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Original Research: COPD |

Efficacy and Safety of a Fixed-Dose Combination of Indacaterol and Glycopyrronium for the Treatment of COPDIndacaterol and Glycopyrronium for COPD: A Systematic Review FREE TO VIEW

Gustavo J. Rodrigo, MD; Vicente Plaza, MD, PhD
Author and Funding Information

From the Departamento de Emergencia (Dr Rodrigo), Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay; and Servei de Pneumologia (Dr Plaza), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.

CORRESPONDENCE TO: Gustavo J. Rodrigo, MD, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas. Av. 8 de Octubre 3020, Montevideo 11300, Uruguay; e-mail: gustavo.javier.rodrigo@gmail.com


FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

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


Chest. 2014;146(2):309-317. doi:10.1378/chest.13-2807
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BACKGROUND:  COPD guidelines recommend the combined use of inhaled, long-acting β2-agonists and long-acting muscarinic antagonists if symptoms are not improved by a single agent. This systematic review assessed the efficacy and safety of the fixed-dose combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium (QVA149) compared with its monocomponents (glycopyrronium and indacaterol) and tiotropium for the treatment of moderate to severe COPD.

METHODS:  This was a systematic review of randomized, placebo-controlled or crossover trials (3-64 weeks). Primary outcomes were trough FEV1, severe adverse events, and serious cardiovascular events.

RESULTS:  Five trials (4,842 patients) were included. Compared with tiotropium, QVA149 showed a significant increase in trough FEV1 (70 mL; P < .0001) and a decreased use of rescue medication (−0.63 puffs/d; P < .0001). Patients receiving QVA149 had a 19% greater likelihood of experiencing a minimal clinical important difference (MCID) in the number needed to treat for benefit (NNTB) (NNTB = 11) and a 16% greater likelihood of achieving an MCID in the St. George’s Respiratory Questionnaire (SGRQ) (NNTB = 11). Similarly, QVA149 vs glycopyrronium showed a significant increase in trough FEV1 (70 mL; P < .0001), a significant reduction in rescue medication use (−0.59; P < .0001), and a significant increase in the rate of patients achieving an MCID in the SGRQ (NNTB = 12). QVA149 showed similar levels of safety and tolerability to both comparators. It was not possible to perform a pooled analysis of data comparing QVA149 vs indacaterol.

CONCLUSIONS:  Once-daily, inhaled QVA149 showed superior efficacy compared with glycopyrronium and the current standard of care, tiotropium, in patients with moderate to severe COPD.

Figures in this Article

COPD is a prominent cause of disability and death worldwide.1 Pharmacotherapy reduces symptoms, frequency, and severity of exacerbations and improves health status and exercise tolerance.2 Bronchodilators are the cornerstone of pharmacologic therapy. Long-acting inhaled bronchodilators are more convenient and more effective at sustaining symptomatic relief than short-acting bronchodilators. Furthermore, longer-acting inhaled therapies improve patient adherence, and the frequency of administration decreases.3 Current guidelines recommend the combined use of inhaled long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) if symptoms are not improved by a single agent.2 Different studies have shown that the complementary mechanisms of action of LABAs and LAMAs significantly improve bronchodilation compared with respective monocomponents.4 Concurrent use of indacaterol and tiotropium once daily provided an increased benefit with no increase in risk of clinically relevant adverse events (AEs) compared with tiotropium monotherapy.5

QVA149 is the first fixed-dose combination of a LABA (indacaterol) and a LAMA (glycopyrronium) available for the treatment of COPD. Both monocomponents are approved as once-daily maintenance treatment of patients with moderate to severe COPD, and safety and efficacy of each have been demonstrated in different studies.610 Recent trials have showed that QVA149 has an AE profile similar to placebo and provides significant, sustained, and clinically meaningful improvements in lung function compared with its monocomponents or tiotropium.11 QVA149 also improves lung function more effectively than salmeterol/fluticasone bid in patients with moderate to severe COPD.12 The aim of this systematic review was to assess the efficacy and safety of the fixed-dose combination QVA149 compared with its monocomponents and tiotropium for the treatment COPD. The hypothesis was that the bronchodilator effect of QVA149 would translate into better outcomes than single bronchodilator therapy, without incurring increased AEs.

We adopted Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to perform this systematic review.13 This study was registered with the International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/PROSPERO) as CRD42013006390 (“Efficacy and safety of a fixed-dose combination of indacaterol and glycopyrronium [QVA149] for the treatment of COPD”).

Search and Selection Criteria

We identified published studies from MEDLINE, Embase, CINAHL, Scopus, and the Cochrane Central Register of Controlled Trials (January 2014) database using the terms “QVA149” or “Ultibro” or “indacaterol” or “glycopyrronium” or “long-acting beta2-agonists” or “long-acting antimuscarinics” and “chronic obstructive pulmonary disease.” Also, we performed a search of relevant files from the drugs manufacturer’s database (http://www.novctrd.com/ctrdWebApp/clinicaltrialrepository/public/login.jsp). The search was without language restriction and included unpublished studies. Trials published solely in abstract form were excluded because the methods and results could not be fully analyzed.

To be included, studies had to meet all the following criteria: (1) adult patients aged ≥ 40 years with stable moderate to severe COPD according GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2009 guidelines14; (2) comparison of inhaled QVA149 vs tiotropium or glycopyrronium or indacaterol; (3) randomized (parallel group or crossover) controlled trials of ≥ 3 weeks’ duration; (4) report at least one of the following outcomes: pulmonary function in terms of trough or predose FEV1, and safety in terms of frequency of serious AEs (SAEs) and serious cardiovascular events (SCVEs) as primary outcomes, and dyspnea (Transition Dyspnea Index [TDI] total score), health status (St. George’s Respiratory Questionnaire [SGRQ] total score), rescue medication use, COPD exacerbations, and withdrawals (total and due to AEs) as secondary outcomes. An SAE was defined as any untoward medical occurrence that sometimes results in death, is life threatening, requires inpatient hospitalization, or results in persistent or significant disability or incapacity.15

Data Extraction and Assessment of Risk of Bias

Titles, abstracts, and citations were independently analyzed by the two authors. From the full text, they independently assessed all studies for inclusion based on the criteria for population intervention, study design, and outcomes. After obtaining full reports about potentially relevant trials, they assessed eligibility. Both authors were independently involved in all stages of study selection, data extraction, and risk of bias assessment. The latter was assessed according to recommendations outlined by the Cochrane Collaboration16 for the following items: (1) adequacy of sequence generation, (2) allocation concealment, (3) blinding of participants and investigators, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective outcome reporting, and other bias. Disagreements were discussed and resolved by consensus.

Data Analysis

Analysis was by intention to treat and included all participants to minimize bias. Outcomes were pooled using mean differences (inverse variance method) or Mantel-Haenszel risk ratios. The precision of the estimates was quantified by the 95% CIs. When effect estimates were significantly different between groups, the number needed to treat for benefit (NNTB) or for harm was obtained. Heterogeneity was measured by the I2 test17 (≤ 25% absence, 26%-39% unimportant, 40%-60% moderate, and 60%-100% substantial). Because selected studies differed in the mixes of participants and interventions, a random-effects model was performed to address this variation across studies for all outcomes.18 As a priori subgroup analysis, we explored the influence of trial duration. Subgroups were compared using the residual χ2 test from the Peto ORs.19 Potential publication bias was analyzed through the use of funnel plot.20P values ≤ .05 (two-tailed test) was considered significant. Meta-analysis was performed with the Review Manager, version 5.2.7 software (Cochrane IMS, 2013; Cochrane Collaboration).

The process of study selection is outlined in Figure 1. Five trials (N = 4,842 patients) met the entry criteria.11,2124 All were randomized, parallel group or crossover22 studies and were sponsored by a single pharmaceutical company (Table 1). Two trials were unpublished.23,24 Five studies compared QVA149 vs tiotropium,11,2124 two compared QVA149 vs glycopyrronium,11,21 and one compared QVA149 vs indacaterol.11 Four trials included two or more comparisons.11,21,22,24 Patients received QVA149 or indacaterol or glycopyrronium in a double-blinded manner and administered via a single-dose dry powder inhaler (Breezhaler device; Novartis Pharma AG) or open-label tiotropium via a single-dose dry powder inhaler (Handihaler device; Boehringer Ingelheim GmbH). Trials enrolled patients with stable COPD that met moderate to severe11,2224 and very severe21 GOLD 2009 criteria14 (average baseline FEV1 = 51% predicted). Of the 4,842 patients selected, 36% had moderate COPD, 53.5% severe COPD, and 9.6% very severe COPD. The mean age of patients was 64 years (75% of male patients). Forty-three percent of patients were current smokers. The duration of studies ranged between 3 and 64 weeks and three were long-term studies.11,21,23 All studies showed a low risk of bias in the six items of the Cochrane instrument.16

Figure Jump LinkFigure 1  Flowchart for identification of studies used.Grahic Jump Location
Table Graphic Jump Location
TABLE 1  ] Characteristics of Included Studies

AE = adverse event; DYS = dyspnea; EX = COPD exacerbation; GLY = glycopyrronium; HS = health status; IND = indacaterol; NA = data not available; OD = once daily; PL = placebo; QVA149 = fixed-dose combination of indacaterol and glycopyrronium; RMU = rescue medication use; TIO = tiotropium; WITH = withdrawal.

a 

Primary outcome.

QVA149 vs Tiotropium

Data from all trials11,2124 showed that the use of QVA149 was associated with a significant increase in (mean change from baseline) trough FEV1 (P < .0001) compared with tiotropium monotherapy (Fig 2). QVA149 provided rapid bronchodilation following the first dose, with statistically significant improvements in trough FEV1 vs tiotropium (range, 60-100 mL) at all time points from day 1 to week 64. The heterogeneity among studies was moderate, but it dropped dramatically (35%) when the only study of patients with very severe COPD was removed.21 There were no significant differences among different time points. Funnel plot tests were not performed, since the number of selected studies was < 10, which is the minimum number recommended.16,19,20 On the contrary, there were no significant differences in SAEs (13.1% vs 12.3%) and SCVEs (1.7% vs 2.3%) among QVA149 and tiotropium (Fig 3). There was no evidence of significant heterogeneity among studies.

Figure Jump LinkFigure 2  Pooled mean difference for trough FEV1 (change from baseline) with 95% CIs of eligible studies comparing QVA149 vs tiotropium. df = degrees of freedom; QVA149 = fixed-dose combination of indacaterol and glycopyrronium.Grahic Jump Location
Figure Jump LinkFigure 3  A, Pooled relative risk for the number of patients with severe adverse events. B, Pooled relative risk for the number of patients with severe cardiovascular events, with 95% CIs of eligible studies comparing QVA149 vs tiotropium. M-H = Mantel-Haenszel. See Figure 2 legend for expansion of other abbreviation.Grahic Jump Location

Regarding secondary outcomes, QVA149 significantly reduced dyspnea as a mean change from baseline (−0.63 points of TDI; P < .0002) and the use of rescue medication (−0.63 puffs/d; P < .0001) (Table 2), compared with tiotropium. QVA149 showed a 19% greater likelihood of experiencing a minimal clinical important difference (MCID) in TDI (≥ 1 point),25 with NNTB = 11. Also, the mean change from baseline of the SGRQ total score was significantly higher with QVA149 than tiotropium (−2.64 units; P < .04). Most importantly, the percentage of patients receiving QVA149 with an MCID in the SGRQ (≥ 4 units of total score) was significantly higher, compared with those receiving tiotropium (63.2% vs 54.2%; P < .0001; NNTB = 11) (Table 2). Moreover, QVA149 reduced the number of COPD exacerbations significantly compared with tiotropium, with NNTB = 19 (estimate based on data from two long-term studies11,20). Finally, there were nonsignificant differences in the rate of any AE (70.7% vs 69.9%), total withdrawals (15.7% vs 16.2%), and withdrawals due to AEs (5.7% vs 4.5%).

Table Graphic Jump Location
TABLE 2  ] Effect of QVA149 vs Tiotropium on Secondary COPD Outcomes

MD = mean difference; NNTB = number needed to treat for benefit; RR = relative risk; SGRQ = St. George’s Respiratory Questionnaire; TDI = Transitional Dyspnea Index. See Table 1 legend for expansion of other abbreviations.

QVA149 vs Glycopyrronium

The analysis of two long-term studies that compared QVA149 vs glycopyrronium11,21 showed that (as a mean change from baseline) trough FEV1 significantly increased by 70 mL (P < .0001) at weeks 12 and 26 with QVA149 (Fig 4). This result was statistically homogeneous. There was no statistically significant difference between the two time points. On the other hand, there were no significant differences in SAEs (15.7% vs 17.1%) and SCVEs (1.9% vs 2.5%) among QVA149 and glycopyrronium (Fig 5).

Figure Jump LinkFigure 4  Pooled mean difference for trough FEV1 (change from baseline) with 95% CIs of eligible studies comparing QVA149 vs glycopyrronium. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5  A, Pooled relative risk for the number of patients with severe adverse events. B, Pooled relative risk for the number of patients with severe cardiovascular events, with 95% CIs of eligible studies comparing QVA149 vs glycopyrronium. See Figure 2 and 3 legends for expansion of abbreviations.Grahic Jump Location

QVA149 significantly improved health status more than glycopyrronium. Data showed significant reductions in the use of rescue medication (−0.59; P < .0001) (Table 3), and the SGRQ total score (−2.18 units; P < .04) in patients receiving QVA149. Also, QVA149 significantly increased the rate of patients achieving an MCID in the SGRQ total score (63.2% of patients receiving QVA149 vs 55.0% of those receiving glycopyrronium; P < .04; NNTB = 12). Furthermore, QVA149 significantly reduced COPD exacerbations compared with glycopyrronium, with NNT = 25. Finally, there were nonsignificant differences in the rate of any AE (78.0% vs 81.1%), total withdrawals (17.3% vs 21.2%), and withdrawals due to AEs (5.4% vs 6.6%).

Table Graphic Jump Location
TABLE 3  ] Effect of QVA149 vs Glycopyrronium on Secondary COPD Outcomes

See Table 1 and 2 legends for expansion of abbreviations.

QVA149 vs Indacaterol

Only one trial presented this comparison11; therefore, it was not possible to perform a pooled analysis of data. In this study, trough FEV1 at week 26 significantly improved with QVA149 compared with indacaterol (mean difference, 70 mL; P < .01). All treatments were well tolerated. The overall incidence of AEs was similar across both treatment groups. The most frequently reported AE was a COPD exacerbation (28.9% and 32.1% in the QVA149 and indacaterol groups, respectively).

Current COPD guidelines recommend the combined use of LABAs and LAMAs when symptoms are not improved by a single agent.1 Given the different mechanisms and duration of action of these agents, they have the potential to provide better outcomes than the individual agents without increasing AEs. QVA149 is the first, once-daily, dual bronchodilator (indacaterol and glycopyrronium) available for the relief of symptoms in adult patients with COPD. QVA149 was approved in the European Union,25 Japan, and Canada26 in the second half of 2013, and the producer plans to file for US Food and Drug Administration approval of QVA149 toward the end of 2014.27 To our knowledge, this is the first systematic review performed to compare the efficacy and safety of this combination with its monocomponents and tiotropium. Our study found that dual bronchodilatation with QVA149, administered once daily, provided superior improvements in lung function compared with glycopyrronium and indacaterol (data from only one study) given alone, as well as tiotropium. QVA149 showed quite similar increases in trough FEV1 in the three comparisons. Of note, the MCID for trough FEV1 of 100 mL is generally used for comparisons vs placebo,2830 and mean improvements of 70 mL vs tiotropium, glycopyrronium, and indacaterol approach this threshold value. So the MCID in FEV1 remains an important but still undetermined issue for patients with COPD.29,30 Further, significant improvements in trough FEV1 were maintained during 26 to 64 weeks (compared with glycopyrronium and with tiotropium), and the onset of action was seen from the first day of treatment. It is interesting that data from a systematic review comparing a LABA (salmeterol, formoterol, or indacaterol) plus tiotropium combination vs tiotropium alone showed a significant mean increase in trough FEV1 of 60 mL.4

These beneficial effects of QVA149 on lung function were paralleled by significant improvements in other important outcomes such as dyspnea, health status, rescue medication use, and COPD exacerbations. Dyspnea is a major contributor to morbidity in COPD and is an independent predictor of poor survival.31 Patients treated with QVA149 had a greater likelihood of experiencing an MCID in TDI (≥ 1 unit) compared with those receiving tiotropium (NNTB = 11), indicating that one of every 11 patients treated with QVA149 obtained this benefit rather than those treated with tiotropium. Likewise, we found statistically significant improvements in total SGRQ score. However, again, the clinical relevance of these findings remains unclear because MCID differences were derived on the basis of differences vs placebo or changes from baseline rather than differences between two active treatments.2830 Even so, compared with tiotropium and glycopyrronium, QVA149-exposed patients had greater likelihood of achieving an MCID improvement in health status (NNTB = 11 and 12, respectively). Also, QVA149 therapy significantly reduced the risk of COPD exacerbations compared with tiotropium and glycopyrronium (NNTB = 19 and 25, respectively). Finally, QVA149 was well tolerated and no potential safety signals were observed with the combination compared with tiotropium, glycopyrronium, and indacaterol. The overall profile of cardiovascular safety was similar to that of the individual LAMAs.

This review was performed according to the methodologic criteria suggested for scientific guidelines.13 Inclusion criteria were clearly defined. Several relevant databases were searched for published and unpublished articles in any language. Risk of bias was formally assessed. The studies were very homogeneous and showed a high methodologic quality. Overall, the effect sizes were consistent and only a few comparisons showed evidence of a substantial heterogeneity. Although the small number of included trials can be considered a limitation of this review, it included a sample of nearly 5,000 subjects. However, several potential limitations should be considered. First, as previously stated, it is difficult to evaluate the clinical significance of spirometric and other clinical end points (ie, TDI and SGRQ). Second, due to the existence of a single study comparing QVA149 vs indacaterol, the findings of this review may not apply to this comparison. Third, tiotropium, chosen as an active comparator instead indacaterol because it is currently the most-used therapy in COPD, was administered in open-label fashion in all studies. Although we acknowledge that this fact might have affected some of the patient-reported outcomes, it should not bias the results in favor of QVA149, especially for objective end points. And finally, given the composition of the trials’ subjects, our results apply mainly to patients with moderate to severe COPD, and sparsely to those with very severe disease.

In September 2013, QVA149 was approved for the maintenance treatment of COPD in the European Union25 and then in Canada.26 It is available as capsules containing a powder for inhalation. Each capsule contains 110 μg indacaterol and 50 μg glycopyrronium. The delivered dose (the dose that leaves the mouthpiece of the inhaler) is 85 μg of indacaterol and 43 μg of glycopyrronium via the Breezhaler device (Novartis Pharma AG). Additionally, new combinations of LABAs and LAMAs agents are under development, namely, vilanterol/umeclidinium, olodaterol/tiotropium, and formoterol/aclidinium.32

In conclusion, once-daily QVA149 suggested superior efficacy compared with glycopyrronium, and with the current standard of care tiotropium, in patients with moderate to severe COPD. The current systematic review supports the concept that combining two bronchodilators may extend the improvements seen with single agents, without an increase in AEs. The suitability of once-daily dosing with QVA149, which is generally preferred by patients,33 and the need for only one inhaler might also help to reduce nonadherence to treatment, which remains high in COPD.3,34 Frequent dosing schedules for chronic diseases contribute to the poor and inconsistent adherence to therapy, which is a major impediment to the successful management of COPD.

Author contributions: G. J. R. served as principal author, had full access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. G. J. R. and V. P. contributed to study concept and design, data interpretation, revision of the article, and approval of the version to be published; G. J. R. contributed to data acquisition and analysis and drafted the article.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Rodrigo has participated as a lecturer, speaker, and advisor in scientific meetings and courses under the sponsorship of Air Products and Chemicals Inc, Almirall SA, AstraZeneca plc, Boehringer Ingelheim GmBH, Esteve SA, GlaxoSmithKline plc, Merck & Co Inc, and Novartis AG. Dr Plaza has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of AstraZeneca plc, GlaxoSmithKline plc, Esteve SA, and Merck & Co Inc.

AE

adverse event

LABA

long-acting β2-agonist

LAMA

long-acting muscarinic antagonist

MCID

minimal clinical important difference

NNTB

number needed to treat for benefit

QVA149

fixed-dose combination of indacaterol and glycopyrronium

SAE

serious adverse event

SCVE

serious cardiovascular event

SGRQ

St. George’s Respiratory Questionnaire

TDI

Transition Dyspnea Index

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Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest. 2002;121(5):1434-1440. [CrossRef] [PubMed]
 
Norman P. New dual-acting bronchodilator treatments for COPD, muscarinic antagonists and β2 agonists in combination or combined into a single molecule. Expert Opin Investig Drugs. 2013;22(12):1569-1580. [CrossRef] [PubMed]
 
Tamura G, Ohta K. Adherence to treatment by patients with asthma or COPD: comparison between inhaled drugs and transdermal patch. Respir Med. 2007;101(9):1895-1902. [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]
 

Figures

Figure Jump LinkFigure 1  Flowchart for identification of studies used.Grahic Jump Location
Figure Jump LinkFigure 2  Pooled mean difference for trough FEV1 (change from baseline) with 95% CIs of eligible studies comparing QVA149 vs tiotropium. df = degrees of freedom; QVA149 = fixed-dose combination of indacaterol and glycopyrronium.Grahic Jump Location
Figure Jump LinkFigure 3  A, Pooled relative risk for the number of patients with severe adverse events. B, Pooled relative risk for the number of patients with severe cardiovascular events, with 95% CIs of eligible studies comparing QVA149 vs tiotropium. M-H = Mantel-Haenszel. See Figure 2 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 4  Pooled mean difference for trough FEV1 (change from baseline) with 95% CIs of eligible studies comparing QVA149 vs glycopyrronium. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5  A, Pooled relative risk for the number of patients with severe adverse events. B, Pooled relative risk for the number of patients with severe cardiovascular events, with 95% CIs of eligible studies comparing QVA149 vs glycopyrronium. See Figure 2 and 3 legends for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Characteristics of Included Studies

AE = adverse event; DYS = dyspnea; EX = COPD exacerbation; GLY = glycopyrronium; HS = health status; IND = indacaterol; NA = data not available; OD = once daily; PL = placebo; QVA149 = fixed-dose combination of indacaterol and glycopyrronium; RMU = rescue medication use; TIO = tiotropium; WITH = withdrawal.

a 

Primary outcome.

Table Graphic Jump Location
TABLE 2  ] Effect of QVA149 vs Tiotropium on Secondary COPD Outcomes

MD = mean difference; NNTB = number needed to treat for benefit; RR = relative risk; SGRQ = St. George’s Respiratory Questionnaire; TDI = Transitional Dyspnea Index. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 3  ] Effect of QVA149 vs Glycopyrronium on Secondary COPD Outcomes

See Table 1 and 2 legends for expansion of abbreviations.

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Norman P. New dual-acting bronchodilator treatments for COPD, muscarinic antagonists and β2 agonists in combination or combined into a single molecule. Expert Opin Investig Drugs. 2013;22(12):1569-1580. [CrossRef] [PubMed]
 
Tamura G, Ohta K. Adherence to treatment by patients with asthma or COPD: comparison between inhaled drugs and transdermal patch. Respir Med. 2007;101(9):1895-1902. [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]
 
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