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* 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{at}mednet ucla.edu
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Abstract |
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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.
Key Words: COPD • dyspnea • exacerbations • quality of life • spirometry • tiotropium
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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65% predicted and an FEV1/FVC ratio of < 70%. The use of long-acting ß2-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 ß-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.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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).
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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).
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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).
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Discussion |
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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 ß-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 19 20 21 22 23 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 ß-agonist. Rodriguez-Carballeira et al24 observed that in COPD patients whose airflow obstruction had previously tested as being irreversible after using the inhaled ß-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 ß-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.20 21 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
27
28
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 ß-agonist agent. ZuWallack et al29
demonstrated that both responders and nonresponders to a short-acting ß-agonist who were subsequently treated with a long-acting ß-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.
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Footnotes |
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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.
Received for publication July 19, 2002. Accepted for publication October 15, 2002.
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