > or = 10 pack years ) of different severities was performed . The efficacy of 18 microg Tiotropium bromide once daily on lung function and exacerbations over 12 weeks was evaluated by respective pulmonary function tests ( spirometry ) before ( trough value ) and 2 hours after inhalation of study medication . RESULTS 1639 patients ( 1236 Tiotropium bromide , 403 placebo ;  FEV1 reversibility after 200 microg Ipratropium bromide + 200 microg Fenoterol : 7.9 + /- 7.5 % predicted [ mean + /- sd ] ) were r and omized . After 12 weeks of treatment Tiotropium bromide led to significant increases of trough FEV1 ( 23 - 24 h after last inhalation ; + 79 + /- 17 ml ) , and 2 h after Tiotropium bromide inhalation ( + 128 + /- 19 ml ) ( all values vs. placebo , adjusted mean + /- se , p < 0.0001 ) . FVC and IVC were also improved significantly . In mild COPD ( FEV1 > or = 50 - 70 % ) improvements were most pronounced ( trough FEV1 + 113 + /- 29 ml , 2 h post-inhalation + 181 + /- 33 ml ; all values vs. placebo . , p < 0.0001 ) . 14.6 % of patients treated with Tiotropium bromide had a COPD exacerbation vs. 19.9 % of patients treated with placebo ( p = 0.0151 ) . The time to first exacerbation was prolonged ( p = 0.0092 vs. placebo ) . CONCLUSION Tiotropium bromide 18 microg once daily led to a persistent improvement of lung function and a reduction of exacerbations in patients with COPD of different severities RATIONALE In the 4-year UPLIFT trial , tiotropium improved lung function and health-related quality of life and decreased exacerbations compared with usual respiratory medications except inhaled anticholinergics in patients with chronic obstructive pulmonary disease ( COPD ) . Mortality and its causes was a secondary endpoint in UPLIFT . OBJECTIVES We describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow-up of discontinued patients . METHODS This study involved a r and omized , double-blind trial comparing tiotropium with placebo in patients with COPD ( > or=40 yr of age ; postbronchodilator FEV(1 ) < or=70 % ; FEV(1)/FVC < or=70 % ) .  Mortality was evaluated during treatment and with follow-up of discontinued patients . Cause of death was adjudicated by an endpoint committee . MEASUREMENTS AND MAIN RESULTS A total of 5,993 patients were r and omized , 3,006 to placebo and 2,987 to tiotropium .  While patients were receiving treatment , there were 792 deaths , with a lower risk in the tiotropium group ( hazard ratio , 0.84 ; 95 % confidence interval [ CI ] , 0.73 - 0.97 ) . Statistical significance was observed at the end of the protocol -defined treatment period ( P = 0.034 ) but not 30 days thereafter ( P = 0.086 ) . Adjustment by GOLD stage , sex , age , baseline smoking behavior , and baseline respiratory medications subgroups did not alter the results of the analysis . The most common causes of death adjudicated by an independent end-point committee were lower respiratory , cancer , general disorders , and cardiac disorders . The hazard ratios for lower respiratory and cardiac mortality during treatment were 0.86 ( 95 % CI , 0.68 - 1.09 ) and 0.86 ( 95 % CI , 0.75 - 0.99 ) , respectively . CONCLUSIONS Treatment with tiotropium over 4 years is associated with decreased mortality , with the effect being most prominent in the cardiac and respiratory systems Ths object of this study was to examine validity , meaningful effect sizes , and patterns of response of the Transition Dyspnea Index ( TDI ) in a clinical trial cohort of chronic obstructive pulmonary disease ( COPD ) patients . The design was a retrospective analysis of data from a r and omized , double-blind placebo-controlled clinical trial . We analyzed fifty clinical investigation sites in United States . There were 921 patients with stable COPD .  Tiotropium 18 microg dry powder or matching placebo was used . Patients were allowed to remain on usual care less ipratropium bromide . Construct validity was demonstrated by significant correlations ( P < .05 ) between Baseline Dyspnea Index ( BDI ) and other baseline measures , as well as between TDI and changes in other measures at the end of 1 year . Concurrent validity was observed by the significant correlation between TDI and dyspnea diary responses . Changes in TDI focal score were in the range of one unit when the group was stratified by a minimal change in the physician 's global evaluation . Significantly less ( P < .05 ) supplemental albuterol was observed in the group of responders defined by a one-unit improvement in TDI . Responders also had few exacerbations and better health status . The validity of the TDI is supported in a large clinical trial setting . A one-unit change in the TDI focal score represented the minimal important difference AIMS Evaluation of tiotropium  efficacy in patients with mild chronic obstructive pulmonary disease ( COPD ) defined by the 2003 Swedish Society of Respiratory Medicine guidelines ( post-bronchodilator FEV1/FVC < 70 % ; FEV1 > 60 % predicted ) . METHODS In this 12-week , r and omised , double-blind , placebo-controlled study of tiotropium 18 mcg once daily versus placebo , respiratory function was assessed on Days 1 , 15 and 85 ( baseline : pre-dose Day 1 ) . RESULTS Mean+/-SD baseline FEV1 ( % predicted ) was 73.4+/-12.5 ( tiotropium , n=107 ; placebo , n=117 ) . Tiotropium significantly improved change from baseline in area under the curve from pre-dose to 2 hours post-dose ( AUC0 - 2 h ) FEV1 versus placebo , by 166+/-26 mL ( mean+/-SE ) at study end ( p<0.0001 ) . With tiotropium , there were significant increases in the change in AUC0 - 2 h FVC versus baseline , and trough FEV1 and FVC , versus placebo , on all test days ( p<0.01 ) . Adverse event rates were similar . CONCLUSION Compared with placebo , tiotropium improved lung function in patients with mild COPD The UPLIFT study ( Underst and ing Potential Long-term Impacts on Function with Tiotropium ) was a double-blind , r and omised , international , multicentric , placebo-controlled clinical trial , investigating with tiotropium ( Spiriva ) the change in the annual rate of decline in FEV1 in chronic obstructive pulmonary disease ( COPD ) . Secondary end points included COPD exacerbation rate with or without hospitalisation , lung function , quality of life and mortality .  5.993 patients were r and omized . In this article , we briefly describe the most important results of the study . While tiotropium did not alter the annual rate of decline in FEV1 ( pre and postbronchodilatation ) , it improved lung function and quality of life , and reduced exacerbations and hospitalisations by comparison with control for up to 4 years . Tiotropium also reduced respiratory and cardiac morbidity In this r and omised double-blind study , patients > or=40 years old with COPD , a smoking history of > or=10 pack-years , a pre-bronchodilator FEV(1 ) of < or=60 % predicted and an FEV(1)/FVC of < or=70 % received tiotropium 5 microg or placebo via Respimat inhaler once daily for 48 weeks . Other medications were permitted except inhaled anticholinergics . Co- primary endpoints were trough FEV(1 ) and the time to first exacerbation . Adverse events were followed and vital status regularly assessed . In all , 3991 patients ( mean age , 65 years [ SD , 9 years ] ) were evaluable . Mean baseline FEV(1 ) was 1.11 L ( 0.40 L ) or 40 % ( 12 % ) of predicted normal . Adjusted mean differences in trough FEV(1 ) and trough FVC at Week 48 ( tiotropium minus placebo ) were 102 and 168 ml respectively ( p < 0.0001 , both ) . Tiotropium delayed time to first exacerbation relative to placebo ( hazard ratio [ HR ] , 0.69 [ 95 % CI , 0.63 - 0.77 ] ) and time to first hospital-treated exacerbation ( HR , 0.73 [ 0.59 - 0.90 ] ) . SGRQ score at Week 48 was 2.9 units lower with tiotropium ( p < 0.0001 ) . Adverse and serious adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials . The rate ratio for a major adverse cardiovascular event during the treatment period + 30 days was 1.12 ( 0.67 - 1.86 ) . By the end of planned treatment ( Day 337 ) 52 patients on tiotropium ( incidence rate per 100 years , 2.94 ) and 38 on placebo ( 2.13 ) had died ( HR = 1.38 [ 0.91 - 2.10 ] ; p = 0.13 ) . Lung function , exacerbations and quality of life were improved by tiotropium 5 microg Respimat but a numerical imbalance was seen in all-cause mortality . The protocol is registered on the European Clinical Trials Data base as trial number 2006 - 001009 - 27 and in the Clinical Trials.gov data base as NCT00387088 BACKGROUND Tiotropium , a once-daily anticholinergic , and salmeterol represent two inhaled , long-acting bronchodilators from different pharmacologic classes . A trial was design ed to examine the efficacy and safety of both compounds with multiple outcome measures , including lung function , dyspnea , and health-related quality of life ( HRQoL ) in patients with COPD . METHODS A 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group study of tiotropium , 18 microg once daily via dry-powder inhaler , compared with salmeterol , 50 microg bid via metered-dose inhaler , was conducted in patients with COPD .  Efficacy was assessed by 12-h monitoring of spirometry , transition dyspnea index ( TDI ) , and the St. George 's Respiratory Question naire ( SGRQ ) . RESULTS A total of 623 patients participated ( tiotropium , n= 209 ; salmeterol , n = 213 ; and  placebo , n = 201 ) . The groups were similar in age ( mean , 65 years ) , gender ( 75 % men ) , and baseline FEV(1 ) ( mean , 1.08 + /- 0.37 L ; percent predicted , 40 + /- 12 % [ + /- SD ] ) . Compared with placebo treatment , the mean predose morning FEV(1 ) following 6 months of therapy increased significantly more for the tiotropium group ( 0.14 L ) than the salmeterol group ( 0.09 L ; p < 0.01 ) . The average FEV(1 ) ( 0 to 12 h ) for tiotropium was statistically superior to salmeterol ( difference , 0.08 L ; p < 0.001 ) . Tiotropium improved TDI focal score by 1.02 U compared with placebo ( p = 0.01 ) , whereas there was no significant change in TDI focal score with salmeterol ( 0.24 U ) . Tiotropium was superior to salmeterol in improving TDI focal score ( p < 0.05 ) . At 6 months , the mean improvement in SGRQ total score vs baseline was tiotropium , - 5.14 U ( p < 0.05 vs placebo ) ; salmeterol , - 3.54 U ( p = 0.4 vs placebo ) ; and placebo , - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo . Both active drugs reduced the need for rescue albuterol ( p < 0.0001 ) . CONCLUSIONS Tiotropium once daily produces superior bronchodilation , improvements in dyspnea , and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD BACKGROUND Chronic obstructive pulmonary disease ( COPD ) and asthma have different diagnostic criteria and treatment paradigms . Both are common and can occur in the same patient . We sought to determine the spirometric effects of tiotropium in COPD patients with concomitant asthma . METHODS A 12-week r and omized , double-blind , placebo-controlled , parallel group trial with tiotropium 18 mcg daily was performed . Patients continued usual respiratory medications except for inhaled anticholinergics . INCLUSION CRITERIA Physician diagnosis of COPD and asthma , age > or= 40 years , smoking > 10 pack years , post-bronchodilator forced expiratory volume in 1s ( FEV(1))<80 % predicted , FEV(1)/forced vital capacity (FVC)<70 % , > or= 12 % , and > or= 200 ml increase in FEV(1 ) following inhaled bronchodilator , treatment with inhaled steroids > or= 1 year . Spirometry was measured serially for 6h on days 1 , 29 and 85 . RESULTS Four hundred and seventy-two patients were r and omized . Baseline characteristics were balanced . Mean age=59.6 years , 61.4 % were men , and FEV(1)=1.55l ( 53.0 % predicted ) . Improvements at 12 weeks with tiotropium were observed for the primary endpoint FEV(1 ) area under the curve ( AUC ) from 0 to 6h ( difference=186+/-24 ml , p<0.001 ) and for morning pre-dose FEV(1 ) ( difference=98+/-23 ml , p<0.001 ) . Significant differences in favor of tiotropium were observed for pre-dose FVC ( difference=128+/-34 ml , p<0.001 ) and FVC AUC 0 - 6h ( difference=232+/-35 ml , p<0.001 ) . Compared to baseline , the mean weekly number of daily puffs of prn salbutamol was reduced by 0.05+/-0.12 puffs/day in the placebo group and by 0.50+/-0.12 puffs/day in the tiotropium group at week 12 ( p<0.05 ) . CONCLUSIONS Patients with COPD and concomitant asthma achieve spirometric improvements with tiotropium along with symptomatic benefit as seen by reduced need for rescue medication Whilst recent large-scale studies have provided much evidence on the natural history and therapeutic response in patients with chronic obstructive pulmonary disease ( COPD ) , relatively little is known about the effect in younger patients . We report a pre-specified post-hoc analysis of 356 patients with COPD ≤ 50 years old from the four year r and omised , double blind placebo controlled Underst and ing Potential Long Term Impact on Function with Tiotropium ( UPLIFT ) trial . Inclusion criteria included a post-bronchodilator forced expiratory volume in 1 s ( FEV(1 ) ) of ≤70 % , FEV(1)/FVC < 0.70 , age ≥40 years , and smoking history of ≥10 pack years . Younger patients had a mean FEV(1 ) of 1.24 L ( 39 % predicted ) and an impaired health-related quality of life ( St. George 's Respiratory Question naire ( SGRQ ) ) compared to the entire UPLIFT population . There were 40.2 % women and 51.1 % current smokers in the younger age group . Tiotropium was associated with a sustained improvement in spirometry and SGRQ . Mean decline in post-bronchodilator FEV(1 ) was 58 ml/year ( placebo ) vs. 38 ml/year ( tiotropium ) ( p = 0.01 ) . Corresponding values for pre-bronchodilator FEV(1 ) were 41 ml/year ( placebo ) compared with 34 ml/year ( tiotropium ) ( p = 0.34 ) . The hazard ratio ( 95%CI ) for an exacerbation in the younger age group was 0.87(0.68 , 1.13 ) ) . The rate of exacerbations was reduced by tiotropium ( rate ratio ( 95%CI ) = 0.73(0.56 , 0.95 ) ) . Tiotropium result ed in sustained bronchodilation , improved quality of life , and a decreased exacerbation rate in younger  patients . Tiotropium also result ed in a significant reduction in the decline in post-bronchodilator FEV(1 ) , suggesting possible disease modification by tiotropium in younger patients with COPD Context Tiotropium , a new once-daily inhaled anticholinergic bronchodilator , has been shown to improve lung function in patients with chronic obstructive pulmonary disease ( COPD ) . Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients . Contribution This r and omized , parallel-group , double-blind , placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period . Caution s The study period was relatively short , and the beneficial effects were modest . The Editors Exacerbations of chronic obstructive pulmonary disease ( COPD ) can lead to costly and clinical ly significant consequences . Proven treatments for exacerbations are only modestly effective ( 1 , 2 ) . Recovery from even mild exacerbations may be protracted ( 3 ) . Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time ( 4 , 5 ) . Patients with severe exacerbations commonly seek care in emergency departments , and many of these patients are hospitalized . In 2000 , COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States ( 6 ) . Economic analyses suggest that hospitalization alone consumes up to 70 % of all medical expenses for patients with COPD ( 7 , 8) . Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need . An expert panel convened by the National Heart , Lung , and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations ( 9 ) . Tiotropium is a newly developed , once-daily inhaled anticholinergic bronchodilator . Because of its very slow dissociation from muscarinic M3 receptors , 1 inhaled dose produces sustained bronchodilation for at least 24 hours ( 10 ) . In controlled clinical trials , compared with placebo or the short-acting anticholinergic bronchodilator ipratropium , tiotropium improved lung function , dyspnea , and health-related quality of life in patients with COPD ( 11 , 12 ) . An analysis of adverse event reports su bmi tted during those studies suggested that tiotropium might also reduce exacerbation and COPD -related hospitalization rates . Therefore , we design ed a clinical trial to prospect ively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD . Methods Study Design Our study was a parallel-group , r and omized , double-blind , placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States . The sole intervention was tiotropium given by inhalation once daily . The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period . The protocol is consistent with the principles of Helsinki . The institutional review boards of participating medical centers approved the study . All trial participants provided written informed consent . Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants . We enrolled enough participants to ensure a minimum of 1800 r and omly assigned patients . Eligibility criteria included an age of 40 years or older , a cigarette smoking history of 10 pack-years or more , a clinical diagnosis of COPD , and an FEV1 of 60 % predicted or less and 70 % or less of the FVC . Exclusion criteria were a clinical diagnosis of asthma , a myocardial infa rct ion within the previous 6 months , a serious cardiac arrhythmia or hospitalization for heart failure within the previous year , known moderate to severe renal impairment , moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction , narrow-angle glaucoma , current radiation or chemotherapy for a malignant condition , or inability to give informed consent . We also excluded patients who took systemic corticosteroids at unstable doses , or in regular daily doses of 20 mg or more of prednisone ( or equivalent ) , or who had not fully recovered from an exacerbation for at least 30 days before the first study visit . We gathered baseline data on respiratory disease and other relevant medical history by question naire . Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a central ly generated blocked r and omization list . We generated a single r and omization and assigned blocks to centers . We provided r and omly assigned patients with training and detailed instructions on the use of the dry powder inhalation device ( H and iHaler , Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach , Germany ) ( 13 ) . Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites . The double-blind remained in place until all patients were clinical ly complete or until a serious adverse event required unblinding . Each morning during the trial , patients inhaled 1 capsule of tiotropium ( 18 g ) or 1 identical placebo capsule . Participants otherwise received usual medical care , except that they could not take any open-label anticholinergic bronchodilator . They continued taking all other respiratory medications ( including inhaled corticosteroids and long-acting -agonists ) , and primary providers were allowed to prescribe additional medications according to medical need . Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions . For purpose s of recall , patients kept a daily diary throughout the treatment period , recording information about specific respiratory symptoms , medications taken for exacerbations , clinic visits , and hospitalizations . We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits . We assessed study drug adherence by query and by counting returned capsules .  Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits . We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy . However , patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits . All open-label bronchodilators and the study drug were withheld overnight before spirometry . Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations ( 14 , 15 ) . Objectives We aim ed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations . Outcome Measures The co primary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation . We defined an exacerbation as a complex of respiratory symptoms ( increase or new-onset ) of more than 1 of the following : cough , sputum , wheezing , dyspnea , or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids , hospitalization , or both . The study team at each site requested discharge summaries for all hospitalizations , wherever they occurred . We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event result ed in a hospitalization . We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours . Admissions to nursing homes or other extended care facilities were not considered hospitalizations . Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation , the frequencies of exacerbations and of exacerbation-related health care utilization ( hospitalizations , hospitalization days , unscheduled clinic visits , antibiotic treatment days , and systemic corticosteroid treatment days ) , the frequencies of all-cause hospitalizations and hospitalization days , and results of spirometry . Statistical Analysis We analyzed the data by using a modified intention-to-treat principle . Therefore , we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event ( for the time-to-event end points ) or their withdrawal from the trial . For the time-to-event end points , we censored patients without an event at the end of their participation in the trial . Although we intended to follow all patients for the full 6 months , some patients were lost to follow-up . We h and led missing data by using longitudinal data analysis methods ( spirometry ) , analysis of observed data only ( number of events ) , or analysis methods for censored data ( time-to-event data ) . For the percentage of patients with an event , we considered that patients who discontinued the study drug therapy before having an event did not have an event . We analyzed the co primary end points by using a CochranMantelHaenszel test with center as a stratum . We used a stepwise procedure to test the percentage of patients with an exacerbation and , if rejected , to test percentage of patients with a hospitalization due to COPD exacerbation , each at a 2-sided level of 0.05 . Because of the prespecified closed testing procedure , no adjustment for multiplicity was required . We calculated that a sample size of 1800 patients would have 80 % power to
BACKGROUND Tiotropium is an anticholinergic agent which has gained widespread acceptance as a once daily maintenance therapy for symptoms and exacerbations of stable chronic obstructive pulmonary disease ( COPD ) .
In the past few years there have been several systematic review s of the efficacy of tiotropium , however , several new trials have compared tiotropium treatment with placebo , including those of a soft mist inhaler , making an up date necessary .
OBJECTIVES To evaluate data from r and omised controlled trials ( RCTs ) comparing the efficacy of tiotropium and placebo in patients with COPD , upon clinical ly important endpoints .