Long-term efficacy of tiotropium in relation to smoking status in the UPLIFT trial Superiority of “triple” therapy with salmeterol/fluticasone propionate and tiotropium bromide versus individual components in moderate to severe COPD The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. The effect of tiotropium on exacerbations and airflow in patients with COPD. Comparable spirometric efficacy of tiotropium compared with salmeterol plus fluticasone in patients with COPD: a pilot study. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium 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. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD Aclidinium bromide provides long-acting bronchodilation in patients with COPD. Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study. Efficient delivery to the lungs of flunisolide aerosol from a new portable hand-held multidose nebulizer. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Safety and pharmacokinetics of single doses of aclidinium bromide, a novel long-acting, inhaled antimuscarinic, in healthy subjects. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebo-controlled 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. 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 The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction.
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 : The combination of salmeterol and fluticasone propionate ( SFC ) and tiotropium bromide ( TIO ) are commonly used treatments in chronic obstructive pulmonary disease ( COPD ) but there are few data on their effectiveness when used together . We compared the effects of SFC 50/500 μg twice daily in addition to TIO 18 μg once daily with the individual treatments alone . Methods : 41 patients with COPD participated in a r and omised , double blind , double dummy , three way crossover study with 2 week washout periods between treatments . Lung function assessment included plethysmography and spirometry . The primary end point was post-dose specific airways conductance ( sGaw ) area under the curve ( AUC0–4 h ) on day 14 . Results : AUC0–4 h sGaw was significantly higher on day 14 after SFC+TIO compared with TIO ( 22 % ) or SFC alone ( 27 % ) ( both p<0.001 ) . SFC+TIO significantly improved trough forced expiratory volume in 1 s compared with TIO alone ( 212 ml , p<0.001 ) and SFC alone ( 110 ml , p = 0.017 ) on day 14 . Inspiratory capacity measurements also showed significant benefits for triple therapy over individual components on day 14 . Subjects receiving SFC+TIO had clinical ly relevant improvements in Transition Dyspnoea Index ( TDI ) total score of 2.2 compared with TIO alone ( p<0.001 ) ( but not SFC alone , 0.7 ; NS ) and used significantly less rescue medication ( 1.0 occasion less daily than TIO ( p<0.001 ) and 0.6 less than SFC ( p = 0.01 ) ) . Conclusion : SFC+TIO triple therapy led to greater improvements in bronchodilation compared with TIO and SFC alone . The advantages of triple therapy are observed across a range of physiologically important parameters , including airway conductance and lung volumes . Triple therapy also led to patient related benefits by improving TDI and use of rescue medication . Trial registration number : NCT00325169 RATIONALE Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination ( salmeterol/fluticasone propionate ) 50/500 microg twice daily and the long-acting bronchodilator ( tiotropium ) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD . METHODS A total of 1,323 patients ( mean age , 64 yr , post-bronchodilator FEV1 , 39 % predicted ) were r and omized in this 2-year , double-blind , double-dummy parallel study . MEASUREMENTS AND MAIN RESULTS Primary endpoint was health care utilization exacerbation rate . Other endpoints included health status measured by St. George 's Respiratory Question naire ( SGRQ ) , mortality , adverse events , and study withdrawal . Probability of withdrawing from the study was 29 % greater with tiotropium than salmeterol/fluticasone propionate ( P = 0.005 ) . The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group ( rate ratio , 0.967 ; 95 % confidence interval [ CI ] , 0.836 - 1.119 ] ; P = 0.656 ) . The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium ( difference 2.1 units ; 95 % CI , 0.1 - 4.0 ; P = 0.038 ) . Mortality was significantly lower in the salmeterol/fluticasone propionate group ; 21 ( 3 % ) of patients in this group died compared with 38 ( 6 % ) in the tiotropium group ( P = 0.032 ) . More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium ( P = 0.008 ) . CONCLUSIONS We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium . More patients failed to complete the study while receiving tiotropium . A small statistically significant beneficial effect was found on health status , with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients . Clinical trial registered with www . clinical trials.gov ( NCT 00361959 ) Background : 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 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 ( n5142 ) 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 ) . 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 r and omised , double-blind , parallel-group , 1-yr study compared the effect of tiotropium 18 microg once daily ( n=500 ) and placebo  ( n=510 ) on exacerbations , associated health re source use ( HRU ) and  airflow limitation in chronic obstructive pulmonary disease ( COPD ) patients . The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40 , the mean weekly morning peak expiratory flow ( PEF ) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second ( FEV1 ) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days , reduced the proportion of patients experiencing more than one exacerbation by 17 % , and decreased the number of exacerbations by 35 % and exacerbation days by 37 % versus placebo . Tiotropium also decreased HRU versus placebo , as indicated by the significant reductions in the use of concomitant respiratory medications , antibiotics and oral steroids , and the number of unscheduled physician contacts . Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study . At the end of the study , tiotropium significantly improved trough ( pre-dose ) FEV1 , forced vital capacity , slow vital capacity and inspiratory capacity versus placebo . In conclusion , tiotropium reduced exacerbations and associated health re source use , and improved airflow over 1 yr in chronic obstructive pulmonary disease patients BACKGROUND International guidelines recommend the long-acting anticholinergic , tiotropium , or long-acting beta 2-agonists as maintenance therapy in patients with moderate-to-very severe chronic obstructive pulmonary disease ( COPD ) . The efficacy of long-acting beta(2)-agonists combined with inhaled corticosteroids ( ICS ) in the treatment of COPD has also been confirmed for severe and very severe COPD , but data comparing tiotropium with the combination of a long-acting beta 2-agonist and an ICS are lacking . METHODS This 6-week multicentre , r and omised , double-blind , triple-dummy pilot study compared the bronchodilator effects of tiotropium 18 microg once daily ( n=56 ) vs. the combination of salmeterol 50 microg plus fluticasone 250 microg twice daily ( n=51 ) in patients with moderate-to-very severe COPD . Serial spirometry was performed over 12h after 6 weeks of treatment . The primary endpoint was forced expiratory volume in 1s ( FEV1 ) area under the curve from 0 to 12h ( AUC0 - 12h ) on Day 43 . RESULTS R and omization failed to provide treatment groups with comparable baseline characteristics for smoking history , current smokers , duration of COPD , FEV1 , forced vital capacity ( FVC ) and reversibility . Mean+/-SD FEV1 was 1.31+/-0.47 l in the tiotropium group vs. 1.46+/-0.53 l in the salmeterol plus fluticasone group . Fewer patients in the tiotropium showed a 12 % and 200 ml acute increase to short-acting bronchodilators at baseline . However , treatment with tiotropium alone result ed in comparable bronchodilation compared with salmeterol plus fluticasone , as measured by all the spirometric parameters at the end of the 6-week study period . FEV1 AUC0 - 12h was 1.55+/-0.03 l in the tiotropium group vs. 1.57+/-0.04 l in the salmeterol plus fluticasone groups ( p=0.63 ) . Trough ( predose ) FEV1 was 1.54+/-0.03 l in the tiotropium group vs. 1.46+/-0.03 l in the combination group ( p=0.07 ) , and peak FEV(1 ) was 1.68+/-0.04 l vs. 1.66+/-0.04 l , respectively , ( p=0.77 ) . FVC AUC0 - 12h , trough and peak were also comparable between groups at study end ( p>0.05 , for all ) . Further , rescue salbutamol use was similar in the tiotropium and combination groups and both treatment regimens were well tolerated . CONCLUSIONS Six weeks of treatment with tiotropium result ed in comparable bronchodilation compared with salmeterol plus fluticasone in patients with moderate-to-very severe COPD , despite tiotropium patients having lower lung function and fewer patients considered reversible at baseline . The results of this pilot study will aid planning for further large-scale comparative studies 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 Tiotropium , a novel once-daily inhaled anticholinergic , has been shown to improve lung function over a 24-h period . In order to extend these findings , health- outcomes were evaluated over 1 yr in chronic obstructive pulmonary disease ( COPD ) patients . Spirometric results , peak expiratory flow rate ( PEFR ) , salbutamol use and effects on dyspnoea , health-related quality of life and COPD exacerbations were assessed in two identical 1-yr r and omized double-blind double-dummy studies of tiotropium 18 µg once daily ( n=356 ) compared with ipratropium 40 µg q.i.d . ( n=179 ) . Screening forced expiratory volume in one second ( FEV1 ) were 1.25±0.43 L ( 41.9±12.7 % of the predicted value ) ( tiotropium ) and 1.18±0.37 L ( 39.4±10.7 % pred ) ( ipratropium )  . Trough FEV1 at 1 yr improved by 0.12±0.01 L with tiotropium and declined by 0.03±0.02 L with ipratropium ( p<0.001 ) . Significant improvement in PEFR , salbutamol use , Transition Dyspnea Index focal score , and the St George 's Respiratory Question naire total and impact scores were seen with tiotropium ( p<0.01 ) . Tiotropium  reduced the number of exacerbations ( by 24 % , p<0.01 ) , and increased time to first exacerbation ( p<0.01 ) and time to first hospitalization for a COPD exacerbation ( p<0.05 ) compared with ipratropium . Apart from an increased incidence of dry mouth in the tiotropium group , adverse events were similar between treatments . Tiotropium was effective in improving dyspnoea , exacerbations , health-related quality of life and lung function in patients with chronic obstructive pulmonary disease , and exceeds the benefits seen with ipratropium . The data support the use of tiotropium once-daily as first-line maintenance treatment in patients with chronic obstructive pulmonary disease 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 This study compared the bronchodilator effects of tiotropium , formoterol and both combined in chronic obstructive pulmonary disease ( COPD ) . A total of 71 COPD patients ( mean forced expiratory volume in one second ( FEV1 ) 37 % predicted ) participated in a r and omised , double-blind , three-way , crossover study and received tiotropium 18 μg q.d . , formoterol 12 μg b.i.d . or both combined q.d . for three 6-week periods . The end-points were 24-h spirometry ( FEV1 , forced vital capacity ( FVC ) ) at the end of each treatment , rescue salbutamol and safety . Compared with baseline ( FEV1 prior to the first dose in the first period ) , tiotropium produced a significantly greater improvement in average daytime FEV1 ( 0–12 h ) than formoterol ( 127 versus 86 mL ) , while average night-time FEV1 ( 12–24 h ) was not different ( tiotropium 43 mL , formoterol 38 mL ) . The most pronounced effects were provided by combination therapy ( daytime 234 mL , night-time 86 mL ) ; both differed significantly from single-agent therapies . Changes in FVC mirrored the FEV1 results . Compared with both single agents , daytime salbutamol use was significantly lower during combination therapy ( tiotropium plus formoterol 1.81 puffs·day−1 , tiotropium 2.41 puffs·day−1 , formoterol 2.37 puffs·day−1 ) . All treatments were well tolerated . In conclusion , in chronic obstructive pulmonary disease patients  , tiotropium q.d . achieved a greater improvement in daytime and comparable improvement in night-time lung function  compared with formoterol b.i.d . A combination of both drugs q.d . was most effective and provided an additive effect throughout the 24-h dosing interval Aclidinium bromide is a novel , long-acting , muscarinic antagonist in phase III development for the maintenance treatment of COPD . This phase IIb study investigated the efficacy and safety of aclidinium for the treatment of moderate to severe COPD to establish the optimal dose for phase III studies . A total of 464 patients with moderate to severe stable COPD were r and omised to double-blind , once-daily treatment with aclidinium ( 25 , 50 , 100 , 200 , or 400microg ) , placebo , or open-label tiotropium ( 18microg ) for 4 weeks . Spirometric measurements were performed at 22 - 24h after the first dose and then at weekly intervals , and from 0.5 to 6h post-dose on day 1 and day 29 . Compared with placebo , aclidinium 200microg and 400microg significantly increased trough FEV(1 ) on day 29 versus baseline . During the first 6h post-dose , the bronchodilatory effect of aclidinium ( all doses ) on day 1 was comparable to that on day 29 . Time to peak FEV(1 ) was 3h for aclidinium 100 - 400microg . Aclidinium was well tolerated , with no dose-dependent effect on ECG , laboratory parameters , or adverse events . The incidence of AEs was generally comparable to placebo . Aclidinium produced sustained bronchodilation over 24h and was well tolerated during this short-term study . Based on these data , aclidinium 200microg was selected as the investigational dose for future clinical trials in COPD Although guidelines recommend combining long-acting bronchodilators in COPD , data are limited . We examined the clinical efficacy and safety of formoterol , tiotropium and the combination in patients with COPD . Eight hundred and forty-seven patients with COPD ( mean FEV(1 ) 52 % predicted ; FEV(1)/FVC 53 % ) were r and omized to receive one of the following four treatments for 24 weeks : formoterol 10 microg b.i.d . plus tiotropium 18 microg o.d . ; formoterol 10 microg b.i.d . ; tiotropium 18 microg o.d . , or placebo . The study was partially blinded ( formoterol and placebo ) . For the primary endpoint , FEV(1 ) 2h post-dose after 24 weeks , there were small differences in favour of the combination therapy versus formoterol ( 0.07 L , p=0.044 ) or tiotropium ( 0.06 L , p=0.066 ) . All three treatments were superior to placebo ( p<0.001 ) . The combination was statistically superior to monotherapy for : the primary endpoint ( p=0.044 vs. formoterol ) ; FEV(1 ) 5 min after the first dose ( p<0.001 ) and at 12 weeks ( p<0.05 vs. tiotropium ) ; and peak expiratory flow averaged over the first 6 weeks ( p<0.001 vs. both ) . The three active treatments were significantly more effective than placebo for secondary endpoints : COPD -related ' bad days ' , symptoms , use of rescue medication and peak expiratory flow , and aspects of health-related quality of life . The overall incidence of adverse events was similar with all active treatments , although COPD -related adverse events were more common with tiotropium . Combined bronchodilator therapy may be a valuable treatment option for patients with COPD In order to provide asthmatic patients with an inhaler that does not use chlorofluorocarbon propellants , a novel multidose h and -held nebulizer ( RESPIMAT , Boehringer Ingelheim Ltd. ) has been developed . This device delivers 200 x 15 microL metered doses of drug solution , but does not use propellants of any kind . In this study of 10 healthy volunteers , the deposition pattern in the lungs and oropharynx of an ethanolic solution of flunisolide delivered via a prototype III multidose nebulizer has been determined by gamma scintigraphy . A comparison was made with the same dose ( 250 micrograms ) of flunisolide delivered by a pressurized metered dose inhaler ( MDI ) and MDI plus Inhacort spacer .  Mean ( SD ) whole lung deposition from the multidose nebulizer ( 39.7 ( 9.9 ) % of the metered dose ) was significantly higher than that from either MDI ( 15.3 ( 5.1 ) % , P < 0.01 ) or MDI plus spacer ( 28.0 ( 7.0 ) % , P = 0.01 ) . A mean 10.4 % of the dose was recovered from an exhaled air filter for the multidose nebulizer , but less than 2 % of the dose for MDI or MDI plus spacer . Oropharyngeal deposition was significantly reduced for the multidose nebulizer ( 39.9 ( 9.4 ) % ) compared to MDI ( 66.9 ( 7.1 ) % ) , but was reduced further for the MDI plus spacer ( 27.3 ( 11.3 ) % ) . The multidose nebulizer delivers an unusually high percentage of an aerosol dose to the lungs , and it " targets " flunisolide to the lungs more effectively than the MDI . The multidose nebulizer could constitute a viable alternative to MDIs in asthma maintenance therapy BACKGROUND The combination of short-acting beta(2)-agonists and anticholinergics in the treatment of COPD has been well documented , but data on combination of long-acting agents are lacking . METHODS A r and omized , open-label , placebo-controlled , three-way crossover study was conducted comparing 2-week treatment periods of tiotropium alone to tiotropium plus formoterol once or twice daily following a 2-week pretreatment period with tiotropium .  Lung function ( FEV(1 ) , FVC , and resting inspiratory capacity [ IC ] ) serially over 24 h was measured in 95 patients with stable COPD at baseline and after 2 weeks of each treatment . RESULTS Mean baseline FEV(1 ) was 1.05 L ( 38 % of predicted ) . There was a circadian variation in FEV(1 ) , FVC , and IC at baseline that was maintained during all treatment periods . Average FEV(1 ) ( 0 to 24 h ) improved by 0.08 L with tiotropium , by 0.16 L with tiotropium plus formoterol once daily , and by 0.20 L with tiotropium plus formoterol twice daily ( p < 0.01 for all comparisons ) . Compared with tiotropium alone , add-on formoterol in the morning produced improvement in FEV(1 ) , FVC , and IC for > 12 h. The second add-on dose of formoterol in the evening caused further improvement in FEV(1 ) for 12 h , but in FVC and IC for < 12 h. Peak increase in FEV(1 ) was 0.23 L ( 22 % of baseline ) with tiotropium and 0.39 L ( 37 % of baseline ) with tiotropium plus formoterol ( p < 0.0001 ) . Compared with tiotropium alone , add-on formoterol once and twice daily reduced the use of rescue salbutamol during the daytime ( p < 0.01 ) and with add-on formoterol twice daily also during the nighttime ( p < 0.05 ) . The combination of tiotropium and formoterol was well tolerated . CONCLUSION In the treatment of COPD , there is benefit from adding formoterol once or twice daily to tiotropium once daily in terms of improvement in airflow obstruction , resting hyperinflation , and the use of rescue salbutamol OBJECTIVE Aclidinium bromide is a novel antimuscarinic being developed for the treatment of chronic obstructive pulmonary disease . The objective of this Phase I study was to determine the maximum tolerated dose ( MTD ) as well as the tolerability , safety and pharmacokinetics of aclidinium in healthy subjects . MATERIAL S AND METHODS 16 healthy subjects were r and omized to receive 5 single ascending doses of aclidinium 600 - 6,000 microg or placebo inhaled via dry powder inhaler , with 7 day washouts . Safety measurements included adverse events ( AEs ) , physical examination , vital signs , pupillometry examination , clinical laboratory tests , and 12-lead electrocardiogram . Pharmacokinetic parameters of aclidinium and its metabolites were assessed . RESULTS The incidence of AEs was comparable between aclidinium and placebo at all doses . Most AEs were mild to moderate with no dose-related or anticholinergic/cardiac AEs . At doses > or= 2,400 microg , only 13 AEs were considered treatment related . Aclidinium ( 600 - 6,000 microg ) did not produce function-limiting or severe AEs in > or= 50 % of subjects ; hence , the prospect ively-defined MTD was not established . Aclidinium was rapidly converted in plasma into alcohol and carboxylic acid metabolites , and was no longer detectable after 3 hours post-dose for all doses . At lower doses , aclidinium was quantifiable only up to 1 hour post-dose in the majority of subjects . Maximum plasma concentrations for aclidinium were reached within 5 - 7 minutes ( all doses ) and declined rapidly . Mean elimination half-lives of aclidinium > 2,400 microg were approximately 1 hour . AUC and Cmax increased proportionately up to 4,800 microg . CONCLUSIONS Aclidinium appears to be safe and well tolerated in single doses of 600 - 6,000 microg 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 Adding a long-acting beta(2)-agonist ( LABA ) by dry powder inhaler ( DPI ) to tiotropium provides significantly increased and sustained bronchodilation in chronic obstructive pulmonary disease ( COPD ) patients over either product alone . To demonstrate similar benefits with a nebulized LABA , a placebo-controlled trial was conducted to evaluate the efficacy and safety of formoterol fumarate inhalation solution in subjects receiving tiotropium as a maintenance treatment for COPD . After a 7 - 14-day screening period using tiotropium 18 microg once daily , subjects with diagnosed COPD ( > or = 25 % to < 65 % predicted FEV(1 ) ) were r and omized to receive 20 microg formoterol fumarate inhalation solution twice daily for nebulization plus tiotropium ( FFIS/TIO ) or nebulized placebo twice daily plus tiotropium ( PLA/TIO ) for 6 weeks . Efficacy was assessed with spirometry at each visit ( Day 1 , Week 1 , 3 , 6 ) , the transition dyspnea index ( TDI ) , and St. George 's Respiratory Question naire ( SGRQ ) . Baseline characteristics were comparable , including mean FEV(1)% predicted . At Week 6 , FEV(1 ) AUC(0 - 3 ) was 1.52 L for FFIS/TIO-treated subjects vs. 1.34 L for PLA/TIO-treated subjects ( p<0.0001 ) . The mean TDI scores in the FFIS/TIO and PLA/TIO groups were 2.30 and 0.16 , respectively ( p=0.0002 ) . SGRQ did not change significantly with 6 weeks treatment , with the exception of FFIS/TIO improvements in symptom score vs. PLA/TIO ( p=0.04 ) . More PLA/TIO- than FFIS/TIO-treated subjects experienced AEs ( 39.7 % vs. 22.9 % ) , COPD exacerbations ( 7.9 % vs. 4.5 % ) , and serious AEs ( 3.2 % vs. 1.5 % ) . Nebulized formoterol fumarate in combination with tiotropium provided statistically and clinical ly significant improvements in bronchodilation and symptom control over tiotropium alone and demonstrated good tolerability 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 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 STUDY OBJECTIVE To compare the safety of salmeterol xinafoate or placebo added to usual asthma care . DESIGN A 28-week , r and omized , double-blind , placebo-controlled , observational study . SETTING Study subjects were seen once in the study physician 's office for screening and were provided all blinded study medication for the entire study period . Follow-up by telephone was scheduled every 4 weeks . PARTICIPANTS Subjects ( > 12 years old ) with asthma as judged by the study physician were eligible . Individuals with a history of long-acting beta2-agonist use were excluded . INTERVENTIONS Salmeterol , 42 mug bid via metered-dose inhaler ( MDI ) , and placebo bid via MDI . MEASUREMENTS AND RESULTS Following an interim analysis in 26,355 subjects , the study was terminated due to findings in African Americans and difficulties in enrollment . The occurrence of the primary outcome , respiratory-related deaths , or life-threatening experiences was low and not significantly different for salmeterol vs placebo ( 50 vs 36 ; relative risk [ RR ] = 1.40 ; 95 % confidence interval [ CI ] , 0.91 to 2.14 ) . There was a small , significant increase in respiratory-related deaths ( 24 vs 11 ; RR , 2.16 ; 95 % CI , 1.06 to 4.41 ) and asthma-related deaths ( 13 vs 3 ; RR , 4.37 ; 95 % CI , 1.25 to 15.34 ) , and in combined asthma-related deaths or life-threatening experiences ( 37 vs 22 ; RR , 1.71 ; 95 % CI , 1.01 to 2.89 ) in subjects receiving salmeterol vs placebo . The imbalance occurred largely in the African-American sub population : respiratory-related deaths or life-threatening experiences ( 20 vs 5 ; RR , 4.10 ; 95 % CI , 1.54 to 10.90 ) and combined asthma-related deaths or life-threatening experiences ( 19 vs 4 ; RR , 4.92 ; 95 % CI , 1.68 to 14.45 ) in subjects receiving salmeterol vs placebo . CONCLUSIONS For the primary end point in the total population , there were no significant differences between treatments . There were small , but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol . Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects . Whether this risk is due to factors including but not limited to a physiologic treatment effect , genetic factors , or patient behaviors leading to poor outcomes remains unknown BACKGROUND A 6-week , multicenter , r and omized , double-blind , parallel-group study was conducted in patients with COPD to compare lung function improvements of tiotropium , 18 microg qd , plus formoterol , 12 microg bid , to salmeterol , 50 microg bid , plus fluticasone , 500 microg bid . METHODS Following a screening visit , subjects entered a run-in period in which they received regular ipratropium . At r and omization , patients were assigned to either tiotropium plus formoterol or salmeterol plus fluticasone . After 6 weeks of treatment , a 12-h lung function profile was obtained . The co primary end points were FEV(1 ) area under the curve for the time period 0 to 12 h ( AUC(0 - 12 ) ) and peak FEV(1 ) . RESULTS A total of 729 patients were screened , and 605 patients were r and omized and treated . A total of 592 patients ( baseline FEV(1 ) , 1.32 + /- 0.43 L/min [ + /-SD ] ) were included in the analysis . After 6 weeks , the 12-h lung function profiles in the group receiving tiotropium plus formoterol were superior to those in the group receiving salmeterol plus fluticasone ( mean difference in FEV(1 ) AUC(0 - 12 ) , 78 mL [ p = 0.0006 ] ; mean difference in FVC AUC(0 - 12 ) , 173 mL , p < 0.0001 ) . Also , peak responses were in favor of tiotropium plus formoterol ( difference in peak FEV(1 ) , 103 mL [ p < 0.0001 ] ; difference in peak FVC , 214 mL [ p < 0.0001 ] ) , as were FEV(1 ) and FVC at each individual time point after dose ( p < 0.05 ) . Predose FVC was significantly higher with the bronchodilator combination , while predose FEV(1 ) and rescue medication use did not differ significantly between groups . Both treatments were well tolerated . CONCLUSIONS Tiotropium plus formoterol was superior in lung function over the day compared to salmeterol plus fluticasone in patients with moderate COPD . Long-term studies in patients with severe COPD are warranted to assess the relative efficacy of different treatment combinations . TRIAL REGISTRATION Clinical trials.gov Identifier : NCT00239421 BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment .  All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) 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 Inhaled corticosteroid therapy has proven efficacy for asthmatics , but the benefit for patients with chronic obstructive pulmonary disease ( COPD ) is less well supported . We hypothesized that withdrawal of inhaled steroids in elderly patients with severe irreversible airway obstruction would not lead to a deterioration in respiratory function . We design ed a prospect i ve , double-blind , r and omized , placebo-controlled , crossover study to follow spirometry , quality of life question naire , six-minute ( 6-min ) walk test , and sputum markers of inflammation during a 6-wk placebo treatment period and a 6-wk treatment period with beclomethasone dipropionate ( BDP ) , 336 microg/d . There were 24 men receiving BDP who entered the study ; 15 completed the study . Their mean age was 66.9 + /- 1.9 yr , and mean FEV(1 ) was 1.61 + /- 0.1 L ( 47 % of predicted ) . There was a significant decrease in the mean FEV(1 ) while using the placebo inhaler ( 1.70 L versus 1.60 L , baseline versus placebo : 95 % CI , 0.002 to 0.195 ; p < 0.05 ) . There was a decrease in the mean percentage change in FEV(1 ) for the study subjects during the placebo treatment period as compared with the BDP treatment period ( -6.28 versus 5.03 % , placebo versus BDP : 95 % CI , -23.38 to 0.76 ; p = 0.06 ) . Six-minute walk test results and sputum analysis for cell count and differential were not significantly different during placebo and BDP treatment periods . Borg scale assessment of dyspnea after exercise was increased while using the placebo inhaler as compared with baseline , and decreased during the BDP treatment period . Chronic Respiratory Disease Question naire ( CRQ ) scores revealed no significant difference between placebo and BDP . This study has demonstrated that in elderly patients with severe irreversible airway obstruction , withdrawal of inhaled corticosteroid therapy leads to a deterioration in ventilatory function and increased exercise-induced dyspnea
PURPOSE OF REVIEW This article review s findings from recently published r and omized controlled trials and systematic review s to provide an up-to- date assessment of the efficacy and safety of tiotropium , the only currently available long-acting muscarinic antagonist , when used alone or in conjunction with other respiratory medications in the treatment of chronic obstructive pulmonary disease ( COPD ) .