Double bronchodilation in chronic obstructive pulmonary disease: a crude analysis from a systematic review

Abstract

Objective
The combination of a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA) in a single inhaler is a viable treatment option for patients with chronic obstructive pulmonary disease (COPD). Here, we systematically review the current knowledge on double bronchodilation for the treatment of COPD, with a specific focus on its efficacy versus placebo and/or monotherapy bronchodilation.

Methods
A systematic review of clinical trials investigating LABA/LAMA combination therapies was conducted. Articles were retrieved from PubMed, Embase, and Scopus on June 26, 2016. We specifically selected clinical trials with a randomized controlled or crossover design published in any scientific journal showing the following characteristics: 1) comparison of different LABA/LAMA combinations in a single inhaler for patients with COPD, 2) dose approved in Europe, and 3) focus on efficacy (versus placebo and/or bronchodilator monotherapy) in terms of lung function, respiratory symptoms, or exacerbations.

Results
We analyzed 26 clinical trials conducted on 24,338 patients. All LABA/LAMA combinations were consistently able to improve lung function compared with both placebo and bronchodilator monotherapy. Improvements in symptoms were also consistent versus placebo, showing some lack of correlation for some clinical end points and combinations versus monotherapy bronchodilation. Albeit being an exploratory end point, exacerbations showed an improvement with LABA/LAMA combinations over placebo in some trials; however, scarce information was available in comparison with bronchodilator monotherapy in most studies.

Conclusion
Our data show consistent improvements for LABA/LAMA combinations, albeit with some variability (depending on the clinical end point, the specific combination, and the comparison group). Clinicians should be aware that these are average differences. All treatments should be tailored at the individual level to optimize clinical outcomes.

Full text

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Open Access Full Text Article
http://dx.doi.org/10.2147/COPD.S132962
Double bronchodilation in chronic obstructive
pulmonary disease: a crude analysis from a
systematic review
Jose Luis Lopez-Campos1,2
Carmen Calero-Acuña1,2
Eduardo Márquez-Martín1
Esther Quintana Gallego1,2
Laura Carrasco-Hernández1
Maria Abad Arranz1
Francisco Ortega Ruiz1,2
1Virgen del Rocio University Hospital,
Biomedicine Institute of Seville (IBiS),
Hospital Universitario Virgen del
Rocío, Universidad de Sevilla, Sevilla,
Spain; 2Centro de Investigación
Biomédica en Red de Enfermedades
Respiratorias (CIBERES), Instituto de
Salud Carlos III, Madrid, Spain
Objective: The combination of a long-acting muscarinic antagonist (LAMA) and a long-acting
β2-agonist (LABA) in a single inhaler is a viable treatment option for patients with chronic
obstructive pulmonary disease (COPD). Here, we systematically review the current knowledge
on double bronchodilation for the treatment of COPD, with a specific focus on its efficacy versus
placebo and/or monotherapy bronchodilation.
Methods: A systematic review of clinical trials investigating LABA/LAMA combination
therapies was conducted. Articles were retrieved from PubMed, Embase, and Scopus on June 26,
2016. We specifically selected clinical trials with a randomized controlled or crossover design
published in any scientific journal showing the following characteristics: 1) comparison of dif-
ferent LABA/LAMA combinations in a single inhaler for patients with COPD, 2) dose approved
in Europe, and 3) focus on efficacy (versus placebo and/or bronchodilator monotherapy) in
terms of lung function, respiratory symptoms, or exacerbations.
Results: We analyzed 26 clinical trials conducted on 24,338 patients. All LABA/LAMA
combinations were consistently able to improve lung function compared with both placebo
and bronchodilator monotherapy. Improvements in symptoms were also consistent versus
placebo, showing some lack of correlation for some clinical end points and combinations versus
monotherapy bronchodilation. Albeit being an exploratory end point, exacerbations showed an
improvement with LABA/LAMA combinations over placebo in some trials; however, scarce
information was available in comparison with bronchodilator monotherapy in most studies.
Conclusion: Our data show consistent improvements for LABA/LAMA combinations, albeit
with some variability (depending on the clinical end point, the specific combination, and the
comparison group). Clinicians should be aware that these are average differences. All treatments
should be tailored at the individual level to optimize clinical outcomes.
Keywords: COPD, bronchodilators, efficacy, systematic review
Introduction
Different combinations of a long-acting muscarinic antagonist (LAMA) and a long-
acting β2-agonist (LABA) in a single inhaler are gaining popularity for the treatment
of chronic obstructive pulmonary disease (COPD).1–3 Owing to their promising
pharmacological efficacy4 and safety,5 LABA/LAMA fixed-dose combination (FDC)
therapies – also known as double bronchodilation –6 are increasingly considered as a
viable therapeutic option for patients with COPD.
Four commercial LABA/LAMA FDCs are currently available in Europe. They
include the indacaterol/glycopyrronium (IND/GLY), umeclidinium/vilanterol
(UMEC/VIL), aclidinium/formoterol (ACLI/FOR), and tiotropium/olodaterol
Correspondence: Jose Luis
Lopez-Campos
Instituto de Biomedicina de Sevilla (IBiS),
Hospital Universitario Virgen del Rocío,
Avenida Manuel Siurot, s/n. 41013
Seville, Spain
Tel/fax +34 95 501 3167
Email lopezcampos@separ.es
Journal name: International Journal of COPD
Article Designation: Original Research
Year: 2017
Volume: 12
Running head verso: Lopez-Campos et al
Running head recto: Double bronchodilation in COPD
DOI: http://dx.doi.org/10.2147/COPD.S132962
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Lopez-Campos et al
(TIO/OLO) combinations. Each combination had undergone
a specific development program and clinical trial testing to
assess its efficacy and safety for patients with COPD. Unfor-
tunately, no direct head-to-head comparison of the available
combinations has been performed yet, the only exception
being a clinical trial assessing tiotropium/indacaterol versus
UMEC/VIL.7 The results of this study indicated similar
improvements in lung function and patient-reported out-
comes over a 12-week period, with comparable tolerability
and safety profiles.7
With direct comparison studies being lacking, indirect
comparisons may be useful to guide clinical decision making.
To date, at least 4 meta-analyses have assessed the compara-
tive efficacy and safety of different double combinations in
patients with COPD.8–11 Moreover, 1 review found small
mean improvements in health-related quality of life and
forced expiratory volume in the first second of expiration
(FEV1) for patients who received a combination of tiotro-
pium and LABA compared with either agent alone.12 Taken
together, these data indicate that 1) all LAMA/LABA FDCs
are characterized by similar efficacy and safety11 and 2) they
performed better than a LAMA or a LABA alone (regardless
of the drugs used).10
However, these analyses are methodologically limited by
the approach used for meta-analyses,13 mainly consisting in
the grouping of different combinations into a unique category9
and/or the collapsing of different monotherapy components
into a single group.10 Unfortunately, this approach may
overlook the specific differences in terms of efficacy of
different LABA/LAMA FDCs. In this context, we reasoned
that a clear, comprehensive, and useful summary of clinical
trial data for the four LABA/LAMA FDCs available in
Europe may be clinically useful. Specifically, this knowl-
edge would provide clinicians with useful information on
the expected outcomes of double bronchodilation in COPD.
Here, we systematically review the current knowledge
on double bronchodilation for the treatment of COPD,
with a specific focus on its efficacy versus placebo and/or
bronchodilator monotherapy. Although direct comparisons
were not feasible, an assessment of average improvements
of different efficacy end points helps clinicians to forecast
the expected average benefits, ultimately informing clinical
decision making.
Methods
A systematic review of clinical trials investigating LABA/
LAMA combination therapies was conducted. Articles were
retrieved from PubMed, Embase, and Scopus on June 26, 2016.
We performed a separate search for each of the available
combinations using the following queries: “QVA149[title]
OR (indacaterol[title] AND glycopyrronium[title])” for the
IND/GLY combination; “umeclidinium[title] AND vilanterol
[title]” for the UMEC/VIL combination; “aclidinium[title]
AND formoterol[title]” for the ACLI/FOR combination;
and “tiotropium[title] AND olodaterol[title]” for the TIO/
OLO combination. Results were filtered using the follow-
ing criteria: 1) “clinical trial” in PubMed; 2) “randomized
controlled trial” and “crossover procedure” (as study type)
in Embase; and 3) “article” (as document type) in Scopus.
We retrieved all the abstracts and selected the clinical trials
with the following characteristics: 1) randomized controlled
or crossover design published in any scientific journal and
conducted in patients with COPD; 2) no language restric-
tions; 3) comparison of each LABA/LAMA FDC in a single
inhaler; 4) dose approved in Europe; and 5) availability of
efficacy data in terms of lung function, respiratory symptoms,
or exacerbations versus placebo, tiotropium, or monotherapy
bronchodilation (using either LABA or LAMA). Because
some articles contained information derived from 2 different
trials, both the number of articles and trials were counted.
Studies comparing double bronchodilation therapy with an
inhaled corticosteroid and LABA combinations or inves-
tigations based on post hoc analyses of patient subgroups
included in previous trials were excluded. We also excluded
the following trials: 1) studies available in a congress
abstract form with an associated full-length article, 2) studies
evaluating doses different from those currently approved in
Europe, 3) studies without a comparison with either placebo
or bronchodilator monotherapy, 4) studies evaluating two
bronchodilators not combined in the same inhaler, 5) studies
providing no efficacy data on lung function, symptoms,
or exacerbations, 6) studies that were not original clinical
research, and 7) studies conducted in patients other than
COPD. After identification of the articles of interest and in
an effort to control for potential publication bias, we also
contacted the Spanish national representatives of the four
companies commercializing the four combinations in Spain.
Our aim was to search for any new trial available in a poster
form presented at international congresses. Posters were
evaluated with the same approach used for original articles;
specifically, posters that met the inclusion criteria were
incorporated in the analysis (even when the data were not
available in a full-length article format). We also reviewed the
poster versions of the selected articles to verify the potential
presence of any additional information not provided in the
corresponding full-length article.

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Double bronchodilation in COPD
Upon selection of all studies (ie, both articles and posters),
the complete content was reviewed, and information on lung
function, symptoms, and exacerbations was retrieved. All the
efficacy data were culled from the last visit (ie, at the end of
each trial) in the intention-to-treat population. Lung function
parameters of interest included FEV1 5 minutes post morning
dose (as a measure of the rapid onset of action), peak FEV1
(defined as the highest FEV1 after morning dose), trough
FEV1 (morning pre-dose), and FEV1 area under the curve
from 0 to 24 hours post morning dose (FEV1 AUC0–24).
The following symptoms were recorded: 1) dyspnea
measured by the transitional dyspnea index (TDI); we specifi-
cally focused on the mean improvements on this scale and
the percentage of patients who showed an improvement of
at least 1 TDI point (which is considered the minimum clini-
cally important difference [MCID]), expressed as percentage
or odds ratio; 2) health-related quality of life as measured
by the St George’s Respiratory Questionnaire (SGRQ); we
specifically focused on the mean improvements on this scale
and the percentage of patients who showed an improvement
of at least 4 points in the questionnaire (which is considered
the MCID), expressed as percentage or odds ratio; 3) rescue
medications, as measured in puffs per day (over a 24-hour
period); and 4) exercise capacity, as measured by either the
endurance time on an exercise test or the endurance shuttle
walking test; we specifically focused on the increase during
endurance tests (expressed in seconds) as well as on the
percentage of increase. We also aimed to include an assess-
ment of daily activities; unfortunately, only the BLAZE14
and MOVE15 trials focusing on the IND/GLY combination
reported such data.
Although exacerbations were not an ad hoc end point
in most trials, available information on exacerbations was
examined; specifically, we collected both the number of
exacerbations occurring during the course of the studies
(expressed as annualized rate ratios) and the time to the first
exacerbation (expressed as hazard ratios). The extent to
which exacerbations were reduced was assessed for all exac-
erbations and moderate-to-severe exacerbations separately.
All the collected efficacy data were summarized in
an Excel spreadsheet, which was shared and checked for
accuracy with the Spanish Medical Departments of the four
pharmaceutical companies developing the four FDCs. The
mean values at the end of the trial were collected for each end
point and presented in tables. We constructed one table for
each comparator (ie, placebo, own LAMA, tiotropium, and
own LABA). The maximum and minimum significant mean
improvements observed in different trials were presented
for all end points in each table. If no significant differences
were evident in a trial, this was noted as the minimum mean
improvement. If significant improvements were absent in all
the available trials, this was noted as not significant. Because
access to raw patient-based data was unavailable, we did
not draw any inference on the direct comparison of results;
similarly, we were unable to analyze confounders. Direct com-
parisons were not the specific focus of our study. We rather
aimed to provide a general summary of the crude average
values of the four different double bronchodilator FDCs, with
the ultimate goal of facilitating their clinical evaluation.
Results
Included and excluded articles (as well as the reasons moti-
vating the exclusion) are shown in Figure 1. Concerning the
IND/GLY combination, two posters reporting the results of
two clinical trials from the IGNITE initiative (RADIATE
and ARISE) were considered as unpublished to date. How-
ever, the ARISE poster was excluded because quantitative
data on the differences between the treatment arms were
not provided. With regard to the ACLI/FOR combination,
a poster presenting an extension of the AUGMENT trial16 was
included. Finally, 2 posters focusing on the TIO/OLO combi-
nation in the MORACTO and TORRACTO trials (from the
TOVITO initiative) were included; they provided data on the
impact of combination therapy on exercise capacity.
The final number of articles and posters included in the
analysis was 7 for the IND/GLY combination, 6 for the
UMEC/VIL combination, 5 for the ACLI/FOR combination,
and 5 for the TIO/OLO combination; there were 7, 8, 3, and 8
trials for each combination, respectively (Figure 1). The
available clinical trials and their methodology are summa-
rized in Table S1. The number of patients who were random-
ized was 6,449 for the IND/GLY combination, 4,011 for the
ACLI/FOR combination, 5,886 for the UMEC/VIL combina-
tion, and 7,992 for the TIO/OLO combination. There were
some differences in terms of patient characteristics across
the trials under scrutiny (Table S2). Patients treated with the
IND/GLY and ACLI/FOR combinations were similar with
regard to lung function impairment and generally included
moderate-to-severe cases; they also showed a considerable
post-bronchodilator reversibility. Notably, patients treated
with the UMEC/VIL combination had more severe disease
and showed a lower reversibility. Patients treated with the
TIO/OLO combination presented with moderate-to-severe
disease and a mean reversibility close to 200 mL.
Efficacy outcomes for each double combination therapy
versus placebo are summarized in Table 1. Lung function

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Lopez-Campos et al
Table 1 Efcacy outcomes for double combinations versus placebo by the end of triala
Variables IND/GLY UMEC/VIL ACLI/FOR TIO/OLO
Lung function
FEV1 5 minutes post morning dose (mL) 290 NAb108–128 NAb
Peak FEV1 (mL) 330 224 298–334 339
Trough FEV1 (mL) 189–219 122–243 130–152 162–207
FEV1 AUC0–24 (mL) 320 NAbNAb280
Symptoms
Dyspnea (TDI) 1.09–1.37 0.7–1.2 1.3–1.44 1.20–2.05
TDI increase $1 point (%) 10.6–17.8 8 16.2–21.6 NAb
TDI increase $1 point (OR) 2.78 1.3–2 2.54–2.8 NAb
HRQL (SGRQ) −3.01 to −4.7 −2.02 to −5.51 NS to −4.36 −4.56 to −4.89
SGRQ increase $4 points (%) NSc10–11 19.5 19.2–21.9
SGRQ increase $4 points (OR) NSc1.5–2 2.3 2.2–2.5
Rescue medication (puffs/day) −0.73 to −1.43 −0.6 to −1.2 −0.66 to −0.91 NAb
Endurance test (seconds) 60 NS to 69.4 NAb54.9–78.6
Endurance SWT (seconds) NAbNAbNAbNSc
Exacerbations
Number of all exacerbations (RR) NAbNAbNS to 0.76 NAb
Time to rst exacerbation, all (HR) 0.7 0.5–0.6 0.72 NAb
Number of moderate-to-severe exacerbations (RR) NAbNAbNS to 0.71 NAb
Time to rst moderate-to-severe exacerbation (HR) 0.7 NAb0.70 NAb
Notes: aData expressed as the minimum and maximum average value from all trials analyzed. bOutcomes with no information in any of the trials evaluated. cOutcomes with
nonsignicant results in all available trials.
Abbreviations: ACLI/FOR, aclidinium/formoterol; AUC0–24, area under the curve from 0 to 24 hours post morning dose; FEV1, forced expiratory volume in the
rst second; HR, hazard ratio; HRQL, heath-related quality of life; IND/GLY, indacaterol/glycopyrronium; NA, not available; NS, not signicant; OR, odds ratio; RR, rate ratio;
SGRQ, St George’s Respiratory Questionnaire; SWT, shuttle walking test; TDI, transitional dyspnea index; TIO/OLO, tiotropium/olodaterol; UMEC/VIL, umeclidinium/
vilanterol.
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Abbreviations: ACLI/FOR, aclidinium/formoterol; IND/GLY, indacaterol/glycopyrronium; TIO/OLO, tiotropium/olodaterol; UMEC/VIL, umeclidinium/vilanterol.
showed an improvement in all of the functional parameters
under scrutiny. Improvements in dyspnea overcame the
MCID for TDI in the majority of studies, with an increase in
the number of patients reaching such MCID versus placebo.
Although all combinations improved SGRQ, the IND/GLY
combination did not increase the number of patients reaching
the MCID for SGRQ in the single study that assessed this end
point versus placebo.17 Most endurance tests conducted on

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Double bronchodilation in COPD
a cycle-ergometer showed an improvement of ~60 seconds
in FDC-treated patients, the only exception being the ACLI/
FOR combination (for which this end point has not been
evaluated). The available information on exacerbations
showed a decrease in the time to the first exacerbation for
all combinations, with the exception being TIO/OLO (for
which this end point has not been evaluated). The decrease
in the duration and number of exacerbations for the ACLI/
FOR combination (versus placebo) observed in the pooled
analysis of the AUGMENT COPD and ACLIFORM studies18
was not replicated in individual trials.16,19 Although daily
activities were not included in this analysis, only the IND/
GLY combination showed some efficacy with respect to
this clinical outcome (with the BLAZE trial showing a 8.8%
increase in the percentage of days in which the patient was
able to perform usual daily activities versus placebo);14 the
same combination produced an increase in activity-related
energy expenditure (with a 36.7 kcal increase per day versus
placebo in the MOVE study).15
Efficacy outcomes when each FDC was compared with its
own LAMA are summarized in Table 2. The onset of action
was reported for all combinations and showed improvements
compared with their own LAMA, the only exception being
UMEC/VIL (for which this outcome was not reported until
15 minutes after administration).
Peak FEV1 was improved by all combinations, with a
slight decrease being reported by UMEC/VIL. Improvements
in trough FEV1 ranged from 22 to 90 mL for all combina-
tions, the only exception being ACLI/FOR. Changes in FEV1
AUC0–24 were investigated for the IND/GLY and TIO/OLO
combinations only. The impact on symptoms was not invari-
ably significant. When reported, the TIO/OLO combination
resulted in significant improvements versus its LAMA
alone for most of the symptoms. With regard to exacerba-
tions, IND/GLY was the only combination that produced
significant improvement over its LAMA alone. When the
same analysis was performed by comparing an FDC against
tiotropium (Table 3), the efficacy parameters were found
to improve slightly. The combination ACLI/FOR did not
present any studies evaluating its efficacy against tiotropium.
With regard to SGRQ, the SPARK study showed that the
IND/GLY combination was significantly superior to both
glycopyrronium and tiotropium at all assessment points until
week 52.20 However, the last visit (conducted at week 64) did
not show significant differences in the number of patients
achieving the MCID.
Efficacy outcomes when each FDC was compared versus
its LABA are summarized in Table 4. None of the FDCs
differed significantly from their LABA with regard to their
onset of action. In line with the LAMA, the improvements
Table 2 Efcacy outcomes for double combinations versus their LAMA by the end of triala
Variables IND/GLY UMEC/VIL ACLI/FOR TIO/OLO
Lung function
FEV1 5 minutes post morning dose (mL) 130 NAb92 79
Peak FEV1 (mL) 130 67–94 121–124 111
Trough FEV1 (mL) 70–90 22–52 NScNS–79
FEV1 AUC0–24 (mL) 120 NAbNAb111
Symptoms
Dyspnea (TDI) NScNScNS–0.44 0.35–0.61
TDI increase $1 point (%) NScNScNScNAb
TDI increase $1 point (OR) NAbNScNScNAb
HRQL (SGRQ) NS to −2.8 NScNSc−1.23 to −2.49
SGRQ increase $4 points (%) NSc,* NAbNSc7.9–11.4
SGRQ increase $4 points (OR) NSc,* NScNSc1.53–1.58
Rescue medication (puffs/day) −0.66 to −0.81 −0.6 −0.36 −0.55
Endurance test (seconds) NAbNAbNAbNSc
Endurance SWT (seconds) NAbNAbNAbNAb
Exacerbations
Number of all exacerbations (RR) 0.85 NAbNScNAb
Time to rst exacerbation, all (HR) NScNScNScNAb
Number of moderate-to-severe exacerbations (RR) 0.88 NAbNScNAb
Time to rst moderate-to-severe exacerbation (HR) NAbNAbNScNSc
Notes: aData expressed as the minimum and maximum average value from all trials analyzed. bOutcomes with no information in any of the trials evaluated. cOutcomes with
nonsignicant results in all available trials. *Signicant differences favoring the double bronchodilation until week 52.
Abbreviations: ACLI/FOR, aclidinium/formoterol; AUC0–24, area under the curve from 0 to 24 hours post morning dose; FEV1, forced expiratory volume in the
rst second; HR, hazard ratio; HRQL, heath-related quality of life; IND/GLY, indacaterol/glycopyrronium; LAMA, long-acting muscarinic antagonist; NA, not available; NS, not
signicant; OR, odds ratio; RR, rate ratio; SGRQ, St George’s Respiratory Questionnaire; SWT, shuttle walking test; TDI, transitional dyspnea index; TIO/OLO, tiotropium/
olodaterol; UMEC/VIL, umeclidinium/vilanterol.

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Table 3 Efcacy outcomes for double combinations versus tiotropium by the end of triala
Variables IND/GLY UMEC/VIL ACLI/FOR TIO/OLO
Lung function
FEV1 5 minutes post morning dose (mL) 120 NAbNAb79
Peak FEV1 (mL) 130 72–95 NAb111
Trough FEV1 (mL) 60–100 60–112 NAbNS to 79
FEV1 AUC0–24 (mL) 110 NAbNAb110
Symptoms
Dyspnea (TDI) 0.49–0.51 NScNAb0.35–0.61
TDI increase $1 point (%) 8.9–17.8 NAbNAbNAb
TDI increase $1 point (OR) 1.78 NScNAbNAb
HRQL (SGRQ) NS to −3.1 NS to −2.1 NAb−1.23 to −2.49
SGRQ increase $4 points (%) NS* to 7.3 NAbNAb7.9–11.4
SGRQ increase $4 points (OR) NSc,* NS to 1.4 NAb1.53–1.58
Rescue medication (puffs/day) −0.45 to −1.08 −0.5 to −0.7 NAb−0.55
Endurance test (seconds) NScNAbNAbNSc
Endurance SWT (seconds) NAbNAbNAbNAb
Exacerbations
Number of all exacerbations (RR) 0.86 NScNAbNAb
Time to rst exacerbation, all (HR) NScNS to 0.5 NAbNAb
Number of moderate-to-severe exacerbations (RR) NScNAbNAbNAb
Time to rst moderate-to-severe exacerbation (HR) NScNAbNAbNSc
Notes: aData expressed as the minimum and maximum average value from all trials analyzed. bOutcomes with no information in any of the trials evaluated. cOutcomes with
nonsignicant results in all available trials. *Signicant differences favoring the double bronchodilation until week 52.
Abbreviations: ACLI/FOR, aclidinium/formoterol; AUC0–24, area under the curve from 0 to 24 hours post morning dose; FEV1, forced expiratory volume in the
rst second; HR, hazard ratio; HRQL, heath-related quality of life; IND/GLY, indacaterol/glycopyrronium; NA, not available; NS, not signicant; OR, odds ratio; RR, rate ratio;
SGRQ, St George’s Respiratory Questionnaire; SWT, shuttle walking test; TDI, transitional dyspnea index; TIO/OLO, tiotropium/olodaterol; UMEC/VIL, umeclidinium/
vilanterol.
Table 4 Efcacy outcomes for double combinations versus their own LABA by the end of triala
Variables IND/GLY UMEC/VIL ACLI/FOR TIO/OLO
Lung function
FEV1 5 minutes post morning dose (mL) NScNAbNScNSc
Peak FEV1 (mL) 120 88–116 116–138 120
Trough FEV1 (mL) 70 90–95 45–81.5 85–92
FEV1 AUC0–24 (mL) 120 NAbNAb115
Symptoms
Dyspnea (TDI) NScNScNS to 0.47 0.42
TDI increase $1 point (%) NScNAbNScNAb
TDI increase $1 point (OR) NAbNScNScNAb
HRQL (SGRQ) NScNScNSc−1.693
SGRQ increase $4 points (%) NScNAbNSc12.7
SGRQ increase $4 points (OR) NAbNScNScNAb
Rescue medication (puffs/day) −0.31 NScNSc−0.28
Endurance test (seconds) NAbNAbNAbNS to 46.6
Endurance SWT (seconds) NAbNAbNAbNAb
Exacerbations
Number of all exacerbations (RR) NAbNAbNScNAb
Time to rst exacerbation all (HR) NAbNScNScNAb
Number of moderate-to-severe exacerbations (RR) NAbNAbNScNAb
Time to rst moderate-to-severe exacerbation (HR) NAbNAbNSc0.83
Notes: aData expressed as the minimum and maximum average value from all trials analyzed. bOutcomes with no information in any of the trials evaluated. cOutcomes with
nonsignicant results in all available trials.
Abbreviations: ACLI/FOR, aclidinium/formoterol; AUC0–24, area under the curve from 0 to 24 hours post morning dose; FEV1, forced expiratory volume in the
rst second; HR, hazard ratio; HRQL, heath-related quality of life; IND/GLY, indacaterol/glycopyrronium; LABA, long-acting β2-agonist; NA, not available; NS, not signicant;
OR, odds ratio; RR, rate ratio; SGRQ, St George’s Respiratory Questionnaire; SWT, shuttle walking test; TDI, transitional dyspnea index; TIO/OLO, tiotropium/olodaterol;
UMEC/VIL, umeclidinium/vilanterol.

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Double bronchodilation in COPD
in lung function were not accompanied by a lower burden
of symptoms or exacerbations for all cases. When reported,
only the TIO/OLO combination produced improvements in
symptoms and exacerbations in most trials.
Discussion
This study is the first systematic review focusing on the
efficacy of LABA/LAMA FDC through the use of a crude
clinical approach that analyzed efficacy data according to dif-
ferent outcomes and comparators. Our data show consistent
improvements for LABA/LAMA combinations, albeit with
some variability (depending on the clinical end point, the
specific combination, and the comparison group).
Here, we specifically focused on efficacy data expressed
in terms of average improvements of different clinical out-
comes. However, it should be noted that a comprehensive
evaluation of different LABA/LAMA FDCs also requires a
careful assessment of safety, costs, and, in the case of respira-
tory medicine, device features. Although a specific analysis of
adverse effects was outside the scope of this study, no major
alarming side effects were reported by any of the trials under
scrutiny. All the LABA/LAMA FDCs had a similar profile
in terms of adverse effects, with COPD worsening being
the most common adverse manifestation. Other reported
side effects included nasopharyngitis, headache, cough, and
upper and lower respiratory tract infections; notably, such
safety profile was similar to that observed with both placebo
and the monocomponents.16,17,21,22 Several cost-effectiveness
analyses of all LABA/LAMA FDCs have been published,23–26
consistently showing that different combinations may have
a similar cost-effectiveness ratio.27 Another key point is the
assessment of the inhaler use. In this regard, a recent study has
shown that the inappropriate handling of the inhaler device
is underestimated in the real-world practice and portends an
increased risk of COPD exacerbations.28
Several key aspects need to be considered when interpret-
ing our results. First, the reviewed articles differ significantly
in terms of the modality by which several key data (eg,
patient characteristics and efficacy outcomes) are expressed.
Although some variables were consistently reported by all
the included trials (eg, age, percentage of men, and smoking),
other clinical data (eg, exacerbations in the previous year or
comorbidities) or efficacy parameters (eg, trough FEV1 or
breathlessness measured by the TDI questionnaire) were not.
For example, the number of patients reaching the MCID in
the TDI or SGRQ can be expressed either as odds ratios or
percentages. Such discrepancies must be taken into account
when different combinations are examined. Other outcomes
(including residual functional capacity, residual volume,
FEV1 AUC in the first hours after morning dose, FEV1 post
dose, percentage of patients improving 100 or 200 mL, and
12% in trough FEV1) were not consistently reported and were
not included in the present analysis. Interestingly, the impact
of the different combinations on symptoms over the 24 hours
of the day has been most extensively studied for the ACLI/
FOR18 combination, followed by IND/GLY.29 In contrast, no
information is available for the UMEC/VIL and TIO/OLO
combinations. Night-time and early morning symptoms have
been recorded differently (night-time rescue medication use,
clinical information in electronic diaries, percentage of nights
with no awakenings, or specific questionnaires) in trials exam-
ining the ACLI/FOR and IND/GLY combinations. Hopefully,
a consensus should be reached on the minimum amount of
information that any clinical trial should include, especially
in terms of the description of included patients and the pre-
sentation of clinical efficacy. Posters obviously include less
information than full-length research articles; consequently,
data derived from should be considered with caution.
A second point that merits consideration is that the avail-
able characteristics of patients included in trials of different
combinations were slightly different. Methodological
variance (eg, open-label comparisons to tiotropium, different
follow-up periods, and use of primary, secondary, or even
exploratory outcomes) was also evident. As a result, a raw
direct comparison between studies appears unfeasible and
was avoided in the present study. At least four meta-analyses
have reviewed the available evidence comparing LABA/
LAMA FDCs. Their results showed 1) no differences
between the various double FDCs compared with placebo11
and 2) the superiority of the combination approach over
monotherapy.9,10 Even though differences versus placebo
were consistent for different combinations, the crude average
values indicated that a better lung function was not invariably
accompanied by symptom improvement.
Third, another important aspect of our study lies in the
assessment of mean values for different efficacy end points.
The mean improvement is a simplified modality to express
the overall pharmacological response. We are aware that an
assessment of the variability of this response (besides average
improvement) would be relevant. In general, real-life clinical
response to treatments may differ significantly from that
observed in a clinical trial, which employs rigid inclusion and
exclusion criteria. Recently, Donohue et al30 have shown that
the magnitude of UMEC/VIL lung function effect is largely

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Lopez-Campos et al
dependent on the response to monotherapy, with quantitatively
greater improvements in patients who are responders to both
umeclidinium and vilanterol monotherapy compared to those
responding to one of the two or none of them. The presentation
of data as mean improvements together with the number of
patients who reached the MCID results is necessary to acquire
a more realistic view of the results.
Another area of debate concerns the MCID. Validated
MCIDs are available for many commonly used outcomes in
COPD, including the 100 mL improvement in trough FEV1,
improvement of $1 unit in the TDI total score, reduction of
4 units in the SGRQ total score, or the increase in 47.5 m
for the incremental shuttle walking test, 45–85 seconds for
the endurance shuttle walking test, and 46–105 seconds for
constant-load cycling endurance tests.31 Although the differ-
ences compared with placebo reached the MCID for several
clinical end points, the differences versus the monotherapy
components did not reach the MCID (when significant) for
all FDCs. However, numerous factors in a clinical trial set-
ting (eg, study duration, withdrawal rate, or baseline sever-
ity) can ultimately influence the measured treatment effects.
In addition, it has been questioned whether the same MCID
should be used to compare treatment efficacy versus placebo
or active treatments.32
Finally, another source of controversy lies in the compari-
son of double bronchodilation versus monotherapy. Despite
consistent improvements in lung function compared with
placebo, the differences with the monotherapy components
were not invariably significant for all the clinical end points
and/or comparisons. Interestingly, the correlation of lung
function impairment with clinical end points seems to be
poor.33 As a consequence, the superior efficacy of LABA/
LAMA combinations versus monotherapies in terms of FEV1
might not be paralleled by similar clinical improvements in
terms of symptoms and exacerbations.
The onset of action (as reported by FEV1 improvement
5 minutes after the morning dose) was found to be signifi-
cantly improved compared with placebo and LAMA, but not
with LABA. These observations suggest that the rapidity of
action of FDCs should be generally ascribed to the LABA.
Owing to the first spirometry being performed 15 minutes
after the morning dose, the UMEC/VIL study did not provide
data at 5 minutes post morning dose.21 However, clinical
results on vilanterol indicate a rapid onset of action,34 sug-
gesting that the effect should be similar when combined with
umeclidinium.
Data on exacerbations should be interpreted with caution.
In all of the reviewed clinical trials, exacerbations were
secondary or even exploratory end points, with the SPARK
study20 being the only one having exacerbations as a pri-
mary end point. Additionally, many trials had a 6-month
follow-up, which implies that the rate had to be annualized.
As a consequence, the available studies are underpowered
to detect differences. Despite these limitations, certain FDCs
were characterized by some differences in the time to the
first exacerbation compared with placebo, with ACLI/FOR
showing a consistent improvement in exacerbation outcomes
versus placebo in the pooled analysis.18 Of note, the differ-
ences in exacerbations versus monotherapy components were
either not available or not significant. Only TIO/OLO showed
an improvement in the time to the first moderate-to-severe
exacerbation compared with the LABA (but not compared
with the LAMA) in the TONADO study although exacerba-
tions were not an end point of the trial.22
Conclusion
This study is a systematic review summarizing the crude
data obtained from different clinical trials focusing on the
efficacy of LABA/LAMA FDCs in patients with COPD.
Our data show consistent improvements for LABA/LAMA
combinations, albeit with some variability (depending on
the clinical end point, the specific combination, and the
comparison group). Clinicians should be aware that these
are average differences. All treatments should be tailored at
the individual level to optimize clinical outcomes.
Acknowledgment
The authors are grateful to the Spanish teams of Novartis,
AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim
for reviewing the efficacy data summarized in the study.
Author contributions
JLLC designed the study and performed the initial search and
wrote the manuscript; JLLC, CCA, and EMM revised the list
of publications and posters. EQG, LCH, and MAA extracted
the information from the articles. FOR supervised the final
draft of the manuscript. All authors contributed toward data
analysis, drafting and critically revising the paper, gave
final approval of the version to be published, and agree to
be accountable for all aspects of the work.
Disclosure
JLLC has received honoraria for lecturing, scientific advice,
participation in clinical studies, or writing publications from
the following sources (listed in alphabetical order): Almirall,
AstraZeneca, Bayer, Boehringer Ingelheim, Cantabria

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Double bronchodilation in COPD
Pharma, Chiesi, Esteve, Faes, Ferrer, GlaxoSmithKline,
Menarini, MSD, Novartis, Pfizer, Rovi, and Takeda, and
reports no other conflicts of interest in this work. All of the
other authors report no conflicts of interest in this work.
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