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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included unpublished studies.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
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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)