Understanding Potential Long-term Impacts On Function With Tiotropium Research Articles

Mortality and Exacerbation Risk by Body Mass Index in Patients with COPD in TIOSPIR and UPLIFT.

RationaleThere is an association between body mass index (BMI) and mortality in chronic obstructive pulmonary disease (COPD), with underweight individuals having higher mortality risk. Mortality and exacerbation risks among individuals with higher BMI are unclear.ObjectivesTo examine the relationship between BMI and adverse outcomes in COPD.MethodsThis post hoc analysis included data from TIOSPIR (Tiotropium Safety and Performance in Respimat) (N = 17,116) and tiotropium-treated patients in UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) (N = 2,986). BMI classes (underweight [BMI < 20 kg/m2], normal weight [BMI 20 to <25 kg/m2], overweight [BMI 25 to <30 kg/m2], obesity class I [BMI 30 to <35 kg/m2], obesity class II [BMI 35 to <40 kg/m2], and obesity class III [BMI ⩾ 40 kg/m2]) were examined for adjusted associations with mortality, exacerbation, and nonfatal cardiovascular event risk using over 50,000 patient-years of cumulative follow-up data. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression models.ResultsIn TIOSPIR, obesity prevalence was 22%, overweight 32%, and underweight 12%. The proportion of females was highest in obesity classes II and III. Overweight and obese participants had better baseline lung function versus other BMI classes; underweight participants were more likely to be current smokers. Underweight participants had a significantly higher risk of death (HR, 1.88; 95% CI, 1.62–2.20; P < 0.0001) and severe exacerbations (HR, 1.31; 95% CI, 1.16–1.47; P < 0.0001) versus normal-weight participants; however, overweight and obese participants were at lower to no additional risk. Results from UPLIFT were similar to TIOSPIR.ConclusionsThese results suggest that there is a strong association between body weight, COPD events, and risk of death. A holistic management approach taking into account respiratory and cardiovascular risk factors and nutritional status is needed to improve the general well-being of patients with COPD.

External Validation of Health Economic Decision Models for Chronic Obstructive Pulmonary Disease (COPD): Report of the Third COPD Modeling Meeting.

To validate outcomes of presently available chronic obstructive pulmonary disease (COPD) cost-effectiveness models against results of two large COPD trials-the 3-year TOwards a Revolution in COPD Health (TORCH) trial and the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial. Participating COPD modeling groups simulated the outcomes for the placebo-treated groups of the TORCH and UPLIFT trials using baseline characteristics of the trial populations as input. Groups then simulated treatment effectiveness by using relative reductions in annual decline in lung function and exacerbation frequency observed in the most intensively treated group compared with placebo as input for the models. Main outcomes were (change in) total/severe exacerbations and mortality. Furthermore, the absolute differences in total exacerbations and quality-adjusted life-years (QALYs) were used to approximate the cost per exacerbation avoided and the cost per QALY gained. Of the six participating models, three models reported higher total exacerbation rates than observed in the TORCH trial (1.13/patient-year) (models: 1.22-1.48). Four models reported higher rates than observed in the UPLIFT trial (0.85/patient-year) (models: 1.13-1.52). Two models reported higher mortality rates than in the TORCH trial (15.2%) (models: 20.0% and 30.6%) and the UPLIFT trial (16.3%) (models: 24.8% and 36.0%), whereas one model reported lower rates (9.8% and 12.1%, respectively). Simulation of treatment effectiveness showed that the absolute reduction in total exacerbations, the gain in QALYs, and the cost-effectiveness ratios did not differ from the trials, except for one model. Although most of the participating COPD cost-effectiveness models reported higher total exacerbation rates than observed in the trials, estimates of the absolute treatment effect and cost-effectiveness ratios do not seem different from the trials in most models.

Cost-effectiveness of tiotropium versus glycopyrronium in moderate to very severe chronic obstructive pulmonary disease in Canada, Spain, Sweden, and the UK.

ObjectivesTiotropium (TIO), Spiriva® Handihaler®, is a well-established bronchodilator, LAMA (long acting muscarinic antagonist), for the treatment of moderate to very severe chronic obstructive pulmonary disease (COPD). Clinical evidence from the SPARK trial suggests that TIO is superior to glycopyrronium (GLY), Seebri® Breezhaler®, in terms of severe exacerbations. This modeling study assessed the cost-effectiveness of TIO versus GLY for Canada (CAN), Spain (ESP), Sweden (SWE), and the UK, making use of this new clinical evidence.MethodsA Markov cohort model, with moderate to very severe (Global Initiative for Chronic Obstructive Lung Disease II–IV) COPD patients, was populated with efficacy data from the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) and SPARK trials as well as costs, utilities, and epidemiological data relevant for each country. Treatment efficacy was modeled as improvements in lung function, quality-adjusted life years (QALYs), and as a lowering of the risk of exacerbations (rate of exacerbations). Risks of exacerbations differed between cohorts based on data from SPARK. Health and cost outcomes were simulated over an approximate lifetime horizon, starting from the age of 65 years. Robustness of results was validated in deterministic sensitivity analyses.ResultsOver the lifetime horizon, patients treated with TIO accumulated −623 (CAN), 1,066 (ESP), 1,137 (SWE), and −169 (UK), respectively, in incremental costs (€2014). TIO generated better health outcomes compared to GLY in all countries, 0.21 (CAN), 0.25 (ESP), 0.23 (SWE), and 0.23 (UK) in incremental QALYs. The cost per QALY gained was found to be €4,281 and €1,137 for ESP and SWE, respectively, while TIO was found to be cost saving in CAN and the UK. The results were mainly driven by the relative risk of severe exacerbations found in SPARK (GLY/TIO relative risk: 1.43, 95% confidence interval: 1.05–1.97, P=0.025).ConclusionThe results from this study show that TIO is a cost-effective treatment compared to GLY in moderate to very severe COPD. The cost per QALY is well below the existing implicit and explicit willingness-to-pay thresholds.

Acute bronchodilator responses decline progressively over 4 years in patients with moderate to very severe COPD

BackgroundWe previously reported a progressive decline in absolute responses of FEV1 and FVC to a near-maximal dose of 2 different short-acting bronchodilators over 4 years. Since varying host factors and the method of expressing the response may impact the time trend of acute bronchodilator responses, we now examined the potential influence of salient host characteristics on changes in bronchodilator responses over time expressed in different ways.MethodsAs part of the 4-year, placebo-controlled Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, pre- and post-bronchodilator spirometry was performed at baseline and 1 month and every 6 months thereafter. Post-bronchodilator values for FEV1 and FVC were analyzed for subjects completing at least the 1 year visit (Placebo – N = 2463; Tiotropium – N = 2579), stratified by GOLD stage, age, gender and smoking status and expressed as absolute, relative (%) and % predicted changes from pre-bronchodilator values. Annual changes in bronchodilator response were estimated using linear mixed effects models.ResultsFor all subjects analyzed, FEV1 and FVC bronchodilator responses showed progressive and highly significant (p < 0.0001) declines over 4 years. Declines were generally larger in patients with severe/very severe than mild/moderate airflow obstruction, in older patients (≥65 yrs) and in former than continuing smokers.ConclusionAcute FEV1 and FVC responses to bronchodilators decline significantly over time in COPD patients, whether expressed as absolute, relative or % predicted changes, potentially impacting on the clinical responses to bronchodilator therapy as well as on the annual rate of decline in post-bronchodilator lung function.ClinicalTrials.gov numberNCT00144339Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-014-0102-5) contains supplementary material, which is available to authorized users.

Republished: Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications

The majority of deaths in COPD are from cardiovascular causes. Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events,...

Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications

The majority of deaths in COPD are from cardiovascular causes. Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events,...

Risks associated with tiotropium in chronic obstructive pulmonary disease: overview of the evidence to date.

Tiotropium is a long-acting inhaled anticholinergic agent that is widely used in the treatment of chronic obstructive pulmonary disease (COPD). It was initially launched as the tiotropium HandiHaler formulation, but this was followed by a newer version based on a potentially more efficient drug delivery device, known as Respimat. This Respimat formulation is available worldwide but has not yet succeeded in gaining regulatory approval in the USA. In the past few years, the adverse effects profile of tiotropium has come under close scrutiny owing to concerns about the possibility of urinary and cardiovascular adverse effects. These concerns appeared to have been alleviated following the publication of data from the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, which was a large trial of 4 years' duration. This trial did not show any excess myocardial infarction, renal or urinary adverse events with tiotropium compared with placebo. However, the risk of urinary retention has been in the spotlight again following publication of two observational studies reporting a significantly increased risk of urinary retention in men recently started on inhaled anticholinergics, especially when prostatic hyperplasia coexists. More recently, a meta-analysis of mortality data for the tiotropium Respimat formulation raised the possibility of an increased risk of death, including death from cardiovascular causes. It is unclear if the more efficient drug delivery offered by the Respimat device is hitting a different part of the dose-toxicity curve. In the absence of any evidence of superior clinical efficacy with tiotropium Respimat compared with tiotropium HandiHaler, some experts have argued that there is no compelling reason to choose the Respimat formulation given the new uncertainties about its safety profile.

Exacerbation frequency and course of COPD

BackgroundExacerbations affect morbidity in chronic obstructive pulmonary disease (COPD). We sought to evaluate the association between exacerbation frequency and spirometric and health status changes over time using data from a large, long-term trial.MethodsThis retrospective analysis of data from the 4-year UPLIFT® (Understanding Potential Long-term Impacts on Function with Tiotropium) trial compared tiotropium with placebo. Annualized rates of decline and estimated mean differences at each time point were analyzed using a mixed-effects model according to subgroups based on exacerbation frequency (events per patient-year: 0, >0–1, >1–2, and >2). Spirometry and the St George’s Respiratory Questionnaire (SGRQ) were performed at baseline and every 6 months (also at one month for spirometry).ResultsIn total, 5992 patients (mean age 65 years, 75% male) were randomized. Higher exacerbation frequency was associated with lower baseline postbronchodilator forced expiratory volume in one second (FEV1) (1.40, 1.36, 1.26, and 1.14 L) and worsening SGRQ scores (43.7, 44.1, 47.8, and 52.4 units). Corresponding rates of decline in postbronchodilator FEV1 (mL/year) were 40, 41, 43, and 48 (control), and 34, 38, 48, and 49 (tiotropium). Values for postbronchodilator forced vital capacity decline (mL/year) were 45, 56, 74, and 83 (control), and 43, 57, 83, and 95 (tiotropium). The rates of worsening in total SGRQ score (units/year) were 0.72, 1.16, 1.44, and 1.99 (control), and 0.38, 1.29, 1.68, and 2.86 (tiotropium). The proportion of patients who died (intention-to-treat analysis until four years [1440 days]) for the entire cohort increased with increasing frequency of hospitalized exacerbations.ConclusionIncreasing frequency of exacerbations worsens the rate of decline in lung function and health-related quality of life in patients with COPD. Increasing rates of hospitalized exacerbations are associated with increasing risk of death.

Tiotropium's cost-effectiveness for the treatment of COPD: a cost-utility analysis under real-world conditions.

BackgroundTiotropium is reimbursed since March 2004 in Belgium for the treatment of Chronic Obstructive Pulmonary Disease (COPD). Questions however remain on this product's value for money. The purpose of this study is to calculate tiotropium's cost-effectiveness under real-world conditions.MethodsStrengths of both observational and RCT data were combined in a model. A large longitudinal (2002-2006) observational dataset of regular tiotropium users (56 321 patients) was analysed to retrieve the baseline risk for exacerbations and exacerbation-related hospitalisations the year before the first delivery of tiotropium. The relative treatment effect from the UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) trial was then applied to this baseline risk to reflect the effect of tiotropium treatment and calculate the intervention's incremental cost-effectiveness ratio (ICER).ResultsAfter 1000 Latin Hypercube simulations, the incremental benefit expressed as quality-adjusted life years (QALY) gained is on average 0.00048 (95% confidence interval (CI) 0.00009 - 0.00092). In combination with a substantial mean incremental cost of €373 per patient (95% CI 279 - 475), this results in an unfavourable average ICER of €1 244 023 (95% CI 328 571 - 4 712 704) per QALY gained. Results were most sensitive to the treatment effect on hospitalisations. Based on our large observational database, up to 89% of the patients were not hospitalised for COPD in the year before the first tiotropium delivery.ConclusionsThe main cause for tiotropium's unfavourable cost-effectiveness ratio is a combination of a relative high price for tiotropium, a low number of hospitalisations without tiotropium treatment (on average 0.14/year) and a non-significant treatment effect (on average 0.94) with respect to avoiding exacerbation-related hospitalisations. From an economic point of view, a revision of reimbursement modalities (e.g. with a lower price) would be justified and would entail a more efficient use of resources.

Mortality in COPD: Causes, Risk Factors, and Prevention

ABSTRACTChronic obstructive pulmonary disease (COPD) is a leading and increasing cause of death, the extent of which is underestimated as a consequence of underdiagnosis and underreporting on death certificates. Data from large trials, such as the Lung Health Study, Towards a Revolution in COPD Health (TORCH), Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT), European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP), and Inhaled Steroids in Obstructive Lung Disease (ISOLDE), have shown that the causes of death in patients with mild COPD are predominantly cancer and cardiovascular disease, but as COPD severity increases, deaths due to non-malignant respiratory disease are increasingly common. In practice, mortality of patients with COPD can be predicted by a variety of measures including: forced expiratory volume in one second (FEV1), the ratio of inspiratory and total lung capacities, exercise capacity, dyspnea scores, and composite indices such as the body-mass index (B), degree of airflow obstruction (O), degree of functional dyspnea (D), and exercise capacity (E) (BODE) index. Smoking cessation improves survival in COPD patients, and in select patients with advanced disease, oxygen therapy, lung volume reduction surgery, or lung transplantation may also improve survival.

Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT(R) trial

The aim of the present study was investigate the long-term effect of tiotropium as first maintenance respiratory medication in chronic obstructive pulmonary disease (COPD). A 4-yr, randomised, multicentre, double-blind, parallel-group, placebo-controlled trial (Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) was conducted. Analysis focused on the effect of tiotropium versus matching placebo in the 810 (13.5%) COPD patients not on other maintenance treatment (long-acting beta-agonists, inhaled corticosteroids, theophyllines or anticholinergics) at randomisation. Spirometry, health-related quality of life (St George's Respiratory Questionnaire (SGRQ) score), exacerbations of COPD and mortality were also analysed. 403 patients (mean+/-sd age 63+/-8 yrs, post-bronchodilator forced expiratory volume in 1 s (FEV(1)) 53+/-12% predicted) received tiotropium and 407 (64+/-8 yrs of age, post-bronchodilator FEV(1) 51+/-12% pred) received placebo. Post-bronchodilator FEV(1) decline was 42+/-4 mL.yr(-1) in the tiotropium group and 53+/-4 mL.yr(-1) in the placebo group (p = 0.026). At 48 months, the morning pre-dose FEV(1) was 134 mL higher in the tiotropium group compared to the placebo group (p<0.001). SGRQ total score declined more slowly in the tiotropium group (difference of 1.05+/-0.34 units.yr(-1); p = 0.002). This was particularly significant for the impact (difference of 1.08+/-0.37 units.yr(-1); p = 0.004) and activity (1.44+/-0.40 units.yr(-1); p<0.001) domains, but not for symptoms (0.26+/-0.50 units.yr(-1); p = 0.6). At 48 months, the difference in total score was 4.6 units (p<0.001) with tiotropium compared to placebo. In patients with COPD who are not on maintenance therapy, tiotropium is associated with significant benefits in disease progression.

Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial

The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study was a randomised, double-blind, placebo-controlled trial undertaken in 487 centres in 37 countries. 5993 patients aged 40 years or more with COPD were randomly assigned to receive 4 years of treatment with either once daily tiotropium (18 microg; n=2987) or matching placebo (n=3006), delivered by an inhalation device. Randomisation was by computer-generated blocks of four, with stratification according to study site. In a prespecified subgroup analysis, we investigated the effects of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease. Primary endpoints were the yearly rates of decline in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and in postbronchodilator FEV(1), beginning on day 30 until completion of double-blind treatment. The analysis included all patients who had at least three measurements of pulmonary function. This study is registered with ClinicalTrials.gov, number NCT00144339. 2739 participants (mean age 64 years [SD 9]) had GOLD stage II disease at randomisation (tiotropium, n=1384; control, n=1355), with a mean postbronchodilator FEV(1) of 1.63 L (SD 0.37; 59% of predicted value). 1218 patients in the tiotropium group and 1157 in the control group had three or more measurements of postbronchodilator pulmonary function after day 30 and were included in the analysis. The rate of decline of mean postbronchodilator FEV(1) was lower in the tiotropium group than in the control group (43 mL per year [SE 2] vs 49 mL per year [SE 2], p=0.024). For prebronchodilator pulmonary function, 1221 patients in the tiotropium group and 1158 in the control group had three or more measurements and were included in the analysis. The rate of decline of mean prebronchodilator FEV(1) did not differ between groups (35 mL per year [SE 2] vs 37 mL per year [SE 2]; p=0.38). Health status, measured with the St George's Respiratory Questionnaire, was better at all timepoints in the tiotropium group than in the control group (p</=0.006 for all timepoints). Time to first exacerbation and time to exacerbation resulting in hospital admission were also longer in the tiotropium group than in the control group (hazard ratio 0.82, 95% CI 0.75-0.90, and 0.74, 0.62-0.88, respectively). Tiotropium seemed to reduce the rate of decline of postbronchodilator FEV(1) in patients with GOLD stage II COPD. This finding and the other improvements in outcomes suggest that treatment of COPD should begin at an early stage of the disease. Boehringer Ingelheim and Pfizer Pharmaceuticals.

A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD.

The long-term use of inhaled anticholinergic agents has recently been suggested to be associated with an excess risk of adverse cardiovascular (CV) outcomes in patients with COPD. We identified 15 published studies that reported on the association between long-term inhaled anticholinergic use and adverse CV outcomes. Only 3 of the studies were adequately designed randomized controlled trials (RCTs). The first RCT that suggested that anticholinergic agents increased the risk of adverse CV outcomes was the Lung Health Study (LHS). Smokers randomized to inhaled ipratropium had a significantly increased risk of CV death than smokers receiving placebo. The LHS results have been questioned as the statistical tests used in the study were not adjusted for multiple tests and endpoints, a convincing dose-effect relationship between ipratropium use and the adverse CV outcomes was not established, and most of the CV deaths in the ipratropium group occurred in patients who were non-compliant to ipratropium. The Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) was a RCT that compared the combination of salmeterol plus fluticasone against tiotropium in patients with COPD. All-cause mortality was significantly lower in the salmeterol plus fluticasone group (3%) compared to the tiotropium group (6%). Fatal CV events occurred in 1% of the salmeterol plus fluticasone group compared to 3% in the tiotropium group. The INSPIRE trial was not designed to be a mortality trial, lacked adequate adjudication of fatal outcomes, and lacked a full intention-to-treat analysis of the data. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was a RCT comparing tiotropium and placebo in patients with COPD. Follow-up in UPLIFT was planned for 1440 days (4 years) plus 30 days (1470 days) of post-treatment follow-up. At 1440 days with 95% of patient outcome accounted for, tiotropium was associated with a significant 13% reduction in all-cause mortality compared to placebo. However, at 1470 days with only 75% of patient outcome accounted for, tiotropium was associated with a non-significant 11% reduction in all-cause mortality compared to placebo. The relative risks for serious CV events, heart failure, and myocardial infarction were all significantly lower with tiotropium than placebo. It is not certain why such a wide disparity in findings exists among the published studies evaluating the CV risks of inhaled anticholinergic agents. Prospective, adequately powered RCTs are needed to provide more evidence for the CV safety of tiotropium.

Insights into interventions in managing COPD patients: lessons from the TORCH and UPLIFT&amp;reg; studies

Influencing the progression of COPD has long been an elusive goal of drug therapy. Directly or indirectly, this has again been investigated in two of the largest, long-term drug trials in COPD: Towards a Revolution in COPD Health (TORCH) and Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT). Neither trial achieved statistical significance in their respective primary outcomes; however, both make considerable contributions to understanding of how the progression of COPD may be influenced. The objective of this article is to review the data from these different trials with a view to what can be learnt about the management of COPD. The long-term improvements in lung function, health-related quality of life, and possibly survival from the use of long-acting bronchodilators in these trials suggest an influence on progression of the disease. With the more optimistic view of benefits from drug treatment of COPD that these trials provide, a review of prescribing practices is warranted.

Lung function decline in COPD trials

To the Editors: In his recent editorial, Suissa 1 has again expressed criticism of the TORCH (Toward a Revolution in Chronic Obstructive Pulmonary Disease (COPD) Health) trial 2. The focus this time is the analysis of rate of decline in lung function 3, and in particular he questions whether the reduction in rate of decline in forced expiratory volume in one second (FEV1) observed with the active treatments (salmeterol, fluticasone or the combination of both treatments) compared with placebo is due to “regression to the mean” caused by missing data. Missing data for lung function and exacerbations are unfortunately inevitable in any long-term trial in COPD. Suissa 1 states that “… measurements were missing so that the pure intent-to-treat analysis was not possible”. Such a “pure intent-to-treat” analysis of lung function or exacerbation data is not possible for any long-term COPD trial, as this would require complete data. In fact, the quantity of missing data for lung function in TORCH is similar to the UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) 4 and OPTIMAL 5 trials quoted in the article by Suissa 1. In TORCH, 4,857 (79%) patients provided lung function data at 48 weeks, OPTIMAL had complete 1-yr lung function data for 322 (72%) patients and, …

Bronchodilator responsiveness in patients with COPD

The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease (COPD) patients, and depends upon the type and dose of bronchodilator and the timing of administration. Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, a 4-yr randomised double-blind trial evaluating the efficacy of 18 mug tiotropium daily in reducing the rate of decline in lung function. After wash-out of respiratory medications, patients received 80 mug ipratropium followed by 400 mug salbutamol. Spirometry was performed before and 90 min following ipratropium administration. The criteria used for forced expiratory volume in one second (FEV(1)) responsiveness were: >or=12% increase over baseline and >or=200 mL; >or=15% increase over baseline; and >or=10% absolute increase in the percentage predicted value. Of the patients, 5,756 had data meeting the criteria for analysis (age 64.5 yrs; 75% male; baseline FEV(1) 1.10 L (39.3% predicted) and forced vital capacity (FVC) 2.63 L). Compared with baseline, mean improvements were 229 mL in FEV(1) and 407 mL in FVC. Of these patients, 53.9% had >or=12% and >or=200 mL improvement in FEV(1), 65.6% had >or=15% improvement in FEV(1), and 38.6% had >or=10% absolute increase in FEV(1) % pred. The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators.