Effects of Tiotropium on Hyperinflation and Treadmill Exercise Tolerance in Mild to Moderate Chronic Obstructive Pulmonary Disease

Transcription

1 Effects of Tiotropium on Hyperinflation and Treadmill Exercise Tolerance in Mild to Moderate Chronic Obstructive Pulmonary Disease Richard Casaburi 1, François Maltais 2, Janos Porszasz 1, Frank Albers 3, Qiqi Deng 3, Ahmar Iqbal 4, Heather A. Paden 3, and Denis E. O Donnell 5 ; on behalf of the Investigators 1 Rehabilitation Clinical Trials Center, Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center, Torrance, California; 2 Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Canada; 3 Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut; 4 Pfizer Inc., New York, New York; and 5 Queen s University and Kingston General Hospital, Kingston, Ontario, Canada Abstract Rationale: Bronchodilator therapy represents a potentially valuable therapeutic option to increase exercise tolerance and enhance lung function in mild to moderate chronic obstructive pulmonary disease (COPD). Objectives: To determine effects of tiotropium on pulmonary hyperinflation and exercise tolerance in patients with symptomatic Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 and 2 COPD who experienced inspiratory capacity decrease greater than or equal to 100 ml during incremental and constant work rate treadmill exercise. Methods: This 22-week, randomized, double-blind, two-period crossover study evaluated the efficacy of once-daily tiotropium bromide (18 mg) versus placebo in patients with GOLD 1 and 2 COPD. Primary endpoint was between-group (tiotropium vs. placebo) difference in inspiratory capacity at isotime (i.e., at the time the shortest test ended) during constant work rate treadmill exercise from baseline to the end of a 6-week treatment period. Key secondary endpoints included differences in exercise duration and exertional dyspnea. Safety was assessed by recording adverse events. Measurements and Main Results: Study population comprised 48 patients with GOLD 1 COPD and 78 patients with GOLD 2 COPD. Resting inspiratory capacity significantly improved with tiotropium versus placebo in the overall (P, ), GOLD 1 (P = ), and GOLD 2(P, ) groups. Isotime inspiratory capacity was significantly enhanced during exercise in the overall (P = ) and GOLD 2 (P = ) groups after tiotropium versus placebo. Tiotropium versus placebo significantly enhanced exercise duration in the GOLD 2 group (P = ) but not in the GOLD 1 or overall patient groups. In the overall group, increase in exercise duration seen with tiotropium was well correlated with the increase in isotime inspiratory capacity (r = 0.463,P, ). Conclusions: Resting and exercise hyperinflation were ameliorated by bronchodilator therapy with tiotropium in the overall GOLD 1 plus 2 COPD group. Exercise tolerance was enhanced in GOLD 2, but not GOLD 1, COPD. Clinical trial registered with (NCT ). Keywords: chronic obstructive pulmonary disease; Global Initiative for Chronic Obstructive Lung Disease; inspiratory capacity; dyspnea; dynamic hyperinflation (Received in original form April 24, 2014; accepted in final form September 20, 2014 ) This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and Pfizer Inc. Writing and editorial support, and formatting assistance was provided by Radhika Bhatia, Ph.D., C.M.P.P. and Jane M. Gilbert, B.Sc., C.M.P.P. of Envision Scientific Solutions, which was contracted, and compensated by BIPI and Pfizer Inc for these services. The funders provided support in the form of salaries for authors F.A., Q.D., A.I., and H.A.P., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the Author Contributions section. Author Contributions: R.C. was the study coordinating investigator, contributed to study design, acquired and interpreted data, and was responsible for manuscript concept, drafting, and revisions. F.M. and D.E.O. acquired and interpreted data and contributed to and reviewed drafts of the manuscript. J.P. participated in study design, acquired and interpreted data, and contributed to and reviewed drafts of the manuscript. F.A. contributed to preparation and design of the study, interpreted data, and contributed to and reviewed drafts of the manuscript. Q.D. contributed to data analysis and contributed to and reviewed drafts of the manuscript. A.I. interpreted data and contributed to and reviewed drafts of the manuscript. H.A.P., as study clinical monitor, participated in study design, interpreted data, and contributed to and reviewed drafts of the manuscript. All authors approved the final manuscript. Correspondence and requests for reprints should be addressed to Richard Casaburi, Ph.D., M.D., Rehabilitation Clinical Trials Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA casaburi@ucla.edu Current address for F.A. and A.I. is GlaxoSmithKline, Five Moore Drive (5.3317), Research Triangle Park, NC This article has an online supplement, which is accessible from this issue s table of contents at Ann Am Thorac Soc Vol 11, No 9, pp , Nov 2014 Copyright 2014 by the American Thoracic Society Originally Published in Press as DOI: /AnnalsATS OC on October 7, 2014 Internet address: Casaburi, Maltais, Porszasz, et al.: Tiotropium and Exercise in Mild to Moderate COPD 1351

2 Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and disability worldwide, and the World Health Organization predicts that it will become the third leading cause of global mortality by 2030 (1). COPD is characterized by progressive airflow obstruction that is not fully reversible (2). Severity of airflow obstruction in COPD is generally classified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, based on spirometric classification of airflow limitation using post-bronchodilator FEV 1 and FVC. Under the 2014 GOLD guidelines, mild airflow limitation (GOLD 1) is defined as FEV 1 / FVC less than 0.7 and FEV 1 greater than or equal to 80% of predicted normal, and moderate airflow limitation (GOLD 2) is defined as FEV 1 /FVC less than 0.7 and FEV 1 greater than or equal to 50% and less than 80% predicted normal (2).* As a consequence of airflow obstruction, patients with COPD exhibit physiological abnormalities during exercise (3); for example, during cycle ergometry these patients develop dynamic hyperinflation (4), which is defined as a progressive increase in end-expiratory lung volume that returns to resting value after exercise cessation. Dynamic hyperinflation along with substantial impairments in breathing dynamics and exercise tolerance in patients with GOLD 1 and 2 COPD compared with healthy control subjects have been reported (4, 5). Exercise tolerance is increasingly compromised with disease progression (6, 7). Compared with healthy individuals, patients with COPD display a significant restriction of small conducting airways due to bronchoconstriction or mucus and, consequently, an increase in peripheral airway resistance (8). These changes are associated with symptoms that are magnified during exercise (4). Intensification of COPD symptoms by physical activity can lead to exercise avoidance and inactivity, further contributing to overall disability and mortality (9). Interestingly, those patients with COPD with greater physical activity have been found to have a reduced rate of lung function decline (10). Furthermore, *The GOLD guidelines (2) issued in January 2014 include other disease staging measures in addition to spirometry; this clinical trial was conducted before this modification. physical inactivity has been found to be a strong independent predictor of both disease exacerbations and mortality (11, 12). Thus, measures to improve exercise tolerance represent a valuable COPD therapeutic management option. Tiotropium, an anticholinergic approved for COPD management, has been associated with significant improvement in exercise tolerance in patients with GOLD 2 to 4 COPD (13 15) related to reductions in both resting and exercise hyperinflation. However, in these studies, only patients with FEV 1 less than or equal to 65% (13, 15) or less than or equal to 50% (14) predicted were included, thus probably excluding patients with GOLD 1 COPD and limiting participation for those at the less severe end of GOLD 2 COPD. The current study aimed to determine effects of tiotropium on pulmonary hyperinflation and symptom-limited exercise in symptomatic patients with GOLD 1 and 2 COPD who experienced dynamic hyperinflation during exercise. Change in constant work rate (CWR) exercise duration was chosen as a measure of change in exercise tolerance. The study had two phases: a Characterization Phase and a Treatment Phase. This article presents data from the Treatment Phase (ClinicalTrials.gov identifier: NCT ). Some results from this study have been reported previously in the form of abstracts (16, 17). Characterization Phase 1 week R Treatment period 1 Methods For additional detail, see the online supplement. Study Design This 22-week, multicenter (11 U.S. and four Canada sites), randomized, double-blind, twoperiod, crossover study (Figure 1) evaluated effects of once-daily tiotropium bromide versus placebo on dynamic hyperinflation and exercise tolerance in patients with symptomatic GOLD 1 and 2 COPD. Patients completing a 2-week Characterization Phase and fulfilling inclusion/exclusion criteria entered the Treatment Phase and were randomized 1:1 to 6 weeks of 18 mg tiotropium or placebo (oral inhalation capsule daily) administered using a HandiHaler device (Boehringer Ingelheim, Ingelheim, Germany). After 4 weeks washout, patients switched treatments. Patients were followed up for 30 days after completion of the last 6-week period of treatment or, in case of discontinuation, after the final dose of study medication. Study Participants Participants were either sex, aged 40 years or older, body mass index 18 to 35 kg/m 2, current or ex-smokers (history > 10 packyears). Patients were symptomatic, defined by baseline dyspnea index focal score less than or equal to 9 (18) and/or daily cough with sputum production. Other inclusion criteria included post-bronchodilator FEV 1 /FVC less Treatment Phase Washout Treatment period 2 Follow-up Phase 1 week 6 weeks 4 weeks 6 weeks 30 days Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 R Incremental Constant work rate Randomization Figure 1. Schematic of the study design. Treatment group 1: tiotropium placebo Treatment group 2: placebo tiotropium 1352 AnnalsATS Volume 11 Number 9 November 2014

3 than 70% and FEV 1 greater than or equal to 50% predicted. Medication for 6 months preceding and throughout the study was recorded. Albuterol was used as rescue medication. Patients gave written informed consent. Pulmonary Function Testing Before ing, spirometry was performed before study drug administration at Visits 3 to 6 and also after study drug administration at Visits 4 and 6. Predicted normal FEV 1 values were calculated (19). variables. The primary analysis, performed on the full analysis set, used a mixed-effect model for change from baseline to after 6 weeks treatment, with terms of treatment and period as fixed effects, period baseline and average of two period baselines as covariates, and subject as a random effect; results are expressed as adjusted mean 6 SE. P, 0.05 was considered statistically significant. Results Baseline Demographics and Characteristics Participants were enrolled into the study between March 16, 2010 and August 1, 2011; the first patient entered the Treatment Phase on April 14, 2010, and the last completed on November 29, Disposition of study subjects is shown in Figure 2. In total, 277 patients were assessed for study eligibility, Exercise Tests Incremental treadmill ing (IET) was conducted using a linearized protocol (20) at Visit 1. Ventilation and gas exchange were measured breath by breath. Dyspnea and leg discomfort scores were elicited and inspiratory capacity (IC) maneuvers performed every 2 minutes during exercise. Speed and inclination were determined for the CWR test to yield work rate equivalent to 80%peakworkrateintheIET.Apractice CWRtestwasperformedatVisit2toassure exercise duration of 4 to 10 minutes; if outside this range, adjustments were made at Visit 3. Patients not meeting exercise duration of 4 to 10 minutes after a second adjustment at Visit 3 were excluded. Subjects not demonstrating IC decrease greater than orequalto100mlintwoofthreebaseline tests (Visits 1 3) were excluded. CWR testing was performed before study drug administration on Visits 3 and 5 and after study drug administration on Visits 4 and 6. Key Endpoints Primary endpoint was between-group (tiotropium vs. placebo) difference in isotime IC during CWR from Week 6 of each treatment period relative to corresponding baseline value. Isotime was shortest end-exercise time reached during both post-treatment and corresponding baseline CWR tests. Key secondary endpoints were isotime dyspnea intensity and CWR test exercise duration difference from baseline to Week 6. Safety Adverse events and vital signs were recorded at Visits 1 to 6; physical examinations were performed at Visits 1 and 6. Statistical Analyses Descriptive analysis results are summarized as mean 6 SD or percent for categorical TREATMENT GROUP 1 63 patients allocated to receive tiotropium first 2 patients did not complete the treatment period: 1 adverse event 1 non-compliant with the protocol 1 patient completed the first treatment period but did not enter the second treatment period: 1 worsening of disease under study 60 patients allocated to receive placebo second 3 patients did not complete the treatment period: 1 worsening of disease under study 2 other adverse events 1 patient completed the treatment period, but exercise data not available: 1 other adverse event 277 patients assessed for study eligibility 126 patients randomized for treatment 151 patients excluded from study: 83 did not meet inclusion criteria 42 met exclusion criteria 12 withdrew consent 12 administrative reasons 2 lost to follow-up 63 patients allocated to receive placebo first 58 patients allocated to receive tiotropium second 56 patients data analyzed 55 patients data analyzed Figure 2. Patient disposition. TREATMENT GROUP 2 5 patients did not complete the treatment period: 1 worsening of disease under study 2 non-compliant with the protocol 2 refused to continue medication 1 patient did not complete the treatment period: 1 lost to follow-up 2 patients completed the treatment period, but exercise data not available: 1 other adverse event 1 worsening of disease under study Casaburi, Maltais, Porszasz, et al.: Tiotropium and Exercise in Mild to Moderate COPD 1353

4 of whom 195 met the GOLD 1 and 2 COPD spirometric criteria and performed an IET test. Of the initially screened patients, 55% (151/277) were excluded from the Treatment Phase (Figure 2). In the overall patient population, the proportion of patients who met all inclusion criteria except that of greater than or equal to 100-ml decrease in IC during at least two out of three of the baseline exercises tests was 23% (38/164 patients); this proportion in GOLD 1 was 26% (17/65 patients) and in GOLD 2 was 21% (21/99 patients). In total, 126 patients were randomized to receive either tiotropium first and placebo second (Treatment Group 1; n = 63) or placebo first and tiotropium second (Treatment Group 2; n = 63). Of the randomized patients, 48 patients were classified as having GOLD 1 COPD and 78 were classified as having GOLD 2 COPD. Patient demographics, Characterization Phase pulmonary function, lung volumes, diffusing capacity for carbon monoxide, and baseline incremental exercise tolerance by GOLD spirometric grade are presented in Table 1. At the time of study entry randomization, 9 (7.1%) patients were receiving combination therapy with Table 1. Patient demographics and baseline pulmonary function by Global Initiative for Chronic Obstructive Lung Disease spirometric grade Characteristics GOLD 1 GOLD 2 Total (GOLD 1 1 2) Patients, n Age, yr Male, n (%) 28 (58.3) 37 (47.4) 65 (51.6) Race, n (%) Black 0 (0.0) 12 (15.4) 12 (9.5) White 48 (100.0) 66 (84.6) 114 (90.5) BMI, kg/m Current smoker, n (%) 19 (39.6) 40 (51.3) 59 (46.8) Smoking history, pack-years Medication history at baseline LABA/ICS, n (%) 2 (4.2) 7 (9.0) 9 (7.1) Anticholinergic, n (%) 3 (6.3) 12 (15.4) 15 (11.9) Spirometry FEV 1, L FEV 1, % predicted* FVC, L FEV 1 /FVC, % IC, L IC, % predicted SVC, L RV, L FRC, L TLC, L sr aw, cmh 2 O/L/s x jj DL CO, ml/min/mm Hg jj Baseline exercise responses Incremental Duration, min Peak work rate, W VȮ 2peak, L/min x ** Dyspnea intensity (peak), Borg score x ** Leg discomfort (peak), Borg score x ** Constant work rate test Duration, min Change in IC (rest to end of exercise), L VȮ 2peak, L/min Dyspnea intensity (peak), Borg score Leg discomfort (peak), Borg score Definition of abbreviations: BMI = body mass index; DLCO = diffusing capacity for carbon monoxide; FRC = functional residual capacity; GOLD = Global Initiative for Chronic Obstructive Lung Disease; IC = inspiratory capacity; ICS = inhaled corticosteroid; LABA = long-acting b 2 -agonist; RV = residual volume; sr aw = specific airway resistance; SVC = slow vital capacity; TLC = total lung capacity; VȮ 2peak = peak oxygen uptake. All values are mean 6 SD, except where indicated. *Predicted normal FEV 1 values were calculated using European Community for Steel and Coal Equations (19). IC % predicted = total lung capacity % predicted functional residual capacity % predicted. n = 47. x n = 77. jj n = 124. n = 76. **n = AnnalsATS Volume 11 Number 9 November 2014

5 long-acting b 2 -agonists (LABA) and inhaled corticosteroids, which were continued for the duration of the study, and 15 (11.9%) patients were receiving treatment with anticholinergics, which were discontinued during the baseline period. The full analysis data set comprised 111 patients (Treatment Group 1 [n = 56], Treatment Group 2 [n = 55]) who completed both full courses of tiotropium and placebo treatment and had available CWR test data. Patient demographics, Characterization Phase pulmonary function, and baseline exercise tolerance in the two treatment groups were similar (see Table E1 in the online supplement). For patients in the full analysis set, at the start of each 6-week treatment period (Visits 3 and 5) baseline FEV 1, FVC, and FEV 1 /FVC were similar, indicating that the treatment received in the first treatment period did not affect baseline values for the second treatment period (Table E2). Exercise Tests The CWR treadmill testing was shown to be capable of yielding initial testing durations within a narrow band (mean 6 SD, min) with a mean 6 SD of change in CWR tests in the placebo period of minutes. Numbers of patients requiring repeat s during the baseline period to ensure they would achieve exercise duration of 4 to 10 minutes during the treatment phase are given in the online supplement. IC The primary efficacy endpoint, which is the between-treatment group difference in the change in isotime IC during CWR exercise from baseline to Week 6 of each treatment period, showed significantly greater improvement for tiotropium compared with placebo (mean 6 SE difference, L; P = ) in all patients (Table 2). Secondary subgroup analysis based on GOLD groups showed that only patients with GOLD 2 COPD had statistically significant isotime IC improvements after tiotropium compared with placebo (mean 6 SE difference, L; P = ; Table 2). The mean change in resting IC, measured post dose when patients were ready to walk on the treadmill, showed significantly greater improvement after 6 weeks of tiotropium compared with 6 weeks of placebo in the overall patient group (mean 6 SE difference, L; P, ; Table 2). This effect of tiotropium on resting IC was also seen when the GOLD 1 and GOLD 2 groups were evaluated separately (mean 6 SE difference, L; P = and L; P, , respectively; Table 2). For the overall group and individual GOLD 1 and 2 groups, time courses of the difference from baseline in IC for the tiotropium and placebo periods are shown in Figure 3; the data show that the positive impact of tiotropium on pulmonary hyperinflation is more pronounced early in the exercise bout. CWR Exercise Duration Overall, the difference in change in CWR exercise duration, from baseline to 6 weeks of treatment, between tiotropium and placebo did not achieve statistical significance (Table 3). Subgroup analysis based on GOLD groups showed CWR exercise duration to be significantly improved in patients with GOLD 2 COPD (mean 6 SE difference, s; P, ), while remaining unchanged in patients with GOLD 1 COPD (Table 3). These findings were replicated when natural log transformation of endurance time changes was used to account for the nonnormal distribution of endurance time change (Table 3). For tests in which patients received tiotropium, the Pearson correlation coefficient for the change in exercise duration versus the change in isotime IC from baseline to 6 weeks of treatment was highly statistically significant (r = [P, ]; Figure 4). If tests in which placebo was administered are included (222 pairs of studies), r = (P, ). Dyspnea Intensity and Leg Discomfort No significant differences in change in dyspnea or leg discomfort (assessed using the Borg scale), between tiotropium and placebo periods, were observed either at isotime or at the end of exercise in the overall patient group or in the individual GOLD 1 or 2 COPD groups (Table 4). The correlation between the change in isotime IC and isotime dyspnea rating in tests in which tiotropium was administered was less strong, but statistically significant (r = [P=0.0087]); if the tests in which placebo was administered were included, the correlation weakened but remained statistically significant (r = [P = ]). Table 2. Change in inspiratory capacity after 6 weeks of treatment with tiotropium or placebo at isotime during constant work rate exercise (full analysis set) Variables GOLD Group Patients, n Tiotropium* Placebo* Tiotropium vs. Placebo 95% CI P Value Change in resting IC before exercise, L Isotime change in IC during CWR exercise test, L to 0.175, to to 0.211, to to to Definition of abbreviations: CI = confidence interval; CWR = constant work rate; GOLD = Global Initiative for Chronic Obstructive Lung Disease; IC = inspiratory capacity. *Adjusted mean 6 SE change from baseline. Adjusted treatment difference mean 6 SE change from baseline. Isotime was defined as the shortest end-exercise time that was reached during both the post-treatment and corresponding baseline constant work rate s. Casaburi, Maltais, Porszasz, et al.: Tiotropium and Exercise in Mild to Moderate COPD 1355

6 Change in IC from baseline (L) Change in IC from baseline (L) Change in IC from baseline (L) GOLD 1+2 COPD Rest Rest Zero grade walking GOLD 1 COPD Rest 110 Zero grade walking GOLD 2 COPD 67 Zero grade walking Tiotropium Placebo CWR exercise (minutes) CWR exercise (minutes) CWR exercise (minutes) Figure 3. Time course of the difference from the baseline test in inspiratory capacity (IC) (mean 6 SE) for the tiotropium and placebo periods in patients with Global Initiative for Obstructive Lung Disease (GOLD) 1 and 2 chronic obstructive pulmonary disease (COPD). The last point on each curve represents end-exercise values. Number of patients is given adjacent to each data point. CWR = constant work rate Pulmonary Function and Exercise Ventilatory Variables Overall, differences in change in isotime and peak exercise VĖ, from baseline to 6 weeks of treatment, between tiotropium and placebo showed significant increases (mean 6 SE difference, L/min; P = and L/min; P = , respectively; Table 5). Subgroup analysis showed isotime VĖ to be significantly increased in patients with GOLD 2 COPD (mean 6 SE difference, L/min; P, ) but not in patients with GOLD 1 COPD. Differences in change in peak exercise VĖ in patients with GOLD 1 and GOLD 2 COPD were also significantly increased (mean 6 SE difference, L/min; P = and L/min; P = , respectively). Overall, the difference in change in isotime VT, from baseline to 6 weeks of treatment, between tiotropium and placebo, showed significant increase (mean 6 SE difference, L; P = ), although differences were not significant for the individual GOLD groups (Table 5). No significant differences in change in peak exercise VT or peak and isotime breathing frequency were observed (Table 5). Overall, pre- and post-bronchodilator FEV 1 were significantly improved after 6 weeks of tiotropium but not after placebo (mean 6 SE difference, L; P, and L; P, , respectively; Table 5); significant improvements were also observed in both GOLD groups individually. Because FEV 1 increased (and despite increased endexercise VĖ), end-exercise breathing reserve (calculated as maximum voluntary ventilation [MVV] minus end-exercise ventilation, where MVV is estimated as 35 3 FEV 1 ; see online supplement) significantly increased by L/min (mean 6 SE difference) with tiotropium treatment versus placebo (P, ; Table 5). Overall and in the GOLD 2 group, the difference in change in peak exercise inspiratory reserve volume, from baseline to 6 weeks of treatment, between tiotropium and placebo significantly increased (mean 6 SE difference, L; P = and L; P = , respectively). After 6 weeks of treatment with tiotropium versus placebo, VĖ peak/ MVV significantly decreased in the 1356 AnnalsATS Volume 11 Number 9 November 2014

7 Table 3. Changes in constant work rate exercise duration from 6 weeks of treatment with tiotropium or placebo from the corresponding baseline values (full analysis set) Variables GOLD Group Patients, n Tiotropium* Placebo* Tiotropium vs. Placebo 95% CI P Value Change in CWR Ln-transformed change in CWR Change in CWR Ln-transformed change in CWR Change in CWR Ln-transformed change in CWR to to Definition of abbreviations: CI = confidence interval; CWR = constant work rate; GOLD = Global Initiative for Chronic Obstructive Lung Disease; Ln = natural logarithm. *Adjusted mean 6 SE change from baseline. Adjusted treatment difference mean 6 SE change from baseline. Data were transformed to natural logarithms; this decision was made by examining the data distribution using a histogram before unblinding. overall and GOLD 2 groups (mean 6 SE difference, and , respectively; both P, ; Table 5). Locus of Symptom Limitations The frequency in the locus of symptom limitations after 6 weeks of tiotropium or placebo treatment are shown in Table 6 (full data are provided in Table E3). Breathing discomfort was the most common reason for stopping exercise. Fewer patients reported breathing discomfort and more patients reported leg discomfort as the limiting symptom after tiotropium treatment; a similar shift in symptom limitation was not seen after placebo treatment. Twenty-four (21.6%) patients who experienced respiratory limitation at baseline did not report limitation after tiotropium treatment compared with eight (7.2%) patients after placebo treatment. Safety Endpoints Adverse events were well balanced between the treatment groups: 35 (28.9%) and 37 (30.1%) patients reported adverse events after treatment with tiotropium and placebo, respectively. There were no deaths recorded during the study. Rescue medication use was low and tended to be lower during tiotropium use than during placebo use. The average number of rescue medication uses per patient during the daytime was 0.75/d on placebo and 0.61/d on tiotropium, and at nighttime it was 0.23/d on placebo and 0.20/d on tiotropium. Additional details on safety endpoints are provided in the online supplement. Discussion Although long-acting anticholinergic bronchodilators (LABAs) are recommended Change in endurance time (seconds) r =0.463 y= x P-value for slope < by the 2014 GOLD guidelines (2) for mild COPD (as an alternative to short-acting bronchodilators) and moderate COPD (as preferred therapy), this subject group is, in actuality, both underdiagnosed and undertreated. For example, a recent U.S. survey by Mapel and colleagues (21) found that only about 30% of patients with mild to moderate COPD received maintenance therapy. The aim of our study was to provide further data to inform the use of 95% confidence limits 95% prediction limits Change in isotime IC (L) Figure 4. Correlation between the change in isotime inspiratory capacity (IC) and the change in endurance time (Pearson correlation coefficient and linear regression) for patients treated with tiotropium. Casaburi, Maltais, Porszasz, et al.: Tiotropium and Exercise in Mild to Moderate COPD 1357

8 Table 4. Changes in dyspnea intensity and leg discomfort from baseline to after 6 weeks of treatment with tiotropium or placebo (full analysis set) Variables GOLD Group Patients, n Tiotropium* Placebo* Tiotropium vs. Placebo 95% CI P Value Change in Borg dyspnea intensity to to to End exercise to to to Change in Borg leg discomfort to to to End exercise to to to Definition of abbreviations: CI = confidence interval; CWR = constant work rate; GOLD = Global Initiative for Chronic Obstructive Lung Disease. *Adjusted mean 6 SE change from baseline. Adjusted treatment difference mean 6 SE change from baseline. Isotime was defined as the shortest end-exercise time reached during both post-treatment and corresponding baseline constant work rate tests. anticholinergic bronchodilators in this patient group by examining the benefits of tiotropium on exercise responses in symptomatic patients with COPD with mild to moderate spirometric impairment who exhibited dynamic hyperinflation during baseline treadmill s. This is the largest cohort to date of patients with COPD with mild to moderate airflow limitation in which the mechanisms of benefit of bronchodilator therapy have been explored. The current study showed that maintenance therapy with tiotropium for 6 weeks significantly improved IC at a standardized time during exercise in symptomatic patients with COPD with mild to moderate airflow obstruction, although by a modest amount. This beneficial effect of tiotropium, however, was not found to have any significant impact on exercise duration. Subgroup analysis showed exercise duration was significantly improved in patients with GOLD 2 COPD but not GOLD 1 COPD. Lung function and breathing reserve were substantially improved in patients with GOLD 1 and 2 COPD, although no significant changes in exertional dyspnea ratings were detected. Overall, tiotropium therapy was well tolerated. The study population was composed of individuals with GOLD 1 and GOLD 2 COPD with evidence of dynamic hyperinflation during treadmill exercise. Dynamic hyperinflation was defined as an appreciable decrease of IC in baseline s. Interestingly, among those patients with COPD screened, most displayed a consistent decrease of 100 ml or more in IC, signifying dynamic hyperinflation. It was reasoned that this subgroup would be a good target for bronchodilator therapy based on data showing decreased hyperinflation during exercise with subsequent improvement in exercise tolerance in patients with severe spirometric abnormality (13 15). This study showed tiotropium to be associated with a statistically significant increase in isotime IC in patients with GOLD 2 COPD, indicating reduced pulmonary hyperinflation in this group. Resting IC was also increased in patients with GOLD 1 and 2 COPD. These results are consistent with existing reports of tiotropium efficacy, which have demonstrated sustained reductions in hyperinflation (at rest and during exercise) in patients with moderate to severe (GOLD 2 and GOLD 3) COPD (13 15). In the present study, although patients with GOLD 1 COPD achieved a near identical increase in isotime IC during CWR exercise to that of patients with GOLD 2 COPD, it failed to achieve statistical significance, likely due to the smaller sample size of the GOLD 1 group. This finding is similar to that from a previous study of patients with GOLD 1 COPD evaluating the efficacy of bronchodilator therapy with the short-acting anticholinergic ipratropium bromide, showing that improvement in IC during exertion achieved statistical significance (3). Similar to the gains realized in IC, exercise duration was also improved in patients with GOLD 2 COPD, indicating that tiotropium therapy confers significant benefits on exercise tolerance in these patients. Overall, exercise duration was approximately 60 seconds longer after tiotropium treatment compared with placebo treatment. The amount of improvement in exercise duration was significantly correlated with the improvement in IC, supporting the role of dynamic hyperinflation in mediating exercise limitation. This accords well with earlier studies of tiotropium efficacy, which demonstrated improved exercise tolerance in patients with moderate and more severe forms of COPD (13, 15, 22). The lack of impact on exercise tolerance detected in patients with GOLD 1 COPD is consistent with earlier smaller studies of ipratropium bromide (3) and ipratropium bromide/ salbutamol (23) in patients with GOLD AnnalsATS Volume 11 Number 9 November 2014

9 Table 5. Changes in pulmonary function and exercise ventilatory variables from baseline to after 6 weeks of treatment with tiotropium or placebo (full analysis set) Variables GOLD Group Patients, n Tiotropium* Placebo* Tiotropium vs. Placebo 95% CI P Value Change in FEV 1,L Pre-bronchodilator to 0.165, to to 0.189, Post-bronchodilator to 0.237, to 0.237, to 0.245, Change in VĖ, L/min to to to End exercise to to to Change in F b, breaths/min to to to End exercise to to to Change in VT, L to to to End exercise to to to Change in IRV, L to to to End exercise to to to Change in breathing reserve, x L/min to 6.47, to to 7.99, Change in VĖ max/mvv to , to to , Definition of abbreviations: CI = confidence interval; CWR = constant work rate; F b = breathing frequency; GOLD = Global Initiative for Chronic Obstructive Lung Disease; IRV = inspiratory reserve volume (calculated as inspiratory capacity minus VT); MVV = maximal voluntary ventilation; VĖ = minute ventilation; VT = tidal volume. *Adjusted mean 6 SE change from baseline. Adjusted treatment difference mean 6 SE change from baseline. Isotime was defined as the shortest end-exercise time that was reached during both the post-treatment and corresponding baseline constant work rate. x Breathing reserve was calculated as (35 3 FEV 1 ) maximum exercise minute ventilation. P value indicates whether tiotropium vs. placebo is significantly different from zero. COPD that also failed to detect significant effects on exercise endurance. This may be because the locus of exercise limitation in GOLD 1 COPD may be more related to the muscles of ambulation than to dyspnea, although, in this study, a substantial number of patients subjectively reported dyspnea as their predominant symptom (Table 6). Consistent with previous findings reported in the literature (13, 15, 22), lung function, pre- and post-bronchodilator FEV 1, and breathing reserve were all significantly improved by tiotropium therapy in the current study. However, in contrast with previous studies, exertional dyspnea was not found to be significantly improved, although dyspnea reduction was weakly correlated with IC increase. After Casaburi, Maltais, Porszasz, et al.: Tiotropium and Exercise in Mild to Moderate COPD 1359

10 Table 6. Locus of symptom limitation relative frequency after 6 weeks of tiotropium or placebo treatment (full analysis set) GOLD Group Locus of Symptom Limitation Relative Frequency (%) Placebo Tiotropium (n=111) Leg discomfort Breathing discomfort Both leg and breathing discomfort Neither leg nor breathing discomfort (n=) Leg discomfort Breathing discomfort Both leg and breathing discomfort Neither leg nor breathing discomfort (n=68) Leg discomfort Breathing discomfort Both leg and breathing discomfort Neither leg nor breathing discomfort 3 7 Definition of abbreviation: GOLD = Global Initiative for Chronic Obstructive Lung Disease. tiotropium treatment, the number of patients citing leg discomfort as the reason for stopping exercise increased, whereas there tended to be fewer patients who cited breathing discomfort. This finding suggests that, in a subgroup of patients at least, exertional dyspnea was reduced sufficiently to shift the locus of discomfort from breathing discomfort to leg discomfort. However, there was no detectable impact on Borg score rating of exertional dyspnea in the overall group. A similar trend was observed in cycle ing after tiotropium treatment (15) in patients with more severe disease, although an important observation was that the number of patients experiencing leg discomfort was higher during cycle ing compared with treadmill testing. This shows that the design of CWR testing is key to accurate assessment of exercise tolerance. The current study offers a number of advantages over existing studies of tiotropium efficacy and exercise tolerance. It is the first multicenter clinical study that enrolled patients with GOLD 1 COPD in an exercise study. In general, earlier studies of bronchodilator therapy have suffered from small patient samples and an array of different s, including the 6-minute walk test, 12-minute walk test, shuttle walk test, incremental work test, and CWR test. The present study was undertaken with a relatively large population of patients (sufficiently powered to reveal differences between patient population groups and treatments; see online supplement) and well-characterized patient groups regarding lung function and ventilation. The balance of sex (roughly 50:50) was better in this study compared with previous studies (3, 13, 15). Moreover, a reproducible, standardized methodology was established to ensure precision throughout the study and to permit comparison of the present study with results from future studies. Treadmill walking to assess exercise tolerance was used because it is well tolerated, comfortable, and, importantly, more similar than cycling to activities of daily living in patients with COPD (24, 25). The incremental treadmill protocol allowed a linear increase in work rate to be imposed, calculated on the basis of each individual s weight. Some potential limitations of this study should also be noted. Treadmill exercise testing was chosen for use in this study, rather than the more established cycle ergometer testing, on the theory that treadmill testing might prove more able to detect improvements in exercise tolerance resulting from improvement in pulmonary function. This supposition is based on cross-sectional studies demonstrating that patients with COPD more frequently complain of breathing limitations rather than leg muscle limitations when performing walking tasks compared with cycling tasks. In this study, CWR treadmill testing, anchored by a linearized treadmill protocol, was shown to be capable of yielding initial testing durations within a narrow band (mean 6 SD, min) and featured a mean 6 SD of change in CWR tests in the placebo period of minutes, which is comparable with that seen in cycle testing (26). However, in this group of patients with mild to moderate airflow limitation, improvement in exercise tolerance was modest and did not achieve statistical significance in the GOLD 1 group. Determining whether treadmill CWR tests are more sensitive measures of improvement in endurance exercise tolerance than cycle CWR tests when interventions designed to improve lung function are investigated will require head-to-head study. Also of note is that, although the isotime decrease in IC was highly statistically significant in the overall group (averaging 65 ml), the minimum clinically important difference for this variable has not been established, so the clinical relevance of this improvement in dynamic hyperinflation cannot be determined. The fact that only symptomatic patients with GOLD 1 and GOLD 2 COPD who demonstrated dynamic hyperinflation on initial testing were studied might be seen as limiting the generalizability of the findings; however, 74% of patients with GOLD 1 and 79% of patients with GOLD 2 COPD considered for the study met the selected criterion for dynamic hyperinflation. Of note, a modest number of the study subjects (7.1%) continued their LABA therapy during this intervention. This may have reduced the potential for dynamic hyperinflation reduction in this subgroup. Furthermore, a study to determine whether the combination of LABA and anticholinergic bronchodilators yields enhanced effects on dynamic hyperinflation and exercise tolerance in this study population would be of interest. Conclusions In summary, this study showed that dynamic hyperinflation during exercise frequently occurs, even in symptomatic patients with mild to moderate COPD. Hyperinflation can be significantly improved with tiotropium bromide; however, this is only translated into improved exercise tolerance in moderate, but not mild, COPD. These results provide additional rationale for bronchodilation therapy in symptomatic patients with GOLD 2 COPD with evidence of dynamic lung hyperinflation. Further research in patients with GOLD 1 COPD should be considered that might seek subgroups that would benefit from bronchodilator therapy or, alternatively, seek non lung-focused strategies to improve exercise tolerance. n 1360 AnnalsATS Volume 11 Number 9 November 2014

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