0
Original Research: COPD |

Once-Daily Umeclidinium/Vilanterol 125/25 μg Therapy in COPDUmeclidinium/Vilanterol 125/25 03BCg in COPD: A Randomized, Controlled Study FREE TO VIEW

Bartolome Celli, MD, FCCP; Glenn Crater, MD, FCCP; Sally Kilbride, MSc; Rashmi Mehta, PhD; Maggie Tabberer, MSc; Chris J. Kalberg, PhD; Alison Church, MD
Author and Funding Information

From the Brigham and Women’s Hospital (Dr Celli), Boston, MA; Medical Division (Dr Crater), GlaxoSmithKline, Mississauga, ON, Canada; GlaxoSmithKline (Mss Kilbride and Tabberer), Stockley Park, Uxbridge, England; and Respiratory (Drs Mehta, Kalberg, and Church), GlaxoSmithKline, Research Triangle Park, NC.

Correspondence to: Bartolome Celli, MD, FCCP, Pulmonary Division, Brigham and Women’s Hospital, 75 Francis St, PBB Clinics 3, Boston, MA 02115; e-mail: BCelli@copdnet.org


Dr Crater is currently at Clinical Development, Aerocrine (Morrisville, NC).

Funding/Support: GlaxoSmithKline funded the design/concept/conduct of the study and manuscript development.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(5):981-991. doi:10.1378/chest.13-1579
Text Size: A A A
Published online

Background:  Combination long-acting bronchodilator therapy may be more effective than long-acting bronchodilator monotherapy in COPD. Our objectives were to compare the efficacy and safety of once-daily umeclidinium bromide (UMEC)/vilanterol (VI) 125/25 μg with placebo and UMEC or VI monotherapy in COPD.

Methods:  This was a double-blind, placebo-controlled, parallel-group study. A total of 1,493 patients were randomized (3:3:3:2) to 24 weeks of treatment with UMEC/VI 125/25 μg, UMEC 125 μg, VI 25 μg, or placebo once daily via dry powder inhaler.

Results:  Primary efficacy end point was trough FEV1 on day 169 (23-24 h postdose). Additional lung-function, symptomatic, and health-related quality-of-life end points were also assessed. Safety evaluations included adverse events, vital signs, ECG, and clinical laboratory measurements. All active treatments significantly improved trough FEV1 vs placebo (0.124-0.238 L, all P < .001). Improvements with UMEC/VI 125/25 μg were significantly greater than for UMEC 125 μg or VI 25 μg (0.079 L and 0.114 L, both P ≤ .001). Improvements for UMEC/VI 125/25 μg vs placebo were observed for the Transition Dyspnea Index (1.0 unit, P < .001), rescue albuterol use at weeks 1 to 24 (−1.5 puffs/d), and St. George’s Respiratory Questionnaire (−3.60 units, P < .001). No safety signals were observed.

Conclusions:  Once-daily UMEC/VI 125/25 μg was well tolerated and provided greater improvements in lung function, health status, and dyspnea scores compared with monotherapy components and placebo over 24 weeks. This study supports the use of UMEC/VI 125/25 μg for the maintenance treatment of COPD.

Trial registry:  ClinicalTrials.gov; No.: NCT01313637; URL: www.clinicaltrials.gov.

Figures in this Article

Long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs) and long-acting β2 agonists (LABAs), are central to the pharmacologic management of COPD.14 With independent and complementary mechanisms for bronchodilation, use of the combination of a LAMA/LABA has been shown to provide significantly greater improvements in lung function compared with LAMA or LABA monotherapy in patients with moderate to severe COPD.515 Combination treatments may also decrease the risk of side effects compared with increasing the dose of a single agent.2 The development of a once-daily LAMA/LABA combination offering sustained therapeutic effect over 24 h has the potential to simplify COPD therapy by reducing both the number of doses and inhalers required for maintenance treatment. A LAMA/LABA combination would also provide a treatment alternative to fixed-dose inhaled corticosteroid/LABA combinations.

A combination of the orally inhaled LAMA umeclidinium bromide (UMEC) and the orally inhaled LABA vilanterol (VI) has been developed as a once-daily maintenance treatment of COPD. Both UMEC and VI have demonstrated clinically significant bronchodilator activity for 24 h and have shown similar adverse event (AE) profiles compared with placebo.1618 This study was conducted to examine the longer-term efficacy and safety of once-daily UMEC/VI 125/25 μg compared with placebo and either monotherapy (UMEC 125 μg or VI 25 μg).

Study Design, Treatments, and Assessments

This was a 24-week, multicenter, randomized, placebo-controlled, parallel-group study in patients with COPD conducted in 153 centers in 14 countries from March 22, 2011, to April 19, 2012. Patients were randomized 3:2 to active treatments and placebo to provide additional safety data for the active treatment arms. Patients were assigned to receive one of four double-blind treatments: UMEC/VI 125/25 μg (delivering 113/22 μg, respectively), UMEC 125 μg (delivering 113 μg), VI 25 μg (delivering 22 μg), and placebo, administered once daily (in the morning) via a dry-powder inhaler. In all patients, plasma pharmacokinetic (PK) samples were collected for population PK analysis, to be reported in detail elsewhere. Details of participating investigators and institutional review boards/ethics committees are provided in e-Appendix 1.

Inclusion Criteria and Lung Function

Eligible patients were as follows: ≥ 40 years of age with a history of COPD,1 current or former smoker with a smoking history of ≥ 10 pack-years, postalbuterol (salbutamol) FEV1/FVC ratio < 0.70, FEV1 ≤ 70% of predicted normal,19 and a score of ≥ 2 on the modified Medical Research Council dyspnea scale20 at screening. Details of exclusion criteria and permitted/prohibited medications are provided in e-Appendix 2. All patients were required to give written informed consent. The study was approved by local review boards/ethics committees and was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines.21

End Points
Lung Function:

The primary efficacy end point was predose trough FEV1 on treatment day 169 (least squares means [LSM] of FEV1 values obtained 23 h and 24 h after dosing on treatment day 168). Other key lung function end points were weighted mean FEV1 over 0 to 6 h postdose at day 168 (secondary end point), time to onset of response (defined as an increase in FEV1 of ≥ 0.100 L above baseline) during 0 to 6 h postdose on day 1, proportion of patients achieving an increase in FEV1 of ≥ 12% and ≥ 0.200 L above baseline at any time during 0 to 6 h postdose on day 1, proportion of patients achieving an increase of ≥ 0.100 L above baseline in trough FEV1, LSM peak FEV1, serial FEV1, and serial and trough FVC. Serial FEV1 over 0 to 24 h postdose was obtained in a subset of patients (24-h subset [n = 199]) to characterize changes in lung function over the entire dosing interval.

Symptoms and Health-Related Quality of Life:

Other key end points included mean Transition Dyspnea Index (TDI) score (secondary end point),22 weekly mean Shortness Of Breath With Daily Activity (SOBDA) score23,24 and rescue albuterol use (both recorded daily using an electronic diary), health-related quality of life (HRQoL) as measured by the St. George’s Respiratory Questionnaire (SGRQ),25 and time to first COPD exacerbation, where an exacerbation was defined as an acute worsening of symptoms of COPD requiring emergency treatment, hospitalization, or the use of any treatment beyond study drug or rescue albuterol.

Safety:

Safety evaluations included the incidence of AEs, vital signs, 12-lead ECG in all patients and 24-h Holter ECG monitoring in the 24-h subset, clinical chemistry, and hematology assessments.

Statistical Analyses

Sample size was calculated to provide sufficient power for both primary and secondary end points and assumed a two-sided 5% significance level (e-Appendix 2). Primary analyses were performed on the intent-to-treat population, defined as all randomized patients who had received at least one dose of the study medication. The analyses were performed using mixed models repeated measures with covariates of baseline FEV1, smoking status, day, center grouping, treatment, day-by-baseline interaction, and day-by-treatment interaction, where day was nominal. The analysis of TDI used Baseline Dyspnea Index (BDI) score in place of baseline FEV1. Time to first COPD exacerbation was analyzed using a Cox proportional hazards model with covariates of treatment, smoking status, and center. Kaplan-Meier plots were presented to show the incidence of exacerbations over time. To account for multiplicity across treatment comparisons and end points, a step-down closed testing procedure was used.

Patients

Of the 2,114 patients enrolled in the study, 1,489 were included in the intent-to-treat population (Fig 1). The majority of patients completed the study (74% to 81% active treatment groups; 67% placebo). Patient disposition and reasons for discontinuation are shown in Figure 1. Across the groups, 54% to 58% of patients reported having a cardiovascular-related current medical condition, and 44% to 50% of patients used inhaled corticosteroids. Patient demographics and baseline characteristics were similar across treatment groups and consistent with moderate to very severe COPD (Table 1).

Figure Jump LinkFigure 1. Study flow diagram. Note: Some patients were classed by the reporting investigator as completers but did not have a day 169 visit or did not complete day 169; others attended a day 169 visit or completed day 169 assessments but were not classed as completers by the reporting investigator. Patients were considered to have completed if they completed the last clinic visit excluding follow-up (visit 9) and did not withdraw at that visit. *Mainly due to COPD exacerbation. UMEC = umeclidinium bromide; VI = vilanterol.Grahic Jump Location
Table Graphic Jump Location
Table 1 —Patient Demographics and Baseline Characteristics

Data are given as mean (SD) or No. (%). A patient was classed as a current smoker at a visit unless they had not smoked in the 6 mo prior to that visit. Smoking pack-y = (number of cigarettes smoked per d/20) × number of y smoked. GOLD = Global Initiative for Obstructive Lung Disease; ICS = inhaled corticosteroid; UMEC = umeclidinium bromide; VI = vilanterol.

a 

Reversible was an increase in FEV1 of ≥ 12% and ≥ 200 mL following administration of albuterol.

b 

Reversible was an increase in FEV1 of ≥ 12% and ≥ 200 mL following administration of both albuterol and ipratropium.

c 

ICS users were defined as those patients who were currently taking ICS medications at the screening visit.

Lung Function

Statistically significant improvements in mean change from baseline in trough FEV1 at day 169 were observed for UMEC/VI 125/25 μg (difference vs placebo, P value [0.238 L, P < .001]). Statistically significant improvements were also observed for UMEC 125 μg and VI 25 μg monotherapies compared with placebo (0.160 L and 0.124 L, respectively; all P < .001) (Fig 2A). Similar improvements were observed at other visits. Statistically significant improvements were also demonstrated for UMEC/VI 125/25 μg compared with VI 25 μg and UMEC 125 μg monotherapies at day 169 (0.114 L, P < .001 and 0.079 L, P < .001, respectively).

Figure Jump LinkFigure 2. Measurement of lung function. A, B, LS means (95% CI) change from baseline in (A) trough FEV1 (L) and (B) 0 to 6-h weighted mean FEV1 (L). Analysis performed using a repeated measures model with covariates of treatment, baseline, smoking status, center group, day, day-by-baseline, and day-by-treatment interactions. P < .001 for all active treatments vs placebo; P < .001 for UMEC/VI 125/25 μg vs either monotherapy. LS = least squares. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Increases in 0 to 6-h weighted mean FEV1 at day 168 were greater with UMEC/VI 125/25 μg compared with placebo (0.287 L, P < .001) and with UMEC 125 μg and VI 25 μg compared with placebo (0.178 L and 0.145 L, respectively; all P < .001) (Table 2). Similar improvements were observed at other visits (Fig 2B). Differences favored UMEC/VI 125/25 μg compared with UMEC 125 μg and VI 25 μg at day 168 (0.109 L and 0.142 L, respectively; all P < .001 (Table 2), and similar improvements were observed at other visits.

Table Graphic Jump Location
Table 2 —Summary of Lung-Function Outcomes

Data presented are LSM (SE) unless otherwise stated. LSM = least squares means; WM = weighted mean. See Table 1 legend for expansion of other abbreviations.

a 

P ≤ .001.

On day 1, UMEC/VI 125/25 μg treatment resulted in improved FEV1 after 15 min (first assessment) compared with placebo (0.131 L, P < .001). The median time to onset during 0 to 6 h postdose day 1 was 22, 27, and 34 min in the UMEC/VI 125/25 μg, VI 25 μg, and UMEC 125 μg treatment groups, respectively. Patients in the UMEC/VI 125/25 μg group had a higher likelihood of achieving this response on day 1 compared with placebo, UMEC 125 μg, and VI 25 μg monotherapies (all P < .001, hazard ratio [HR] comparison).

Peak FEV1 improvements for UMEC/VI 125/25 μg relative to baseline over 6 h on day 1 and day 168 were 0.308 L and 0.341 L, respectively. At day 168, UMEC/VI 125/25 μg provided improvements in peak FEV1 compared with placebo, UMEC 125 μg, and VI 25 μg (all P < .001) (Table 2).

Greater improvements in LSM change from baseline in trough FVC were observed at all time points for UMEC/VI 125/25 μg, UMEC 125 μg, and VI 25 μg compared with placebo (P < .001) (e-Table 1). In a subgroup of 199 patients who underwent serial spirometry over 24 h (Fig 3), UMEC/VI 125/25 μg provided greater increases from baseline in FEV1 compared with the placebo, VI 25 μg, and UMEC 125 μg monotherapy treatment groups.

Figure Jump LinkFigure 3. Twenty-four-hour serial FEV1 subgroup [n = 199]: LS mean (95% CI) change from baseline in FEV1 over time on d 1 (L). Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two FEV1 assessments made 30 min and 5 min predose on d 1), smoking status, center group, day, day-by-baseline, and day-by-treatment interactions. For comparisons at 24 h: *P < .001 vs placebo; †P ≤ .004 vs placebo; §P < .001 for UMEC/VI 125/25 vs UMEC 125 and VI 25. See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location
Symptoms and Rescue Albuterol Use

Treatment with UMEC/VI 125/25 μg resulted in an improvement in TDI focal score at all assessment visits compared with placebo (all P < .001) (Fig 4, Table 3). At days 28, 84, and 168, the odds of a TDI focal score response (ie, an improvement of > 1 unit) were higher for UMEC/VI 125/25 μg compared with UMEC 125 μg, VI 25 μg, or placebo (OR, 2.5-3.7, 1.7-2.4, and 1.5-2.1 for UMEC/VI 125/25 μg, UMEC 125 μg, and VI 25 μg, respectively; all P ≤ .010). Similarly, the percentages of TDI focal score responders at days 28, 84, and 168 were greater for UMEC/VI 125/25 μg compared with placebo (55%, 55%, and 49% compared with 26%, 30%, and 30%). At day 168, UMEC/VI 125/25 μg was associated with an improvement in mean SOBDA score compared with placebo (P = .002) and greater reductions in rescue albuterol use compared with UMEC 125 μg, VI 25 μg, and placebo over weeks 1 to 24 (all P ≤ .001) (Table 3).

Figure Jump LinkFigure 4. LS mean Transition Dyspnea Index (TDI) focal score. Analysis performed using a repeated measures model with covariates of treatment, Baseline Dyspnea Index (BDI) focal score, smoking status, center group, day, day-by-BDI focal score, and day-by-treatment interactions. *P ≤ .001 vs placebo; †P ≤ .01 vs placebo; for comparisons of UMEC/VI 125/25 vs UMEC 125 or VI 25: ‡P ≤ .001; §P ≤ .01; ¶P ≤ .05. See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location
Table Graphic Jump Location
Table 3 —Summary of Symptomatic and Quality-of-Life Outcomes

SGRQ = St. George’s Respiratory Questionnaire; SOBDA = Shortness of Breath with Daily Activities; TDI = Transition Dyspnea Index. See Table 1 and 2 legends for expansion of other abbreviations.

a 

P ≤ .001.

b 

P < .01.

c 

P < .05.

d 

Response is defined as a difference between mean posttreatment SOBDA score and baseline SOBDA score of −0.1 or less.

e 

Response is defined as an SGRQ total score of 4 units below baseline (score on d 1) or lower.

HRQoL and COPD Exacerbations

Throughout the study, UMEC/VI 125/25 μg was associated with an improvement in mean SGRQ total score compared with placebo (P ≤ .001) (Table 3) (difference at day 28: −4.45 points; day 84: −5.01 points; and day 169: −3.60 points). On-treatment COPD exacerbations were reported more frequently in the placebo group (14%) compared with the three treatment groups (6%-8%). Analysis of time to first COPD exacerbation showed that all treatments resulted in a lower risk of COPD exacerbation compared with placebo (UMEC/VI 125/25 μg [HR 0.4; 95% CI, 0.2, 0.6]; UMEC 125 μg [HR 0.5; CI, 0.3, 0.8]; VI 25 μg [HR 0.5; CI, 0.3, 0.8], all P ≤ .006 for comparisons with placebo). A Kaplan-Meier plot of time to first exacerbation is presented as Figure 5.

Figure Jump LinkFigure 5. Kaplan-Meier plot of time-to-first COPD exacerbation (intent-to-treat population). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Safety

The incidence of treatment-emergent AEs was similar across treatment groups (Table 4). The most frequent AEs were nasopharyngitis, headache, and cough. Drug-related AEs reported by ≥ 1% of patients in any treatment group included cough (0.5%-1.2% for active treatments, 0 for placebo), dyspnea (0.2%-0.5% for active treatments, 1.1% for placebo), and dry mouth (0.5%-1.7% for active treatments, 0.4% for placebo). The number of serious AEs (SAEs) reported are shown in Table 4 and were comparable between treatment groups. Six deaths occurred during the study. Causes of death were metastatic lung cancer (two cases; UMEC 125 μg and VI 25 μg groups), arteriosclerosis (placebo group), pneumonia (placebo group), metastatic pancreatic carcinoma (UMEC 125 μg group), and acute myocardial infarction (VI 25 μg group). No deaths were considered related to the study drug.

Table Graphic Jump Location
Table 4 —Treatment-Emergent AEs and SAEs

Data presented in absolute numbers and as proportion of the total (%). AE = adverse event; SAE = serious adverse event. See Table 1 legend for expansion of other abbreviations.

a 

With onset on or after the date of first dose of study drug and up to 1 d after the date of the last recorded dose of study drug.

b 

Includes both on-treatment and posttreatment AEs.

c 

AEs of COPD were identified as worsening of the patient’s underlying disease.

No clinically meaningful changes in vital signs, 12-lead and Holter ECG parameters, and clinical laboratory tests were observed for UMEC/VI 125/25 μg, UMEC 125 μg, and VI 25 μg, compared with placebo. The overall incidence of patients with one or more abnormal, clinically significant, postbaseline ECG across treatment groups ranged from 17% to 21% (22% for placebo).

Pharmacokinetics

Population PK analyses indicated no difference in the systemic exposure of UMEC or VI when administered as UMEC/VI combination therapy or monotherapies. There were no effects of patient demographics on PK.

This long-term study of patients with moderate to severe COPD treated with the once-daily combination bronchodilator UMEC/VI 125/25 μg revealed three important findings. First, UMEC/VI 125/25 μg provides significant improvements in measures of lung function compared with placebo, UMEC 125 μg, and VI 25 μg throughout the 24-week treatment period. Second, the improvement in lung function is associated with improvements in patient-reported dyspnea and HRQoL health status compared with placebo. Third, the incidence of AEs was similar across the treatment groups. Taken together, these findings support the efficacy, safety, and pharmacologic rationale for once-daily LAMA/LABA combination therapy.

The results presented here extend those of previous studies, which have reported improvements in lung function with various doses of UMEC and VI monotherapies and UMEC/VI combination therapy in patients with COPD.1618,26,27 Lung function findings from this study demonstrate that both UMEC 125 μg and VI 25 μg are efficacious compared with placebo and contribute to the bronchodilator efficacy of UMEC/VI 125/25 μg over the entire 24-h dosing interval, showing that both are effective bronchodilators suitable for once-daily dosing.

In this study, the highest incremental increase in FEV1 was provided by UMEC/VI 125/25 μg combination therapy (0.238 L vs placebo), which was sustained for 24 weeks. However, direct comparisons between UMEC/VI combination treatment and approved LAMA (eg, tiotropium and aclidinium) or LABA monotherapies (eg, indacaterol) and/or other LAMA/LABA combinations are difficult as head-to-head data are not yet available. Between-study comparisons should also be avoided as equivalent optimal treatment doses have not yet been established.

However, in similarly-designed, 6-month, placebo-controlled studies, tiotropium improved mean trough FEV1 by 0.120 L (18 μg daily dose)28 and aclidinium improved trough FEV1 by 0.099 and 0.128 L (200 μg and 400 μg doses, respectively).29 The once-daily LABA, indacaterol, which is available at multiple recommended doses worldwide, improved trough FEV1 vs placebo by 0.160 L and 0.180 L at 26 weeks (150 μg and 300 μg doses, respectively)30 and by 0.120 L at 12 weeks (75 μg dose).31 Further studies are required to directly compare the efficacy of UMEC/VI with other LAMA and LABA monotherapies and combinations.

Long-term dual bronchodilator therapy can also improve HRQoL.32 The improvements observed here on patient-reported outcomes (TDI, SOBDA, SGRQ) for all active treatments suggest that patients experience a reduction in symptoms of breathlessness and consequent improvements in health status. The improvements in these measures observed with the combination UMEC/VI 125/25 μg compared with either monotherapy further supports the use of combination therapy, as do the reductions in rescue albuterol use with UMEC/VI 125/25 μg relative to both monotherapies and placebo.

Previous reports have shown that the use of LABAs increases the risk of side effects such as headache, tremor, increased BP, and tachycardia.33,34 LAMAs are associated with dry mouth, GI events (eg, constipation), ocular events (eg, blurred vision, glaucoma), and urinary retention,35 and prior studies have also suggested that LAMAs are associated with increased cardiovascular effects.36,37 In light of these findings, cardiovascular effects were closely monitored in the present study. No clinically meaningful effects were observed in vital signs and ECG assessments for any active treatment and the incidences of LAMA- and LABA-associated AEs were low. A small study of shorter duration by Feldman et al18,26 reported that a higher dose of UMEC/VI (500/25 μg) than administered here was well tolerated, with no clinically significant effect compared with placebo on the incidence of AEs in COPD. The results presented here confirm and extend these findings at a lower dose and across a longer treatment duration.

This is one of the first studies to report on the longer-term benefit of a once-daily LABA/LAMA combination. Fixed-dose combinations of short-acting bronchodilators are used extensively in COPD, but are limited by frequent dosing. Although not tested prospectively, data obtained from retrospective studies in patients with COPD suggest that those started on once-daily regimens manifested greater adherence to treatment than patients with more frequent dosing38; furthermore, increased adherence to treatment was associated with fewer inpatient and emergency ward visits.38

Similar to many COPD studies, the use of concomitant therapies such as inhaled corticosteroid or short-acting bronchodilator therapy (eg, rescue albuterol) was permitted. While these treatments reflect real-world treatment scenarios, and despite their use being withheld prior to spirometry, their full impact in a clinical trial remains unknown. In addition, the longer-term effects (beyond 24 weeks) of UMEC/VI therapy are still to be determined. However, studies using LAMA and LABA monotherapies over a longer term suggest that the effectiveness over 24 weeks is similar to that reported for up to 3 years.3941 Finally, how patients with milder airflow obstruction would respond is unknown and should be the subject of future studies.

In summary, the combination therapy UMEC 125/25 μg was well tolerated in patients with moderate to severe COPD and produced improvements in lung function, dyspnea, and HRQoL compared with placebo, UMEC 125 μg, and VI 25 μg over 24 weeks of treatment. Both UMEC 125 μg and VI 25 μg were shown to be efficacious compared with placebo. The clinical benefits over monotherapy components, together with the convenience of a once-daily dosing regimen, support the use of UMEC/VI 125/25 μg as a long-term maintenance treatment in COPD.

Author contributions: As guarantor of this manuscript, Dr Celli had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Celli: contributed to the design of the study, analysis of the data, and preparation of the manuscript; reviewed the manuscript and provided final approval of the submitted version; and agreed to be listed as an author.

Dr Crater: contributed to the study design and conduct, analysis of the data, and preparation of the manuscript; reviewed the manuscript and provided final approval of the submitted version; and agreed to be listed as an author.

Ms Kilbride: contributed to the review of the manuscript, performed statistical analysis of study data, provided final approval of the submitted version, and agreed to be listed as an author.

Dr Mehta: contributed to the design of the study, analysis of the data, and preparation of the manuscript; reviewed the manuscript and provided final approval of the submitted version; and agreed to be listed as an author.

Ms Tabberer: contributed to the design of the study, development of the analysis plan, interpretation of data, and preparation of the manuscript; reviewed the manuscript and provided final approval of the submitted version; and agreed to be listed as an author.

Dr Kalberg: contributed to the design of the study, analysis of the data, and preparation of the manuscript; reviewed the manuscript and provided final approval of the submitted version; and agreed to be listed as an author.

Dr Church: contributed to the study design and conduct, analysis of the data, and preparation of the manuscript; reviewed the manuscript and provided final approval of the submitted version; and agreed to be listed as an author.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Celli has participated in advisory boards for GlaxoSmithKline; Boehringer Ingelheim GmbH; Almirall, S.A.; AstraZeneca; Aeris; Deep Breeze Ltd; Takeda Pharmaceutical Company Limited; and Novartis Corp. The Pulmonary Division where Dr Celli is employed has received funds for research studies from GlaxoSmithKline; Boehringer Ingelheim GmbH; Forrest Medical, LLC; AstraZeneca; and Aeris. Dr Celli and his family do not have shares or interest in any company, and Dr Celli has not received tobacco money or stocks in any tobacco-related companies. Dr Crater was an employee of GlaxoSmithKline at the time of the study and manuscript preparation and held stocks/shares in GlaxoSmithKline. At the time of the manuscript submission, he was an employee of Aerocrine and did not receive any fees relating to the study or manuscript development. Drs Kalberg, Mehta and Church and Mss Kilbride and Tabberer are employees of, and hold stocks/shares in, GlaxoSmithKline.

Role of sponsors: GlaxoSmithKline funded the design/concept/conduct of the study and manuscript development.

Other contributions: Editorial assistance with the preparation of the manuscript was provided by Stuart Wakelin, PhD, and Louisa Pettinger, PhD, from FWG Scientific Communications, funded by GlaxoSmithKline.

Additional information: The e-Appendixes and e-Table can be found in the “Supplemental Materials” area of the online article.

AE

adverse event

BDI

Baseline Dyspnea Index

HR

hazard ratio

HRQoL

health-related quality of life

LABA

long-acting β2 agonist

LAMA

long-acting muscarinic antagonist

LSM

least squares means

PK

pharmacokinetic

SAE

serious adverse event

SGRQ

St. George’s Respiratory Questionnaire

SOBDA

Shortness of Breath With Daily Activity

TDI

Transition Dyspnea Index

UMEC

umeclidinium bromide

VI

vilanterol

Celli BR, MacNee W; ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23(6):932-946. [CrossRef] [PubMed]
 
Global strategy for the diagnosis, management and prevention of COPD 2011. GOLD website. http://www.goldcopd.org/. Accessed May 11, 2013.
 
Brusasco V. Reducing cholinergic constriction: the major reversible mechanism in COPD. Eur Respri Rev. 2006;15(99):32-36. [CrossRef]
 
Barnes PJ. The role of anticholinergics in chronic obstructive pulmonary disease. Am J Med. 2004;117(suppl 12A):24S-32S. [PubMed]
 
Cazzola M, Molimard M. The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010;23(4):257-267. [CrossRef] [PubMed]
 
Mahler DA, D’Urzo A, Bateman ED, et al; INTRUST-1 and INTRUST-2 Study Investigators. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax. 2012;67(9):781-788. [CrossRef] [PubMed]
 
Maltais F, Beck E, Webster D, et al. Four weeks once daily treatment with tiotropium+olodaterol (BI 1744) fixed dose combination compared with tiotropium in COPD patients. Eur Respir J. 2010;38(suppl 5):1014s.
 
Reisner C, Rennard SI, Fogarty C, et al. Pearl Therapeutics' combination LAMA/LABA MDI (GFF-MDI, PT003) provides a significant benefit on home peak expiratory flow rate (PEFR) and reduces the need for rescue albuterol use compared to its components administered alone, Spiriva(R) Handihaler(R), And Foradil(R) Aerolizer(R) in a randomized, double-blind, placebo-controlled phase 2B study in patients with COPD. Am J Respir Crit Care Med. 2012;185:A2259.
 
Reisner C, Rose ES, Strom S, et al. Fixed combination of glycopyrrolate and formoterol mdi (GFF-MDI) demonstrates superior inspiratory capacity (IC) compared to tiotropium dpi (TIO) following 7 days dosing, in a randomized, double-blind, placebo-controlled phase 2b study in patients with COPD. Eur Respir J. 2011;38(suppl 55):150s.
 
van der Molen T, Cazzola M. Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes. Prim Care Respir J. 2012;21(1):101-108. [CrossRef] [PubMed]
 
van Noord JA, Buhl R, Laforce C, et al. QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease. Thorax. 2010;65(12):1086-1091. [CrossRef] [PubMed]
 
Tashkin DP, Celli B, Decramer M, et al. Bronchodilator responsiveness in patients with COPD. Eur Respir J. 2008;31(4):742-750. [CrossRef] [PubMed]
 
van Noord JA, Aumann J-L, Janssens E, et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J. 2005;26(2):214-222. [CrossRef] [PubMed]
 
van Noord JA, Aumann JL, Janssens E, et al. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest. 2006;129(3):509-517. [CrossRef] [PubMed]
 
Tashkin DP, Pearle J, Iezzoni D, Varghese ST. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. COPD. 2009;6(1):17-25. [CrossRef] [PubMed]
 
Donohue JF, Anzueto A, Brooks J, Mehta R, Kalberg C, Crater G. A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD. Respir Med. 2012;106(7):970-979. [CrossRef] [PubMed]
 
Hanania NA, Feldman G, Zachgo W, et al. The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. Chest. 2012;142(1):119-127. [CrossRef] [PubMed]
 
Feldman G, Walker RR, Brooks J, Mehta R, Crater G. Safety and tolerability of the GSK573719/vilanterol combination in patients with COPD. Am J Respir Crit Care Med. 2012;185:A2938.
 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159(1):179-187. [CrossRef] [PubMed]
 
Launois C, Barbe C, Bertin E, et al. The modified Medical Research Council scale for the assessment of dyspnea in daily living in obesity: a pilot study. BMC Pulm Med. 2012;12:61. [CrossRef] [PubMed]
 
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH harmonised tripartite guideline: guideline for good clinical practice E6(R1). ICH website. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf. Accessed May 11, 2013.
 
Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest. 1984;85(6):751-758. [CrossRef] [PubMed]
 
Howard K, Berry P, Petrillo J, et al. Development of the shortness of breath with daily activities questionnaire (SOBDA). Value Health. 2012;15(8):1042-1050. [CrossRef] [PubMed]
 
Watkins ML, Wilcox TK, Tabberer MM, et al. Shortness of Breath with. Daily Activities Questionnaire: validation and responder thresholds in patients with chronic obstructive pulmonary disease. BMJ Open. 2013;3(10):e003048. [CrossRef] [PubMed]
 
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992;145(6):1321-1327. [CrossRef] [PubMed]
 
Feldman G, Walker RR, Brooks J, Mehta R, Crater G. 28-Day safety and tolerability of umeclidinium in combination with vilanterol in COPD: a randomized placebo-controlled trial. Pulm Pharmacol Ther. 2012;25(6):465-471. [CrossRef] [PubMed]
 
Church A, Beerahee M, Brooks J, Mehta R, Shah P. Umeclidinium (GSK573719) dose response and dosing interval in COPD. Poster P2121. Presented at: European Respiratory Society (ERS) Annual Congress 2012; September 1-5, 2012; Vienna, Austria.
 
Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for 6 months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax. 2006;61(1):91. [CrossRef] [PubMed]
 
Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J. 2012;40(4):830-836. [CrossRef] [PubMed]
 
Donohue JF, Fogarty C, Lötvall J, et al; INHANCE Study Investigators. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010;182(2):155-162. [CrossRef] [PubMed]
 
Kerwin EM, Gotfried MH, Lawrence D, Lassen C, Kramer B. Efficacy and tolerability of indacaterol 75 μg once daily in patients aged ≥40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies. Clin Ther. 2011;33(12):1974-1984. [CrossRef] [PubMed]
 
Aaron SD, Vandemheen KL, Fergusson D, et al; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146(8):545-555. [CrossRef] [PubMed]
 
GlaxoSmithKline. Salmeterol prescribing information. GlaxoSmithKline website. http://us.gsk.com/products/assets/us_serevent_diskus.pdf. Accessed August 21, 2012.
 
Novartis. Indacaterol prescribing information. Novartis website. http://www.pharma.us.novartis.com/product/pi/pdf/arcapta.pdf. Accessed August 21, 2012.
 
Boehringer Ingelheim. Tiotropium prescribing information. Boehringer Ingelheim website. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Spiriva/Spiriva.pdf. Accessed August 21, 2012.
 
Anthonisen NR, Connett JE, Enright PL, Manfreda J; Lung Health Study Research Group. Hospitalizations and mortality in the lung health study. Am J Respir Crit Care Med. 2002;166(3):333-339. [CrossRef] [PubMed]
 
Salpeter SR. Do inhaled anticholinergics increase or decrease the risk of major cardiovascular events? A synthesis of the available evidence. Drugs. 2009;69(15):2025-2033. [CrossRef] [PubMed]
 
Toy EL, Beaulieu NU, McHale JM, et al. Treatment of COPD: relationships between daily dosing frequency, adherence, resource use, and costs. Respir Med. 2011;105(3):435-441. [CrossRef] [PubMed]
 
Jenkins CR, Jones PW, Calverley PM, et al. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res. 2009;10:59. [CrossRef] [PubMed]
 
Tashkin D, Celli B, Kesten S, Lystig T, Decramer M. Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial. Respir Med. 2010;104(10):1495-1504. [CrossRef] [PubMed]
 
Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med. 2008;178(4):332-338. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Study flow diagram. Note: Some patients were classed by the reporting investigator as completers but did not have a day 169 visit or did not complete day 169; others attended a day 169 visit or completed day 169 assessments but were not classed as completers by the reporting investigator. Patients were considered to have completed if they completed the last clinic visit excluding follow-up (visit 9) and did not withdraw at that visit. *Mainly due to COPD exacerbation. UMEC = umeclidinium bromide; VI = vilanterol.Grahic Jump Location
Figure Jump LinkFigure 2. Measurement of lung function. A, B, LS means (95% CI) change from baseline in (A) trough FEV1 (L) and (B) 0 to 6-h weighted mean FEV1 (L). Analysis performed using a repeated measures model with covariates of treatment, baseline, smoking status, center group, day, day-by-baseline, and day-by-treatment interactions. P < .001 for all active treatments vs placebo; P < .001 for UMEC/VI 125/25 μg vs either monotherapy. LS = least squares. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. Twenty-four-hour serial FEV1 subgroup [n = 199]: LS mean (95% CI) change from baseline in FEV1 over time on d 1 (L). Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two FEV1 assessments made 30 min and 5 min predose on d 1), smoking status, center group, day, day-by-baseline, and day-by-treatment interactions. For comparisons at 24 h: *P < .001 vs placebo; †P ≤ .004 vs placebo; §P < .001 for UMEC/VI 125/25 vs UMEC 125 and VI 25. See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. LS mean Transition Dyspnea Index (TDI) focal score. Analysis performed using a repeated measures model with covariates of treatment, Baseline Dyspnea Index (BDI) focal score, smoking status, center group, day, day-by-BDI focal score, and day-by-treatment interactions. *P ≤ .001 vs placebo; †P ≤ .01 vs placebo; for comparisons of UMEC/VI 125/25 vs UMEC 125 or VI 25: ‡P ≤ .001; §P ≤ .01; ¶P ≤ .05. See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5. Kaplan-Meier plot of time-to-first COPD exacerbation (intent-to-treat population). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Patient Demographics and Baseline Characteristics

Data are given as mean (SD) or No. (%). A patient was classed as a current smoker at a visit unless they had not smoked in the 6 mo prior to that visit. Smoking pack-y = (number of cigarettes smoked per d/20) × number of y smoked. GOLD = Global Initiative for Obstructive Lung Disease; ICS = inhaled corticosteroid; UMEC = umeclidinium bromide; VI = vilanterol.

a 

Reversible was an increase in FEV1 of ≥ 12% and ≥ 200 mL following administration of albuterol.

b 

Reversible was an increase in FEV1 of ≥ 12% and ≥ 200 mL following administration of both albuterol and ipratropium.

c 

ICS users were defined as those patients who were currently taking ICS medications at the screening visit.

Table Graphic Jump Location
Table 2 —Summary of Lung-Function Outcomes

Data presented are LSM (SE) unless otherwise stated. LSM = least squares means; WM = weighted mean. See Table 1 legend for expansion of other abbreviations.

a 

P ≤ .001.

Table Graphic Jump Location
Table 3 —Summary of Symptomatic and Quality-of-Life Outcomes

SGRQ = St. George’s Respiratory Questionnaire; SOBDA = Shortness of Breath with Daily Activities; TDI = Transition Dyspnea Index. See Table 1 and 2 legends for expansion of other abbreviations.

a 

P ≤ .001.

b 

P < .01.

c 

P < .05.

d 

Response is defined as a difference between mean posttreatment SOBDA score and baseline SOBDA score of −0.1 or less.

e 

Response is defined as an SGRQ total score of 4 units below baseline (score on d 1) or lower.

Table Graphic Jump Location
Table 4 —Treatment-Emergent AEs and SAEs

Data presented in absolute numbers and as proportion of the total (%). AE = adverse event; SAE = serious adverse event. See Table 1 legend for expansion of other abbreviations.

a 

With onset on or after the date of first dose of study drug and up to 1 d after the date of the last recorded dose of study drug.

b 

Includes both on-treatment and posttreatment AEs.

c 

AEs of COPD were identified as worsening of the patient’s underlying disease.

References

Celli BR, MacNee W; ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23(6):932-946. [CrossRef] [PubMed]
 
Global strategy for the diagnosis, management and prevention of COPD 2011. GOLD website. http://www.goldcopd.org/. Accessed May 11, 2013.
 
Brusasco V. Reducing cholinergic constriction: the major reversible mechanism in COPD. Eur Respri Rev. 2006;15(99):32-36. [CrossRef]
 
Barnes PJ. The role of anticholinergics in chronic obstructive pulmonary disease. Am J Med. 2004;117(suppl 12A):24S-32S. [PubMed]
 
Cazzola M, Molimard M. The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010;23(4):257-267. [CrossRef] [PubMed]
 
Mahler DA, D’Urzo A, Bateman ED, et al; INTRUST-1 and INTRUST-2 Study Investigators. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax. 2012;67(9):781-788. [CrossRef] [PubMed]
 
Maltais F, Beck E, Webster D, et al. Four weeks once daily treatment with tiotropium+olodaterol (BI 1744) fixed dose combination compared with tiotropium in COPD patients. Eur Respir J. 2010;38(suppl 5):1014s.
 
Reisner C, Rennard SI, Fogarty C, et al. Pearl Therapeutics' combination LAMA/LABA MDI (GFF-MDI, PT003) provides a significant benefit on home peak expiratory flow rate (PEFR) and reduces the need for rescue albuterol use compared to its components administered alone, Spiriva(R) Handihaler(R), And Foradil(R) Aerolizer(R) in a randomized, double-blind, placebo-controlled phase 2B study in patients with COPD. Am J Respir Crit Care Med. 2012;185:A2259.
 
Reisner C, Rose ES, Strom S, et al. Fixed combination of glycopyrrolate and formoterol mdi (GFF-MDI) demonstrates superior inspiratory capacity (IC) compared to tiotropium dpi (TIO) following 7 days dosing, in a randomized, double-blind, placebo-controlled phase 2b study in patients with COPD. Eur Respir J. 2011;38(suppl 55):150s.
 
van der Molen T, Cazzola M. Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes. Prim Care Respir J. 2012;21(1):101-108. [CrossRef] [PubMed]
 
van Noord JA, Buhl R, Laforce C, et al. QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease. Thorax. 2010;65(12):1086-1091. [CrossRef] [PubMed]
 
Tashkin DP, Celli B, Decramer M, et al. Bronchodilator responsiveness in patients with COPD. Eur Respir J. 2008;31(4):742-750. [CrossRef] [PubMed]
 
van Noord JA, Aumann J-L, Janssens E, et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J. 2005;26(2):214-222. [CrossRef] [PubMed]
 
van Noord JA, Aumann JL, Janssens E, et al. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest. 2006;129(3):509-517. [CrossRef] [PubMed]
 
Tashkin DP, Pearle J, Iezzoni D, Varghese ST. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. COPD. 2009;6(1):17-25. [CrossRef] [PubMed]
 
Donohue JF, Anzueto A, Brooks J, Mehta R, Kalberg C, Crater G. A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD. Respir Med. 2012;106(7):970-979. [CrossRef] [PubMed]
 
Hanania NA, Feldman G, Zachgo W, et al. The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. Chest. 2012;142(1):119-127. [CrossRef] [PubMed]
 
Feldman G, Walker RR, Brooks J, Mehta R, Crater G. Safety and tolerability of the GSK573719/vilanterol combination in patients with COPD. Am J Respir Crit Care Med. 2012;185:A2938.
 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159(1):179-187. [CrossRef] [PubMed]
 
Launois C, Barbe C, Bertin E, et al. The modified Medical Research Council scale for the assessment of dyspnea in daily living in obesity: a pilot study. BMC Pulm Med. 2012;12:61. [CrossRef] [PubMed]
 
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH harmonised tripartite guideline: guideline for good clinical practice E6(R1). ICH website. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf. Accessed May 11, 2013.
 
Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest. 1984;85(6):751-758. [CrossRef] [PubMed]
 
Howard K, Berry P, Petrillo J, et al. Development of the shortness of breath with daily activities questionnaire (SOBDA). Value Health. 2012;15(8):1042-1050. [CrossRef] [PubMed]
 
Watkins ML, Wilcox TK, Tabberer MM, et al. Shortness of Breath with. Daily Activities Questionnaire: validation and responder thresholds in patients with chronic obstructive pulmonary disease. BMJ Open. 2013;3(10):e003048. [CrossRef] [PubMed]
 
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992;145(6):1321-1327. [CrossRef] [PubMed]
 
Feldman G, Walker RR, Brooks J, Mehta R, Crater G. 28-Day safety and tolerability of umeclidinium in combination with vilanterol in COPD: a randomized placebo-controlled trial. Pulm Pharmacol Ther. 2012;25(6):465-471. [CrossRef] [PubMed]
 
Church A, Beerahee M, Brooks J, Mehta R, Shah P. Umeclidinium (GSK573719) dose response and dosing interval in COPD. Poster P2121. Presented at: European Respiratory Society (ERS) Annual Congress 2012; September 1-5, 2012; Vienna, Austria.
 
Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for 6 months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax. 2006;61(1):91. [CrossRef] [PubMed]
 
Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J. 2012;40(4):830-836. [CrossRef] [PubMed]
 
Donohue JF, Fogarty C, Lötvall J, et al; INHANCE Study Investigators. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010;182(2):155-162. [CrossRef] [PubMed]
 
Kerwin EM, Gotfried MH, Lawrence D, Lassen C, Kramer B. Efficacy and tolerability of indacaterol 75 μg once daily in patients aged ≥40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies. Clin Ther. 2011;33(12):1974-1984. [CrossRef] [PubMed]
 
Aaron SD, Vandemheen KL, Fergusson D, et al; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146(8):545-555. [CrossRef] [PubMed]
 
GlaxoSmithKline. Salmeterol prescribing information. GlaxoSmithKline website. http://us.gsk.com/products/assets/us_serevent_diskus.pdf. Accessed August 21, 2012.
 
Novartis. Indacaterol prescribing information. Novartis website. http://www.pharma.us.novartis.com/product/pi/pdf/arcapta.pdf. Accessed August 21, 2012.
 
Boehringer Ingelheim. Tiotropium prescribing information. Boehringer Ingelheim website. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Spiriva/Spiriva.pdf. Accessed August 21, 2012.
 
Anthonisen NR, Connett JE, Enright PL, Manfreda J; Lung Health Study Research Group. Hospitalizations and mortality in the lung health study. Am J Respir Crit Care Med. 2002;166(3):333-339. [CrossRef] [PubMed]
 
Salpeter SR. Do inhaled anticholinergics increase or decrease the risk of major cardiovascular events? A synthesis of the available evidence. Drugs. 2009;69(15):2025-2033. [CrossRef] [PubMed]
 
Toy EL, Beaulieu NU, McHale JM, et al. Treatment of COPD: relationships between daily dosing frequency, adherence, resource use, and costs. Respir Med. 2011;105(3):435-441. [CrossRef] [PubMed]
 
Jenkins CR, Jones PW, Calverley PM, et al. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res. 2009;10:59. [CrossRef] [PubMed]
 
Tashkin D, Celli B, Kesten S, Lystig T, Decramer M. Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial. Respir Med. 2010;104(10):1495-1504. [CrossRef] [PubMed]
 
Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med. 2008;178(4):332-338. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Supporting Data

Online Supplement

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543