Online Data Supplement

LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a

systematic review and meta-analysis

Gustavo J Rodrigo, David Price, Antonio Anzueto, Dave Singh, Pablo Altman, Giovanni

Bader, Francesco Patalano, Robert Fogel, Konstantinos Kostikas

 

Methods

Literature Search and Terms used

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)

guidelines were used to perform this systematic review (Liberati et al 2015). Literature

searches were performed from the earliest available date until August 2015, and were

conducted in PubMed/MEDLINE, Embase, and Cochrane Library databases. Searches for

relevant studies were also performed on https://clinicaltrials.gov/, the National Institutes of

Health clinical trial database, and on drug manufacturer’s databases (Novartis,

https://www.novartisclinicaltrials.com/TrialConnectWeb/home.nov; GSK. http://www.gsk-

clinicalstudyregister.com/; AstraZeneca, http://www.astrazenecaclinicaltrials.com/;

Boehringer Ingelheim, https://www.boehringer-ingelheim.com/clinical_trials.html). The

search terms used included: long-acting β2-agonists (indacaterol, vilanterol, formoterol,

olodaterol) OR long-acting antimuscarinics (glycopyrronium, umeclidinium, aclidinium,

tiotropium) OR QVA149, Ultibro, Anoro, Duaklir, Spiolto AND chronic obstructive

pulmonary disease or COPD. Literature searches were without language restriction, and

included unpublished studies. The bibliographies of studies included in the meta-analysis

were also manually screened to identify additional studies. Trials published solely in

abstract form were excluded because the methods and results could not be fully analyzed.

Inclusion criteria

For inclusion in the meta-analysis, studies were required to be of a randomized, parallel

group, controlled design of greater than 4 weeks’ duration, and which compared

LABA/LAMA FDCs with single-agent LAMAs or LABA/ICS combinations. The studies were

to have been conducted in adult patients aged ≥ 40 years with stable moderate-to-very

severe COPD according to the American Thoracic Society and the European Respiratory

(ATS-ERS1) or GOLD guidelines (GOLD 2015, Celli et al 2004).

Study treatments were restricted to all currently available LABA/LAMA combinations at the

approved doses of these combinations and their comparators (in the US or EU) as shown

in Table S1.

Table S1: Currently available COPD treatments used in the studies

LABA/LAMA FDCs LAMA LABA/ICS

IND/GLY 110/50 μg OD TIO 18 μg OD SAL/FP 50/250 BID

IND/GLY 27.5/15.6 μg BID TIO 5 μg OD SAL/FP; 50/500 μg BID

UMEC/VI 62.5/25 μg OD GLY 50 μg OD FOR/BUD; 4.5/80 μg BID

ACLI/FOR 400/12 μg BID GLY12.5 μg BID FOM/BUD; 4.5/160 μg BID

TIO/OLO 5/5 μg OD UMEC 62.5 μg OD

ACLI 400 μg BID

ACLI, aclidinium; BID, twice daily; BUD, budesonide; FP, fluticasone propionate; FOR, formoterol; GLY,

glycopyrronium; IND, indacaterol; OD, once dailiy; SAL, salmeterol; TIO, tiotropium; UMEC, umeclidinium;

VI, vilanterol.

Trials employing the same treatments and dose regimens were allocated to the same

study subgroup to enable comparisons to be made between treatments; this is

recommended for meta-analyses that include only a few studies per subgroup (Borenstein

et al 2009). The overall treatment effect for all study subgroups combined enabled

comparisons to be made for each drug class.

Selected studies were also required to report at least one of the following outcomes: lung

function (trough/pre- or post-dose and/or peak FEV1); dyspnea (i.e., Transitional Dyspnea

Index [TDI] total score); health status (i.e., St. George’s Respiratory Questionnaire

[SGRQ] total score); rescue medication use (reduction in number of puffs/day); COPD

exacerbations; pneumonia incidence; safety (frequency of adverse events [AE], serious

AEs [SAE], and cardiac/cardiovascular events); withdrawal from treatment (due to AEs or

to lack of efficacy); or mortality while on treatment.

The primary outcome was trough FEV1; secondary outcomes included peak FEV1,

Transitional Dyspnea Index (TDI), Saint George’s Respiratory Questionnaire (SGRQ),

rescue medication use, and adverse events (AEs). For efficacy endpoints, the effect of

study treatments was established at protocolled time points for each individual trial

(Weeks 12, 24 or 26, and 52, dependent on the trial). Safety outcomes were assessed

throughout the entire duration of the trials.

Study Selection, Data Extraction and Risk of Bias Assessment

The study selection process is described in Figure S1.

Based on study inclusion criteria, two authors (GR and DP) reviewed the search results for

potentially relevant article titles and abstracts. When necessary, full text articles were

retrieved. The reviewers worked independently during all stages of study selection and

data extraction. Disagreements between reviewers, if any, were to be resolved by

discussion to obtain a consensus in the group. In the event, there were no disagreements

and a total of 18 studies (comprising 23 clinical trials in total) fulfilled the eligibility criteria;

all were included in the analysis (N=20,185).

The risk of bias of eligible trials was assessed by applying the Cochrane collaborations

tool (Higgins et al 2011a). Results are detailed below.

Data Analysis

Outcomes were pooled as forest plots using mean differences (inverse variance [IV] or

generic IV method), Mantel-Haenszel risk ratios (RRs), or risk differences (RDs). The

precision of the estimates was quantified with 95% confidence intervals (CIs).

Heterogeneity was assessed using the I2 test (0% to 40%, unimportant; 30% to 60%,

moderate; 50% to 90%, substantial; and 75% to 100%: considerable heterogeneity)

(Higgins et al 2011b). However, as the selected studies differed in the mixes of

participants and interventions, a random-effects model was used in all outcomes to

address the variation across studies (Borenstein et al 2009).

In studies comparing a LABA/LAMA FDC with two subgroups of LAMA, the subgroups

were combined using the formulae described in the Cochrane Handbook (Higgins et al

2011b). For analysis, CIs and standard errors (SE) of mean were converted to SE and

standard deviation, respectively, as per the formulae in the Cochrane Handbook (Higgins

et al 2011b).

For studies that reported results only in graphical form, numerical values from the graphs

were extracted using Adobe® Reader® XI inbuilt measuring tool, version 11.0.06, (Adobe

Systems Incorporated, San Jose [California]).

Publically available clinical study reports of trial data were used whenever necessary to

pool maximum data for analysis.

Subgroup analyses were performed for each LABA/LAMA FDC versus LAMA or

LABA/ICS. When effect estimates were significantly different between groups, the number

needed to treat for benefit (NNTB) or for harm (NNTH) was calculated

(http://graphpad.com/quickcalcs/NNT1/) with 95% CIs. In all analyses P-values were

based on a two-tailed test with P < 0.05 considered statistically significant. The meta-

analysis of selected studies was performed using Review Manager, version 5.3.5 software

(Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

Risk of Bias Assessment:

The risk of bias within each of the eligible trials was assessed by applying the Cochrane

collaborations tool (Higgins et al 2011a) and assessing the potential of biasing results for

each of the following fields: random sequence generation, allocation concealment,

methods of blinding, incomplete data and selective reporting.

Across the six items of the Cochrane instrument, the majority of the studies were judged to

have a low risk of bias (Figure S2). Within individual trials, however, one study (Asai et al

2013; Novartis sponsored CQVA149A1301) had an open-label design so there was no

blinding of patients, providers or outcome assessors, and in another (Decramer et al 2014;

GSK sponsored), outcome data were incomplete (potentially introducing attrition bias).

Each of these trials was considered to be at high risk of bias. In addition, in some trials,

details of the following were not provided: methods for generating the random sequence (3

trials), allocation concealment (6 trials), blinding of patients, providers and outcome

assessors (2 trials). In addition, outcome data were incomplete in 6 trials and selective

reporting was assumed in 7 trials (Figure S3).

Effect of Treatment on Remaining Outcomes and Time points

Figures S4 to S14 show the effect of each treatment on the outcomes and time points

that are not included in the main body of the manuscript.

   

References

S1. 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. PLoS Med 2009: 6: e1000100.

S2. GOLD. Global initiative for chronic obstructive lung disease (GOLD): Global Strategy for the Diagnosis, Management, and Prevention of chronic obstructive pulmonary disease. 2017; Available from: http://www.goldcopd.com

S3. 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. The European respiratory journal 2004: 23: 932-946.

S4. 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. 2011a;343:d5928. BMJ 2011; 343: d5928.

S5. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011b. Available from www.cochrane-handbook.org.

S6. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to meta-analysis. Chichester (West Sussex): John Wiley & Songs, Ltd., 2009.

S7. Asai K, Minakata Y, Hirata K, et al. QVA149 once-daily is safe and well tolerated and improves lung function and health status in Japanese patients with COPD: The ARISE study. 2013.

S8. 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: 472-486.

S9. Bateman ED, Ferguson GT, Barnes N, Gallagher N, Green Y, Henley M, Banerji D. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. The European respiratory journal 2013: 42(6): 1484-1494.

S10. Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandstrom T, Taylor AF, D'Andrea P, Arrasate C, Chen H, Banerji D. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. The Lancet Respiratory medicine 2013: 1(3): 199-209.

S11. Larbig M, Taylor AF, Maitra S, Schubert-Tennigkeit A, Banerji D. Efficacy and safety of IND/GLY (indacaterol/glycopyrronium) versus placebo and tiotropium in symptomatic patients with moderat-to-severe COPD: the 52-week RADIATE study. Respirology (Carlton, Vic) 2015; 20: A438.

S12. Mahler DA, Kerwin E, Ayers T, FowlerTaylor A, Maitra S, Thach C, Lloyd M, Patalano F, Banerji D. FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease. American journal of respiratory and critical care medicine 2015: 192(9): 1068-1079.

S13. 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: 472-486.

S14. Donohue JF, Maleki-Yazdi MR, Kilbride S, et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. . Respiratory medicine 2013: 107: 1538-1546.

S15. Maleki-Yazdi MR, Kaelin T, Richard N, et al. 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. Respiratory medicine 2014: 108: 1752-1760.

S16. D'Urzo AD, Rennard S, Kerwin EM, et al. AUGMENT COPD study investigators. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res. 2014;15:123. Respiratory research 2014: 15: 123.

S17. Singh D, Jones PW, Bateman ED, et al. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. . BMC pulmonary medicine 2014: 14: 178.

S18. Buhl R, Maltais F, Abrahams R, et al. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4). The European respiratory journal 2015: 45: 969-979.

S19. Singh D, Ferguson GT, Bolitschek J, et al. Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. . Respiratory medicine 2015: 109: 1312-1319.

S20. Vogelmeier CF, Bateman ED, Pallante J, Alagappan VK, D'Andrea P, Chen H, Banerji D. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. The Lancet Respiratory medicine 2013: 1(1): 51-60.

S21. Zhong N, Wang C, Zhou X, et al. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. International journal of chronic obstructive pulmonary disease 2015: 10: 1015-1026.

S22. Donohue JF, Worsley S, Zhu CQ. Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbations. Respiratory medicine 2015: 109: 870-881.

S23. Singh D, Worsley S, Zhu CQ, et al. Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial. . BMC pulmonary medicine 2015: 15: 91.

S24. Vogelmeier C, Paggiaro PL, Dorca J, Sliwinski P, Mallet M, Kirsten AM, Beier J, Seoane B, Segarra RM, Leselbaum A. Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study. Eur Respir J. 2016 Aug 4. pii: ERJ-00216-2016. doi: 10.1183/13993003.00216-2016. [Epub ahead of print]

 

Figure S1: PRISMA flow diagram identifying studies included in the meta-analysis Study selection process

 

 

Figure S2: Overall risk of bias assessment for all component studies

 

Figure S3: Methodological quality summary: reviewers’ judgements for each component trial. Green indicates a low risk of bias, yellow an unclear risk, and red a high risk.

Figure S4: Pooled mean difference for trough FEV1 (change from baseline, L) at (a) weeks 24-26 and (b) week 52, with 95% CIs for eligible studies comparing approved doses of LABA/LAMA combinations with approved LAMAs.

(a)

(b)

 

Figure S5: Pooled mean difference for peak FEV1 at weeks 12 and 24-26, with 95% CIs for eligible studies comparing approved doses of LABA/LAMA combinations with (a) approved LAMAs and (b) approved LABA/ICS..

a) (i) At week 12

(ii) At weeks 24-26

b) (i) At week 12

 

(ii) At weeks 24-26

Figure S6: Pooled mean difference for TDI focal score at weeks 12 and 24-26, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMA combinations with (a) approved LAMAs and (b) approved LABA/ICS combinations.

(a) (i) At week 12

(ii)At week 24

(b) (i) At week 12

(ii) At week 26

 

Figure S7: Pooled mean difference for SGRQ total score at weeks 12, 24-26, and 52, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMA combinations with (a) approved LAMAs and (b) approved LABA/ICS combinations.

(a)(i) At week 12

(ii)At week 24

 

(iii) At week 52

 

(b) (i) At week 12

(ii) At week 26

 

Figure S8: Pooled mean difference with 95% CIs for reduction in rescue medication use (puffs per day) at end of treatment for eligible studies comparing approved doses of LABA/LAMA combinations with (a) approved LAMAs and (b) approved LABA/ICS combinations.

(a)

 

(b)

 

Figure S9: Pooled relative risk of SAE incidence at end of treatment, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMAs with approved doses of (a) LAMAs and (b) LABA/ICS combinations.

(a)

(b)

Figure S10: Pooled relative risk of pneumonia incidence, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMAs with approved doses of LAMAs

   

Figure S11: Pooled relative risk of cardiac/cardiovascular disorders, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMAs with (a) approved doses of LAMAs and (b) LABA/ICS

(a)

 

(b)

Figure S12: Pooled relative risk of deaths, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMAs with (a) approved doses of LAMAs and (b) LABA/ICS

(a)

(b)

Figure S13: Pooled relative risk of withdrawals due to AEs, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMAs with approved doses of (a) LAMAs and (b) LABA/ICS

(a)

(b)

Figure S14: Pooled relative risk of withdrawals due to lack of efficacy, with 95% CIs, for eligible studies comparing approved doses of LABA/LAMAs with approved doses of (a) LAMAs and (b) LABA/ICS

(a)

(b)