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Clinical Investigations: COPD |

Long-term Treatment Benefits With Tiotropium in COPD Patients With and Without Short-term Bronchodilator Responses* FREE TO VIEW

Donald Tashkin; Steven Kesten
Author and Funding Information

*From the Pulmonary Division (Dr. Tashkin), David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA; and Boehringer Ingelheim Pharmaceuticals, Inc (Dr. Kesten), Ridgefield, CT.

Correspondence to: Donald Tashkin, MD, FCCP, David Geffen School of Medicine at UCLA, Pulmonary Division, CHS Rm 37–131, 10833 Le Conte Ave, Los Angeles, CA 90095-3075; e-mail: DTashkin@mednet. ucla.edu



Chest. 2003;123(5):1441-1449. doi:10.1378/chest.123.5.1441
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Objectives: To determine whether long-term symptomatic improvement occurs in COPD patients with maintenance bronchodilator therapy despite a nonsignificant short-term improvement in FEV1 following bronchodilator inhalation obtained at a single time point.

Methods: Data obtained during two identical 1-year, placebo-controlled trials of tiotropium, 18 μg once daily, were analyzed retrospectively to determine the associations of long-term improvements in lung function and patient health status with short-term improvements in FEV1, as measured on the first day of treatment. Based on the presence or absence of a short-term improvement in FEV1 of ≥ 12% and ≥ 200 mL, respectively, patients who had been treated with tiotropium were characterized as being responsive to tiotropium (TIO-R) or poorly responsive to tiotropium (TIO-PR).

Results: Baseline characteristics were similar other than baseline FEV1, which was higher in the TIO-R group than in both the TIO-PR and placebo groups (p < 0.05). Baseline FEV1 was 1.08 L in the TIO-R group (n = 263), 0.95 L in the TIO-PR (n = 255), and 0.99 L in the placebo group (n = 328). The mean (± SD) morning predose FEV1 at 1 year significantly (p < 0.001) improved in patients in both of the tiotropium treatment subgroups (TIO-R group, 212 ± 17 mL; TIO-PR group, 94 ± 17 mL) relative to those treated with placebo. Statistically significant improvements in both tiotropium-treated groups also were noted over 1 year for dyspnea (p < 0.001), as assessed by the transition dyspnea index (TDI) [TIO-R group, 1.36 ± 0.23 L; TIO-PR group, 0.86 ± 0.23 L] relative to the placebo group. Patient health status assessed by the St. George Respiratory Questionnaire (SGRQ) showed statistically significant improvements over placebo for the TIO-R and TIO-PR groups (−3.96 ± 0.99 and −3.05 ± 1.00 L, respectively; p < 0.005). There was a significant correlation of the first-dose short-term FEV1 response to the end-of-trial trough response (r = 0.43), but there was only a weak correlation to TDI focal score (r = 0.17) or SGRQ total score (r= −0.12).

Conclusions: Tiotropium was effective in the treatment of patients with COPD, irrespective of the presence or absence of a short-term response on the first day of treatment. The short-term bronchodilator response should not be used as a definitive criterion for prescribing long-term treatment with inhaled bronchodilators.

Figures in this Article

The bronchodilator responsiveness test assesses the change in forced expiratory volumes and flow rates in response to an inhaled bronchodilator, and has been used to characterize airflow obstruction as either “reversible” or “nonreversible.”1 A positive bronchodilator response has been defined by a short-term increase in FEV1, after bronchodilator administration, of at least 12% and 200 mL above the baseline.2 The absence of this degree of bronchodilator response suggests that airflow obstruction may be poorly reversible or fixed, a finding that may be used to assist in distinguishing COPD from asthma. The bronchodilator most commonly used for this procedure is a short-acting β-agonist.23 However, several studies46 have suggested that the short-term response to this class of bronchodilators may not be predictive of either the phenotype of airflow limitation (ie, reversible or nonreversible) or the long-term response to other pharmacologic agents such as long-acting inhaled β2-agonist or anticholinergic bronchodilators. Furthermore, it should be noted that many patients with COPD are bronchodilator-responsive, indicating that the airflow limitation in COPD patients should not be viewed as entirely irreversible.8 Anticholinergic therapy is recommended as the first-line maintenance bronchodilator medication in the treatment of stable COPD patients.1,910 Tiotropium is a new, long-acting, inhaled anticholinergic bronchodilator that improves lung function following once-daily dosing.1112 The prolonged duration of action and pharmacologic profile are attributed to muscarinic receptor subtype kinetic selectivity and to the slow dissociation from binding to the M3 receptor.13 Two large, 1-year studies were conducted in the United States evaluating the safety and efficacy of tiotropium in patients with COPD. The results showed that tiotropium improved lung function, dyspnea, and health-related quality of life (HRQOL) in the COPD patient study group as a whole and that these results were maintained over the duration of the study.11

We sought to evaluate whether the presence or absence of predefined commonly accepted criteria for a short-term bronchodilator response could be relied on to predict the potential long-term functional and symptomatic benefits of maintenance bronchodilator therapy in patients with COPD. A retrospective analysis was performed using the data from the two 1-year studies11 to determine the relationship between the short-term response to tiotropium and the long-term efficacy of this long-acting anticholinergic bronchodilator, with respect to lung function and patient health outcomes.

Study Design

A retrospective analysis was performed using two identical 1-year clinical trials11 that had been designed to establish the efficacy and safety of tiotropium in patients with COPD. A total of 50 clinical centers participated in these double-blind, placebo-controlled, parallel-group comparison trials. All patients had a clinical diagnosis of COPD, as defined by the American Thoracic Society.1 Patients were required to have an FEV1 of ≤ 65% predicted and an FEV1/FVC ratio of < 70%. The use of long-acting β2-agonist agents and other anticholinergic agents was not permitted. Patients were permitted as-needed albuterol metered-dose inhaler use and stable doses of theophylline, inhaled glucocorticosteroids, and the equivalent of ≤ 10 mg per day oral prednisone throughout the study period. Patients also were required to be at least 40 years of age and to have a smoking history of at least 10 pack-years. Patients were excluded if they had received a clinical diagnosis of asthma, atopy, or allergic rhinitis, or a peripheral blood eosinophil count of ≥ 600 cells/μL.

Following a 2-week baseline period to establish and document clinical stability, patients were randomly assigned within each study center to receive either tiotropium, 18 μg, or a matching dose of a placebo. Clinic visits were scheduled on the first day of the study drug administration and after 1, 7, 13, 26, 39, and 52 weeks of therapy. Subjects took, by inhalation, active medication (tiotropium) or placebo once each morning by capsule that appeared to be identical via a dry-powder inhaler device (HandiHaler; Boehringer Ingelheim GmbH; Ingelheim, Germany).14 The trials were approved by institutional review boards, and all patients provided written informed consent.

Spirometric Testing

Spirometric testing was conducted during each clinic visit. The drug was administered at the same time each day (ie, between 7:00 am and 9:00 am). On test days, FEV1 and FVC were recorded 60 min prior to dosing, just prior to dosing, and 30, 60, 120, and 180 min after the study drug administration. At least three adequate spirometric maneuvers were performed, and the greatest FEV1 and FVC were used in subsequent analyses. The predicted normal values for FEV1 and FVC were derived from standard equations.15 Trough values for FEV1 and FVC were calculated as the mean of the two predose measurements (ie, those measured 23 to 24 h after the previous dose of the study drug). In order to ensure standardized conditions on spirometric test days, subjects discontinued theophylline therapy 24 h prior to undergoing spirometric testing. Therapy with albuterol and inhaled corticosteroids was stopped at least 12 h prior to spirometric testing.

Bronchodilator Responsiveness

Responsive patients were delineated based on bronchodilator responses after the first dose of tiotropium in the group randomized to receive the active study drug. The short-term responses to short-acting β-agonists were not assessed. Patients who were responsive to tiotropium (TIO-R) were defined as those whose FEV1 values improved by ≥ 12% and ≥ 200 mL compared to baseline within 180 min after the initial dose of tiotropium had been administered on the first day of the study.1 The other patients receiving tiotropium were classified as being poorly responsive to tiotropium (TIO-PR).

Peak Expiratory Flow Rate

Each subject performed peak expiratory flow rate (PEFR) measurements in his/her home twice daily (on arising and at bedtime) [AirWatch Monitor; Enact Health Management Systems; Mountain View, CA].

Dyspnea, HRQOL, and Exacerbations

Dyspnea at baseline was assessed with the baseline dyspnea index (BDI).16 Changes from baseline were measured using the transition dyspnea index (TDI).16 The BDI/TDI instrument has three domains (ie, functional impairment, magnitude of task, and magnitude of effort), with the values summed for a combined focal score. HRQOL status was evaluated with the St. George Respiratory Questionnaire (SGRQ).17 The SGRQ has the following three component subscales: symptoms (due to respiratory distress); activity (disturbance of physical activity); and impacts (the psychosocial effects of the disease). The SGRQ total score reflects overall patient health status. Exacerbations of COPD were defined as the new onset or increase of more than one respiratory symptom lasting for at least 3 days. Exacerbations were captured as adverse events.

Statistical Analysis

Patients in the tiotropium group were divided into two groups (TIO-R and TIO-PR), based on the FEV1 response to the first dose of the study drug, as described above. The outcomes for the TIO-R and TIO-PR groups were compared with those from the patients receiving placebo using one-way analysis of variance. The weekly mean values for both the morning and evening PEFRs were computed if patients had reported at least four observations for the week. The baseline characteristics were compared among groups using t tests for continuous variables and the Fisher exact test for the prevalence of the use of pulmonary medication. Simple correlation coefficients of day 1 short-term FEV1 response with the end-of-trial trough FEV1 response, TDI focal score, and SGRQ total score (ie, difference from baseline) were calculated. The missing data were imputed using the last-observation-carried-forward method, except in patients (5% of patients) who had withdrawn from the study due to worsening of COPD, in which case the missing data were imputed using the least favorable observation prior to study withdrawal. Statistical significance was considered to occur at p < 0.05. No correction (eg, Bonferroni correction) was made for multiple comparisons.

Patient Demographics

A total of 921 patients were enrolled in the two combined studies (tiotropium groups, 550 patients; placebo group, 371 patients). Baseline demographics and lung function (Table 1 ), and the pulmonary medications used (Table 2 ) were similar among the groups except for baseline FEV1, which was higher in the TIO-R group than in both the TIO-PR and placebo groups (p < 0.05). While these differences were statistically significant, they were only modest in magnitude. On average, patients were in their seventh decade and were predominantly men. The mean FEV1 was 1.04 L (SD, 0.41 L) for the tiotropium group and 0.99 L (SD, 0.43 L) for the placebo group. The mean duration with a clinical diagnosis of COPD was 8.5 years, and this value was similar for each of the study populations.

The percentage of responsive patients was 51% among those patients receiving tiotropium therapy, based on a minimum increase of 12% and 200 mL above the baseline FEV1 within 3 h following the administration of the first dose of tiotropium.

Spirometry

According to the definitions for responsiveness (ie, achieving FEV1 increases of both ≥ 12% and ≥ 200 mL), the mean peak percentage change from baseline FEV1 within 3 h following the first dose of tiotropium or placebo was 37.1% in the TIO-R group, 14.7% in the TIO-PR group, and 8.9% in the placebo group. Over the ensuing year of observation, improvements in FEV1 were observed in both the TIO-R and TIO-PR groups compared to the placebo group (Fig 1 ). At the end of the study (day 344), the TIO-R and TIO-PR groups demonstrated a significant (p < 0.001) improvement in mean (SE) peak change in FEV1 from the day 1 baseline value compared to the placebo group (Table 3 ). Additionally, the trough FEV1 response (ie, the change from baseline) in the both the TIO-R and TIO-PR groups was significantly (p < 0.001) improved at the end of study compared to the placebo group. Similarly, patients who were characterized as being either TIO-R or TIO-PR showed significant (p < 0.001) improvements after 1 year for the trough FVC response compared to the placebo group (Table 3) . FVC was consistently increased following the administration of tiotropium in both the TIO-R and TIO-PR groups compared to the placebo group over the year of observation (p < 0.001) [Fig 2 ] . The magnitude of improvements was superior in the TIO-R group compared with the TIO-PR group. A correlation was observed between the short-term bronchodilator response and the end-of-trial trough FEV1 response (r = 0.43).

PEFR

At baseline, morning and evening PEFR values were similar among the three groups. At the end of the trial, PEFR, measured by the patient at home, was significantly (p < 0.01) higher in both the TIO-R and TIO-PR groups compared to the placebo group for the measurements obtained in the morning (ie, after awakening) and evening (ie, prior to bedtime) [Table 3] . There were no statistically significant differences noted between the TIO-R and TIO-PR groups at the end of study.

Dyspnea

Comparisons of the BDI scores were similar among the three groups at baseline except that for the TIO-PR group vs the TIO-R group (p < 0.05). The mean (± SD) BDI values were 6.28 ± 1.92, 5.77 ± 2.05, and 6.21 ± 2.16, respectively, for the TIO-R, TIO-PR, and placebo groups. At the end of the trial, patients in both tiotropium groups showed significant (p < 0.001) improvement in breathlessness (ie, positive TDI focal score) compared to those in the placebo group, although the difference in the TDI score between the TIO-R and TIO-PR groups was also significant (p < 0.05) [Table 4 ] . Last, the percentage of patients achieving a clinically significant positive TDI focal score (ie, ≥ 1 U) was significantly (p < 0.05) higher in both the TIO-R and TIO-PR groups compared to the placebo group. There was a weak correlation between the short-term bronchodilator response and the end-of-trial TDI focal score (r= 0.17).

Albuterol Use

At baseline, the mean (± SD) albuterol use was highest in the TIO-PR group (TIO-R group, 3.1 ± 2.3 puffs per day; TIO-PR group, 4.2 ± 3.0 puffs per day; and placebo group, 3.5 ± 2.6 puffs per day). Patients in both the TIO-R and TIO-PR groups had administered fewer inhalations of albuterol per day at the end of study (p < 0.001) compared to an increase among patients in the placebo group (Table 4) . There were no significant differences between the TIO-R and TIO-PR groups in the reduction in albuterol use.

Health Status

At baseline, the SGRQ total scores (mean ± SE) for the TIO-R, TIO-PR, and placebo groups were similar (44.2 ± 15.5, 49.2 ± 16.0, and 46.9 ± 15.9, respectively). SGRQ total scores for the TIO-R and TIO-PR groups were significantly improved compared with those for the placebo group at the end of the study (p < 0.001) [Table 4] . A higher proportion of patients in the tiotropium groups compared to the placebo group demonstrated a clinically meaningful improvement of at least 4 U in the SGRQ total score after 1 year (TIO-R group, 51%; TIO-PR group, 48%; placebo group, 30%; p < 0.05 [both active groups vs placebo group]). No significant differences were observed between the TIO-R and TIO-PR groups.

From day 1 to the end of the study, the improvement in the SGRQ impacts score was significantly greater with the administration of tiotropium than with the administration of placebo. The difference between each of the two tiotropium groups and the placebo group in terms of the impacts score on day 344 was −3.64 ± 0.07 and −4.31 ± 0.07, respectively, for TIO-R and TIO-PR groups (p < 0.005). There were no statistically significant differences noted between the TIO-R and TIO-PR groups. There was a weak correlation between the short-term bronchodilator response and the end-of-trial SGRQ total score (r = −0.12).

Exacerbations

The proportion of patients experiencing at least one exacerbation as well as associated hospitalizations was significantly less in the TIO-R group compared to the placebo group (Table 5 ). In addition, the frequency of exacerbations and associated hospitalizations as well as the number of days spent in the hospital were significantly less in the TIO-R group compared to the placebo group. In the TIO-PR group, the data from these analyses of exacerbations fell between those for the placebo group and those for the TIO-R group. The differences were not statistically different from those for the other groups (except for the frequency of exacerbations, which were significantly [p < 0.05] less frequent in the TIO-R group).

Safety and Adverse Effects

The proportion of patients experiencing an adverse event over the course of the 1-year study was similar in the tiotropium and placebo groups, and no differences among the TIO-R, TIO-PR, and placebo groups were noted. The only adverse event that differed significantly between the tiotropium and placebo treatment groups, irrespective of responder status, was dry mouth, which occurred in 16% of TIO-R patients, 16% of TIO-PR patients, and 2.7% of placebo patients. Dry mouth was mild in the majority of patients who experienced this side effect, and < 1% of subjects withdrew from the study because of this event.

The assessment of the short-term response to inhaled short-acting bronchodilators has formed part of the culture of lung function testing in obstructive lung disease for some time as a putative means of distinguishing the diagnosis of asthma from that of COPD or other obstructive lung diseases and also as a guide to pharmacotherapy. The premise has been that the airflow obstruction in asthma patients is reversible, while that in COPD is irreversible. However, as additional data have become available, it has become increasingly clear that the notion that the airflow limitation observed in COPD patients is irreversible is not accurate.48 In addition to the use of reversibility testing, overreliance on any measure derived from spirometry is likely to result in an inadequate evaluation when used as the sole criterion for assessing the nature or severity of obstructive disease or responses to interventions. In the management of COPD, therefore, consideration should be given to the assessment of other outcome measures, including breathlessness and HRQOL.910 Furthermore, decisions regarding maintenance pharmacotherapy should be made only after a sufficient course of treatment to evaluate the potential impact not only on lung function, but also on symptoms of breathlessness, on limitations in daily activities, and on health status.

In the present analysis, treatment with tiotropium, a once-daily inhaled anticholinergic agent that has its effect through prolonged M3 receptor antagonism, or placebo (added to usual care with the exclusion of long-acting β-agonists and short-acting anticholinergic bronchodilators) was evaluated in 846 patients with COPD.11 For the purpose of the present analysis, patients were retrospectively categorized as bronchodilator responders or poor responders based on American Thoracic Society criteria for a significant improvement in airflow limitation (ie, change in FEV1 of ≥ 12% and ≥ 200 mL),18 following the first dose of tiotropium. Patients who met or exceeded these criteria were classified as responders, and the remainder were classified as poor responders. Bronchodilator responsiveness was observed in approximately 51% of patients following their first dose of tiotropium. After 1 year of daily administration of the study drug, patients who had received tiotropium demonstrated improved FEV1 and FVC values compared to those who had received placebo, irrespective of their first-dose FEV1 response or lack of response to tiotropium, although the improvements observed in the poorly responsive patient population were generally less than those seen in the responsive group. Moreover, patients who were characterized as being either responsive or poorly responsive on first-dose treatment with tiotropium demonstrated significant improvements in dyspnea (as measured by the TDI), the need for rescue bronchodilator use, and health status (as assessed by the SGRQ) compared with those receiving placebo.

A significantly reduced percentage of patients with exacerbations and associated hospitalizations as well as number of exacerbations and associated hospitalizations was observed in the TIO-R group compared to the placebo group, but not in the TIO-PR group compared to the placebo group. However, there was no significant difference between the TIO-R and TIO-PR groups (except for the number of exacerbations). Thus, since the values of the TIO-R group were significantly different from those of the placebo group, but not from those of TIO-PR group, the data are not inconsistent with a possible modest benefit in the TIO-PR group over the placebo group in exacerbation rate and hospitalizations, which cannot be shown statistically with the number of patients studied.

Several methodological issues arise from a close scrutiny of the short-term bronchodilator test. Published studies4,1923 evaluating the reliability and utility of the short-term bronchodilator response in differentiating patients with COPD from those with asthma have suggested that the test does not reliably distinguish asthma from COPD. In addition, the class of bronchodilator used to determine the short-term bronchodilator response may have had an influence on the ability to characterize the airflow limitation in patients with COPD. The bronchodilator most commonly used for reversibility testing is a short-acting β-agonist. Rodriguez-Carballeira et al24 observed that in COPD patients whose airflow obstruction had previously tested as being irreversible after using the inhaled β-agonist terbutaline, their airflow obstruction became reversible in response to the anticholinergic agent ipratropium. Nisar and colleagues7 found that approximately one third of patients with moderately severe-to-severe COPD (ie, mean FEV1, 32 to 40% of predicted) responded significantly to both albuterol and ipratropium, one third of patients responded to one but not the other, and the remaining one third of patients responded to neither. Despite these and other observations of class-selective, short-term bronchodilator responsiveness, low-dose, short-acting β-agonists remain the agents of choice for reversibility testing due to their rapid onset of action.,25 New treatment paradigms are beginning to emerge, however, that require clinicians to recognize that an absent or diminished response to one agent does not preclude a favorable response to another class of bronchodilators.1,26

Some investigators also have evaluated the reproducibility of the bronchodilator test, which has implications for interpreting results in the clinical setting.2021 In a trial evaluating the reproducibility of the bronchodilator test over three years, Anthonisen and Wright20 noted that the interindividual and intraindividual variability in short-term FEV1 responses to isoproterenol was considerable and was difficult to separate from random variations of FEV1 data. Approximately 50% of patients responded significantly on any occasion, but cumulatively > 80% were responders after three separate challenges. It should be noted that in the present analysis we were unable to evaluate potential intraindividual variations in the bronchodilator test due to the significant improvements in the predose FEV1 arising from the prolonged bronchodilator activity with tiotropium. Nevertheless, the results indicate that significant improvements can be achieved over the course of 1 year with tiotropium therapy, irrespective of the ability to demonstrate a predefined short-term response following the first dose of medication. A correlation was observed between the short-term bronchodilator response and the final spirometric results. However, the correlation with dyspnea and health status was minor, suggesting that the initial lung function response is somewhat predictive of the magnitude of lung function improvements observed but is not predictive of more patient-focused outcomes.

Numerous studies have documented appreciable long-term improvement in lung function with bronchodilator therapy in COPD patients who were not specifically selected based on standard reversibility criteria.4,11,2728 For example, Rennard et al4 observed that patients were able to benefit from the long-term use of salmeterol or ipratropium, independent of their short-term responsiveness to a short-acting β-agonist agent. ZuWallack et al29 demonstrated that both responders and nonresponders to a short-acting β-agonist who were subsequently treated with a long-acting β-agonist (salmeterol) alone, theophylline alone, or the combination of both agents achieved significant lung function improvement during 12 weeks of treatment with salmeterol alone compared to the theophylline-only treatment group. The data from the present analysis support and extend the findings from these studies by demonstrating that patients who were poorly responsive to the first dose of a long-acting anticholinergic bronchodilator (ie, peak improvement of ≤ 12% and ≤ 200 mL from baseline FEV1) still benefited from long-term treatment with the same anticholinergic bronchodilator compared to patients treated with placebo. Moreover, these benefits included not only a sustained improvement in lung function (increases in both peak and trough FEV1 and FVC), but also a significant and persistent improvement in other health outcomes, including dyspnea, the need for rescue bronchodilator use, and HRQOL. Objective measurements of health outcomes such as dyspnea have been shown to be only weakly correlated with changes in FEV1,30 implying that they reflect physiologic changes that may not be captured by standard measures of lung function and are thus complementary to spirometry. It is noteworthy, therefore, that the poor-responder group showed long-term favorable responses in these other health outcomes, in addition to spirometric improvement.

In summary, the present retrospective analysis has demonstrated that treatment with tiotropium, 18 μg once daily, is associated with improved dyspnea, improved bronchodilation, reduced use of rescue medications, and improvements in the health status of COPD patients compared with COPD patients who were treated with placebo. These improvements occurred over the time period of 1 year and were achieved irrespective of the patient’s first-dose bronchodilator reversibility profile. Patients with and without a first-dose short-term improvement in FEV1 of at least 12% and 200 mL benefited from maintenance treatment with tiotropium with clinically meaningful and statistically significant improvements in lung function, dyspnea, and health status compared to those receiving treatment with placebo. We conclude that the bronchodilator reversibility test does not accurately predict whether benefits may be achieved with maintenance bronchodilator therapy and therefore should not be used to guide decisions about whether to prescribe a bronchodilator to COPD patients.

Abbreviations: BDI = baseline dyspnea index; HRQOL = health-related quality of life; SGRQ = St. George Respiratory Questionnaire; TDI = transition dyspnea index; TIO-PR = poorly responsive to tiotropium; TIO-R = responsive to tiotropium

Dr. Tashkin is a consultant for Boehringer Ingelheim, and Dr. Kesten is an employee of Boehringer Ingelheim.

This research was supported by Boehringer Ingelheim Pharmaceuticals, Inc.

Table Graphic Jump Location
Table 1. Demographic and Baseline Characteristics of the TIO-R, TIO-PR, and Placebo Groups*
* 

Values given as mean ± SD, unless otherwise indicated.

 

p < 0.05 (TIO-R vs two other groups).

 

Using the criteria of Morris et al.15

§ 

p < 0.05 (TIO-R vs TIO-PR groups).

Table Graphic Jump Location
Table 2. Baseline Pulmonary Medication in the TIO-R, TIO-PR, and Placebo Groups
Figure Jump LinkFigure 1. Mean FEV1 before and after treatment with tiotropium on days 1 (top), 8 (middle), and 344 (bottom) of the study. For all time points following drug administration, tiotropium significantly (p < 0.001) improved lung function in both the TIO-R and TIO-PR groups compared to the placebo group.Grahic Jump Location
Table Graphic Jump Location
Table 3. Lung Function Changes From Baseline at the End of the Trial*
* 

Values given as mean ± SD.

 

p < 0.001 (vs placebo group).

 

p < 0.001 (vs TIO-PR group).

§ 

p < 0.01 (vs placebo group).

Figure Jump LinkFigure 2. Mean FVC before and after treatment with tiotropium on days 1 (top), 8 (middle), and 344 (bottom) of the study. For all time points following drug administration, tiotropium significantly (p < 0.001) improved lung function in both the TIO-R group (top) and TIO-PR group (middle) compared to the placebo group.Grahic Jump Location
Table Graphic Jump Location
Table 4. Health Outcome Changes From Baseline at the End of the Trial*
* 

Values given as mean ± SD or %.

 

p < 0.001 (vs placebo group).

 

p < 0.05 (vs TIO-PR group).

§ 

p < 0.05 (vs placebo group).

Table Graphic Jump Location
Table 5. COPD Exacerbations and Associated Hospitalizations in the TIO-R, TIO-PR, and Placebo Groups
* 

p < 0.01 (vs placebo group).

 

p < 0.05 (TIO-R vs TIO-PR group).

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American Thoracic Society.. Lung function testing: selection of reference values and interpretative strategies.Am Rev Respir Dis1991;144,1202-1218. [PubMed]
 
Fujimoto, K, Kubo, K, Yamamoto, H, et al Eosinophilic inflammation in the airway is related to glucocorticoid reversibility in patients with pulmonary emphysema.Chest1999;115,697-702. [PubMed]
 
Anthonisen, NR, Wright, EC Bronchodilator response in chronic obstructive pulmonary disease.Am Rev Respir Dis1986;133,814-819. [PubMed]
 
Dompeling, E, van Schayck, CP, Molema, J, et al A comparison of six different ways of expressing the bronchodilating response in asthma and COPD: reproducibility and dependence of prebronchodilator FEV1.Eur Respir J1992;5,975-981. [PubMed]
 
Kesten, S, Rebuck, AS Is the short-term response to inhaled beta-adrenergic agonist sensitive or specific for distinguishing between asthma and COPD?Chest1994;105,1042-1045. [PubMed]
 
Ulrik, CS, Backer, V Nonreversible airflow obstruction in life-long nonsmokers with moderate to severe asthma.Eur Respir J1999;14,892-896. [PubMed]
 
Rodriguez-Carballeira, M, Heredia, JL, Gomez, L, et al Contribution of ipratropium bromide to the bronchodilator test in patients with chronic obstructive pulmonary disease.Pulm Pharmacol Ther1999;12,43-48. [PubMed]
 
Clark, TJ Definition of asthma for clinical trials.Br J Dis Chest1977;71,225-227. [PubMed]
 
Ferguson, GT, Enright, PL, Buist, AS, et al Office spirometry for lung health assessment in adults: a consensus statement from the National Lung Health Education Program.Chest2000;117,1146-1161. [PubMed]
 
Vincken, W, van Noord, JA, Greefhorst, APM, et al Improved health outcomes in patients with COPD during one year treatment with tiotropium.Eur Respir J2002;19,209-216. [PubMed]
 
COMBIVENT Inhalation Aerosol Study Group.. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial.Chest1994;105,1411-1419. [PubMed]
 
ZuWallack, RL, Mahler, DA, Reilly, D, et al Salmeterol plus theophylline combination therapy in the treatment of COPD.Chest2001;119,1661-1670. [PubMed]
 
Mahler, DA, Harver, A Clinical measurement of dyspnea. Mt.1990,75-126 Futura Publishing Co. Kisco, NY:
 

Figures

Figure Jump LinkFigure 1. Mean FEV1 before and after treatment with tiotropium on days 1 (top), 8 (middle), and 344 (bottom) of the study. For all time points following drug administration, tiotropium significantly (p < 0.001) improved lung function in both the TIO-R and TIO-PR groups compared to the placebo group.Grahic Jump Location
Figure Jump LinkFigure 2. Mean FVC before and after treatment with tiotropium on days 1 (top), 8 (middle), and 344 (bottom) of the study. For all time points following drug administration, tiotropium significantly (p < 0.001) improved lung function in both the TIO-R group (top) and TIO-PR group (middle) compared to the placebo group.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Demographic and Baseline Characteristics of the TIO-R, TIO-PR, and Placebo Groups*
* 

Values given as mean ± SD, unless otherwise indicated.

 

p < 0.05 (TIO-R vs two other groups).

 

Using the criteria of Morris et al.15

§ 

p < 0.05 (TIO-R vs TIO-PR groups).

Table Graphic Jump Location
Table 2. Baseline Pulmonary Medication in the TIO-R, TIO-PR, and Placebo Groups
Table Graphic Jump Location
Table 3. Lung Function Changes From Baseline at the End of the Trial*
* 

Values given as mean ± SD.

 

p < 0.001 (vs placebo group).

 

p < 0.001 (vs TIO-PR group).

§ 

p < 0.01 (vs placebo group).

Table Graphic Jump Location
Table 4. Health Outcome Changes From Baseline at the End of the Trial*
* 

Values given as mean ± SD or %.

 

p < 0.001 (vs placebo group).

 

p < 0.05 (vs TIO-PR group).

§ 

p < 0.05 (vs placebo group).

Table Graphic Jump Location
Table 5. COPD Exacerbations and Associated Hospitalizations in the TIO-R, TIO-PR, and Placebo Groups
* 

p < 0.01 (vs placebo group).

 

p < 0.05 (TIO-R vs TIO-PR group).

References

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American Thoracic Society.. Standardization of spirometry: 1994 update.Am J Respir Crit Care Med1995;152,1107-1136. [PubMed]
 
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Cazzola, M, Vinciguerra, A, Di Perna, F, et al Early reversibility to salbutamol does not always predict bronchodilation after salmeterol in stable chronic obstructive pulmonary disease.Respir Med1998;92,1012-1016. [PubMed] [CrossRef]
 
Dorinsky, PM, Reisner, C, Ferguson, GT, et al The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD.Chest1999;115,966-971. [PubMed]
 
Nisar, M, Earis, JE, Pearson, MG, et al Acute bronchodilator trials in chronic obstructive pulmonary disease.Am Rev Respir Dis1992;146,555-559. [PubMed]
 
Mahler, DA, Donohue, JF, Barbee, RA, et al Efficacy of salmeterol xinafoate in the treatment of COPD.Chest1999;115,957-965. [PubMed]
 
Siafakas, NM, Vermeire, P, Pride, NB, et al Optimal assessment and management of chronic obstructive pulmonary disease (COPD): European Respiratory Society Task Force.Eur Respir J1995;8,1398-1420. [PubMed]
 
National Institutes of Health... Global Initiative for Chronic Obstructive Lung Disease (GOLD), global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (executive summary). 2001; National Institutes of Health. Bethesda, MD:.
 
Casaburi, R, Mahler, DA, Jones, PA, et al A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.Eur Respir J2002;19,217-224. [PubMed]
 
Littner, MR, Ilowite, JS, Tashkin, DP, et al Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease.Am J Respir Crit Care Med2000;161,1136-1142. [PubMed]
 
Disse, B, Speck, GA, Rominger, KL, et al Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease.Life Sci1999;64,457-464. [PubMed]
 
Chodosh, S, Flanders, JS, Kesten, S, et al Effective delivery of particles with the HandiHaler dry powder inhalation system over a range of chronic obstructive pulmonary disease severity.J Aerosol Med2001;14,309-315. [PubMed]
 
Morris, JF, Koski, A, Temple, WP, et al Fifteen-year interval spirometric evaluation of the Oregon predictive equations.Chest1988;93,123-127. [PubMed]
 
Mahler, DA, Weinberg, DH, Wells, CK, et al The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes.Chest1984;85,751-758. [PubMed]
 
Jones, PW, Quirk, FH, Baveystock, CM, et al A self-complete measure of health status for chronic airflow limitation: the St. George’s respiratory questionnaire.Am Rev Respir Dis1992;145,1321-1327. [PubMed]
 
American Thoracic Society.. Lung function testing: selection of reference values and interpretative strategies.Am Rev Respir Dis1991;144,1202-1218. [PubMed]
 
Fujimoto, K, Kubo, K, Yamamoto, H, et al Eosinophilic inflammation in the airway is related to glucocorticoid reversibility in patients with pulmonary emphysema.Chest1999;115,697-702. [PubMed]
 
Anthonisen, NR, Wright, EC Bronchodilator response in chronic obstructive pulmonary disease.Am Rev Respir Dis1986;133,814-819. [PubMed]
 
Dompeling, E, van Schayck, CP, Molema, J, et al A comparison of six different ways of expressing the bronchodilating response in asthma and COPD: reproducibility and dependence of prebronchodilator FEV1.Eur Respir J1992;5,975-981. [PubMed]
 
Kesten, S, Rebuck, AS Is the short-term response to inhaled beta-adrenergic agonist sensitive or specific for distinguishing between asthma and COPD?Chest1994;105,1042-1045. [PubMed]
 
Ulrik, CS, Backer, V Nonreversible airflow obstruction in life-long nonsmokers with moderate to severe asthma.Eur Respir J1999;14,892-896. [PubMed]
 
Rodriguez-Carballeira, M, Heredia, JL, Gomez, L, et al Contribution of ipratropium bromide to the bronchodilator test in patients with chronic obstructive pulmonary disease.Pulm Pharmacol Ther1999;12,43-48. [PubMed]
 
Clark, TJ Definition of asthma for clinical trials.Br J Dis Chest1977;71,225-227. [PubMed]
 
Ferguson, GT, Enright, PL, Buist, AS, et al Office spirometry for lung health assessment in adults: a consensus statement from the National Lung Health Education Program.Chest2000;117,1146-1161. [PubMed]
 
Vincken, W, van Noord, JA, Greefhorst, APM, et al Improved health outcomes in patients with COPD during one year treatment with tiotropium.Eur Respir J2002;19,209-216. [PubMed]
 
COMBIVENT Inhalation Aerosol Study Group.. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial.Chest1994;105,1411-1419. [PubMed]
 
ZuWallack, RL, Mahler, DA, Reilly, D, et al Salmeterol plus theophylline combination therapy in the treatment of COPD.Chest2001;119,1661-1670. [PubMed]
 
Mahler, DA, Harver, A Clinical measurement of dyspnea. Mt.1990,75-126 Futura Publishing Co. Kisco, NY:
 
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