Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD Tiotropium in patients with moderate COPD naive to maintenance therapy: a randomised placebo-controlled trial Tiotropium and exercise training in COPD patients: Effects on dyspnea and exercise tolerance A dose-ranging study of tiotropium delivered via Respimat® Soft MistTM Inhaler or HandiHaler® in COPD patients Absence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary disease. Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease The effect of tiotropium on exacerbations and airflow in patients with COPD. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD Tiotropium improves FEV1 in patients with COPD irrespective of smoking status. Tiotropium Respimat Soft Mist Inhaler versus HandiHaler to improve sleeping oxygen saturation and sleep quality in COPD Treadmill endurance during 2-year treatment with tiotropium in patients with COPD: a randomized trial. Tiotropium 5microg via Respimat and 18microg via HandiHaler; efficacy and safety in Japanese COPD patients. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD Efficacy and safety of tiotropium in COPD patients in primary care – the SPiRiva Usual CarE (SPRUCE) study Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD. Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in COPD Safety and efficacy of tiotropium in patients switching from HandiHaler to Respimat in the TIOSPIR trial A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease Use of tiotropium Respimat Soft Mist Inhaler versus HandiHaler and mortality in patients with COPD Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. A randomized study of tiotropium Respimat Soft Mist inhaler vs. ipratropium pMDI in COPD. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Cardiovascular safety of tiotropium in patients with COPD. Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Efficacy of Tiotropium Inhalation Powder in African-American Patients with Chronic Obstructive Pulmonary Disease The Effect of Tiotropium on Hyperinflation and Exercise Capacity in Chronic Obstructive Pulmonary Disease [Efficacy of tiotropium bromide (Spiriva) in patients with chronic-obstructive pulmonary disease (COPD) of different severities]. Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD. 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. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD. Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator The efficacy of tiotropium administered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients.
The aim of this study was to test the hypothesis that use of tiotropium , a new long-acting anticholinergic bronchodilator , would be associated with sustained reduction in lung hyperinflation and , thereby , would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease . A r and omised , double-blind , placebo-controlled , parallel-group study was conducted in 187 patients ( forced expiratory volume in one second 44±13 % pred ) : 96 patients received 18 µg tiotropium and 91 patients received placebo once daily for 42 days . Spirometry , plethysmographic lung volumes , cycle exercise endurance and exertional dyspnoea intensity at 75 % of each patient 's maximal work capacity were compared . On day 42 , the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to  placebo : vital capacity and inspiratory capacity ( IC ) increased , with inverse decreases in residual volume and functional residual capacity  . Tiotropium  increased post-dose exercise endurance time by 105±40 s ( 21 % ) as compared to placebo on day 42 . At a st and ardised time near end-exercise ( isotime ) , IC , tidal volume and minute ventilation all increased , whilst dyspnoea decreased by 0.9±0.3 Borg scale units . In conclusion , the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise . Result ant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance Background : The benefits of pharmacotherapy with tiotropium H and iHaler 18 μg for patients with chronic obstructive pulmonary disease ( COPD ) have been previously demonstrated . However , few data exist regarding the treatment of moderate disease ( Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stage II ) . Aims : To determine whether tiotropium improves lung function/patient-reported outcomes in patients with GOLD stage II COPD naive to maintenance therapy . Methods : A r and omised 24-week double-blind placebo-controlled trial of tiotropium 18 μg once daily ( via H and iHaler ) was performed in maintenance therapy – naive patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity ( FVC ) ratio < 0.7 and post-bronchodilator FEV1 ⩾50 and < 80 % . Results : A total of 457 patients were r and omised ( 238 tiotropium , 219 placebo ; mean age 62 years ; FEV1 1.93 l ( 66 % predicted ) )  . Tiotropium was superior to placebo in mean change from baseline in post-dose FEV1 area under the curve from 0 to 3 h ( AUC0–3h ) at week 24 ( primary endpoint ) : 0.19 vs. −0.03 l ( least-squares mean difference 0.23 l , P<0.001 ) . FVC AUC0–3h , trough and peak FEV1 and FVC were significantly improved with tiotropium versus placebo ( P<0.001 ) . Compared with placebo , tiotropium  provided numerical improvements in physical activity ( P = NS ) . Physician ’s Global Assessment ( health status ) improved ( P=0.045 ) with less impairment on the Work Productivity and Activity Impairment question naire ( P=0.043 ) at week 24 . The incidence of exacerbations , cough , bronchitis and dyspnoea was lower with tiotropium than placebo . Conclusions : Tiotropium  improved lung function and patient-reported outcomes in maintenance therapy – naive patients with GOLD stage II COPD , suggesting benefits in initiating maintenance therapy early 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 This was a multicenter , r and omized , double-blind within device , parallel-group , dose-ranging study . COPD patients ( n = 202 ; 86 % male ; mean age : 61 years ) were r and omized to receive tiotropium 1.25 μg , 2.5 μg , 5 μg , 10 μg , or 20 μg Respimat ® SMI ( a novel , propellant-free device ) ; tiotropium 18 μg H and iHaler ® ; placebo Respimat ® ; or placebo H and iHaler ® for 3 weeks . The primary endpoint was trough FEV1 on Day 21 . Other assessment s included FVC , PEFR , rescue medication use , safety , and pharmacokinetics . In general , all active treatments improved the primary and secondary endpoints on Day 21 ( steady state ) compared with placebo . Tiotropium 5 μg Respimat ® , 20 μg Respimat ® , and tiotropium 18 μg H and iHaler ® were statistically significantly higher than placebo for the primary endpoint ( mean change in trough FEV1 was 150 mL ( both Respimat ® doses ) versus 20 mL ( placebo Respimat ® ) ; p < 0.05 ; and 230 mL ( H and iHaler ® ) versus −90 mL ( placebo H and iHaler ® ) ; p ≤ 0.001 ) . The urinary excretion ( up to 2 hours post-dose ) of tiotropium 5–10 μg Respimat ® was comparable with tiotropium 18 μg H and iHaler ® ; the overall incidence of adverse events was comparable across treatment groups . Tiotropium 5 and 10 μg Respimat ® improve lung function in COPD patients and appear to be comparable with tiotropium 18 μg H and iHaler ® 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 Background : In chronic obstructive pulmonary disease ( COPD ) , the degree of circadian variation in forced expiratory volume in 1 second ( FEV1 ) and the influence of anticholinergic blockade is not known . Tiotropium is a long acting inhaled anticholinergic bronchodilator that increases daytime FEV1 in COPD . We hypothesised that tiotropium would modify the overnight change in FEV1 , and this would be unaffected by the timing of drug administration . Methods : A double blind , r and omised , placebo controlled trial was conducted with tiotropium 18 mg once daily in the morning ( 09.00 hours ) , evening ( 21.00 hours ) , or an identical placebo .  Patients with stable COPD ( n=121 , FEV1=41 % predicted ) underwent spirometric tests every 3 hours for 24 hours at baseline and after 6 weeks of treatment . Results : There were no significant differences at baseline between the groups . Tiotropium improved mean ( SE ) FEV1 ( over 24 hours ) in the morning ( 1.11 ( 0.03 ) l ) and evening ( 1.06 ( 0.03 ) l ) groups compared with placebo ( 0.90 ( 0.03 ) l ) , and nocturnal FEV1 ( mean of 03.00 and 06.00 hours ) in the morning ( 1.03 ( 0.03 ) l ) and evening ( 1.04 ( 0.03 ) l ) groups compared with placebo ( 0.82 ( 0.03 ) l ) at the 6 week visit ( p<0.01 ) . FEV1 before morning or evening dosing was similar , while the peak FEV1 moved later in the day with active treatment . The mean percentage change in FEV1 from 09.00 hours to 03.00 hours ( the nocturnal decline in FEV1 ) was −2.8 % in the morning group , −1.0 % in the evening group , and −12.8 % in the placebo group . The magnitude of the peak to trough change in FEV1 was not statistically different . Conclusions : Tiotropium produced sustained bronchodilation throughout the 24 hour day without necessarily abolishing circadian variation in airway calibre This r and omised , double-blind , parallel-group , 1-yr study compared the effect of tiotropium 18 microg once daily ( n=500 ) and placebo  ( n=510 ) on exacerbations , associated health re source use ( HRU ) and  airflow limitation in chronic obstructive pulmonary disease ( COPD ) patients . The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40 , the mean weekly morning peak expiratory flow ( PEF ) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second ( FEV1 ) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days , reduced the proportion of patients experiencing more than one exacerbation by 17 % , and decreased the number of exacerbations by 35 % and exacerbation days by 37 % versus placebo . Tiotropium also decreased HRU versus placebo , as indicated by the significant reductions in the use of concomitant respiratory medications , antibiotics and oral steroids , and the number of unscheduled physician contacts . Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study . At the end of the study , tiotropium significantly improved trough ( pre-dose ) FEV1 , forced vital capacity , slow vital capacity and inspiratory capacity versus placebo . In conclusion , tiotropium reduced exacerbations and associated health re source use , and improved airflow over 1 yr in chronic obstructive pulmonary disease patients 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 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 Purpose Patients with chronic obstructive pulmonary disease ( COPD ) have poor sleep quality as a result of various alterations in oxygenation parameters and sleep macro- and micro-architecture . There is a shortage of data to support the efficacy of long-acting inhaled anticholinergic agents in improving these adverse effects , which are known to have a negative impact on clinical outcomes . We aim ed to compare the tiotropium Respimat Soft Mist Inhaler and the H and iHaler in terms of their effects on sleeping oxygen saturation ( SaO2 ) and sleep quality in patients with COPD . Methods In a r and omized , open-label , parallel-group trial involving 200 patients with mild to moderate COPD ( resting arterial oxygen tension > 60 mmHg while awake ) , we compared the effects of 6 months ’ treatment with the two devices on sleeping SaO2 and sleep quality . Overnight polysomnography and pulmonary function testing  were performed at baseline and after 6 months ’ treatment . Results A total of 188 patients completed the trial . Both groups showed significant improvement in minimum sleep SaO2 and time of sleep spent with SaO2 below 90 ( TST90 ) compared to baseline . The patients using the Respimat had significantly better TST90 than did those using the H and iHaler .  Sleep disturbance was highly variable in these patients , but the sleep stage duration s were significantly better in the Respimat group . Conclusions Sleeping SaO2 can be improved by tiotropium delivered using either the H and iHaler device or the Respimat Soft Mist Inhaler . However , the patients who used the Respimat device had significantly better TST90 and sleep architecture parameters BACKGROUND Disease progression in COPD is associated with a decline in exercise performance over time . We assessed whether tiotropium might mitigate this by determining its effect on treadmill endurance time ( ET ) over 2 years . METHODS This was a r and omized , double-blind , placebo-controlled trial of tiotropium , 18 μg daily , in patients with COPD ( FEV1/FVC < 70 % ; postbronchodilator FEV1 < 65 % ) . The primary end point was ET at 90 % of baseline maximum work rate at 96 weeks . Secondary end points were ET at other visits , ET by smoking status , spirometry , and St. George 's Respiratory Question naire ( SGRQ ) . RESULTS A total of 519 patients were r and omized ( tiotropium 260 , placebo 259 ) . Mean age was 65 years , 77 % were men , 34 % were continuing smokers , and mean FEV1 was 1.25 L ( 44 % predicted ) . Significantly more patients discontinued placebo ( hazard ratio [ 95 % CI ] , 0.61 [ 0.44 - 0.83 ] ) . Baseline ET was 301 s ( improvement tiotropium/placebo was 13 % overall ; P = .009 ; 18 % at 48 weeks , P = .004 ; 13 % at 96 weeks , P = .106 ) . In patients with baseline ET between 2 and 10 min ( n = 404 ) , improvement at 96 weeks was 19 % ( P = .04 ) . Current smokers had higher ET with tiotropium vs placebo ( P = .018 ) . FEV1/FVC improved with tiotropium ( P < .01 ) . SGRQ total score at 96 weeks improved with tiotropium vs placebo by 4.03 units ( P = .007 ) . CONCLUSIONS Treadmill ET was numerically greater over 2 years with tiotropium vs placebo . However , the 96-week difference was not statistically significant . Spirometry and health status also improved with tiotropium over 2 years , attesting to the benefits of long-acting bronchodilator therapy . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00525512 ; URL : www . clinical trials.gov BACKGROUND AND OBJECTIVES To compare the efficacy and safety of tiotropium inhaled via Respimat Soft Mist Inhaler , a multidose propellant-free inhaler and H and iHaler , a single-dose dry powder inhaler , in a phase 2 study of Japanese COPD patients . METHODS Patients with FEV(1)<or=70 % predicted , FEV(1)/FVC < or=70 % and a smoking history of > 10 pack-years received tiotropium once daily via Respimat ( 5microg ) and H and iHaler ( 18microg ) for 4 weeks each in a r and omised , double-blind , double-dummy , two-way crossover study . Lung function , adverse events , pharmacokinetics and safety were assessed . RESULTS Of 184 patients screened , 134 were evaluable . The trough FEV(1 ) response on Day 29 showed Respimat to be non-inferior to H and iHaler ( mean treatment difference , 0.008L ; 95 % CI , -0.009 to + 0.024L ; p<0.001 ) . Peak and average FEV(1 ) and FVC responses on Day 1 and Day 29 were very similar for the two treatments . Tiotropium  plasma levels and excretion kinetics showed a similar profile of systemic exposure for the two formulations of tiotropium . Adverse events were reported by similar numbers of patients on each treatment , i.e. 27.9 and 30.6 % in the Respimat and H and iHaler groups , respectively . CONCLUSIONS In Japanese patients with COPD , tiotropium Respimat 5microg and tiotropium H and iHaler 18microg showed a similar profile of efficacy , safety and pharmacokinetics 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 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 We have previously shown that tiotropium at 18 mug reduces lung hyperinflation and dyspnea during exercise and improves exercise tolerance in patients with COPD . The present study was design ed to gain further insight into the duration of improvements . DESIGN , PATIENTS , AND INTERVENTIONS A r and omized , double-blind , placebo-controlled , parallel-group study was conducted in 261 COPD patients ( mean age , 62.5 + /- 7.4 years [ + /- SD ] ; 189 men and 72 women ; mean FEV1 , 1.2 + /- 0.4 L [ 43 + /- 12.7 % predicted ] ) . On day 0 ( first dose ) , day 21 , and day 42 of treatment , pulmonary function tests were performed before and 1 h 20 min after dosing , followed by a constant work rate cycle ergometry test ( 75 % maximum work capacity ) to symptom limitation at 2.25 h after dosing . On day 42 , an additional constant work rate cycle ergometry test was performed at 8 h after dosing . RESULTS Adjusted mean ( + /- SE ) endurance time ( ET ) on day 42 was 803 + /- 40 s ( tiotropium ) , vs 568 + /- 42 s ( placebo ) at 2.25 h after dosing ( primary end point ; treatment difference , 236 + /- 58 s ; p = 0.0001 ) and 665 + /- 40 s ( tiotropium ) vs 494 + /- 42 s ( placebo ) at 8 h after dosing ( treatment difference , 171 + /- 58 s ; p = 0.0035 ) . Adjusted mean dyspnea intensity at isotime on day 42 was 4.60 + /- 0.16 Borg units ( tiotropium ) , vs 5.65 + /- 0.16 Borg units ( placebo ) at 2.25 h after dosing ( p < 0.001 ) , and 5.54 + /- 0.17 Borg units ( tiotropium ) vs 6.51 + /- 0.18 Borg units ( placebo ) at 8 h after dosing ( p < 0.001 ) . Adjusted mean pre-exercise inspiratory capacity ( IC ) on day 42 was 2.41 + /- 0.03 L ( tiotropium ) vs 2.19 + /- 0.03 L ( placebo ) at 2.25 h after dosing ( p < 0.001 ) , and 2.31 + /- 0.03 L ( tiotropium ) vs 2.16 + /- 0.03 L ( placebo ) at 8 h after dosing ( p < 0.001 ) . The significant increase in IC with tiotropium compared with placebo was maintained throughout exercise . CONCLUSIONS The present study confirms that tiotropium reduces lung hyperinflation at rest and during exercise , reduces exertional dyspnea , and improves symptom-limited exercise tolerance in COPD patients . Furthermore , this study shows that this improvement is present at 2.25 h and at 8 h after dosing after 6 weeks of treatment Oxygen desaturation occurs during sleep in severe chronic obstructive pulmonary disease ( COPD ) , especially during rapid eye movement ( REM ) sleep , due to hypoventilation and ventilation-perfusion mismatching , but the possible contribution of airflow limitation is unclear . In a r and omised , placebo-controlled , double-blind study of severe , stable COPD patients , the authors compared 4 weeks treatment with a long-acting inhaled anticholinergic agent ( tiotropium ) , taken in the morning ( tiotropium-AM ) , or in the evening ( tiotropium-PM ) , on  sleeping arterial oxygen saturation ( Sa , O2 ) and sleep quality . Overnight polysomnography  was performed at baseline and after 4 weeks treatment . A total of 95 patients with awake resting arterial oxygen tension ≤9.98 kPa ( 75 mmHg ) were r and omised , with a mean age of 66.4 yrs and mean forced expiratory volume in one second ( FEV1 ) of 32 % predicted . A total of 80 patients completed the study , of which 56 fulfilled the polysomnographic criterion of at least 2 h sleep in both sleep study nights and represent the group analysed . Tiotropium  significantly improved spirometry  compared with placebo . Both tiotropium-AM and tiotropium-PM groups had higher Sa , O2 during REM than placebo ( + 2.41 % and + 2.42 % , respectively , and both pooled and tiotropium-PM groups had higher Sa , O2 during total sleep time ( + 2.49 % and + 3.06 % , respectively ) . End-of-treatment FEV1 correlated with Sa , O2 during REM sleep , however , tiotropium did not change sleep quality . Sustained anticholinergic blockade improves sleeping arterial oxygen saturation without affecting sleep quality Objectives This post hoc analysis of TIOtropium Safety and Performance In Respimat ( TIOSPIR ) evaluated safety and exacerbation efficacy in patients with stable ( ≥2 months ) use of tiotropium H and iHaler 18 µg ( HH18 ) prior to study entry , to evaluate whether there was a difference in risk for patients who switched from  HH18 to tiotropium Respimat 2.5 µg ( R2.5 ) or 5 µg ( R5 ) . Setting TIOSPIR ( n=17 135 ) was an international , Phase IIIb/IV , r and omised , double-blind , parallel-group , event-driven trial . Participants Patients from TIOSPIR with chronic obstructive pulmonary disease ( COPD ) and postbronchodilator ratio of forced expiratory volume in 1 s to forced vital capacity ≤0.70 , receiving HH18 before study entry , were analysed ( n=2784 ) . Interventions Patients were r and omised to once-daily tiotropium R2.5 ( n=914 ) , R5 ( n=918 ) or HH18 ( n=952 ) for 2–3 years . Primary and secondary outcome measures Primary outcomes : time to death ( safety ) and time to first COPD exacerbation ( efficacy ) . Secondary outcomes : number of exacerbations and time to first major adverse cardiovascular event ( MACE ) . Results Baseline characteristics were similar in all groups . Respimat had a similar mortality risk versus HH18 ( vital status follow-up , HR ; 95 % CI R2.5 : 0.87 ; 0.64 to 1.17 ; R5 : 0.79 ; 0.58 to 1.07 ) with no significant differences in the risk and rates of exacerbations and severe exacerbations across treatment groups . Risk of MACE and fatal MACE was similar for Respimat versus HH18 ( HR ; 95 % CI MACE R2.5 : 0.73 ; 0.47 to 1.15 ; R5 : 0.69 ; 0.44 to 1.08 ; fatal MACE R2.5 : 0.57 ; 0.27 to 1.19 ; R5 : 0.67 ; 0.33 to 1.34 ) . Overall risk of a fatal event ( on treatment ) was lower for R5 versus HH18 ( HR ; 95 % CI R2.5 : 0.78 ; 0.55 to 1.09 ; R5 : 0.62 ; 0.43 to 0.89 ) . Conclusions This analysis indicates that it is safe to switch patients from tiotropium H and iHaler to tiotropium Respimat , and that the efficacy is maintained over the switch . Trial registration number NCT01126437 ; Post- results 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 Tiotropium , a long-acting anticholinergic , is delivered via H and iHaler or via Respimat . R and omised controlled trials suggest that use of tiotropium Respimat increases the risk of dying . We compared the risk of mortality between tiotropium Respimat versus H and iHaler . Within the Integrated Primary Care Information data base , we defined a source population of patients , aged ≥40 years , with ≥1 year of follow-up . Based on prescription data , we defined episodes of tiotropium use ( Respimat or H and iHaler ) . The risk of mortality , within these episodes , was calculated using a Cox proportional hazard regression analysis . From the source population , 11 287 patients provided 24 522 episodes of tiotropium use . 496 patients died  while being exposed to H and iHaler or Respimat . Use of Respimat was associated with almost 30 % increased risk of dying ( adjusted HR 1.27 , 95 % CI 1.03–1.57 ) with the highest risk for cardiovascular/cerebrovascular death ( adjusted HR 1.56 , 95 % CI 1.08–2.25 ) . The risk was higher in patients with co-existing cardiovascular disease ( adjusted HR 1.36 , 95 % CI 1.07–1.73 ) than in patients without ( adjusted HR 1.02 , 95 % CI 0.61–1.71 ) . Use of tiotropium Respimat was associated with an almost 30 % increase of mortality compared with H and iHaler and the association was the strongest for cardiovascular/cerebrovascular death . It is unclear whether this association is causal or due to residual confounding by chronic obstructive pulmonary disease severity . Tiotropium Respimat was associated with a 30 % increase in mortality compared with H and iHaler in COPD The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo . In total 154 patients with chronic obstructive pulmonary disease ( COPD ) were included in this multicenter , r and omized , double-blind within-solution ( 1.25 , 2.5 , 5 µg , and placebo ) , and open-label powder 18 µg , crossover study , including 4-week treatment periods . Primary end points were peak plasma concentration ( Cmax , ss ) , and area under the plasma concentration – time profile ( AUC0–6h , ss ) , both at steady state . The pharmacodynamic response was assessed by serial spirometry ( forced expiratory volume in 1 second/forced vital capacity ) . Safety was evaluated as adverse events and by electrocardiogram/Holter . Tiotropium was rapidly absorbed with a median tmax , ss of 5–7 minutes postdosing for both devices . The gMean ratio of solution 5 µg over powder 18 µg was 81 % ( 90 % confidence interval , 73–89 % ) for Cmax , ss and 76 % ( 70–82 % ) for AUC0–6h , ss , indicating that bioequivalence was not established . Dose ordering for bronchodilation was observed . Powder 18 µg and solution 5 µg were most effective , providing comparable bronchodilation . All treatments were well tolerated with no apparent relation to dose or device . Comparable bronchodilator  efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD BACKGROUND Tiotropium + olo date rol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease ( COPD ) . The OTEMTO 1 and 2 studies investigated the effects of tiotropium + olo date rol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD . METHODS In these two replicate , double-blind , parallel-group , placebo-controlled trials , patients were r and omised to receive tiotropium + olo date rol 5/5 μg , 2.5/5 μg , tiotropium 5 μg or placebo for 12 weeks , via the Respimat ( ® ) inhaler . Primary end points were St George 's Respiratory Question naire ( SGRQ ) total score , forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 3 h ( AUC0 - 3 ) response and trough FEV1 response . RESULTS In OTEMTO 1 and 2 , tiotropium + olo date rol 5/5 μg improved SGRQ total score by 4.89 ( 95 % confidence interval [ CI ] -6.90 , -2.88 ) and 4.56 ( 95 % CI -6.50 , -2.63 ) units versus placebo ( both p < 0.0001 ) , and 2.49 ( 95 % CI -4.47 , -0.51 ; p < 0.05 ) and 1.72 ( 95 % CI -3.63 , 0.19 ) units versus tiotropium 5 μg . Tiotropium + olo date rol 2.5/5 μg significantly improved SGRQ score compared to placebo . Both doses significantly improved FEV1 AUC0 - 3 response compared to placebo and tiotropium 5 μg . Tiotropium + olo date rol 5/5 and 2.5/5 μg also significantly improved trough FEV1 response compared to placebo ( both studies ) and separated from tiotropium 5 μg in OTEMTO 2 . Adverse-event incidence was similar between treatment groups . CONCLUSION Tiotropium + olo date rol improved lung function and quality of life compared to placebo and tiotropium 5 μg . TRIAL REGISTRATION Clinical Trials.gov : NCT01964352 and NCT02006732 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 BACKGROUND This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination ( FDC ) of the long-acting muscarinic antagonist tiotropium and the long-acting β2-agonist olo date rol in patients with chronic obstructive pulmonary disease . METHODS This was a r and omised , double-blind , placebo-controlled , Phase III trial with an incomplete crossover design . Patients received four of the following six treatment options for 6 weeks each : placebo , olo date rol 5 μg , tiotropium 2.5 μg , tiotropium 5 μg , tiotropium + olo date rol FDC 2.5/5 μg and tiotropium + olo date rol FDC 5/5 μg , all delivered via the Respimat ( ® ) inhaler . The primary end point was forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 24 h ( AUC0 - 24 ) response after 6 weeks of treatment ; key secondary end points were FEV1 AUC from 0 to 12 h and AUC from 12 to 24 h , and further end points included lung-volume parameters measured using body plethysmography ( subset of patients ) , measures of peak and trough FEV1 , and incidence of adverse events . RESULTS A significant improvement in FEV1 AUC0 - 24 response was observed with tiotropium + olo date rol 5/5 μg and 2.5/5 μg versus placebo and monotherapies after 6 weeks of treatment ; mean response with tiotropium + olo date rol 5/5 μg versus placebo was 0.280 L ( p < 0.0001 ) . Differences to monotherapies with tiotropium + olo date rol 5/5 μg were 0.115 L versus olo date rol 5 μg , 0.127 L versus tiotropium 2.5 μg and 0.110 L versus tiotropium 5 μg ( p < 0.0001 for all comparisons ) . Secondary end points supported these data . No safety concerns were identified . CONCLUSIONS Overall , this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olo date rol over tiotropium or olo date rol alone , with no observed difference in tolerability . Clinical Trials.gov number : NCT01559116 BACKGROUND A study was undertaken to record exacerbations and health re source use in patients with COPD during 6 months of treatment with  tiotropium , salmeterol , or matching placebos . METHODS Patients with COPD were enrolled in two 6-month r and omised , placebo controlled , double blind , double dummy studies of tiotropium 18 micro g once daily via H and iHaler or salmeterol 50 micro g twice daily via a metered dose inhaler . The two trials were combined for analysis of heath outcomes consisting of exacerbations , health re source use , dyspnoea ( assessed by the transitional dyspnoea index , TDI ) , health related quality of life ( assessed by St George 's Respiratory Question naire , SGRQ ) , and spirometry . RESULTS 1207 patients participated in the study  ( tiotropium 402 , salmeterol 405 , placebo 400 ) . Compared with placebo , tiotropium but not salmeterol was associated with a significant delay in the time to onset of the first exacerbation . Fewer COPD exacerbations/patient year occurred in the tiotropium group ( 1.07 ) than in the placebo group ( 1.49 , p<0.05 ) ; the salmeterol group ( 1.23 events/year ) did not differ from placebo . The tiotropium group had 0.10 hospital admissions per patient year for COPD exacerbations compared with 0.17 for salmeterol and 0.15 for placebo ( not statistically different ) . For all causes ( respiratory and non-respiratory ) tiotropium , but not salmeterol , was associated with fewer hospital admissions while both groups had fewer days in hospital than the placebo group . The number of days during which patients were unable to perform their usual daily activities was lowest in the tiotropium group ( tiotropium 8.3 ( 0.8 ) , salmeterol 11.1 ( 0.8 ) , placebo 10.9 ( 0.8 ) , p<0.05 ) . SGRQ total score improved by 4.2 ( 0.7 ) , 2.8 ( 0.7 ) and 1.5 ( 0.7 ) units during the 6 month trial for the tiotropium , salmeterol and placebo groups , respectively ( p<0.01 tiotropium v placebo ) . Compared with placebo , TDI focal score improved in both the tiotropium group ( 1.1 ( 0.3 ) units , p<0.001 ) and the salmeterol group ( 0.7 ( 0.3 ) units , p<0.05 ) . Evaluation of morning pre-dose FEV(1 ) , peak FEV(1 ) and mean FEV(1 ) ( 0 - 3 hours ) showed that tiotropium was superior to salmeterol while both active drugs were more effective than placebo . CONCLUSIONS Exacerbations of COPD and health re source usage were positively affected by daily treatment with tiotropium . With the exception of the number of hospital days associated with all causes , salmeterol twice daily result ed in no significant changes compared with placebo . Tiotropium also improved health related quality of life , dyspnoea , and lung function in patients with COPD 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 The efficacy and safety of aclidinium bromide bid , a novel , long-acting , muscarinic antagonist , was assessed in patients with moderate to severe COPD . METHODS In this phase IIa r and omized , double-blind , double-dummy , crossover trial , patients with moderate to severe COPD received aclidinium 400 μg bid , tiotropium 8 μg once daily , and placebo for 15 days , with a 9- to 15-day washout between treatment periods . Treatments were administered through the Genuair or H and iHaler dry powder inhalers . The primary end point was mean change from baseline in FEV(1 ) AUC(0 - 12/12h ) ( area under the curve where the numbers represent the time period for which data were collected divided by the number of hours over which the data are averaged [ eg , 0 - 12 h postdose divided by 12 h ] ) on day 15 . Secondary end points were changes from baseline in FEV(1 ) AUC(12 - 24/12h ) , FEV(1 ) AUC(0 - 24/24h ) , morning predose FEV(1 ) , peak FEV(1 ) , and COPD symptom scores . RESULTS Thirty patients with COPD were r and omized , and 27 completed the study . Mean change from baseline in FEV(1 ) AUC(0 - 12/12h ) at day 15 was significantly greater for aclidinium and tiotropium over placebo ( P < .0001 ) . Mean changes from baseline in FEV(1 ) AUC(12 - 24/12h ) , FEV(1 ) AUC(0 - 24/24h ) , morning predose FEV(1 ) , and peak FEV(1 ) at day 15 were significantly greater for aclidinium and tiotropium over placebo ( P < .0001 for all except P < .001 for FEV(1 ) AUC(12 - 24/12h ) tiotropium vs placebo ) . Improvements were significantly greater with aclidinium vs tiotropium on day 1 for all of the normalized AUC values of FEV(1 ) as well as on day 15 for FEV(1 ) AUC(12 - 24/12h ) ( P < .05 for all ) . COPD symptoms were significantly improved from baseline with aclidinium vs placebo ( P < .05 ) but not with tiotropium . CONCLUSIONS In patients with COPD  , aclidinium 400 μg bid compared with placebo provided clinical ly meaningful improvements in 24-h bronchodilation that generally were comparable to tiotropium 18 μg daily but with significant differences in favor of aclidinium observed in the average nighttime period . Larger studies with longer treatment duration are ongoing to confirm the efficacy  of aclidinium 400 μg bid on bronchodilation and COPD symptoms . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00868231 ; URL : www . clinical trials.gov 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 Background : Responsiveness to pharmacologic agents may differ among sub population s compared with the general population . In patients of African descent , possible differences have been observed for inhaled beta-agonists . However , pharmacologic responsiveness to a long-acting anticholinergic has not been prospect ively evaluated . Methods : An 8-week , r and omized , placebo-controlled clinical trial was conducted to assess the efficacy of the once-daily , inhaled anticholinergic tiotropium in COPD patients of African descent . African-American COPD patients ≥40 years , FEV1 ≤ 65 % predicted , FEV1/FVC ≤70 % were included .  Spirometry  ( pre- study drug , and 0.5 , 1 , 2 and 3 hours post-dose ) and  the University of California , San Diego Shortness of Breath Question naire ( SOBQ )  were performed at baseline and at 4 and 8 weeks . Data on use of rescue medication and on adverse events ( including COPD exacerbations ) were also collected . Results : R and omized patients ( n = 166 ) were ( mean ± SD ) 62.5 ± 9.3 years ; baseline mean FEV1 1.02 ± 0.37 L ( 41 ± 13 % predicted ) ; 67.5 % were male . A total of 160 patients were eligible for efficacy evaluation . At 8 weeks , mean FEV1 AUC0 − 3 response was 180 mL greater with tiotropium ( n = 78 ) than with placebo ( n = 82 ) , ( p < 0.0001 ) . Difference ( tiotropium – placebo ) for mean peak FEV1 response was 182 mL ( p < 0.0001 ) and 122 mL ( p = 0.002 ) for mean trough FEV1 response . There were no significant differences in SOBQ or use of rescue medication between the groups . No patients in the tiotropium group experienced a COPD exacerbation compared with 12 in patients receiving placebo . Conclusion : Tiotropium  significantly improved pulmonary function in African-American COPD patients 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 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 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 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 In patients with COPD , changes in inspiratory capacity ( IC ) have shown a higher correlation to patient-focused outcomes , such as dyspnea with exercise , than other st and ard spirometric measurements . Changes in IC reflect changes in hyperinflation . Tiotropium is a once-daily inhaled anticholinergic that has its effect through prolonged M3 muscarinic receptor antagonism and has demonstrated sustained improvements in spirometric and health outcomes . We sought to evaluate changes in resting IC and lung volumes after long-term administration of tiotropium . METHODS To evaluate the effect of tiotropium , 18 micro g/d , on IC , a 4-week , r and omized , double-blind , placebo-controlled study was conducted in 81 patients with stable COPD . At each of the visits ( weeks 0 , 2 , and 4 ) FEV(1 ) , FVC , IC , slow vital capacity ( SVC ) , and thoracic gas volume ( TGV ) were measured prior to study drug ( - 60 and - 15 min ) and after study drug ( 30 min , 60 min , 120 min , and 180 min ) . RESULTS Mean age was 64 years ; 62 % were men .  Mean baseline FEV(1 ) was 1.12 L ( 43 % predicted ) . The mean differences ( tiotropium - placebo )  in FEV(1 ) trough ( morning before drug ) , peak , and area under the curve over 3 h values ( adjusted for baseline and center differences ) at week 4 were 0.16 L , 0.22 L , and 0.22 L , respectively ( p < 0.01 for all ) ; differences in IC for these variables were 0.22 L , 0.35 L , and 0.30 L ( p < 0.01 for all ) . Differences in TGV were - 0.54 L , - 0.60 L , and - 0.70 L , respectively ( p < 0.01 for all ) . The percentage improvement in area under the curve above baseline with tiotropium  was similar among FEV(1 ) and lung volumes ( FEV(1 ) , 18 % ; FVC , 20 % ; SVC , 16 % ; IC , 16 % ; TGV , 14 % ) . CONCLUSIONS Observed improvements in IC and reductions in TGV with once-daily tiotropium reflect improvements in hyperinflation that are maintained over 24 BACKGROUND To determine the safety and efficacy of BEA2180 , an anticholinergic agent in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS Smokers or ex-smokers ≥40 years with COPD and a postbronchodilator forced expiratory volume in 1 s ( FEV1 ) < 80 % predicted and FEV1/forced vital capacity ≤70 % participated in this multinational , r and omised , double-blind , parallel study . Patients received BEA2180 ( 50 , 100 or 200 μg ) , tiotropium ( 5 μg ) or placebo once daily via Respimat Soft Mist ™ . The primary endpoint was trough FEV1 after 24 weeks . Secondary endpoints included Transition Dyspnoea Index ( TDI ) focal score , St George 's Respiratory Question naire ( SGRQ ) total score , exacerbations and adverse events . RESULTS Patients ( n = 2080 , 64.5 % male ) had a mean age of 64.2 years and a baseline FEV1 of 1.2 L.  Trough FEV1 at 24 weeks with all BEA2180 doses ( 0.044 - 0.087 L ) and tiotropium 5 μg ( 0.092 L ) was significantly higher ( p < 0.0001 ) than placebo ( -0.034 L ) and BEA2180 ( 200 μg ) was noninferior to tiotropium . Mean TDI focal scores were higher with BEA2180 ( 1.43 - 1.48 ) or tiotropium ( 1.46 ) versus placebo ( 0.94 ; p ≤ 0.01 for all ) . Mean SGRQ total scores also improved with BEA2180 ( 40.1 - 40.7 ) or tiotropium ( 39.5 ) compared with placebo ( 43.0 , p < 0.01 for all ) . COPD exacerbation rates were reduced for all active treatments , reaching statistical significance for BEA2180 ( 50 and 200 μg ) ( p < 0.05 , for both ) . CONCLUSION All study doses of BEA2180 improved lung function , reduced symptoms and exacerbations , and improved health status in COPD ; all treatments were well tolerated . Clinical trial identifier : NCT00528996 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 , a once daily inhaled anticholinergic delivered via H and iHaler , provides bronchodilation for > 24h and improves patient-centred outcomes . The Respimat Soft Mist Inhaler ( SMI ) , a novel , propellant-free inhaler , has been developed and proposed as an alternative delivery device for use with tiotropium . METHODS In a pre-specified , pooled analysis of two 30-week , double-blind , double-dummy , crossover studies , 207 patients with Chronic Obstructive Pulmonary Disease ( COPD ) were r and omised to receive once daily tiotropium 5 microg or 10 microg ( aqueous solution delivered via Respimat SMI ) , tiotropium 18 microg ( inhalation powder via H and iHaler ) or placebo . The primary endpoint was trough forced expiratory volume in 1s ( FEV(1 ) ) response . Forced vital capacity ( FVC ) , peak expiratory flow rate ( PEFR ) , rescue medication use , safety and pharmacokinetics ( in a subgroup of patients ) were also assessed . RESULTS Both tiotropium doses delivered by Respimat SMI were significantly superior to placebo and non-inferior to tiotropium 18 microg H and iHaler on the primary endpoint ( all p<0.0001 ) . All active treatments were significantly superior to placebo ( all p<0.0001 ) and both doses of tiotropium Respimat SMI were non-inferior to tiotropium 18 microg H and iHaler on the secondary spirometry variables and rescue medication use . The systemic exposure was similar between tiotropium 5 microg Respimat SMI and tiotropium 18 microg H and iHaler but was higher for tiotropium 10 microg Respimat SMI . All active treatments were well tolerated . CONCLUSIONS Tiotropium 5 microg Respimat SMI is comparable with tiotropium 18 microg H and iHaler in terms of efficacy , pharmacokinetics and safety .  Respimat SMI is an effective alternative , multi-dose delivery device for tiotropium
Tiotropium is now delivered via two different inhaler devices : the original H and ihaler 18 μg once daily , which uses a powder formulation ; and the newer Respimat Soft Mist Inhaler ( SMI ) 5 μg once daily .
It has been question ed whether the two devices can be assumed to have the same safety profile , although the TIOSPIR trial showed that tiotropium when administered via Respimat SMI 5 μg is not less safe than H and ihaler 18 μg .
Therefore , we have carried out a safety evaluation of tiotropium H and ihaler 18 µg versus tiotropium Respimat SMI 5 µg and 2.5 µg , via systematic review and network meta- analysis of the currently available clinical evidence .