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Blood Eosinophils and Response to Maintenance COPD Treatment: Data from
the FLAME Trial
Nicolas Roche1, Kenneth R. Chapman2, Claus F. Vogelmeier3, Felix J.F. Herth4, Chau
Thach5, Robert Fogel5, Petter Olsson6, Francesco Patalano7, Donald Banerji5, and
Jadwiga A. Wedzicha8
1Service de Pneumologie AP-HP, University Paris Descartes (EA2511), Paris,
France; 2Asthma and Airway Centre, University Health Network and University of
Toronto, Toronto, Ontario, Canada; 3Department of Medicine, Pulmonary and Critical
Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität
Marburg, Marburg, Germany; Member of the German Center for Lung Research
(DZL); 4Department of Pneumology and Critical Care Medicine, Thoraxklinik,
University of Heidelberg and Translational Lung Research Center Heidelberg,
German Center for Lung Research, Heidelberg, Germany; 5Novartis Pharmaceuticals
Corporation, East Hanover, NJ, USA; 6Novartis Sverige AB, Täby, Sweden; 7Novartis
Pharma AG, Basel, Switzerland; 8National Heart and Lung Institute, Imperial College
London, London, UK.
Correspondence and requests for reprints should be addressed to:
Professor Nicolas Roche
Service de Pneumologie AP-HP
27 rue du Faubourg Saint Jacques
Paris 75014, France
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Author Contributions
All authors were involved in drafting, reviewing, and critically revising the manuscript
and approved the final version of the text.
Support
Medical writing support for this article was funded by Novartis Pharma AG, Basel,
Switzerland.
Running Head
Efficacy of IND/GLY vs SFC by Blood Eosinophils
Descriptor
9.14 COPD: Pharmacological Treatment
Total Word Count
2,994 [limit = 3,500]
At a Glance Commentary:
Scientific Knowledge on the Subject:
Inhaled corticosteroids can contribute to exacerbation risk reduction in some chronic
obstructive pulmonary disease patients, but are associated with adverse events such
as pneumonia, suggesting their use should be limited to those who would benefit.
Post-hoc analyses suggest that patients with high blood eosinophils have better
clinical outcomes with inhaled corticosteroids than patients with low blood
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eosinophils. In FLAME, exacerbation reduction was greater with
indacaterol/glycopyrronium versus fluticasone/salmeterol in patients with a history of
exacerbations, whether or not blood eosinophils were above 2% (a suggested value
for this putative biomarker). Suitability of blood eosinophils as a biomarker is
currently under debate.
What This Study Adds to the Field:
We analyzed the FLAME outcomes further, considering a range of eosinophil cut-
offs. Our analysis indicates that indacaterol/glycopyrronium is significantly superior to
fluticasone/salmeterol in preventing exacerbations in patients with <2% and ≥2%
blood eosinophils as well as <3%, <5% and <150 cells/μl. At no cut-off was
fluticasone/salmeterol superior to indacaterol/glycopyrronium for exacerbation
prevention. We suggest that, at present, blood eosinophils should not be used to
determine who should receive an inhaled corticosteroid/long-acting β2-agonist over a
dual bronchodilator.
[word count = 188 (limit = 200)]
Online Data Supplement:
This article has an online data supplement, which is accessible from this issue's table
of content online at www.atsjournals.org
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ABSTRACT
Rationale: Post-hoc analyses suggest that blood eosinophils have potential as a
predictive biomarker of inhaled corticosteroid efficacy in the management of chronic
obstructive pulmonary disease.
Objectives: We prospectively investigated the value of blood eosinophils as a
predictor of responsiveness to an inhaled corticosteroid/long-acting β2-agonist
combination versus a long-acting β2-agonist/long-acting muscarinic antagonist
combination for exacerbation prevention.
Methods: We conducted prespecified analyses of data from the FLAME study,
which compared once-daily long-acting β2-agonist/long-acting muscarinic antagonist
indacaterol/glycopyrronium 110/50 μg with twice-daily long-acting β2-agonist/inhaled
corticosteroid salmeterol/fluticasone combination 50/500 μg in patients with ≥1
exacerbation in the preceding year. Subsequent post-hoc analyses were conducted
to address further cut-offs and endpoints.
Measurements and Main Results: We compared treatment efficacy according to
blood eosinophil percentage (<2% and ≥2%, <3% and ≥3%, and <5% and ≥5%) and
absolute blood eosinophil count (<150 cells/μl, 150 to <300 cells/μl, and ≥300
cells/μl). Indacaterol/glycopyrronium was significantly superior to
salmeterol/fluticasone for the prevention of exacerbations (all severities, or moderate
or severe) in the <2%, ≥2%, <3%, <5% and <150 cells/ul subgroups, and at no cut-
off was salmeterol/fluticasone superior to indacaterol/glycopyrronium. Furthermore,
the rate of moderate or severe exacerbations did not increase with increasing blood
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eosinophils. The incidence of pneumonia was higher in patients receiving
salmeterol/fluticasone than indacaterol/glycopyrronium in both the <2% and ≥2%
subgroups.
Conclusions: Our prospective analyses indicate that indacaterol/glycopyrronium
provides superior or similar benefits over salmeterol/fluticasone regardless of blood
eosinophil levels in patients with COPD.
Clinical trial registered with www.c linicaltrials.gov (NCT01782326).
[word count = 235 (limit = 250)]
Key words: bronchodilation; COPD; exacerbations; inhaled corticosteroids; QVA149
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INTRODUCTION
A range of pharmacological treatments for chronic obstructive pulmonary disease
(COPD) reduce exacerbation risk, including long-acting bronchodilators (long-acting
muscarinic antagonists [LAMA] and long-acting β2-agonists [LABA]; alone or in
combination) and inhaled corticosteroids (ICS) in combination with LABA (1-9).
A LABA/LAMA combination is recommended as initial therapy by the Global Initiative
for chronic Obstructive Lung Disease (GOLD) for patients with a high symptom level
who are at increased risk of exacerbation, determined by their exacerbation history
(GOLD D) (9). LABA/ICS are only recommended as an alternative treatment in
GOLD D patients who develop further exacerbations after initial LABA/LAMA
therapy, or with a history and/or findings suggestive of asthma-COPD overlap (9).
These recommendations are largely based on the FLAME study, which
demonstrated the superiority of LABA/LAMA indacaterol/glycopyrronium (IND/GLY)
versus LABA/ICS salmeterol/fluticasone propionate combination (SFC) in
exacerbation prevention in patients with ≥1 exacerbation in the previous year (10).
There are safety concerns associated with ICS use (11-14). Therefore the
identification of patients in whom ICS treatment would be effective is needed, to
reduce unnecessary exposure of patients to risks. Furthermore, identifying optimal
responders to each treatment strategy is necessary for treatment personalization in
COPD (15).
Evidence has emerged suggesting that sputum eosinophils may predict
responsiveness to ICS (16-19). However, results are conflicting and there are
technical challenges associated with assessing sputum samples in clinical practice
(16, 17, 20, 21). Several studies have suggested that sputum eosinophil count may
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correlate with peripheral blood eosinophil count (18, 22, 23), leading many to
propose blood eosinophils as a potential biomarker for the relative efficacy of ICS in
exacerbation prevention. Several blood eosinophil cut-offs have been studied in
post-hoc analyses, which suggested that blood eosinophils could predict the efficacy
of LABA/ICS in preventing exacerbations relative to bronchodilator monotherapy or
placebo (24-27). Although currently under debate, GOLD suggest that ‘high’ blood
eosinophils may be considered as a parameter to support ICS use in GOLD D
patients (9).
Our objective was to examine the relationship between baseline blood eosinophils
and the rate of exacerbations with IND/GLY compared with SFC through analysis of
data from FLAME (10). This analysis is the first prospective evaluation of blood
eosinophils as a predictor of response to an ICS-containing regimen versus a dual
bronchodilator, supplemented and supported by post-hoc analyses. Some of the
results of this study have been reported previously in the form of a manuscript and
an abstract (10, 28).
METHODS
Study Design
The FLAME study design has been reported previously (10). Briefly, FLAME
(NCT01782326) was a 52-week, multicenter, double-blind, active-controlled study
that evaluated the efficacy of IND/GLY 110/50 μg once daily (Novartis Pharma AG,
Basel, Switzerland) compared with SFC 50/500 μg twice daily (GlaxoSmithKline plc,
London, UK) in exacerbation prevention in patients with moderate-to-very severe
airflow limitation and at least one documented exacerbation in the previous year.
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The primary objective of FLAME was to demonstrate the non-inferiority of IND/GLY
to SFC with regards to the rate of all COPD exacerbations (mild/moderate/severe) at
52 weeks. Superiority of IND/GLY versus SFC for the same endpoint (if non-
inferiority was met) was an important secondary objective. Other secondary
objectives included time to first exacerbation (all) and rate and time to first moderate
or severe exacerbation, health status (St George’s Respiratory Questionnaire
[SGRQ-C]), trough forced expiratory volume in one second (FEV1), trough forced
vital capacity (FVC), and rescue medication. Safety endpoints were also assessed.
Patients
Eligible patients had a post-bronchodilator FEV1 ≥25 and <60% predicted, a post-
bronchodilator FEV1/FVC <0.70 and ≥1 documented COPD exacerbation (requiring
treatment with systemic corticosteroids and/or antibiotics) in the previous 12 months.
Exclusion criteria included any history of asthma and a blood eosinophil count >600
cells/μl. Further inclusion and exclusion criteria have been described previously (10).
Assessments and Variables
Exacerbations were defined as a worsening of symptoms, according to modified
Anthonisen criteria (29). A COPD exacerbation (worsening of symptoms for >2
consecutive days) was considered mild (not treated with systemic corticosteroids
and/or antibiotics), moderate (treated with systemic corticosteroids and/or
antibiotics), or severe (hospitalization or an emergency department visit >24 hours).
Further details on the assessment of exacerbations, secondary efficacy endpoints
and safety can be found in the Online Supplement.
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Blood eosinophils were measured at the start of run in (Day –28, [run in] Visit 101),
at the start of the treatment period (Day 1 [baseline], Visit 201), during the treatment
period (Day 183, Visit 208), and at the end of the treatment period (Day 365, Visit
212), as well as at study drug discontinuation (Figure E1).
Statistical Analyses
Details on the statistical analysis of efficacy and safety endpoints (Table E1) can be
found in the Online Supplement.
Blood eosinophil cut-offs were applied to measurements at the start of the treatment
period according to percentage of total white blood cell count (<2% and ≥2%, <3%
and ≥3%, and <5% and ≥5%) and absolute eosinophil count (<150 cells/µl, 150 to
<300 cells/µl, and ≥300 cells/µl). These correspond to cut-offs reported and
discussed most often in the literature. Demographic and safety data were analyzed
using only the <2% and ≥2% cut-offs, as conducted in earlier, post-hoc analyses (24,
27). No substantial differences were noted compared with the analysis of the total
study population, therefore no further data cuts were analyzed.
Analysis of exacerbation rate by blood eosinophils was prespecified, as was the time
to first exacerbation for all exacerbations (at cut-offs of <150 cells/µl, 150 to <300
cells/µl, and ≥300 cells/µl). The remaining analyses were conducted post hoc.
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RESULTS
Patients
Patients excluded from FLAME due to blood eosinophils >600 cells/μl
Between study entry and randomization, 163 (3.1%) patients failed screening (at the
run-in visit) due to a blood eosinophil count >600 cells/μl. Subjects could fail
screening due to multiple inclusion or exclusion criteria.(10)
Patient Demographics
Baseline blood eosinophil percentage was similar in the IND/GLY (median 2.4%;
interquartile range [IQR] 1.5–3.6%) and SFC (median 2.3%; IQR 1.4–3.7%)
treatment arms (Table E2). Baseline absolute cell count was also similar in the
IND/GLY and SFC treatment arms (median 180 cells/μl; IQR 110–280 cells/μl for
both; Table E2). Patients with ≥2%, ≥3% and ≥5% blood eosinophils represented
60.9%, 36.9% and 12.5% of the study population, respectively (Table E3).
Distribution of baseline blood eosinophils was similar in the two treatment arms
(Figures E2A and E2B).
Patients with blood eosinophils <2% and ≥2% were relatively similar with regards to
demographic and disease characteristics (Table 1). Of note, there were no
differences in baseline lung function (FEV1% predicted), bronchodilator reversibility
or the proportion of GOLD D patients (GOLD 2015 criteria) in each subgroup.
Slightly more patients in the blood eosinophils ≥2% subgroup had ≥2 exacerbations
in the previous year compared with the <2% subgroup (20.9% versus 16.9%,
respectively).
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Exacerbations
Rate of Exacerbations with Increasing Baseline Blood Eosinophils
In the overall study population, there was no evidence for an increase in the rate of
moderate or severe exacerbations with increasing baseline eosinophils (percent
change in exacerbation rate per unit increase in eosinophils: 7% [95% CI –20%,
42%]; P = 0.653).
Rate of Exacerbations by Treatment and Baseline Blood Eosinophils
As published previously (10), in both the <2% and ≥2% subgroups, IND/GLY
significantly reduced the annualized rate of moderate or severe exacerbations (RR
0.80 [P = 0.004] and 0.85 [P = 0.010], respectively) and all exacerbations (rate ratio
[RR] 0.84 [P = 0.004] and 0.90 [P = 0.030], respectively) compared with SFC
(Figures 1A and 1B).
Similar relative reductions in exacerbation rate were observed in the <3% and <5%
subgroups for moderate or severe exacerbations (RR 0.81 [P = 0.001] for both) and
all exacerbations (RR 0.86 [P = 0.001] and 0.87 [P < 0.001], respectively; Figures
1A and 1B). There were no statistically significant difference in exacerbation rates
observed in the ≥3% and ≥5% subgroups with IND/GLY versus SFC for moderate or
severe exacerbations (RR 0.86 [P = 0.059] and 0.94 [P = 0.652], respectively) and
all exacerbations (RR 0.91 [P = 0.139] and 0.93 [P = 0.518], respectively; Figures
1A and 1B). Notably, the subgroups reduced in size as blood eosinophil percentage
increased (<3%: n = 2078; ≥3%: n = 1,220; <5%: n = 2886; ≥5%: n = 412).
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IND/GLY was also significantly superior to SFC for reductions in the rate of moderate
or severe exacerbations and all exacerbations in the <150 cells/μl subgroup (both
P < 0.001); the reductions observed in the 150 to <300 cells/μl and ≥300 cells/μl
subgroups were not statistically significant (Figures 1A and 1B). There were fewer
patients in the ≥300 cells/μl subgroup [n = 735] compared with the <150 cells/μl [n =
1,277] and 150 to <300 cells/μl [n = 1,286] subgroups. The RRs approached 1 as
blood eosinophil cut off increased (Figures 1A and 1B).
Time to First Exacerbation by Treatment and Baseline Blood Eosinophils
In the <2% and ≥2% subgroups, IND/GLY significantly reduced the risk of moderate
or severe exacerbations (hazard ratio [HR] 0.70 [P < 0.001] and 0.83 [P = 0.005],
respectively) and all exacerbations (HR 0.81 [P = 0.001] and 0.86 [P = 0.003],
respectively) compared with SFC (Figures 2A and 2B).
Similar relative reductions in exacerbation risk were seen in the <3% and <5%
subgroups for moderate or severe exacerbations (HR 0.73 [P < 0.001] and 0.74
[P < 0.001], respectively) and all exacerbations (HR 0.81 [P < 0.001] and 0.83
[P < 0.001], respectively; Figures 2A and 2B). In the ≥3% and ≥5% subgroups, the
risk reduction with IND/GLY compared with SFC did not reach statistical significance
for moderate or severe exacerbations and all exacerbations (Figures 2A and 2B).
Using absolute blood eosinophil count cut-offs, IND/GLY was significantly superior to
SFC for reductions in the risk of moderate or severe exacerbations and all
exacerbations in the <150 cells/μl subgroup (both P < 0.001). The risk reduction for
moderate or severe exacerbations with IND/GLY compared with SFC reached
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significance in the 150 to <300 cells/μl subgroup but not in the ≥300 cells/μl
subgroup (Figure 2A).
Other Secondary Endpoints
IND/GLY significantly improved mean SGRQ-C score at Week 52 (Table E4), and
significantly improved the proportion of patients achieving a 4-unit change in SGRQ-
C total score at Week 52 compared with SFC in the <2% subgroup (Table E4).
IND/GLY significantly improved trough FEV1 and FVC at Week 52 (Table E5) and
significantly reduced rescue medication use over 52 weeks compared with SFC in
both the <2% and ≥2% subgroups (Table E6).
Similar trends in health status, lung function and rescue medication outcomes were
observed in the <150 cells/μl, ≥150 cells/μl, <300 cells/μl, and ≥300 cells/μl
subgroups, compared with those observed in the <2% and ≥2% subgroups (Tables
E4–E6).
Safety
Safety
The incidence of adverse events and serious adverse events was similar between
both treatment arms and between the <2% and ≥2% subgroups. The rate of
pneumonia was low overall, but was higher in the SFC arm than the IND/GLY arm in
both the <2% and ≥2% subgroups (5.5% vs 4.1% in the <2% subgroup; 4.3% vs
2.6% in the ≥2% subgroup; Table E7). The number of adjudicated major adverse
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cardiac events and/or cardiovascular deaths was similar between both treatment
arms (Table E8).
Change in Blood Eosinophils Over Time
Change in Blood Eosinophils Between Run-in Visit and Baseline
There was a slight increase in mean blood eosinophils in the total population
between the run-in visit and baseline (0.3%; 21 cells/μl), with a smaller change
observed in median blood eosinophils (0.1%; 0 cells/μl) (Table E9). Prior ICS use did
not affect the change in blood eosinophils.
Change in Blood Eosinophils Between Baseline and Weeks 26 and 52
There were minimal changes in mean blood eosinophils from baseline to Weeks 26
and 52 in the IND/GLY arm (–0.06% and –0.05%, respectively; –3 cells/μl and
–3 cells/μl, respectively; Table 2). In the SFC arm, there were small reductions in
mean blood eosinophils from baseline to Weeks 26 and 52 (–0.29% and –0.37%,
respectively; –19 cells/μl and –25 cells/μl, respectively; Table 2). The between-group
difference in change from baseline in mean blood eosinophils was significant using
both percentage and absolute blood eosinophil count (Table 2).
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DISCUSSION
Finding an accessible, easy-to-measure biomarker for patients who may benefit from
ICS is important, to avoid unnecessary exposure to ICS-associated risks (11-14).
One such biomarker could be blood eosinophils, with post-hoc analyses suggesting
that ≥2% may be a suitable cut-off for relative ICS efficacy (24, 25, 27). However,
these retrospective analyses examined only the relative efficacy of LABA/ICS versus
bronchodilator monotherapy or placebo (24-27). FLAME was the first trial to
prospectively study the influence of blood eosinophils on LABA/ICS efficacy versus a
LABA/LAMA.
We found that IND/GLY was significantly superior to SFC for exacerbation
prevention in patients, independent of blood eosinophil count above or below 2%.
There were minimal differences in the rate ratios for moderate or severe
exacerbations between the <2%, <3% and <5% subgroups (RR of 0.80, 0.81 and
0.81, respectively). Although the rate ratio in the ≥3% subgroup still favored
IND/GLY, the difference did not reach statistical significance. At a cut-off of ≥5%, the
two treatments appeared approximately similar (RR 0.94). This suggests that any
ICS benefit was observed primarily in those with the highest blood eosinophil levels.
However, it is notable that at no cut-off was SFC statistically superior to IND/GLY for
exacerbation rate. Furthermore, the rate of moderate or severe exacerbations did not
increase with increasing baseline blood eosinophils, which differs from previous
analyses (30, 31).
The results of our analysis contrast with earlier findings from Pascoe et al. who found
that patients with ≥2% blood eosinophils gained a greater benefit from fluticasone
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furoate/vilanterol versus vilanterol monotherapy compared with patients with blood
eosinophils <2% (24). A cut-off of ≥2% is associated with a number of limitations.
Firstly, blood eosinophil percentage levels are variable, and blood eosinophils levels
may oscillate above and below 2% (24, 32). Secondly, blood eosinophil percentage
is relative to patients’ white blood cell count, therefore absolute blood eosinophil
count may in fact be within the normal range or even low at 2% if white blood cell
count is low.
In another post-hoc study, Siddiqui et al. found that patients with blood eosinophils
≥279.8 cells/μl gained a greater benefit from beclomethasone/formoterol versus
formoterol monotherapy compared with patients with lower blood eosinophils (26).
Although high eosinophil counts may identify patients more likely to respond to ICS
relative to placebo or LABA monotherapy, such markers may be irrelevant when
comparing ICS with a more effective dual bronchodilator regimen, particularly when
considering the efficacy of LAMAs in reducing exacerbations (2, 33-37) and
reductions in exacerbation rate with a LAMA plus a LABA relative to LABA
monotherapy (4).
Our protocol excluded patients with a history of asthma and patients with a blood
eosinophil count >600 cells/µl at the run-in visit (a routine exclusion criterion
throughout the IND/GLY clinical development program, predating discussions
concerning blood eosinophils as a biomarker). The results of analyses from other
studies may have been skewed by the inclusion of patients with an asthmatic
component to their obstructive airways disease or a small subset of patients with
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higher eosinophil counts, associated with Th2-driven airways inflammation.
However, reversibility level in FLAME was similar to other studies (4, 10, 38-40), and
only 3.1% of screened patients in FLAME were excluded based on the upper blood
eosinophil criterion, a benchmark we feel is reflective of the majority of patients with
moderate-to-very severe airflow limitation and an exacerbation history. Thus,
although we cannot exclude a benefit of SFC over IND/GLY in patients with
extremely high blood eosinophil counts, the FLAME data are applicable to
approximately 97% of COPD patients. Notably, in the majority of analyses (including
FLAME), 54–70% of patients had blood eosinophils ≥2% (24, 25, 27, 41).
Blood eosinophils may still serve a purpose in identifying patients potentially at risk
following withdrawal of ICS from their triple regimen. In analyses of data from
WISDOM, withdrawal of ICS had a more deleterious effect in patients with blood
eosinophils ≥4% or ≥400 cells/μl than those with lower eosinophil counts (42).
Further analyses indicated that ICS withdrawal only resulted in an increased
exacerbation rate in patients with both a high blood eosinophil count (≥300 cells/μl
and ≥400 cells/μl) and a history of ≥2 exacerbation, a subset representing less than
4% of the WISDOM population (43, 44). Blood eosinophils may also help to identify
patients who would benefit from the addition of ICS to a dual bronchodilator. This
hypothesis will be specifically tested as a prespecified secondary endpoint in the
IMPACT trial, which will compare triple therapy with a LABA/LAMA and a LABA/ICS
(45).
Mean blood eosinophils increased slightly between the run-in visit and baseline in
FLAME, possibly due to artificial ‘capping’ of variability in blood eosinophils at the
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run-in visit (but not baseline) to a maximum of 600 cells/μl. This hypothesis is
supported by the fact that prior ICS use did not affect mean change. Blood
eosinophil count decreased slightly over the study in those receiving SFC. This
effect, combined with a greater lowering of urine cortisol observed with SFC versus
IND/GLY (10), likely represents manifestations of systemic exposure to fluticasone
propionate, as systemic corticosteroids are known to reduce blood eosinophils.
Consistent with the overall study population (10), the incidence of pneumonia was higher
with SFC versus IND/GLY irrespective of blood eosinophil counts. The rate of pneumonia
was marginally higher in those with <2% blood eosinophils than those with ≥2% blood
eosinophils, echoing findings from a post-hoc analysis that suggested rates of pneumonia
were slightly lower in COPD patients with higher eosinophil counts and putatively more
responsive to ICS (41).
CONCLUSION
In our analysis, IND/GLY consistently provided superior benefits over SFC
regardless of blood eosinophil levels. Indeed, there was no cut-off at which SFC was
superior to IND/GLY. We believe that, at present, blood eosinophils should not be
used in COPD patients to determine who should receive LABA/ICS instead of
LABA/LAMA and that further evidence is required. Whether ICS can provide
additional benefits when added to LABA/LAMA, and whether blood eosinophils can
be used to predict this benefit, remain to be elucidated.
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ACKNOWLEDGMENTS
Statistical analyses were performed by a statistician employed by DataMap (Sankt
Georgen, Germany). Editorial and technical support in preparation of the manuscript
was provided by Elizabeth Andrew, a professional medical writer at CircleScience,
an Ashfield company, part of UDG Healthcare plc. The statistical analyses and
medical writing support were funded by Novartis Pharma AG (Basel, Switzerland).
Author disclosures are available with the text of this article at www.atsjournals.org.
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FIGURES
Figure 1A. Rate ratios of moderate to severe COPD exacerbations by blood eosinophils cut off
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Definition of abbreviations: CI = confidence interval; COPD = chronic obstructive pulmonary disease; GLY = glycopyrronium; IND =
indacaterol; RR = rate ratio; SFC = salmeterol/fluticasone propionate combination.
18
434
435
436
Figure 1B. Rate ratios of all COPD exacerbations (mild/moderate/severe) by blood eosinophils cut off
19
437
438
Definition of abbreviations: CI = confidence interval; COPD = chronic obstructive pulmonary disease; GLY = glycopyrronium; IND =
indacaterol; RR = rate ratio; SFC = salmeterol/fluticasone propionate combination.
20
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440
Figure 2A. Hazard ratios and estimated time to first moderate or severe COPD exacerbation by blood eosinophil cut-off
21
441
442
*Because less than 50% of patients in the indacaterol–glycopyrronium group had an exacerbation, the time by which at least 25%
of patients had a first moderate or severe exacerbation was calculated instead of the median time
Definition of abbreviations: CI = confidence interval; COPD = chronic obstructive pulmonary disease; GLY = glycopyrronium; IND =
indacaterol; SFC = salmeterol/fluticasone propionate combination.
22
443
444
445
446
447
448
Figure 2B. Hazard ratios and estimated time to first mild, moderate or severe (all) COPD exacerbation by blood eosinophil cut-off
23
449
450
Definition of abbreviations: CI = confidence interval; COPD = chronic obstructive pulmonary disease; GLY = glycopyrronium; IND =
indacaterol; SFC = salmeterol/fluticasone propionate combination.
24
451
452
TABLES
TABLE 1. BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS BY <2% AND ≥2% BLOOD EOSINOPHILS
<2% Blood Eosinophils at Baseline ≥2% Blood Eosinophils at Baseline
Variable
IND/GLY
110/50 μg
q.d.
(n = 629)
SFC
50/500 μg
b.i.d.
(n = 672)
Total
(n = 1,301)
IND/GLY
110/50 μg
q.d.
(n = 1,043)
SFC
50/500 μg
b.i.d.
(n = 1,005)
Total
(n = 2,048)
Age (years) 64.1 (8.08) 64.2 (7.66) 64.2 (7.86) 65.0 (7.73) 64.6 (7.72) 64.8 (7.73)
Male, n (%) 473 (75.2) 478 (71.1) 951 (73.1) 819 (78.5) 775 (77.1) 1594 (77.8)
Duration of COPD (years) 7.1 (5.13) 7.3 (5.45) 7.2 (5.30) 7.3 (5.43) 7.3 (5.43) 7.3 (5.43)
ICS use at screening, n (%) 349 (55.5) 368 (54.8) 717 (55.1) 603 (57.8) 570 (56.7) 1173 (57.3)
LABA use at screening, n (%) 414 (65.8) 440 (65.5) 854 (65.6) 711 (68.2) 687 (68.4) 1398 (68.3)
LAMA use at screening, n (%) 370 (58.8) 416 (61.9) 786 (60.4) 631 (60.5) 610 (60.7) 1241 (60.6)
LABA/ICS use at screening, n (%) 285 (45.3) 308 (45.8) 593 (45.6) 498 (47.7) 469 (46.7) 967 (47.2)
25
453
454
455
Triple therapy use at screening, n (%) 205 (32.6) 224 (33.3) 429 (33.0) 357 (34.2) 360 (35.8) 717 (35.0)
Smoking status at screening, n (%)
Ex-smoker 364 (57.9) 381 (56.7) 745 (57.3) 648 (62.1) 629 (62.6) 1277 (62.4)
Current smoker 265 (42.1) 291 (43.3) 556 (42.7) 395 (37.9) 376 (37.4) 771 (37.6)
Severity of COPD (GOLD 2015), n (%)
Low risk and less symptoms (Group A) 1 (0.2) 0 1 (0.1) 1 (0.1) 0 1 (0.0)
Low risk and more symptoms (Group B) 138 (21.9) 177 (26.3) 315 (24.2) 260 (24.9) 244 (24.3) 504 (24.6)
High risk and less symptoms (Group C) 0 1 (0.1) 1 (0.1) 1 (0.1) 1 (0.1) 2 (0.1)
High risk and more symptoms (Group D) 485 (77.1) 489 (72.8) 974 (74.9) 774 (74.2) 756 (75.2) 1530 (74.7)
Severity of airflow limitation (GOLD 2011–2014),
n (%)
Mild (GOLD 1) 0 0 0 0 0 0
Moderate (GOLD 2) 196 (31.2) 229 (34.1) 425 (32.7) 362 (34.7) 333 (33.1) 695 (33.9)
26
Severe (GOLD 3) 380 (60.4) 384 (57.1) 764 (58.7) 589 (56.5) 593 (59.0) 1182 (57.7)
Very severe (GOLD 4) 47 (7.5) 54 (8.0) 101 (7.8) 84 (8.1) 70 (7.0) 154 (7.5)
Pre-bronchodilator FEV1, L 1.02 (0.33) 1.00 (0.32) 1.01 (0.32) 1.01 (0.32) 1.01 (0.32) 1.01 (0.32)
Post-bronchodilator FEV1, L 1.21 (0.35) 1.20 (0.35) 1.21 (0.35) 1.22 (0.34) 1.22 (0.36) 1.22 (0.35)
Post-bronchodilator FEV1, % predicted 43.8 (9.42) 44.1 (9.47) 43.9 (9.44) 44.2 (9.50) 44.2 (9.41) 44.2 (9.45)
Post-bronchodilator FEV1, reversibility % of
baseline value21.4 (15.83) 21.8 (15.26)
21.6
(15.53)22.7 (16.15) 23.1 (16.50)
22.8
(16.32)
Post-bronchodilator FEV1/FVC, % 41.6 (9.86) 41.2 (9.67) 41.4 (9.76) 41.7 (9.81) 41.7 (10.03) 41.7 (9.92)
Number of COPD exacerbations in the previous
year,
n (%)
0 0 0 0 1 (0.1) 1 (0.1) 2 (0.1)
1 511 (81.2) 569 (84.7) 1080 (83.0) 836 (80.2) 781 (77.7) 1617 (79.0)
≥2 118 (18.8) 102 (15.2) 220 (16.9) 206 (19.8) 223 (22.2) 429 (20.9)
27
CAT score 17.0 (7.15) 16.5 (7.07) 16.7 (7.11) 16.8 (7.02) 16.7 (6.91) 16.8 (6.97)
mMRC Dyspnea Scale, n (%)
Grade 0 0 0 0 1 (0.1) 0 1 (0.0)
Grade 1 1 (0.2) 1 (0.1) 2 (0.2) 1 (0.1) 1 (0.1) 2 (0.1)
Grade 2 455 (72.3) 479 (71.3) 934 (71.8) 740 (70.9) 728 (72.4) 1468 (71.7)
Grade 3 164 (26.1) 176 (26.2) 340 (26.2) 274 (26.3) 254 (25.3) 528 (25.8)
Grade 4 9 (1.4) 16 (2.4) 25 (1.9) 27 (2.6) 22 (2.2) 49 (2.4)
Data are mean (SD) unless otherwise stated.
Definition of abbreviations: b.i.d. = twice daily; CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease;
FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; GLY = glycopyrronium; GOLD = Global Initiative for
chronic Obstructive Lung Disease; ICS = inhaled corticosteroid; IND = indacaterol; LABA = long-acting β2-agonist; LAMA = long-
acting muscarinic antagonist; mMRC = modified Medical Research Council; q.d. = once daily; SD = standard deviation; SFC =
salmeterol/fluticasone propionate combination; SGRQ-C = St George’s Respiratory Questionnaire C.
28
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457
458
459
460
461
462
TABLE 2. CHANGE IN BLOOD EOSINOPHILS FROM BASELINE TO WEEKS 26 AND 52 BY ABSOLUTE CELL COUNT AND
PERCENTAGE
Treatment Difference
Visit Treatment LSM (SE) Comparator LSM (SE) 95% CI P value
Blood Eosinophils (%)
Baseline All 2.835
Week 26 CFB IND/GLY –0.06 (0.047) SFC 0.24 (0.066) 0.11, 0.37 < 0.001
SFC –0.29 (0.047)
Week 52 CFB IND/GLY –0.05 (0.048) SFC 0.32 (0.069) 0.18, 0.45 < 0.001
SFC –0.37 (0.049)
Blood Eosinophils (cells/μl)
Baseline All 216
Week 26 CFB IND/GLY –3 (3.7) SFC 16 (5.2) 6, 26 0.002
SFC –19 (3.7)
Week 52 CFB IND/GLY –3 (3.8) SFC 22 (5.4) 11, 33 < 0.001
SFC –25 (3.9)
29
463
464
All LSMs, SEs, CIs, and P values are from a Mixed Model for Repeated Measures. Change from baseline in eosinophils (% or
cells/μl) = treatment + baseline value + visit + treatment*visit interaction + baseline value*visit interaction. Baseline raw means are
not from the model. Baseline is defined as the pre-dose value at run-in visit 102 (scheduled Day 1, 45 to 20 min pre-dose) or, if
missing, as last value measured prior to first dose.
Number of patients included in the analysis: IND/GLY = 1,465, SFC = 1,431
Definition of abbreviations: b.i.d. = twice daily; CFB = change from baseline; CI = confidence interval; GLY = glycopyrronium; IND =
indacaterol; LSM = Least-squares mean, q.d. = once daily; SE = standard error of the mean; SFC = salmeterol/fluticasone
propionate combination.
30
465
466
467
468
469
470
471
472
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