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Original Research: COPD |

A Systematic Review of the Efficacy and Safety of a Fixed-Dose Combination of Umeclidinium and Vilanterol for the Treatment of COPDUmeclidinium/Vilanterol for COPD FREE TO VIEW

Gustavo J. Rodrigo, MD; Hugo Neffen, MD
Author and Funding Information

From the Departamento de Emergencia (Dr Rodrigo), Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay; and Unidad de Medicina Respiratoria (Dr Neffen), Hospital de Niños “O. Allassia,” Santa Fe, Argentina.

CORRESPONDENCE TO: Gustavo J. Rodrigo, MD, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, 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. 2015;148(2):397-407. doi:10.1378/chest.15-0084
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BACKGROUND:  COPD 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. This systematic review tested the hypothesis that the bronchodilator effect of the LABA/LAMA combination, umeclidinium (UMEC)/vilanterol (VIL), would translate into better outcomes without incurring increased adverse events (AEs).

METHODS:  This was a systematic review of randomized, placebo-controlled or crossover trials (> 4 weeks) involving UMEC/VIL compared with its monocomponents, tiotropium, or fluticasone/salmeterol. Primary outcomes were trough FEV1, serious adverse events (SAEs), and serious cardiovascular events (SCVEs).

RESULTS:  Eleven trials from 10 studies (9,609 patients) showed that UMEV/VIL provided superior improvements in lung function compared with UMEC, VIL, tiotropium, and fluticasone propionate/salmeterol (mean trough FEV1, 60, 110, 90, and 90 mL, respectively; P < .0001). Also, UMEC/VIL had a greater likelihood of demonstrating a minimal clinically important difference on the Transition Dyspnea Index compared with UMEC and VIL (number needed to treat for benefit [NNTB] = 14 and 10, respectively). UMEC/VIL therapy significantly reduced the risk of COPD exacerbations compared with UMEC and VIL (NNTB = 42 and 41, respectively). On the contrary, we noted no significant differences between UMEC/VIL and tiotropium with respect to dyspnea, health status, or risk of COPD exacerbation. Regarding safety issues, the incidence of AEs, SAEs, SCVEs, and mortality on treatment was similar across treatments, suggesting reduced safety concerns with the use of the UMEC/VIL combination.

CONCLUSIONS:  Once-daily inhaled UMEC/VIL showed superior efficacy compared with its monocomponents, tiotropium, and fluticasone/combination in patients with moderate to severe COPD.

Figures in this Article

Bronchodilators are the cornerstone of pharmacologic therapy of COPD. They reduce symptoms and the frequency and severity of exacerbations and improve health status and exercise tolerance.1 In moderate to severe COPD, the coadministration of different bronchodilator classes has been established to be more effective in subjective and objective COPD parameters in comparison with the use of a single drug class.24 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.5 In the past 2 years, at least two LABA/LAMA fixed-dose combinations have been licensed in Europe. One involves the combination of umeclidinium (UMEC) and vilanterol (VIL) (UMEC/VIL) (Anoro Ellipta; GlaxoSmithKline). UMEC/VIL is an inhaled, fixed-dose combination of two 24-h bronchodilators, the LAMA UMEC and the LABA VIL, as a once-daily treatment of COPD. Recent trials have shown that UMEC/VIL has a good safety profile and provides significant and sustained improvements in lung function compared with its monocomponents or tiotropium.6,7 The aim of this systematic review was to assess all available evidence on the efficacy and safety of the combination UMEC/VIL compared with its monocomponents and tiotropium, or a combination of LABA plus inhaled corticosteroid (ICS), for the treatment of COPD. The hypothesis was that the bronchodilator effect of UMEC/VIL would translate into better outcomes without incurring increased adverse events (AEs).

Search and Selection Criteria

We adopted Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform this systematic review.8 This study was registered in the International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/PROSPERO) as CRD42014015463.

Published studies were identified from MEDLINE, EMBASE, CINAHL, SCOPUS, and the Cochrane Controlled Trials Register (CENTRAL) databases (February 2015) using the terms “umeclidinium” or “vilanterol” or “Anoro” or “GSK 573719” or “GSK 642444” or “long-acting beta2-agonists” or “long-acting antimuscarinics” and “chronic obstructive pulmonary disease” or “COPD.” In addition, we performed a search of relevant files from the drug manufacturer’s database (http://www.gsk-clinicalstudyregister.com/) and from the ClinicalTrials.gov registry of clinical trials (http://clinicaltrials.gov/). The search was without language restriction and included unpublished studies. Trials published solely in abstract form were excluded.

To be included, studies had to meet all the following criteria: (1) adult patients aged ≥ 40 years with stable moderate to very severe COPD according to the American Thoracic Society and the European Respiratory Society9 or GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines5; (2) a comparison of inhaled UMEC/VIL and UMEC or VIL or tiotropium, or a LABA/ICS combination; (3) randomized (parallel group or crossover) controlled trials of > 4 weeks’ duration; and (4) report at least one of the following outcomes: pulmonary function (trough or predose FEV1), 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),10 health status (St. George’s Respiratory Questionnaire [SGRQ] total score),11 COPD exacerbations, withdrawals (total, and caused by AEs or lack of efficacy), AEs and mortality on treatment as secondary outcomes. An SAE was defined as any untoward medical occurrence that sometimes results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, or results in persistent or significant disability/incapacity.12

Data Extraction and Assessment of Risk of Bias

Titles, abstracts, and citations were analyzed independently by the two authors (G. J. R. and H. N.). From the full text, we 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, we assessed eligibility. The authors were involved independently in all stages of study selection, data extraction, and risk of bias assessment. The last was assessed according to recommendations outlined in the Cochrane Handbook.13 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), Mantel-Haenszel risk ratios, or risk differences. The precision of the estimates was quantified by 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 test14 (≤ 25%, absence; 26%-39%, unimportant; 40%-60%, moderate; and 60%-100%, substantial). A fixed-effects model was used when there was no evidence of significant heterogeneity in the analysis. If significant heterogeneity was found, a random-effects model was used.15 As an a priori subgroup analysis, we analyzed the differences between UMEC/VIL doses (125 μg/25 μg vs 62.5 μg/25 μg). Subgroups were compared using the residual χ2 test from the Peto ORs.16 Potential publication bias was analyzed quantitatively by means of Egger’s regression using a significant level of P < .1.14 Otherwise, a P value of < .05 (two-tailed test) was considered significant. A meta-analysis was performed with Review Manager 5.3.5 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

The process of study selection is outlined in Figure 1. Ten studies with 11 randomized controlled trials (9,609 patients) met the entry criteria.6,7,1724 One study included data from two different trials.7 All were parallel group or crossover studies19,20 and were sponsored by a single pharmaceutical company (Table 1). Five studies were unpublished,19,20,2224 five compared UMEC/VIL 125/25 μg or 62.5/25 μg vs VIL 25 μg,6,7,17,19,20 two vs tiotropium 18 μg,7,21 six vs UMEC 125 μg or 62.5 μg,6,7,1720 and three vs fluticasone propionate/salmeterol (FSC) 250/50 μg.2224 Five studies included two or more comparisons.6,7,17,19,20 UMEC/VIL, UMEC, or VIL were administered via a multiple-dose dry powder inhaler (ELLIPTA; GlaxoSmithKline), tiotropium via a single-dose dry powder inhaler (HANDIHALER, Boehringer-Ingelheim GmbH), and FSC via a multiple-dose inhaler (DISKUS, GlaxoSmithKline). Trials enrolled patients with stable COPD that was mostly moderate to severe (90% of patients had an average baseline FEV1 of 48% predicted). The mean age of patients was 62 years (68% men). Approximately 50% of patients were current smokers and were treated concomitantly with an ICS. The duration of studies ranged from 12 to 52 weeks. All studies showed a low risk of bias in the six items of the Cochrane instrument.13

Figure Jump LinkFigure 1 –  Flowchart for identification of studies used. RCT = randomized controlled trial.Grahic Jump Location
Table Graphic Jump Location
TABLE 1 ]  Characteristics of Included Studies

DIS = dyspnea; EX = COPD exacerbation; FSC = fluticasone propionate/salmeterol; HS = health status; ICS = inhaled corticosteroid; MULT = Multicenter; NA = data not available; OD = once daily; P = primary outcome; SAF = safety; TIO = tiotropium; UMEC = umeclidinium; VIL = vilanterol.

UMEC/VIL vs UMEC

Five trials compared UMEC/VIL 125/25 μg with UMEC 125 μg6,7,1820 and three trials UMEC/VIL 62.5 μg with UMEC 62.5 μg.17,19,20 Overall, UMEC/VIL was associated with a significant increase (mean change from baseline) in trough FEV1 (P < .0001) compared with UMEC monotherapy (Fig 1A). At the end of treatment, the mean difference was 60 mL. Heterogeneity among studies was moderate, and funnel plot tests were not performed because the number of selected studies was < 10, the minimum number recommended.13 However, publication bias was not evident with Egger’s test (P = .64). Concerning safety, there were no significant differences in SAEs (4.9% vs 6.2%) or SCVEs (0.9% vs 1.2%) between UMEC/VIL and UMEC (Table 2).

Table Graphic Jump Location
TABLE 2 ]  Effect of UMEC/VIL vs UMEC on COPD Outcomes

AE = adverse event; MD = mean difference; NNTB = number needed to treat for benefit; RD = risk difference; RR = relative risk; SAE = serious adverse event; SCVE = serious cardiovascular event; SGRQ = St. George’s Respiratory Questionnaire; TDI = Transition Dyspnea Index. See Table 1 legend for expansion of other abbreviations.

Regarding secondary outcomes (Table 2), UMEC/VIL significantly increased the percentage of patients achieving a rise of > 100 mL above baseline in trough FEV1 (53.5% vs 44.0%, P < .0001), the mean change from baseline in peak FEV1 at the end of treatment (100 mL, P < .0001), the percentage of patients with a minimal clinically important difference (MCID) in TDI at the end of treatment (≥ 1 point) (56.4% vs 49.3%, NNTB = 14), and the percentage of patients achieving an MCID in the SGRQ (≥ 4 points) (49.3% vs 42.0%, NNTB = 16), compared with UMEC alone.25 On the other hand, UMEC/VIL reduced significantly the number of patients with at least one COPD exacerbation (6.4% vs 8.6%, NNTB = 42), total withdrawals (16.8% vs 21.7%, NNTB = 20), and withdrawals because of lack of efficacy (19.6% vs 25.2%, NNTB = 49). There was no statistically significant difference in the number of deaths on treatment (0.11% vs 0.61%). There was no evidence of significant heterogeneity among studies. In subgroup analysis defined by UMEC dose, there were no significant differences between UMEC 125 μg/VIL 25 μg and UMEC 62.5 μg/VIL 25 μg in all outcomes analyzed.

UMEC/VIL vs VIL

The analysis of five studies that compared UMEC/VIL (125/25 μg or 62.5 μg) with VIL 25 μg6,7,17,19,20 showed that the mean change from baseline in trough FEV1 increased significantly by 110 mL (P < .0001) at the end of treatment (Fig 2B). Publication bias was not evident with Egger’s test (P = .69). Safety outcomes showed a significant decrease in SAEs (3.8% vs 6.2%, NNTB = 41) and no statistical difference in SCVEs (0.48% vs 1.24%). UMEC/VIL significantly improved the percentage of patients achieving an increase of > 100 mL in trough FEV1 (53.6% vs 37.9%, NNTB = 6) and the mean change from baseline in peak FEV1 at the end of treatment (120 mL, P < .0001) (Table 3). Also, UMEC/VIL presented a 21% greater likelihood of experiencing an MCID in TDI (57.5% vs 47.5%, NNTB = 10). Furthermore, UMEC/VIL reduced COPD exacerbations significantly (6.1% vs 8.5%, NNTB = 41), total withdrawals (16.3% vs 21.8%, NNTB = 18), withdrawals because of lack of efficacy (4.1% vs 7.0%, NNTB = 33), and SAEs (3.8% vs 6.2%, NNTB = 41) compared with VIL. Finally, there were nonsignificant differences in the percentage of patients achieving an MCID in the SGRQ, in the rate of withdrawals because of AEs, in the rate of AEs (45.4% vs 45.1%), and in the rate of deaths on treatment (0.16% vs 0.45%). There was no evidence of significant heterogeneity among studies, and subgroup analysis revealed no significant differences between both doses of UMEC/VIL in any of the outcomes measured.

Figure Jump LinkFigure 2 –  A-D, Pooled mean difference for trough FEV1 (change from baseline, L) with 95% CIs of eligible studies comparing UMEC/VIL and A, UMEC; B, VIL; C, tiotropium; and D, FSC. df = degrees of freedom; FSC = fluticasone/salmeterol; UMEC = umeclidinium; VIL = vilanterol.Grahic Jump Location
Table Graphic Jump Location
TABLE 3 ]  Effect of UMEC/VIL vs VIL on COPD Outcomes

See Table 1 and 2 legends for expansion of abbreviations.

UMEC/VIL vs Tiotropium

Three trials from two studies presented this comparison.7,21 One study included two different trials.7 Data showed that trough FEV1 at the end of treatment (as mean change from baseline) improved significantly with UMEC/VIL compared with tiotropium (mean difference, 90 mL; P < .0001) (Egger’s test P = .53) (Fig 2C). There were no significant differences in the rates of SAEs (4.9% vs 4.7%) or SCVEs (0.15% vs 0.38%) among UMEC/VIL and tiotropium (Table 4). Also, UMEC/VIL significantly improved the percentage of patients achieving an increase of > 100 mL in trough FEV1 (55.8% vs 43.7%, NNTB = 8), and also increased peak FEV1 (mean change from baseline, 80 mL; P < .0001). The remaining variables showed no significant differences between UMEC/VIL and tiotropium. Again, the analysis of most of the outcomes did not present heterogeneity, and the subgroup analysis did not show any statistically significant difference between the two doses of UMEC/VIL.

Table Graphic Jump Location
TABLE 4 ]  Effect of UMEC/VIL vs Tiotropium on COPD Outcomes

See Table 1 and 2 legends for expansion of abbreviations.

UMEC/VIL vs FSC

Three trials were included in this analysis.2224 The mean change from baseline of trough FEV1 was significantly higher with UMEC/VIL than with FSC (90 mL, P < .0001) (Fig 2C). There were no differences in the remaining variables. The pooled analysis was homogeneous, and subgroup analysis did not show any difference (Table 5).

Table Graphic Jump Location
TABLE 5 ]  Effect of UMEC/VIL vs FSC on COPD Outcomes

See Table 1 and 2 legends for expansion of abbreviations.

Given the different mechanisms and durations of action of the LABA/LAMA combination, the use of these agents has the potential to provide better outcomes than the individual agents without increasing adverse effects. One of these combinations is the UMEC/VIL combination, recently licensed in United States.26 To our knowledge, this is the first systematic review to compare the efficacy and safety of the UMEC/VIL combination with its monocomponents, tiotropium and FSC. Our study found that dual bronchodilatation with UMEC/VIL administered once daily, provided superior bronchodilation compared with UMEC, VIL, tiotropium and FSC. UMEC/VIL showed quite similar increases in trough FEV1 in the four comparisons. In assessing this finding, it should be noted that the MCID for a trough FEV1 of 100 mL is generally used for comparisons vs placebo,25,27,28 and that mean improvements between 60 to 120 mL vs UMEC, VIL, tiotropium, and FSC, approach this threshold value. However, this remains an important but still undetermined issue for patients with COPD, because the MCID for direct comparisons between UMEC/VIL and monocomponents has not yet been established.3,29 Most important was the finding that the percentage of patients achieving an increase > 100 mL above baseline in trough FEV1 was significantly higher with UMEC/VIL than with all comparators (NNTB 6 to 9). Additionally, patients receiving UMEC/VIL showed a significant increase in peak FEV1 compared with UMEC, VIL, tiotropium, and FSC (90-120 mL). Regarding safety issues, the incidence of AEs, SAEs, and SCVEs and mortality on treatment was similar across treatments, suggesting reduced safety concerns with the use of the UMEC/VIL combination. Finally, these findings are very similar to those found in previous studies with other LABA/LAMA combinations.3,4

The improvement of UMEC/VIL in lung function was associated with improvements in patient-reported dyspnea, health status, and COPD exacerbations. Patients treated with UMEC/VIL had a greater likelihood of experiencing an MCID on the TDI compared with those treated with UMEC and VIL (NNTB = 14 and 10, respectively). On the other hand, UMEC/VIL increased significantly the probability of achieving an MCID in the SGRQ compared with UMEC (NNTB 14), but not with VIL. In addition, UMEC/VIL therapy significantly reduced the risk of COPD exacerbations compared with UMEC and VIL (NNTB = 42 and 41, respectively). On the contrary, we noted no significant differences with respect to dyspnea, health status, and risk of COPD exacerbation between UMEC/VIL and tiotropium. Again, the clinical relevance of these findings remains unclear for the same reasons set out relative to lung function. Both doses of UMEC/VIL were equally effective and safe, without significant differences in any of the variables analyzed, supporting the selection of the dose of 62.5/25 μg by the US Food and Drug Administration.26 In December 2013, UMEC/VIL (Anoro Ellipta; GlaxoSmithKline) was approved for the maintenance treatment of COPD by the US Food and Drug Administration.

Several potential limitations of this review should be considered. First, as stated previously, it is difficult to evaluate the clinical significance of spirometric and other clinical end points. Second, the impact of permitted concurrent medications throughout the study, including ICS up to a maximum daily dose of 1,000 μg fluticasone propionate or equivalent in about 50% of patients, still remains unknown. And finally, given the composition of the trials sample, our results apply to patients with moderate to severe COPD. In fact, the population characteristics of this review were similar to those of other studies of LAMA/LABA combinations.3

Taken together, our findings support the efficacy and safety of UMEC/VIL for the treatment of moderate to severe COPD. However, according to the guidelines,5 monotherapy should be the first choice for maintenance treatment in patients with stable COPD, whereas LAMA/LABA combination therapy should be recommended in patients with COPD who remain symptomatic or have exacerbations despite treatment with a LAMA or LABA. Therefore, it is very important to establish whether there is a real advantage in using the combination UMEC/VIL instead of UMEC, VIL, or tiotropium alone. According to our review, the use of UMEC/VIL presents advantages compared with UMEC and VIL in terms of improvements in lung function, dyspnea, health-related quality of life, and COPD exacerbations. Still, the advantages of UMEC/VIL over tiotropium are less clear, consisting only of an improvement in lung function. A key question here is whether this benefit of UMEC/VIL leads to a significant and clinically meaningful improvement in the patient. This finding would suggest that although a comparison UMEC and tiotropium was not made in this study, the benefits were lower with tiotropium than with UMEC. Thus, it is crucial to know how UMEC differs not only from tiotropium, but also from other LAMAs. Additionally, trials comparing a UMEC/VIL fixed-dose combination with other dual bronchodilator fixed-dose combinations are needed to assess the real advantages of UMEC/VIL over other therapies. The economic impact of the use of this combination should also be considered (cost-benefit analysis). And finally, we must consider the problem of adherence. Suboptimal adherence to inhaled treatments is very common among patients with COPD. The suitability of once-daily dosing and the need for only one inhaler may help reduce nonadherence to treatment.29,30 In this regard, a UMEC/VIL combination fully meets such a requirement. Thus, although small in terms of efficacy, the advantage of an UMEC/VIL combination could be increased by improving adherence.

Author contributions: G. J. R. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. G. J. R. contributed to the acquisition and analysis of the data and drafting of the submitted article; and G. J. R. and H. N. contributed to the conception and design of the study, interpretation of the data, critical revision of the article for important intellectual content, and final approval of the version to be published.

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, AstraZeneca, Boehringer-Ingelheim GmbH, Laboratorios del Dr Esteve SA, GlaxoSmithKline, Merck Sharp and Dohme, and Novartis AG. Dr Neffen has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Schering-Plough Corporation, GlaxoSmithKline, Novartis AG, and AstraZeneca.

AE

adverse event

FSC

fluticasone propionate/salmeterol

ICS

inhaled corticosteroid

LABA

long-acting β2-agonist

LAMA

long-acting muscarinic antagonist

MCID

minimal clinically important difference

NNTB

number needed to treat for benefit

SAE

serious adverse event

SCVE

serious cardiovascular event

SGRQ

St. George’s Respiratory Questionnaire

TDI

Transition Dyspnea Index

UMEC

umeclidinium

VIL

vilanterol

Cazzola M, Segreti A, Matera MG. New developments in the combination treatment of COPD: focus on umeclidinium/vilanterol. Drug Des Devel Ther. 2013;7:1201-1208. [CrossRef] [PubMed]
 
Rodrigo GJ, Plaza V, Castro-Rodríguez JA. Comparison of three combined pharmacological approaches with tiotropium monotherapy in stable moderate to severe COPD: a systematic review. Pulm Pharmacol Ther. 2012;25(1):40-47. [CrossRef] [PubMed]
 
Rodrigo GJ, Plaza V. Efficacy and safety of a fixed-dose combination of indacaterol and Glycopyrronium for the treatment of COPD: a systematic review. Chest. 2014;146(2):309-317. [CrossRef] [PubMed]
 
Rodrigo GJ, Plaza V. Efficacy and safety of indacaterol and glycopyrronium in COPD: an update. Chest. 2014;146(2):e75. [CrossRef] [PubMed]
 
Global initiative for the diagnosis, management, and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) website. http://www.goldcopd.com/uploads/users/files/GOLD_Report_2014_Oct30.pdf. Updated 2014. Accessed December 15, 2014.
 
Celli B, Crater G, Kilbride S, et al. Once-daily umeclidinium/vilanterol 125/25 mcg therapy in COPD: a randomized, controlled study. Chest. 2014;145(5):981-991. [CrossRef]
 
Decramer M, Anzueto A, Kerwin E, et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med. 2014;2(6):472-486. [CrossRef] [PubMed]
 
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W65-W94. [CrossRef] [PubMed]
 
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]
 
Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir Med. 1991;85(suppl B):25-31. [CrossRef] [PubMed]
 
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]
 
Clinical safety data management: definitions and standards for expedited reporting. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) website. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_Guideline.pdf. Accessed December 11, 2014.
 
Higgins JP, Altman DG, Gøtzsche PC, et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. [CrossRef] [PubMed]
 
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560. [CrossRef] [PubMed]
 
Borenstein M, Hedges LV, Higgins JPT, et al. Introduction to Meta-analysis. Chichester, England: John Wiley and Sons, Ltd; 2009.
 
Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity, combining results from several studies in meta-analysis.. In:Egger M, Smith Altman DG., eds. Systematic Reviews in Health Care: Meta-analysis in Context. London, England: BMJ; 2001:285-312.
 
Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013;107(10):1538-1546. [CrossRef] [PubMed]
 
Donohue JF, Niewoehner D, Brooks J, O’Dell D, Church A. Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. Respir Res. 2014;15:78. [PubMed]
 
GSK. An exercise endurance study to evaluate the effects of treatment of chronic obstructive pulmonary disease (COPD) patients with a dual bronchodilator: GSK573719/GW642444. Study B. Protocol ID 114418 (NCT01323660). GSK Clinical Study Register. http://www.gsk-clinicalstudyregister.com/study/114418?study_ids=114418#rs. Accessed December 10, 2014.
 
GSK. An exercise endurance study to evaluate the effects of treatment of chronic obstructive pulmonary disease (COPD) patients with a dual bronchodilator: GSK573719/GW642444. Study A. Protocol ID 114417 (NCT01328444). GSK Clinical Study Register. http://www.gsk-clinicalstudyregister.com/study/114417?study_ids=114417#rs. Accessed December 10, 2014.
 
Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Respir Med. 2014;108(12):1752-1760. [CrossRef] [PubMed]
 
GSK. An exercise endurance study to evaluate the effects of treatment of chronic obstructive pulmonary disease (COPD) patients with a dual bronchodilator: GSK573719/GW642444. Study A. Protocol ID 114930 (NCT01817764). GSK Clinical Study Register. http://www.gsk-clinicalstudyregister.com/study/114930?study_ids=114930#rs. Accessed December 10, 2014.
 
GSK. A randomized, multi-center, double-blind, double-dummy, parallel group study to evaluate the efficacy and safety of umeclidinium bromide/vilanterol compared with fluticasone propionate/salmeterol over 12 weeks in subjects with COPD. Protocol ID 116134 (NCT01822899). GSK Clinical Study Register. http://www.gsk-clinicalstudyregister.com/study/116134?study_ids=116134#rs. Accessed December 10, 2014.
 
GSK. A randomized, multi-center, double-blind, double-dummy, parallel group study to evaluate the efficacy umeclidinium/vilanterol compared with fluticasone propionate/salmeterol over 12 weeks in subjects with COPD. Protocol ID 114951 (NCT01879410). GSK Clinical Study Register. http://www.gsk-clinicalstudyregister.com/study/114951?study_ids=114951#rs. Accessed December 10, 2014.
 
Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha JA. Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med. 2014;189(3):250-255. [CrossRef] [PubMed]
 
FDA approves Anoro Ellipta to treat chronic obstructive pulmonary disease. US Food and Drug Administration. website. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm379057.htm. December 18, 2013. Accessed December 8, 2014.
 
Cazzola M, MacNee W, Martinez FJ, et al; American Thoracic Society; European Respiratory Society Task Force on outcomes of COPD. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J. 2008;31(2):416-469. [CrossRef] [PubMed]
 
Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 2005;2(1):111-124. [CrossRef] [PubMed]
 
Vestbo J, Anderson JA, Calverley PM, et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax. 2009;64(11):939-943. [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. RCT = randomized controlled trial.Grahic Jump Location
Figure Jump LinkFigure 2 –  A-D, Pooled mean difference for trough FEV1 (change from baseline, L) with 95% CIs of eligible studies comparing UMEC/VIL and A, UMEC; B, VIL; C, tiotropium; and D, FSC. df = degrees of freedom; FSC = fluticasone/salmeterol; UMEC = umeclidinium; VIL = vilanterol.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Characteristics of Included Studies

DIS = dyspnea; EX = COPD exacerbation; FSC = fluticasone propionate/salmeterol; HS = health status; ICS = inhaled corticosteroid; MULT = Multicenter; NA = data not available; OD = once daily; P = primary outcome; SAF = safety; TIO = tiotropium; UMEC = umeclidinium; VIL = vilanterol.

Table Graphic Jump Location
TABLE 2 ]  Effect of UMEC/VIL vs UMEC on COPD Outcomes

AE = adverse event; MD = mean difference; NNTB = number needed to treat for benefit; RD = risk difference; RR = relative risk; SAE = serious adverse event; SCVE = serious cardiovascular event; SGRQ = St. George’s Respiratory Questionnaire; TDI = Transition Dyspnea Index. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 3 ]  Effect of UMEC/VIL vs VIL on COPD Outcomes

See Table 1 and 2 legends for expansion of abbreviations.

Table Graphic Jump Location
TABLE 4 ]  Effect of UMEC/VIL vs Tiotropium on COPD Outcomes

See Table 1 and 2 legends for expansion of abbreviations.

Table Graphic Jump Location
TABLE 5 ]  Effect of UMEC/VIL vs FSC on COPD Outcomes

See Table 1 and 2 legends for expansion of abbreviations.

References

Cazzola M, Segreti A, Matera MG. New developments in the combination treatment of COPD: focus on umeclidinium/vilanterol. Drug Des Devel Ther. 2013;7:1201-1208. [CrossRef] [PubMed]
 
Rodrigo GJ, Plaza V, Castro-Rodríguez JA. Comparison of three combined pharmacological approaches with tiotropium monotherapy in stable moderate to severe COPD: a systematic review. Pulm Pharmacol Ther. 2012;25(1):40-47. [CrossRef] [PubMed]
 
Rodrigo GJ, Plaza V. Efficacy and safety of a fixed-dose combination of indacaterol and Glycopyrronium for the treatment of COPD: a systematic review. Chest. 2014;146(2):309-317. [CrossRef] [PubMed]
 
Rodrigo GJ, Plaza V. Efficacy and safety of indacaterol and glycopyrronium in COPD: an update. Chest. 2014;146(2):e75. [CrossRef] [PubMed]
 
Global initiative for the diagnosis, management, and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) website. http://www.goldcopd.com/uploads/users/files/GOLD_Report_2014_Oct30.pdf. Updated 2014. Accessed December 15, 2014.
 
Celli B, Crater G, Kilbride S, et al. Once-daily umeclidinium/vilanterol 125/25 mcg therapy in COPD: a randomized, controlled study. Chest. 2014;145(5):981-991. [CrossRef]
 
Decramer M, Anzueto A, Kerwin E, et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med. 2014;2(6):472-486. [CrossRef] [PubMed]
 
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W65-W94. [CrossRef] [PubMed]
 
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]
 
Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir Med. 1991;85(suppl B):25-31. [CrossRef] [PubMed]
 
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]
 
Clinical safety data management: definitions and standards for expedited reporting. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) website. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_Guideline.pdf. Accessed December 11, 2014.
 
Higgins JP, Altman DG, Gøtzsche PC, et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. [CrossRef] [PubMed]
 
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560. [CrossRef] [PubMed]
 
Borenstein M, Hedges LV, Higgins JPT, et al. Introduction to Meta-analysis. Chichester, England: John Wiley and Sons, Ltd; 2009.
 
Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity, combining results from several studies in meta-analysis.. In:Egger M, Smith Altman DG., eds. Systematic Reviews in Health Care: Meta-analysis in Context. London, England: BMJ; 2001:285-312.
 
Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013;107(10):1538-1546. [CrossRef] [PubMed]
 
Donohue JF, Niewoehner D, Brooks J, O’Dell D, Church A. Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. Respir Res. 2014;15:78. [PubMed]
 
GSK. An exercise endurance study to evaluate the effects of treatment of chronic obstructive pulmonary disease (COPD) patients with a dual bronchodilator: GSK573719/GW642444. Study B. Protocol ID 114418 (NCT01323660). GSK Clinical Study Register. http://www.gsk-clinicalstudyregister.com/study/114418?study_ids=114418#rs. Accessed December 10, 2014.
 
GSK. An exercise endurance study to evaluate the effects of treatment of chronic obstructive pulmonary disease (COPD) patients with a dual bronchodilator: GSK573719/GW642444. Study A. Protocol ID 114417 (NCT01328444). GSK Clinical Study Register. http://www.gsk-clinicalstudyregister.com/study/114417?study_ids=114417#rs. Accessed December 10, 2014.
 
Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Respir Med. 2014;108(12):1752-1760. [CrossRef] [PubMed]
 
GSK. An exercise endurance study to evaluate the effects of treatment of chronic obstructive pulmonary disease (COPD) patients with a dual bronchodilator: GSK573719/GW642444. Study A. Protocol ID 114930 (NCT01817764). GSK Clinical Study Register. http://www.gsk-clinicalstudyregister.com/study/114930?study_ids=114930#rs. Accessed December 10, 2014.
 
GSK. A randomized, multi-center, double-blind, double-dummy, parallel group study to evaluate the efficacy and safety of umeclidinium bromide/vilanterol compared with fluticasone propionate/salmeterol over 12 weeks in subjects with COPD. Protocol ID 116134 (NCT01822899). GSK Clinical Study Register. http://www.gsk-clinicalstudyregister.com/study/116134?study_ids=116134#rs. Accessed December 10, 2014.
 
GSK. A randomized, multi-center, double-blind, double-dummy, parallel group study to evaluate the efficacy umeclidinium/vilanterol compared with fluticasone propionate/salmeterol over 12 weeks in subjects with COPD. Protocol ID 114951 (NCT01879410). GSK Clinical Study Register. http://www.gsk-clinicalstudyregister.com/study/114951?study_ids=114951#rs. Accessed December 10, 2014.
 
Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha JA. Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med. 2014;189(3):250-255. [CrossRef] [PubMed]
 
FDA approves Anoro Ellipta to treat chronic obstructive pulmonary disease. US Food and Drug Administration. website. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm379057.htm. December 18, 2013. Accessed December 8, 2014.
 
Cazzola M, MacNee W, Martinez FJ, et al; American Thoracic Society; European Respiratory Society Task Force on outcomes of COPD. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J. 2008;31(2):416-469. [CrossRef] [PubMed]
 
Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 2005;2(1):111-124. [CrossRef] [PubMed]
 
Vestbo J, Anderson JA, Calverley PM, et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax. 2009;64(11):939-943. [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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