Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. The effect of tiotropium on exacerbations and airflow in patients with COPD. Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Treadmill endurance during 2-year treatment with tiotropium in patients with COPD: a randomized trial. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD Impact of preventing exacerbations on deterioration of health status in COPD A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial. Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naïve patients. A one-year trial of tiotropium Respimat plus usual therapy in COPD patients. Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD. COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT). Tiotropium versus salmeterol for the prevention of exacerbations of COPD. Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial.
Background Debate continues as to whether acute bronchodilator responsiveness ( BDR ) predicts long-term outcomes in COPD . Furthermore , there is no consensus on a threshold for BDR . Methods At baseline and during the 4-year Underst and ing Potential Long-term Improvements in Function with Tiotropium ( UPLIFT ® ) trial , patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg . Patients were split according to three BDR thresholds : ≥12 % + ≥200 mL above baseline ( criterion A ) , ≥15 % above baseline ( criterion B ) ; and ≥10 % absolute increase in percent predicted FEV1 values ( criterion C ) . Several outcomes ( pre-dose spirometry , exacerbations , St. George 's Respiratory Question naire [ SGRQ ] total score ) were assessed according to presence or absence of BDR in the treatment groups . Results 5783 of 5993 r and omized patients had evaluable pre- and post-bronchodilator spirometry at baseline . Mean age ( SD ) was 64 ( 8) years , with 75 % men , mean post-bronchodilator FEV1 1.33 ± 0.44 L ( 47.6 ± 12.7 % predicted ) and 30 % current smokers . At baseline , 52 % , 66 % , and 39 % of patients had acute BDR using criterion A , B , and C , respectively . The presence of BDR was variable at follow-up visits . Statistically significant improvements in spirometry and health outcomes  occurred with tiotropium regardless of the baseline BDR or criterion used . Conclusions A large proportion of COPD patients  demonstrate significant acute BDR . BDR in these patients is variable over time and differs according to the criterion used . BDR status at baseline does not predict long-term response to tiotropium . Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD RATIONALE Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination ( salmeterol/fluticasone propionate ) 50/500 microg twice daily and the long-acting bronchodilator ( tiotropium ) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD . METHODS A total of 1,323 patients ( mean age , 64 yr , post-bronchodilator FEV1 , 39 % predicted ) were r and omized in this 2-year , double-blind , double-dummy parallel study . MEASUREMENTS AND MAIN RESULTS Primary endpoint was health care utilization exacerbation rate . Other endpoints included health status measured by St. George 's Respiratory Question naire ( SGRQ ) , mortality , adverse events , and study withdrawal . Probability of withdrawing from the study was 29 % greater with tiotropium than salmeterol/fluticasone propionate ( P = 0.005 ) . The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group ( rate ratio , 0.967 ; 95 % confidence interval [ CI ] , 0.836 - 1.119 ] ; P = 0.656 ) . The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium ( difference 2.1 units ; 95 % CI , 0.1 - 4.0 ; P = 0.038 ) . Mortality was significantly lower in the salmeterol/fluticasone propionate group ; 21 ( 3 % ) of patients in this group died compared with 38 ( 6 % ) in the tiotropium group ( P = 0.032 ) . More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium ( P = 0.008 ) . CONCLUSIONS We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium . More patients failed to complete the study while receiving tiotropium . A small statistically significant beneficial effect was found on health status , with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients . Clinical trial registered with www . clinical trials.gov ( NCT 00361959 ) BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) often present with severe acute exacerbations requiring hospital treatment . However , little is known about the prognostic consequences of these exacerbations . A study was undertaken to investigate whether severe acute exacerbations of COPD exert a direct effect on mortality . METHODS Multivariate techniques were used to analyse the prognostic influence of acute exacerbations of COPD treated in hospital ( visits to the emergency service and admissions ) , patient age , smoking , body mass index , co-morbidity , long term oxygen therapy , forced spirometric parameters , and arterial blood gas tensions in a prospect i ve cohort of 304 men with COPD followed up for 5 years . The mean ( SD ) age of the patients was 71 ( 9 ) years and forced expiratory volume in 1 second was 46 (17)% . RESULTS Only older age ( hazard ratio ( HR ) 5.28 , 95 % CI 1.75 to 15.93 ) , arterial carbon dioxide tension ( HR 1.07 , 95 % CI 1.02 to 1.12 ) , and acute exacerbations of COPD were found to be independent indicators of a poor prognosis . The patients with the greatest mortality risk were those with three or more acute COPD exacerbations ( HR 4.13 , 95 % CI 1.80 to 9.41 ) . CONCLUSIONS This study shows for the first time that severe acute exacerbations of COPD have an independent negative impact on patient prognosis . Mortality increases with the frequency of severe exacerbations , particularly if these require admission to hospital This r and omised , double-blind , parallel-group , 1-yr study compared the effect of tiotropium 18 microg once daily ( n=500 ) and placebo  ( n=510 ) on exacerbations , associated health re source use ( HRU ) and  airflow limitation in chronic obstructive pulmonary disease ( COPD ) patients . The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40 , the mean weekly morning peak expiratory flow ( PEF ) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second ( FEV1 ) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days , reduced the proportion of patients experiencing more than one exacerbation by 17 % , and decreased the number of exacerbations by 35 % and exacerbation days by 37 % versus placebo . Tiotropium also decreased HRU versus placebo , as indicated by the significant reductions in the use of concomitant respiratory medications , antibiotics and oral steroids , and the number of unscheduled physician contacts . Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study . At the end of the study , tiotropium significantly improved trough ( pre-dose ) FEV1 , forced vital capacity , slow vital capacity and inspiratory capacity versus placebo . In conclusion , tiotropium reduced exacerbations and associated health re source use , and improved airflow over 1 yr in chronic obstructive pulmonary disease patients BACKGROUND Gender differences may occur in many chronic diseases . We have examined the influence of gender in chronic obstructive pulmonary disease ( COPD ) on long-term responses to tiotropium . METHODS Subgroup analysis of data from the Underst and ing the Potential Long-term Impact of Tiotropium ( UPLIFT ) trial ( 4-year , r and omized , double-blind , placebo-controlled trial of tiotropium in patients with COPD ) . RESULTS Of 5992 patients , 75 % were men and 25 % women . Mean age was 65 and 63 years , respectively . Baseline post-bronchodilator forced expiratory volume in 1s ( FEV(1))=47 % predicted(men ) and 49 % predicted(women ) . St George 's Respiratory Question naire ( SGRQ ) total score was 44.9 and 48.7units , respectively . At 48 months , improvement in trough FEV(1 ) over control was 92mL(men ) and 77mL(women ) ( p<0.001 for both ) , with no differences in the rate of decline ( trial primary endpoint ) . Hazard ratio ( HR ) ( 95 % confidence interval [ CI ] ) for first exacerbation ( tiotropium/placebo ) was 0.87(0.81 , 0.93)(men ) and 0.83(0.74 , 0.94)(women ) . Number of exacerbations ( per patient-year ) was reduced with tiotropium in men ( from 0.82 to 0.71 ) and women ( from 0.92 to 0.77 ) ( p<0.005 for both ) . HR ( 95 % CI ) for a hospitalized exacerbation was 0.89(0.79 , 0.99 ) and 0.77(0.62 , 0.94 ) , respectively . HR ( 95 % CI ) for mortality during treatment was 0.85(0.72 , 0.99)(men ) and 0.85(0.62 , 1.18)(women ) . Improvements in SGRQ total score ( tiotropium-control ) at 1 , 2 , 3 and 4 years were : -2.8 , -2.3 , -3.6 , -2.4(men ) and -2.7 , -2.6 , -2.6 , -2.1(women ) ( p<0.05 for all ) . CONCLUSION Long-term treatment of COPD with tiotropium improves lung function , exacerbations and health status in men and women , with similar magnitudes of benefit . Boehringer Ingelheim trial 205.235 ; Clinical Trials.gov : NCT00144339 BACKGROUND We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease ( COPD ) and a history of at least one moderate to severe exacerbation in the previous 12 months . METHODS In this multicentre , r and omised , blinded , double-dummy , parallel group study , we enrolled patients aged 40 years or older with severe COPD and at least one exacerbation within the previous year . We used a computer-generated sequence to r and omly allocate patients ( 1:1 ; stratified by baseline inhaled corticosteroid use , with the balance of treatments maintained at country level ) to receive either indacaterol ( 150 μg ) or tiotropium ( 18 μg ) once-daily for 52 weeks . Our primary and key secondary objectives were to investigate whether indacaterol was non-inferior to tiotropium  for trough forced expiratory volume in 1 s ( FEV1 ) at week 12 ( primary endpoint ) , and for rate of exacerbations at week 52 ( secondary endpoint ) . Analysis population s for the primary and key secondary endpoints were per- protocol sets . The safety set included all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT00845728 . FINDINGS Between March 16 , 2009 , and July 5 , 2012 , we enrolled and r and omly allocated 3444 patients : 1723 to indacaterol and 1721 to tiotropium . At week 12 , the estimated least squares mean trough FEV1 difference between the groups was -0.011 L ( least squares mean with indacaterol [ n=1450 ] 1.134 L [ SE 0.008 ] vs tiotropium [ n=1467 ] 1.145 L [ 0.008 ] ; one-sided 97.5 % CI lower limit -0.026 L ; p<0.0001 ) . The lower limit of the 97.5 % CI was above the prespecified non-inferiority margin of -0.055 L , suggesting that indacaterol was non-inferior to tiotropium . Indacaterol did not show non-inferiority in terms of annualised exacerbation rates : 0.79 ( indacaterol , n=1529 ) versus 0.61 ( tiotropium , n=1543 ) ; ratio 1.29 ( one-sided 97.5 % CI upper limit 1.44 ) . In the safety set , we recorded no between-group difference in the number of patients who had adverse events  ( indacaterol 1119 [ 65 % ] of 1721 patients vs tiotropium 1065 [ 62 % ] of 1718 patients ) or serious adverse events  ( indacaterol , 263 [ 15 % ] of 1721 patients vs tiotropium , 255 [ 15 % ] of 1718 patients ) . Respiratory disorders , particularly worsening of COPD , were the most common adverse events ( COPD : indacaterol , 747 [ 43 % ] of 1721 patients and tiotropium , 665 [ 39 % ] of 1718 patients ) and serious adverse events ( COPD : indacaterol , 147 [ 9 % ] of 1721 patients and tiotropium , 121 [ 7 % ] of 1718 patients ) . INTERPRETATION Indacaterol and tiotropium provided clinical ly relevant improvements in lung function with comparable safety profiles . Tiotropium afforded greater protection from exacerbations , although the absolute number of events was small and the difference between treatments is of uncertain clinical importance . The present data offer evidence consistent with current guidelines . FUNDING Novartis Pharma AG 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 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 Exacerbations of chronic obstuctive pulmonary disease ( COPD ) are associated with worse health status . The Inhaled Steroids in Obstructive Lung Disease in Europe ( ISOLDE ) study showed that treatment with fluticasone propionate ( FP ) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo . The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations . Rates of deterioration in St George 's Respiratory Question naire ( SGRQ ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs . Exacerbation rates were skewed and could not be normalised , therefore , patients were stratified into three exacerbation groups : none , infrequent ( < 1.65 exacerbations·yr−1 ) and frequent ( > 1.65 exacerbations·yr−1 ) . There were 91 patients with no exacerbations , 285 with infrequent exacerbations and 235 with frequent exacerbations . Frequent exacerbations were independently associated with a worse baseline SGRQ score ( p<0.0001 ) and a more rapid rate of deterioration in health status ( p=0.0003 ) . Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score . Statistical modelling showed the beneficial effect of fluticasone propionate  on deterioration in health status to be largely due to its effect on exacerbation frequency 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 BACKGROUND We evaluated the effect of dual , longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease ( COPD ) . METHODS In this parallel-group study , 2224 patients ( aged ≥40 years , Global Initiative for Chronic Obstructive Lung Disease stages III-IV , and one or more moderate COPD exacerbation in the past year ) were r and omly assigned ( 1:1:1 ; via interactive voice response or web system ; stratified for smoking status ) to once-daily QVA149 ( fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg ) , glycopyrronium 50 μg , or tiotropium 18 μg for 64 weeks . Assignment to QVA149 and glycopyrronium was double-blind ; tiotropium was open-label . Efficacy was assessed in all patients r and omly assigned to treatment groups who received at least one dose of study drug ; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group . The primary objective was to show superiority  of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations ( defined by worsening symptoms and categorised by treatment requirements ) during treatment . This completed trial is registered at Clinical Trials.gov , NCT01120691 . FINDINGS Between April 27 , 2010 , and July 11 , 2012 , 741 patients were r and omly assigned to receive QVA149 , 741 to receive glycopyrronium , and 742 to receive tiotropium ( 729 , 739 , and 737 patients , respectively , analysed for efficacy ) . QVA149 significantly reduced the rate of moderate to severe exacerbations  versus glycopyrronium by 12 % ( annualised rate of exacerbations 0·84 [ 95 % CI 0·75 - 0·94 ] vs 0·95 [ 0·85 - 1·06 ] ; rate ratio 0·88 , 95 % CI 0·77 - 0·99 , p=0·038 ) . Adverse events ( including exacerbations ) were reported for 678 ( 93 % ) of 729 patients on QVA149 , 694 ( 94 % ) of 740 on glycopyrronium , and 686 ( 93 % ) of 737 on tiotropium . Incidence of serious adverse events was similar between groups ( 167 [ 23 % ] patients on QVA149 , 179 [ 24 % ] on glycopyrronium , and 165 [ 22 % ] on tiotropium ) ; COPD worsening was the most frequent serious adverse event ( 107 [ 15 % ] patients on QVA149 , 116 [ 16 % ] on glycopyrronium , 87 [ 12 % ] on tiotropium ) . INTERPRETATIONS The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium , with concomitant improvements in lung function and health status . These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD . FUNDING Novartis Pharma AG RATIONALE Indacaterol is the first once-daily , long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To demonstrate greater efficacy of indacaterol versus placebo on FEV(1 ) at 24 hours post dose ( trough ) after 12 weeks , to compare efficacy with placebo and tiotropium , and to evaluate safety and tolerability over 26 weeks . MEASUREMENTS Patients with moderate-to-severe COPD were r and omized to double-blind indacaterol 150 or 300 microg or placebo , or open-label tiotropium 18 microg , all once daily , for 26 weeks . The primary efficacy outcome was trough FEV(1 ) at 12 weeks . Additional analyses ( not adjusted for multiplicity ) included transition dyspnea index ( TDI ) , health status ( St George 's Respiratory Question naire [ SGRQ ] ) , and exacerbations . Serum potassium , blood glucose , and QTc interval were measured . RESULTS A total of 1,683 patients ( age , 63.3 yr ; post-bronchodilator FEV(1 ) , 56 % predicted ; FEV(1)/FVC , 0.53 ) were r and omized to the four treatment arms . Trough FEV(1 ) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium ( all P < 0.001 vs. placebo ) . At Week 26 , for indacaterol 150/300 microg , respectively , versus placebo , TDI increased ( 1.00/1.18 , P < 0.001 ) and SGRQ total score decreased ( -3.3/-2.4 , P < 0.01 ) ; corresponding results with tiotropium were 0.87 ( P < 0.001 ) for TDI and ( -1.0 , P = not significant ) for SGRQ total score . The incidence of adverse events , low serum potassium , high blood glucose , and prolonged QTc interval was similar across treatments . CONCLUSIONS Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD . Clinical trial registered with clinical trials.gov ( NCT 00463567 ) 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 AND OBJECTIVE Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions . We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial . METHODS Subgroup analysis from a r and omized , double-blinded , placebo-controlled trial of tiotropium 18 µg daily in COPD . Primary end-point was rate of decline in FEV(1 ) . Secondary end-points included spirometry at individual time points , health-related quality of life ( St George 's Respiratory Question naire ) , exacerbations and mortality . RESULTS Of 5992 patients , 362 were from Asian centres ( 100 from Japan ) . Mean age 66 years , 95 % men , 13 % current smokers , BMI : 21 kg/m(2 ) ; post-bronchodilator FEV(1 ) : 44 % predicted ; St George 's Respiratory Question naire total score : 44 units . No treatment effect was observed for rate of decline in FEV(1 ) although annual decline was less in Asian patients . Morning pre-bronchodilator FEV(1 ) and forced vital capacity improved in Asian patients ( P < 0.05 ) . Tiotropium  reduced number of exacerbations ( rate ratio ( 95 % confidence interval ( CI ) ) : 0.73 ( 0.57 - 0.94 ) ) . Hazard ratios ( 95%CI ) for exacerbations and hospitalized exacerbations  ( tiotropium/control ) were 0.81 ( 0.62 - 1.05 ) and 0.85 ( 0.61 - 1.19 ) , respectively . St George 's Respiratory Question naire total score improved by 1.5 - 6.1 units ( P < 0.05 for months 18 , 24 , 30 and 36 ) with tiotropium . Fatal events occurred in 34 tiotropium ( 18.5 % ) and 42 control ( 23.6 % ) patients . CONCLUSIONS In COPD patients from Asia  , tiotropium  improves lung function , improves health-related quality of life and reduces exacerbations over 4 years of treatment The objective of this study was to investigate the effect of tiotropium compared with salmeterol on exacerbations in patients with moderate ( Global Initiative for Chronic Obstructive Lung Disease [ GOLD ] stage II ) chronic obstructive pulmonary disease ( COPD ) and those naïve to maintenance respiratory therapy  in the 1-year Prevention Of Exacerbations with Tiotropium in COPD ( POET- COPD ( ® ) ) trial ( NCT00563381 ) . Time to first exacerbation ( primary endpoint ) and rates of exacerbations were analyzed using exploratory Cox and Poisson regression ( adjusting for time on treatment ) . Of 7376 r and omized patients , 3614 were GOLD stage II ( tiotropium n = 1781 ;  salmeterol n = 1833 ) and 1343 were maintenance therapy naïve ( tiotropium  n = 672 ; salmeterol n = 671 )  . Tiotropium significantly increased time to first exacerbation vs. salmeterol in GOLD stage II patients ( hazard ratio [ HR ] , 0.88 ; 95 % confidence interval [ CI ] : 0.79 - 0.99 ; p = 0.028 ) and maintenance therapy naïve patients ( HR , 0.79 ; 95 % CI , 0.65 - 0.97 ; p = 0.028 ) . Annual exacerbation rates were also significantly lower with tiotropium in the maintenance naïve subgroup compared with salmeterol ( rate ratio [ RR ] , 0.77 ; 95 % CI , 0.63 - 0.94 ; p = 0.012 ) . In the GOLD stage II subgroup , the rate of hospitalized exacerbations per year was significantly lower with tiotropium than with salmeterol ( RR , 0.70 ; 95 % CI , 0.57 - 0.85 ; p < 0.001 ) ; tiotropium also significantly prolonged time to first hospitalized exacerbation  versus salmeterol in this subgroup ( HR , 0.66 ; 95 % CI , 0.48 - 0.91 ; p = 0.012 ) . In conclusion , results from this prespecified subgroup analysis support the selection of tiotropium as first-choice maintenance therapy for patients with GOLD stage II 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 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 Whilst recent large-scale studies have provided much evidence on the natural history and therapeutic response in patients with chronic obstructive pulmonary disease ( COPD ) , relatively little is known about the effect in younger patients . We report a pre-specified post-hoc analysis of 356 patients with COPD ≤ 50 years old from the four year r and omised , double blind placebo controlled Underst and ing Potential Long Term Impact on Function with Tiotropium ( UPLIFT ) trial . Inclusion criteria included a post-bronchodilator forced expiratory volume in 1 s ( FEV(1 ) ) of ≤70 % , FEV(1)/FVC < 0.70 , age ≥40 years , and smoking history of ≥10 pack years . Younger patients had a mean FEV(1 ) of 1.24 L ( 39 % predicted ) and an impaired health-related quality of life ( St. George 's Respiratory Question naire ( SGRQ ) ) compared to the entire UPLIFT population . There were 40.2 % women and 51.1 % current smokers in the younger age group . Tiotropium was associated with a sustained improvement in spirometry and SGRQ . Mean decline in post-bronchodilator FEV(1 ) was 58 ml/year ( placebo ) vs. 38 ml/year ( tiotropium ) ( p = 0.01 ) . Corresponding values for pre-bronchodilator FEV(1 ) were 41 ml/year ( placebo ) compared with 34 ml/year ( tiotropium ) ( p = 0.34 ) . The hazard ratio ( 95%CI ) for an exacerbation in the younger age group was 0.87(0.68 , 1.13 ) ) . The rate of exacerbations was reduced by tiotropium ( rate ratio ( 95%CI ) = 0.73(0.56 , 0.95 ) ) . Tiotropium result ed in sustained bronchodilation , improved quality of life , and a decreased exacerbation rate in younger  patients . Tiotropium also result ed in a significant reduction in the decline in post-bronchodilator FEV(1 ) , suggesting possible disease modification by tiotropium in younger patients with COPD BACKGROUND Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease ( COPD ) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent . We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD . METHODS In a 1-year , r and omized , double-blind , double-dummy , parallel-group trial , we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year . RESULTS A total of 7376 patients were r and omly assigned to and treated with tiotropium ( 3707 patients ) or salmeterol ( 3669 patients ) . Tiotropium , as compared with salmeterol , increased the time to the first exacerbation ( 187 days vs. 145 days ) , with a 17 % reduction in risk ( hazard ratio , 0.83 ; 95 % confidence interval [ CI ] , 0.77 to 0.90 ; P<0.001 ) . Tiotropium also increased the time to the first severe exacerbation ( hazard ratio , 0.72 ; 95 % CI , 0.61 to 0.85 ; P<0.001 ) , reduced the annual number of moderate or severe exacerbations ( 0.64 vs. 0.72 ; rate ratio , 0.89 ; 95 % CI , 0.83 to 0.96 ; P=0.002 ) , and reduced the annual number of severe exacerbations ( 0.09 vs. 0.13 ; rate ratio , 0.73 ; 95 % CI , 0.66 to 0.82 ; P<0.001 ) . Overall , the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups . There were 64 deaths ( 1.7 % ) in the tiotropium group and 78 ( 2.1 % ) in the salmeterol group . CONCLUSIONS These results show that , in patients with moderate-to-very-severe COPD  , tiotropium is more effective than salmeterol in preventing exacerbations . ( Funded by Boehringer Ingelheim and Pfizer ; Clinical Trials.gov number , NCT00563381 . ) BACKGROUND The effect of β2-adrenergic receptor ( ADRB2 ) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease ( COPD ) is unclear . We aim ed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol . METHODS We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year r and omised , double-blind , double-dummy , parallel-group Prevention Of Exacerbations with Tiotropium in COPD ( POET- COPD ) trial , comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD . One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the sub study . R and om assignment of patients to treatment groups was not stratified according to genotypes . Genomic DNA was extracted from whole-blood specimens and sample s were genotyped for the two SNPs , rs1042713 ( Arg16Gly ) and rs1042714 ( Gln27Glu ) . All assays were done in technical duplicates and 10 % of sample s that were r and omly chosen were repeated as technical duplicates in a second independent genotyping process . Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data . An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD ( cough , sputum , wheezing , dyspnoea , or chest tightness ) , with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids ( moderate exacerbations ) , or admission to hospital ( severe exacerbations ) . POET- COPD is registered with Clinical Trials.gov , number NCT00563381 . FINDINGS 5125 patients gave informed consent for genotyping . The distributions of ADRB2 genotypes were well matched among groups . Polymorphisms at aminoacid 27 did not affect exacerbation outcomes . In the salmeterol group , patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly ( p=0·0130 ) and Gly16Gly ( p=0·0018 ) genotypes ( proportion of patients with at least one exacerbation was 32·3 % in Arg16Arg , 39·8 % in Arg16Gly , and 42·1 % in Gly16Gly ) . By contrast , exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group . The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids ( ICS ) . In patients untreated with ICS at baseline , Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly ( vs Arg16Gly p=0·0164 ; Arg16Arg p=0·0316 ; proportion of patients with at least one exacerbation was 28·3 % in Arg16Arg , 31·6 % in Arg16Gly , and 39·2 % in Gly16Gly ) , whereas in patients on ICS at baseline , only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly ( p=0·0198 ; not Arg16Gly p=0·64 ; proportion of patients with at least one exacerbation was 35·9 % in Arg16Arg , 46·7 % in Arg16Gly , and 44·8 % in Gly16Gly ) . The respiratory disorders , in particular worsening of COPD , were the most common serious adverse events . INTERPRETATION Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes , suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting β-agonists ( LABAs ) . However , the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospect i ve validation will be needed to advance the mechanistic underst and ing of β-adrenergic polymorphisms and their association with clinical features of COPD . FUNDING Boehringer Ingelheim and Pfizer
BACKGROUND Exacerbation frequency is related to disease progression , quality of life , and prognosis in COPD .
Earlier diagnosis , along with interventions aim ed at preventing exacerbations and delaying progression , may help reduce the global burden of disease .
Long-acting inhaled bronchodilators are effective at maintaining symptom relief and are recommended as first-choice therapy for more symptomatic patients and those at risk of exacerbation .