A Systematic Review of the Efficacy and Safety of a Fixed-Dose Combination of Umeclidinium and Vilanterol for the Treatment of COPD

[ Original Research COPD ] A Systematic Review of the Efficacy and Safety of a Fixed-Dose Combination of Umeclidinium and Vilanterol for the Treatment of COPD Gustavo J. Rodrigo, MD ; and Hugo Neffen, MD BACKGROUND: COPD guidelines recommend the combined use of inhaled long-acting b 2 -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 FEV, serious adverse events (SAEs), and serious cardiovascular events (SCVEs). RESULTS: Eleven trials from 0 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 FEV, 60, 0, 90, and 90 ml, respectively; P,.000). 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] 5 4 and 0, respectively). UMEC/VIL therapy significantly reduced the risk of COPD exacerbations compared with UMEC and VIL (NNTB 5 42 and 4, 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. CHEST 205; 48 ( 2 ): 397-407 Manuscript received January 3, 205; revision accepted February 20, 205; originally published Online First March 2, 205. ABBREVIATIONS: AE 5 adverse event; FSC 5 fluticasone propionate/ salmeterol; ICS 5 inhaled corticosteroid; LABA 5 long-acting b 2 -agonist; LAMA 5 long-acting muscarinic antagonist; MCID 5 minimal clinically important difference; NNTB 5 number needed to treat for benefit; SAE 5 serious adverse event; SCVE 5 serious cardiovascular event; SGRQ 5 St. George s Respiratory Questionnaire; TDI 5 Transition Dyspnea Index; UMEC 5 umeclidinium; VIL 5 vilanterol AFFILIATIONS: 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. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Gustavo J. Rodrigo, MD, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevideo 300, Uruguay; e-mail: gustavo.javier.rodrigo@gmail.com 205 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 0.378/chest.5-0084 journal.publications.chestnet.org 397

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. 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. 2-4 Current guidelines recommend the combined use of inhaled long-acting b 2 -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 oncedaily 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). Materials and Methods 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 CRD420405463. Published studies were identified from MEDLINE, EMBASE, CINAHL, SCOPUS, and the Cochrane Controlled Trials Register (CENTRAL) databases (February 205) using the terms umeclidinium or vilanterol or Anoro or GSK 57379 or GSK 642444 or longacting 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: () adult patients aged 40 years with stable moderate to very severe COPD according to the American Thoracic Society and the European Respiratory Society 9 or GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines 5 ; (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 FEV ), 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), 0 health status (St. George s Respiratory Questionnaire [SGRQ] total score), 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. 2 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. 3 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 I 2 test 4 ( 25%, absence; 26%-39%, unimportant; 40%-60%, moderate; and 60%-00%, 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. 5 As an a priori subgroup analysis, we analyzed the differences between UMEC/VIL doses (25 mg/25 m g vs 62.5 mg/25 mg ). Subgroups were compared using the residual x 2 test from the Peto ORs.6 Potential publication bias was analyzed quantitatively by means of Egger s regression using a significant level of P,.. 4 O t he r w is e, a P value of,.05 (two-tailed test) was considered significant. A metaanalysis was performed with Review Manager 5.3.5 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 204). Results The process of study selection is outlined in Figure. Ten studies with randomized controlled trials (9,609 patients) met the entry criteria. 6,7,7-24 One study included data from two different trials. 7 All were parallel group or crossover studies 9,20 and were sponsored by a single pharmaceutical company ( Table ). Five studies were unpublished, 9,20,22-24 five compared UMEC/VIL 25/25 m g or 62.5/25 m g vs VIL 25 mg,6,7,7,9,20 two vs tiotropium 8 m g, 7,2 six vs UMEC 25 mg or 62.5 mg, 6,7,7-20 and three vs fluticasone propionate/salmeterol (FSC) 250/50 m g. 22-24 Five studies included two or 398 Original Research [ 48 # 2 CHEST AUGUST 205 ]

( P 5.64). Concerning safety, there were no significant differences in SAEs (4.9% vs 6.2%) or SCVEs (0.9% vs.2%) between UMEC/VIL and UMEC ( Table 2 ). Figure Flowchart for identification of studies used. RCT 5 randomized controlled trial. more comparisons.6,7,7,9,20 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 multipledose inhaler (DISKUS, GlaxoSmithKline). Trials enrolled patients with stable COPD that was mostly moderate to severe (90% of patients had an average baseline FEV 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 2 to 52 weeks. All studies showed a low risk of bias in the six items of the Cochrane instrument. 3 UMEC/VIL vs UMEC Five trials compared UMEC/VIL 25/25 mg with UMEC 25 mg6,7,8-20 and three trials UMEC/VIL 62.5 mg with UMEC 62.5 mg. 7,9,20 Overall, UMEC/VIL was associated with a significant increase (mean change from baseline) in trough FEV ( P,.000) compared with UMEC monotherapy ( Fig A ). 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, 0, the minimum number recommended. 3 However, publication bias was not evident with Egger s test Regarding secondary outcomes ( Table 2 ), UMEC/VIL significantly increased the percentage of patients achieving a rise of. 00 ml above baseline in trough FEV (53.5% vs 44.0%, P,.000), the mean change from baseline in peak FEV at the end of treatment (00 ml, P,.000), the percentage of patients with a difference (MCID) in TDI at the end of treatment ( point) (56.4% vs 49.3%, NNTB 5 4), and the percentage of patients achieving an MCID in the SGRQ ( 4 points) (49.3% vs 42.0%, NNTB 5 6), 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 5 42), total withdrawals (6.8% vs 2.7%, NNTB 5 20), and withdrawals because of lack of efficacy (9.6% vs 25.2%, NNTB 5 49). There was no statistically significant difference in the number of deaths on treatment (0.% vs 0.6%). There was no evidence of significant heterogeneity among studies. In subgroup analysis defined by UMEC dose, there were no significant differences between UMEC 25 mg/vil 25 m g and UMEC 62.5 m g/vil 25 m g in all outcomes analyzed. UMEC/VIL vs VIL The analysis of five studies that compared UMEC/VIL (25/25 m g or 62.5 m g) with VIL 25 mg6,7,7,9,20 showed that the mean change from baseline in trough FEV increased significantly by 0 ml ( P,.000) at the end of treatment ( Fig 2B ). Publication bias was not evident with Egger s test ( P 5.69). Safety outcomes showed a significant decrease in SAEs (3.8% vs 6.2%, NNTB 5 4) and no statistical difference in SCVEs (0.48% vs.24%). UMEC/VIL significantly improved the percentage of patients achieving an increase of. 00 ml in trough FEV (53.6% vs 37.9%, NNTB 5 6) and the mean change from baseline in peak FEV at the end of treatment (20 ml, P,.000) (Table 3 ). Also, UMEC/VIL presented a 2% greater likelihood of experiencing an MCID in TDI (57.5% vs 47.5%, NNTB 5 0). Furthermore, UMEC/VIL reduced COPD exacerbations significantly (6.% vs 8.5%, NNTB 5 4), total withdrawals (6.3% vs 2.8%, NNTB 5 8), withdrawals because of lack of efficacy (4.% vs 7.0%, NNTB 5 33), and SAEs (3.8% vs 6.2%, NNTB 5 4) 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 journal.publications.chestnet.org 399

TABLE ] Characteristics of Included Studies Study/Year Location and Duration, wk Randomized Patients, No. (% Men) Mean Age, y Mean Baseline FEV, % Predicted Current Smokers, % Concomitant ICS, % Outcomes Measured Comparisons of Interest Celli et al 6 /204 MULT, 24,489 (65) 62 48 47 47 FEV (P), DIS, HS, EX, SAF UMEC/VIL 25/25 m g OD vs UMEC 25 m g OD vs VIL 25 m g OD Decramer et al 7 /204 Study MULT, 24 696 (69) 63 47 5 44 FEV (P), DIS, HS, EX, SAF UMEC/VIL 25/25 m g OD vs UMEC/VIL 62.5/25 m g OD vs TIO 8 m g OD vs VIL 25 m g OD Study 2 MULT, 24 869 (68) 64 47 45 52 FEV (P), DIS, HS, EX, SAF UMEC/VIL 25/25 m g OD vs UMEC/VIL 62.5/25 m g OD vs TIO 8 m g OD vs UMEC 25 m g OD Donohue et al 7 /203 MULT, 24,532 (7) 63 47 50 5 FEV (P), DIS, HS, EX, SAF UMEC/VIL 62.5/25 m g OD vs UMEC 62.5 m g OD vs VIL 25 m g OD Donohue et al 8 /204 MULT, 52 562 (67) 6 54 50 34 SAF (P), FEV, EX UMEC/VIL 25/25 m g OD vs UMEC 25 m g OD GSK 448 9 MULT, 2 307 (55) 63 45 47 48 FEV (P), SAF UMEC/VIL 25/25 m g OD vs UMEC/VIL 62.5/25 m g OD vs UMEC 25 m g OD vs UMEC 62.5 m g OD vs VIL 25 m g OD GSK 447 20 MULT, 2 348 (56) 62 45 60 5 FEV (P), SAF UMEC/VIL 25/25 m g OD vs UMEC/VIL 62.5/25 m g OD vs UMEC25 m g OD vs UMEC 62.5 m g OD vs VIL 25 m g OD Maleki-Yazdi et al 2 /204 MULT, 24 905 (68) 62 46 56 50 FEV (P), DIS, HS, EX, SAF UMEC/VIL 25/25 m g OD vs UMEC/VIL 62.5/25 m g OD GSK 4930 22 MULT, 2 905 (68) 62 47 49 5 FEV (P), SAF UMEC/VIL 62.5/25 m g OD vs FSC 250/50 m g bid GSK 634 23 MULT, 2 76 (72) 62 49 NA NA FEV (P), SAF UMEC/VIL 62.5/25 m g OD vs FSC 500/50 m g bid GSK 495 24 MULT, 2 700 (76) 63 47 48 48 FEV (P), SAF UMEC/VIL 62.5/25 m g OD vs FSC 250/50 m g bid DIS 5 dyspnea; EX 5 COPD exacerbation; FSC 5 fl uticasone propionate/salmeterol; HS 5 health status; ICS 5 inhaled corticosteroid; MULT 5 Multicenter; NA 5 data not available; OD 5 once daily; P 5 primary outcome; SAF 5 safety; TIO 5 tiotropium; UMEC 5 umeclidinium; VIL 5 vilanterol. 400 Original Research [ 48 # 2 CHEST AUGUST 205 ]

TABLE 2 ] Effect of UMEC/VIL vs UMEC on COPD Outcomes Outcome Study/Year No. Estimate Effect (95% CI) I 2 % ( P Value) Percent of patients achieving an increase. 00 ml above baseline in trough FEV Donohue et al 7 /203,007 RR.22 (. to.33) 0 (.000) NNTB 9 (6 to 4) Mean change from baseline in peak FEV at the end of treatment difference in TDI at end of treatment ( point) difference in SGRQ at end of treatment ( 4 points) Patients with at least one COPD exacerbation Donohue et al 7 /203; GSK 448 9 ; GSK 447 20 Donohue et al 7 /203 Donohue et al 7 /203 Donohue et al 7 /203 Total withdrawals Donohue et al 7 /203; Donohue et al 8 /204; GSK 448 9 ; GSK 447 20 Withdrawals because of AEs Donohue et al 7 /203; Donohue et al 8 /204; GSK 448 9 ; GSK 447 20 Withdrawals because of lack of efficacy Donohue et al 7 /203; Donohue et al 8 /204; GSK 448 9 ; GSK 447 20 Any AE Donohue et al 7 /203; Donohue et al 8 /204; GSK 448 9 ; GSK 447 20 2,280 MD 20.0 ( 2.20 to 20.80) 52 (.000),09 RR.4 (.05 to.24) 0 (.002) NNTB 4 (9 to 38) 875 RR.4 (.04 to.26) 0 (.007) NNTB 6 (9 to 59) 2,078 RR 0.74 (0.54 to 0.98) 0 (.04) NNTB 42 (2 to 0) 3,268 RR 0.87 (0.76 to 0.98) 0 (.03) NNTB 20 (0 to 294) 3,268 RR 0.80 (0.60 to.06) 0 (.9) 3,268 RR 0.69 (0.5 to 0.94) 0 (.02) NNTB 49 (28 to 245) 3,268 RR.00 (0.93 to.07) 0 (.98) (Continued) journal.publications.chestnet.org 40

TABLE 2 ] (continued) Outcome Study/Year No. Estimate Effect (95% CI) I 2 % ( P Value) SAEs Higgens et al 4 /2003; Borenstein et al 5 /2009; Deeks et al 6 /200; Donohue et al 7 /203 SCVEs Donohue et al 7 /203; Donohue et al 8 /204 3,268 RR 0.87 (0.66 to.6) 0 (.36) 2,544 RR 0.75 (0.36 to.58) 30 (.45) Deaths on treatment Donohue et al 7 /203; Donohue et al 8 /204; GSK 448 9 ; GSK 447 20 3,268 RD 20.0 ( 20.0 to 0.00) (.29) AE 5 adverse event; MD 5 mean difference; NNTB 5 number needed to treat for benefit; RD 5 risk difference; RR 5 relative risk; SAE 5 serious adverse event; SCVE 5 serious cardiovascular event; SGRQ 5 St. George s Respiratory Questionnaire; TDI 5 Transition Dyspnea Index. See Table legend for expansion of other abbreviations. (45.4% vs 45.%), and in the rate of deaths on treatment (0.6% 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. UMEC/VIL vs Tiotropium Three trials from two studies presented this comparison. 7,2 One study included two different trials. 7 Data showed that trough FEV at the end of treatment (as mean change from baseline) improved significantly with UMEC/VIL compared with tiotropium (mean difference, 90 ml; P,.000) (Egger s test P 5.53) ( Fig 2C ). There were no significant differences in the rates of SAEs (4.9% vs 4.7%) or SCVEs (0.5% vs 0.38%) among UMEC/VIL and tiotropium ( Table 4 ). Also, UMEC/VIL significantly improved the percentage of patients achieving an increase of. 00 ml in trough FEV (55.8% vs 43.7%, NNTB 5 8), and also increased peak FEV (mean change from baseline, 80 ml; P,.000). 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. UMEC/VIL vs FSC Three trials were included in this analysis. 22-24 The mean change from baseline of trough FEV was significantly higher with UMEC/VIL than with FSC (90 ml, P,.000) (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 ). Discussion 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 FEV in the four comparisons. In assessing this finding, it should be noted that the MCID for a trough FEV of 00 ml is generally used for comparisons vs placebo,25,27,28 and that mean improvements between 60 to 20 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. 00 ml above baseline in trough FEV 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 FEV compared 402 Original Research [ 48 # 2 CHEST AUGUST 205 ]

Figure 2 A-D, Pooled mean difference for trough FEV (change from baseline, L) with 95% CIs of eligible studies comparing UMEC/VIL and A, UMEC; B, VIL; C, tiotropium; and D, FSC. df 5 degrees of freedom; FSC 5 fluticasone/salmeterol; UMEC 5 umeclidinium; VIL 5 vilanterol. journal.publications.chestnet.org 403

TABLE 3 ] Effect of UMEC/VIL vs VIL on COPD Outcomes Outcome Study/Year No. Estimate Effect (95% CI) I 2 % ( P Value) Percent of patients achieving an increase. 00 ml above baseline in trough FEV Donohue et al 7 /203,22 RR.4 (.29 to.54) 0 (.000) NNTB 6 (5 to 8) Mean change from baseline in peak FEV at the end of treatment difference in TDI at end of treatment ( point) difference in SGRQ at end of treatment ( 4 points) Patients with at least one COPD exacerbation Donohue et al 7 /203; GSK 448 9 ; GSK 447 20 Donohue et al 7 /203 Donohue et al 7 /203 Donohue et al 7 /203 Total withdrawals Donohue et al 7 /203; GSK 448 9 ; GSK 447 20 Withdrawals because of AEs Donohue et al 7 /203; GSK 448 9 ; GSK 447 20 Withdrawals because of lack of efficacy Donohue et al 7 ; GSK 448 9 ; GSK 447 20 Any AE Donohue et al 7 /203; GSK 448 9 ; GSK 447 20 SAEs Donohue et al 7 /203; GSK 448 9 ; GSK 447 20 SCVEs Donohue et al 7 /203 Deaths on treatment Donohue et al 7 /203; GSK 448 9 ; GSK 447 20 2,565 MD 20.2 ( 20.5 to 20.0) 82 (.000),200 RR.2 (.2 to.3) 0 (.000) NNTB 0 (7 to 7) 2,24 RR.06 (0.97 to.5) 0 (.22) 2,466 RR 0.72 (0.54 to 0.95) 0 (.02) NNTB 4 (22 to 297) 3,39 RR 0.78 (0.64 to 0.96) 0 (.02) NNTB 8 (0 to 58) 3,39 RR 0.88 (0.65 to.8) 0 (.52) 3,39 RR 0.62 (0.4 to 0.94) 0 (.02) NNTB 33 (2 to 73) 3,39 RR.02 (0.95 to.0) 0 (.56) 3,39 RR 0.68 (0.50 to 0.92) 9 (.04) NNTB 4 (22 to 532) 2,286 RR 0.42 (0.6 to.08) 42 (.07) 3,39 RD 20.00 ( 20.0 to 0.00) 0 (.75) See Table and 2 legends for expansion of abbreviations. 404 Original Research [ 48 # 2 CHEST AUGUST 205 ]

TABLE 4 ] Effect of UMEC/VIL vs Tiotropium on COPD Outcomes Outcome Study/Year No. Estimate Effect (95% CI) I 2 % ( P Value) Percent of patients achieving an increase. 00 ml above baseline in trough FEV Decramer et al 7 /204,664 RR.28 (.6 to.4) 34 (.0003) Mean change from baseline in peak FEV at the end of treatment NNTB 8 (6 to 3) Decramer et al 7 /204,366 MD 20.08 ( 20.09 to 20.07) 45 (.000) difference in TDI at end of treatment ( point) Maleki-Yazdi et al 2 /204 2,455 RR.04 (0.96 to.2) 0 (.40) difference in SGRQ at end of treatment ( 4 points) Decramer et al 7 /204,502 RR 0.97 (0.88 to.07) 0 (.56) Patients with at least one COPD exacerbation Maleki-Yazdi et al 2 /204 Total withdrawals Maleki-Yazdi et al 2 /204 Withdrawals because of AEs Maleki-Yazdi et al 2 /204 Withdrawals because of lack of efficacy Maleki-Yazdi et al 2 /204 Any AE Maleki-Yazdi et al 2 /204 SAEs Maleki-Yazdi et al 2 /204 SCVEs Higgens et al 4 /2003 Deaths on treatment Higgens et al 4 /2003 2,588 RR.04 (0.77 to.40) 39 (.80) 2,609 RR. (0.93 to.32) 2 (.23) 2,609 RR.06 (0.78 to.44) 0 (.72) 2,609 RR 0.70 (0.49 to.0) 0 (.06) 2,609 RR.09 (0.98 to.5) 0 (.06) 2,609 RR.05 (0.75 to.48) 62 (.76) 2,609 RD 20.00 ( 20.0 to 0.00) 2,609 RD 20.00 ( 20.0 to 0.00) 0 (.66) 0 (.2) See Table and 2 legends for expansion of abbreviations. with UMEC, VIL, tiotropium, and FSC (90-20 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 5 4 and 0, respectively). On the other hand, UMEC/VIL increased significantly the probability of achieving an MCID in the SGRQ compared with UMEC (NNTB 4), but not with VIL. In addition, UMEC/VIL therapy significantly reduced the risk of COPD exacerbations compared with UMEC and VIL (NNTB 5 42 and 4, 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 m g by the US Food and Drug Administration. 26 In December 203, 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 journal.publications.chestnet.org 405

TABLE 5 ] Effect of UMEC/VIL vs FSC on COPD Outcomes Outcome Study No. Estimate Effect (95% CI) I 2 % ( P Value) Total withdrawals GSK 4930 22 ; GSK 634 23 ; GSK 495 24 2,23 RR 0.88 (0.66 to.7) 42 (.38) Withdrawals because of AEs Withdrawals because of lack of efficacy GSK 4930 22 ; GSK 634 23 ; GSK 495 24 GSK 4930 22 ; GSK 634 23 ; GSK 495 24 2,23 RR 0.76 (0.44 to.3) 0 (.32) 2,23 RR.9 (0.6 to 2.29) 0 (.6) Any AE GSK 4930 22 ; GSK 634 23 ; GSK 495 24 SAEs GSK 4930 22 ; GSK 634 23 ; GSK 495 24 SCVEs GSK 4930 22 ; GSK 634 23 ; GSK 495 24 Deaths on treatment GSK 4930 22 ; GSK 634 23 ; GSK 495 24 2,23 RR 0.96 (0.84 to.0) 0 (.52) 2,23 RR 0.96 (0.55 to.67) 44 (.88) 2,23 RR.00 (0.25 to 3.98) 0 (.99) 2,23 RD 0.00 ( 20.00 to 0.0) 0 (.68) See Table and 2 legends for expansion of abbreviations. concurrent medications throughout the study, including ICS up to a maximum daily dose of,000 mg 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 Conclusions 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. 406 Original Research [ 48 # 2 CHEST AUGUST 205 ]

Acknowledgments 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. 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