The Effect of Tiotropium on Hyperinflation and Exercise Capacity in Chronic Obstructive Pulmonary DiseaseVerkindre C.a · Bart F.a · Aguilaniu B.b · Fortin F.c · Guérin J.-C.d · Le Merre C.e · Iacono P.f · Huchon G.g
aCentre Hospitalier Germon et Gauthier, Béthune, bHYLAB Laboratoire de Physiologie Clinique, Grenoble, cCLEFAR, Clinique de la Louvière, Lille, dHôpital Croix Rousse, Lyon, eCHR, Service de Pneumologie, Médecine Interne A, Nîmes, fBoehringer Ingelheim France, Reims, et gPneumologie et Réanimation Hôtel-Dieu, Paris, France Corresponding Author
Background: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, which results in the progressive development of dyspnea and exercise limitation. Objective and Methods: To compare the effect of tiotropium with placebo on forced vital capacity (FVC) in patients with moderate-to-severe COPD and lung hyperinflation, using exercise endurance, dyspnea and health-related quality of life (HRQoL) as secondary endpoints. One hundred patients were randomized to receive either tiotropium 18 μg once daily or placebo for 12 weeks. Results: Trough (predose) FVC was significantly improved with tiotropium compared to placebo on day 42 (0.27 ± 0.08 liters) and 84 (0.20 ± 0.08 liters; p < 0.05 for both). Trough inspiratory capacity (IC) was also significantly improved with tiotropium compared to placebo on day 42 (0.16 ± 0.07 liters) and 84 (0.15 ± 0.07 liters; p < 0.05 for both). Tiotropium increased the mean distance walked during the shuttle walking test by 33 ± 12 (day 42) and 36 ± 14 m (day 84) compared to placebo (p < 0.05 for both). On day 84, 59% of the patients in the tiotropium group and 35% of the patients in the placebo group had significant and clinically meaningful improvements in the St. George’s Respiratory Questionnaire total score (p < 0.05). Numerical decreases in the focal score in the Transition Dyspnea Index in patients receiving tiotropium versus placebo suggest that tiotropium also improved dyspnea during activities of daily living. Conclusion: Tiotropium 18 μg once daily reduced hyperinflation with consequent improvements in walking distance and HRQoL in patients with COPD and lung hyperinflation.
Copyright © 2006 S. Karger AG, Basel
The key characteristic of chronic obstructive pulmonary disease (COPD) is progressive airflow limitation. For the patient, this leads to increased dyspnea, decreased exercise capacity and reduced health-related quality of life (HRQoL) . It has been suggested that dynamic lung hyperinflation resulting from expiratory airflow limitation, rather than airflow limitation per se, is a significant contributor to exertional dyspnea and exercise limitation in COPD [2, 3]. Indeed, there is increasing evidence to suggest that forced expiratory volume in 1 s (FEV1) – the gold standard for assessing bronchodilator responsiveness – is only weakly correlated with patient-centered outcomes, such as dyspnea [4, 5]. Indices of lung hyperinflation, e.g. forced vital capacity (FVC) and inspiratory capacity (IC), may be better predictors of functional improvements than FEV1 [4, 5]. Bronchodilators reduce lung hyperinflation by decreasing the degree of airflow limitation [6,7,8], and so are likely to influence exercise performance.
One of the most important symptoms in COPD is dyspnea. However, the perception of breathlessness varies considerably from patient to patient even when the degree of airflow limitation is similar. Dyspnea is primarily driven by activity, and clinical studies have documented a correlation between the increase in dyspnea and the ventilatory index . Moreover, the relationship between this increase and the perception of dyspnea and exercise has been shown in patients when tested under laboratory conditions. However, these exercise results may not be readily comparable to activities undertaken during daily life.
A variety of exercise-testing protocols are available, which can be categorized as ‘laboratory based’ or ‘field based’. Laboratory-based testing, typified by cycle ergometry, provides the most closely standardized conditions and the greatest amount of information of all the physiological systems involved in exercise. Field-based tests, on the other hand, are frequently used because they require less technological support and, crucially, provide a test of exercise capacity that more closely mimics the patient’s activity in daily life . One commonly used field-based test is the shuttle-walk test (SWT), which may provide a more sensitive test of exercise-induced hypoxia than cycle ergometry [11,12,13]. There have been few publications of large-scale studies describing effects of long-acting bronchodilators on exercise tolerance in COPD. Further, no studies have demonstrated the efficacy of long-acting bronchodilators on field-based tests in exercise tolerance .
Tiotropium (Boehringer Ingelheim, Ingelheim, Germany), a once-daily, long-acting anticholinergic, has been shown in long-term studies to provide sustained improvements in spirometric measurements as well as improvements in dyspnea and health status [15,16,17]. However, lung volume measurements were never assessed as primary endpoints. Tiotropium has also been shown to improve exercise capacity in COPD patients during a constant-load cycle ergometry test .
In this study, we investigated the effects of tiotropium on FVC (an indirect measure of lung hyperinflation) and explored the relationship between changes in lung volumes and dyspnea, HRQoL, and exercise endurance assessed using the SWT.
Patients and Methods
Male and female outpatients aged ≥40 years with at least a 10 pack-year smoking history and moderate-to-severe COPD (FEV1 ≤50% of predicted, and FEV1/slow vital capacity, SVC, ≤70%) , with lung hyperinflation (residual volume, RV, measured using whole-body plethysmography ≥125% of predicted) were eligible for inclusion in the study. RV is a static lung volume that reflects lung hyperinflation .
Exclusion criteria were: a history of asthma, allergic rhinitis or atopy; a blood esinophil count ≥600 cells/mm3; a recent history of myocardial infarction (within the previous year), congestive heart failure (within the previous 3 years), or cardiac arrhythmia requiring drug therapy; recent lower respiratory tract infection; regular use of supplemental oxygen; oral corticosteroid use at unstable doses during the 6 weeks prior to entering the study or at a stable dose exceeding the equivalent of 10 mg prednisone daily.
This study (study code No. 205.215) was a 12-week multicenter, randomized, double-blind, parallel-group comparison of once-daily inhaled tiotropium 18 μg with placebo (fig. 1). The trial was performed at 10 sites in France. Following a screening visit (day –14), eligible patients underwent a 2-week run-in period. On day 1 of the study, patients were randomized 1:1 to receive tiotropium 18 μg once daily or placebo, delivered via the HandiHaler® device (Boehringer Ingelheim) . Assessments were conducted on days 1, 42 and 84, and the study was concluded with a 2-week follow-up period. During the treatment period, patients were permitted oral corticosteroids (at a dose of ≤10 mg/day prednisone or equivalent), inhaled corticosteroids, theophylline preparations, mucolytic agents and salbutamol metered-dose inhaler, as needed, for acute symptom relief. Use of short-acting anticholinergics, oral β2-agonists, or long-acting β2-agonists was not allowed. The study protocol was approved by an ethics committee, and all participants gave written informed consent.
|Fig. 1. Study design.|
The primary endpoint was the change from baseline in trough FVC. Although IC is a better surrogate measure of hyperinflation than FVC, FVC was chosen as the primary endpoint as it is a more reproducible volume measure determined using spirometry. Spirometry was performed at screening, and on study days 1, 42 and 84. FVC, IC and SVC were measured to assess indirectly lung volumes and FEV1 to assess airflow limitation. All spirometric data were recorded 30 min prior to dosing and 2 h after drug administration. Trough response was defined as the predose value at each clinic visit after randomization, i.e. approximately 23–24 h after the previous dose of trial medication. Peak response was defined as the postdose value at each clinic visit after randomization. All spirometric tests were conducted in triplicate and the highest measurements were used in subsequent analyses. To ensure standardized conditions on spirometry test days, salbutamol and short- and long-acting theophylline were stopped at least 12, 24 and 48 h prior to testing, respectively.Predicted normal reference spirometry values from the European Community for Coal and Steel  were used. Each patient also performed daily peak expiratory flow rate (PEFR) measurements (morning and evening) and recorded the highest of three readings on his/her diary card.
Exercise capacity was assessed using the incremental SWT [22, 23], which was conducted at screening and after the postdose spirometry tests (approximately 155 min postdose) at each visit during the treatment period. The course was established on a corridor using marker cones and the speed of walking was dictated by a timed signal played on a cassette recorder. The test was ended if the subject was unable to continue (due to dyspnea or any other reason), or was unable to reach the next marker cone before the timer sounded.
Exertional dyspnea was assessed in each patient immediately before and after the SWT using the modified Borg scale . In addition, dyspnea during activities of daily living was evaluated on day 1 using the baseline dyspnea index (BDI) . Changes from baseline were measured using the transition dyspnea index (TDI) on days 42 and 84 . The BDI and TDI are composed of three domains (functional impairment, magnitude of task and magnitude of effort). For the BDI, each component scale is rated from 0 (severe dyspnea) to 4 (no dyspnea) and the TDI from –3 (major deterioration) to +3 (major improvement). The ratings for each of the three categories of BDI and TDI were added to form baseline (0–12) and transitional focal scores (–9 to +9), respectively. For the transitional focal score, a difference ≥1 unit is considered clinically meaningful .
HRQoL was determined using the St. George’s Respiratory Questionnaire (SGRQ) before treatment on days 1, 42 and 84 of the treatment period . The SGRQ is a 76-item questionnaire, split into three subscores: symptoms, assessing distress due to respiratory symptoms; activity, assessing the effects of breathlessness on mobility and physical activity, and impacts, assessing the psychosocial impact of disease. The SGRQ total score consists of all three subscores. Scores are weighted and range from 0 to 100, with higher scores indicating a poorer HRQoL. A difference ≥4 units is considered clinically meaningful .
Adverse events were monitored throughout the treatment period.
A sample of 98 patients (49 per group) was required to provide 80% power to detect a between-group difference of 0.23 liters in the primary endpoint (FVC) based on a standard deviation of 0.4 liters at a 5% confidence level.
An intent-to-treat method with the last observation carried forward was used for all analyses, except when patients discontinued due to worsening COPD, when the least favorable data prior to discontinuation were carried forward. The difference between the two treatment groups was assessed using an analysis of covariance (ANCOVA) with terms for treatment and study center. The baseline data were used as covariates. Associations between variables were assessed using the Pearson correlation. Statistical significance was considered at p < 0.05. Summary data are expressed as means ± SE unless otherwise stated.
One patient in the tiotropium group was excluded from the intent-to-treat efficacy analysis because of the absence of efficacy data, and 8 patients in the placebo group were not included in the analysis of trough variables because trough lung function was not measured on day 1. Consequently, the number of patients included in the efficacy analysis differs depending on the parameter under consideration.
A total of 100 patients were randomized, with 46 receiving tiotropium and 54 receiving placebo. The two treatment groups were well matched at baseline (table 1).
|Table 1. Patient characteristics at baseline (means ± SD)|
Tiotropium improved trough FVC by 10.7% on day 42 and by 8.0% on day 84 compared with placebo (fig. 2a). Similarly, tiotropium improved peak FVC by 19.3% on day 1, by 18.1% on day 42 and by 18.2% on day 84 compared with placebo (fig. 2b). Hyperinflation was reduced with tiotropium compared with placebo, as indicated by improvements in trough IC of 7.1% on day 42 and 6.8% on day 84 (fig. 3a). Tiotropium also improved peak IC by 12.3% on day 1, by 22.5% on day 42 and by 18.3% on day 84 compared with placebo (fig. 3b). Tiotropium induced an improvement in peak SVC on days 42 and 84 compared with placebo (p <0.05; table 2). In addition, airflow limitation was reduced with tiotropium compared to placebo; trough and peak FEV1 were increased on days 42 and 84 (table 2) and PEFR was higher for both morning (30 ± 14 l/min; p <0.05) and evening (34 ± 14 l/min; p <0.05) measurements on day 84.
|Table 2. Adjusted mean (SE) lung function parameters at trough (predose) and peak (postdose) responses (means adjusted for center effects and baseline)|
|Fig. 2. Mean trough (a, predose) and peak (b, postdose) FVC (2) and IC (3), and SWT (4, conducted postdose). Adjusted means (± 2 SE) are shown (* p <0.05, ** p <0.001 vs. placebo).|
|Fig. 3. Mean trough (a, predose) and peak (b, postdose) FVC (2) and IC (3), and SWT (4, conducted postdose). Adjusted means (± 2 SE) are shown (* p <0.05, ** p <0.001 vs. placebo).|
Tiotropium significantly increased SWT distance by 33 ± 12 m (10.8%) on day 42 and by 36 ± 14 m (11.8%) on day 84 compared with placebo (p < 0.05; fig. 4). There was no significant correlation between improvement in SWT and IC (r = –0.09) or SGRQ total (r = 0.14) and subscores (symptoms r = 0.08, activity r = 0.21, impacts r = 0.08) in the tiotropium group on day 84.
|Fig. 4. Mean trough (a, predose) and peak (b, postdose) FVC (2) and IC (3), and SWT (4, conducted postdose). Adjusted means (± 2 SE) are shown (* p <0.05, ** p <0.001 vs. placebo).|
There was no significant difference between groups in the Borg dyspnea scores after exercise on any study day, suggesting that patients had effectively exercised to exhaustion in the SWT. In the tiotropium group, mean Borg scores at peak exercise were 4.33 ± 0.25 (placebo: 4.45 ± 0.23) on day 1, 4.08 ± 0.27 (placebo: 4.66 ± 0.24) on day 42 and 4.21 ± 0.24 (placebo4.55 ± 0.22) onday 84. At study end, tiotropium improved the transitional focal score by 1.28 ± 0.89 units compared with placebo, however this difference did not achieve statistical significance (table 3). There was a small but significant correlation between transitional focal score and FVC on day 84 (r = 0.23, p < 0.05) but not day 42 (r = 0.03, p = 0.51). There was no correlation between transitional focal score and IC on day 84 (r = 0.03, p = 0.81) or day 42 (r = 0.009, p = 0.92). The use of rescue medication was similar in the tiotropium and placebo groups over the entire treatment period (1.73 ± 0.18 vs. 1.86 ± 0.17 puffs/day, respectively).
|Table 3. Adjusted mean (SE) BDI and TDI focal scores and the change from baseline in the SGRQ scores (means adjusted for center effects and baseline)|
On day 84, the difference in the SGRQ total score between the tiotropium and placebo groups was statistically significant (p <0.05) and clinically meaningful (i.e. ≥4 units; table 3). Further, on day 84, 59% of the patients in the tiotropium group had clinically meaningful improvements in SGRQ total scores compared with 35% of patients in the placebo group (p < 0.05).
One patient (2%) in the tiotropium group and 6 patients (11%) in the placebo group discontinued the trial because of adverse events. No patients in the tiotropium group, and 2 patients (4%) in the placebo group discontinued because of an exacerbation. The only adverse event judged by the investigator to be related to tiotropium was dry mouth, which occurred in 1 patient (2%) in the tiotropium group. However, dry mouth was reported as mild and did not lead to study discontinuation.
COPD is characterized by incomplete, reversible airflow limitation. Physiologically, this progressive airflow limitation is associated with air trapping and hyperinflation. It has been reported that bronchodilators may decrease the degree of hyperinflation measured by increases in thoracic gas volume or reductions in IC . The present study demonstrates that tiotropium, given once daily for 12 weeks, significantly decreases lung hyperinflation measured by FVC, IC and SVC. Airway obstruction also improved with tiotropium, which was demonstrated by significant improvements in FEV1and PEFR. This finding is consistent with other studies that have shown significant improvement in spirometric measurements of airflow limitation with tiotropium [15,16,17]. Treatment with tiotropium also resulted in significantly improved exercise capacity in the SWT. Patient-reported outcomes showed that tiotropium, compared with placebo, provided a measurable improvement in dyspnea (reflected by the TDI score) and a consistent and significant improvement in the health status (measured by the SGRQ total score).
Previous observations from large-scale, long-term studies have indicated that tiotropium 18 μg once daily improves FVC [15, 17, 28]. However, this is the first study to show this effect as a primary outcome. As FVC is an indirect measure of air trapping due to premature small airway closure , the results suggest that tiotropium might mitigate this premature closure and thereby air trapping during a forced expiratory maneuver. These results are in line with those of Celli et al. , who demonstrated a significant effect of tiotropium on IC (measured using plethysmography) as the primary outcome, reflecting a reduction in lung hyperinflation. In the same study, tiotropium reduced trough thoracic gas volume by 0.54 liters, an effect that is similar in magnitude to that reported after lung volume reduction surgery .
Reduced hyperinflation was shown to be the most important factor in explaining the reduction in dyspnea and improvements in exercise capacity that can occur after bronchodilator use [4, 5]. O’Donnell et al. [18 ] have previously demonstrated that, over 6 weeks, tiotropium reduces resting hyperinflation and improves exercise endurance in constant-load cycle ergometry. In this study, we have now shown that tiotropium also provides significant improvements in SWT distance compared with placebo. At study end, tiotropium increased the mean distance walked by 36 m compared with placebo, which could be considered a clinically meaningful improvement . Cycle ergometry and the SWT provide different, but complementary, information. As mentioned previously, the cycle ergometry test is highly standardized and reproducible, and provides extensive physiological data. However, the SWT requires less technological support and may more closely mimic activities undertaken during daily life .
The improvements in exercise capacity can be explained by the increase in airflow and reduction in hyperinflation after tiotropium administration. Although patients in both groups had similar mean end-of-exercise Borg dyspnea scores, patients in the tiotropium group walked further than those in the placebo group before reaching their ventilatory limit. There were improvements in walking distance after the first dose of tiotropium, suggesting an acute effect of improved lung mechanics.
Sustained bronchodilation, with consequent reduction in hyperinflation, would have reduced the degree of dyspnea that the patients experienced during their daily lives . Large-scale trials have shown that tiotropium improves the transitional focal score compared with placebo or ipratropium [15,16,17]. In this study, the improvement in transitional focal scores  with tiotropium did not reach statistical significance as the study was not adequately powered to detect these differences. However, there was a trend towards improvement, and the fact that the difference from placebo exceeded a 1-unit change is compatible with a clinically meaningful reduction in dyspnea during day-to-day activities with tiotropium .
Improvements in dyspnea may allow patients to increase their daily activity levels and so reverse the chronic inactivity and muscle deconditioning that are thought to be important factors in the loss of muscle mass and strength in patients with COPD . Evidence that a training effect might have occurred in this study is provided by the fact that, although the bronchodilator improvements were rapid (from day 1 of treatment), the improvements in exercise capacity took longer to manifest fully. For instance, IC was significantly increased to near maximal levels on day 1, with only a small further increase between day 1 and day 42, whereas exercise capacity was only slightly increased on day 1 but progressively increased to day 42. A recent study by Casaburi et al.  provides further evidence that tiotropium can enhance the exercise training effect. The results of this study showed that tiotropium, in combination with pulmonary rehabilitation, improved endurance in a constant work rate treadmill task and that these improvements were sustained for 3 months following pulmonary rehabilitation completion.
Ultimately, an important goal of treatment in COPD is to improve patients’ HRQoL. There was a significant improvement in SGRQ total scores, showing that tiotropium improved the patients’ overall HRQoL. It is noteworthy that SGRQ activity scores, an assessment of the disturbance of physical activities and mobility caused by dyspnea, were improved in the tiotropium group.
In contrast to previous studies [4, 5, 18], we did not find a significant correlation between dyspnea or exercise capacity and changes in IC. This may simply be because the study was not powered to investigate such differences, or it may be due to methodological differences. For instance, exercise capacity was assessed using an incremental test in this study as opposed to constant-load cycle ergometry, which was used in the previous studies. Further, we measured IC at rest, rather than at isotime (i.e. after a standardized period of exercise). Although IC at rest is strongly correlated with exertional dyspnea in cycle ergometry , IC at isotime is a more powerful predictor of exertional dyspnea . To our knowledge, no other study has examined the spirometric correlates of exercise performance on the SWT, hence our results require confirmation in a study designed to investigate this further.
In conclusion, this study found that, compared with placebo, administration of tiotropium 18 μg once daily for 12 weeks improved airflow, reduced lung hyperinflation, and increased exercise capacity with concomitant benefits in HRQoL. The improvements in exercise capacity are likely to be a direct consequence of reduced hyperinflation, possibly reinforced by increased patient activity during daily life. Previous long-term studies have demonstrated that tiotropium significantly improves airflow compared with shorter-acting agents, such as ipratropium  and salmeterol [16, 28]. If, as we hypothesize, a sustained reduction in hyperinflation can augment a training effect mediated through increased activities of daily living, it is possible that tiotropium may provide greater improvements in exercise capacity than shorter-acting bronchodilators. This hypothesis requires testing in comparative trials.
This study was supported by Boehringer Ingelheim and Pfizer.
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Lead Investigators and Participating Centers: B. Aguilaniu, UCPX, Laboratoire de Physiopathologie de l’Exercice, Grenoble; F. Bart, Centre Hospitalier Germon et Gauthier, Béthune; D. Caillaud, CHU, Hôpital Gabriel Montpied, Service de Pneumologie, Clermont- Ferrand; F. Fortin, CLEFAR, Clinique de la Louvière, Lille; H. Guenard, Centre François Magendi, Hôpital de Haut Lévêque, Pessac; J.-C. Guérin, Hôpital Croix Rousse, Lyon; C. Le Merre, CHR, Hôpital Gaston Doumergue, Service de Pneumologie, Médecine Interne A, Nîmes; G. Huchon, Pneumologie et Réanimation Hôtel-Dieu, Paris; J.F. Muir, Centre Hospitalier, Bois Guillaume; B. Wallaert, Hôpital A. Calmette, Département de Pneumologie et Immuno-Allergologie, Lille, France.
Received: January 27, 2005
Accepted after revision: July 20, 2005
Published online: November 7, 2005
Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 3, Number of References : 34
Respiration (International Journal of Thoracic Medicine)
Vol. 73, No. 4, Year 2006 (Cover Date: June 2006)
Journal Editor: Bolliger, C.T. (Cape Town)
ISSN: 0025–7931 (print), 1423–0356 (Online)
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