A proposal for the withdrawal of inhaled corticosteroids in the clinical practice of chronic obstructive pulmonary disease
Miravitlles et al. Respiratory Research
A proposal for the withdrawal of inhaled corticosteroids in the clinical practice of chronic obstructive pulmonary disease
Marc Miravitlles 0 8
Borja G. Cosío 6 7
Aurelio Arnedillo 12 13
Myriam Calle 10 11
Bernardino Alcázar-Navarrete 15
Cruz González 14
Cristóbal Esteban 4 9
Juan Antonio Trigueros 5
José Miguel Rodríguez González-Moro 2
José Antonio Quintano Jiménez 3
Adolfo Baloira 1
0 Pneumology Department, Hospital Universitari Vall d'Hebron , P. Vall d'Hebron 119-129, 08035 Barcelona , Spain
1 Servicio de Neumología, Complejo Hospitalario Universitario de Pontevedra , Pontevedra , Spain
2 Pneumology Department, Hospital Universitary “Príncipe de Asturias”, Alcalá de Henares , Madrid , Spain
3 Centro de Salud Lucena I , Lucena, Córdoba , Spain
4 Red de Investigación en Servicios Sanitarios y Enfermedades Crónicas (REDISSEC) , Bilbao , Spain
5 Health Center Menasalbas, Autonomic Health Service , Toledo , Spain
6 Department of Respiratory Medicine, Hospital Universitario Son Espases-IdISBa , Palma de Mallorca , Spain
7 CIBER de Enfermedades Respiratorias (CIBERES) , Barcelona , Spain
8 Pneumology Department, Hospital Universitari Vall d'Hebron , P. Vall d'Hebron 119-129, 08035 Barcelona , Spain
9 Pneumology Department of Hospital Galdakao-Usansolo , Biscay , Spain
10 Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid , Madrid , Spain
11 Pulmonary Department, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos , Madrid , Spain
12 Medicine Department, University of Cádiz , Cádiz , Spain
13 Pneumology, Allergy and Thoracic Surgery Department, Hospital Universitario Puerta del Mar , Cádiz , Spain
14 Department of Respiratory Medicine, Hospital Clínico Universitario and Instituto de Investigación Sanitaria (INCLIVA) Valencia , Valencia , Spain
15 Respiratory Department, AIG de Medicina, Hospital de Alta Resolución de Loja, Agencia Sanitaria Hospital de Poniente , Loja, Granada , Spain
According to the current clinical practice guidelines for chronic obstructive pulmonary disease (COPD), the addition of inhaled corticosteroids (ICS) to long-acting β2 agonist therapy is recommended in patients with moderate-tosevere disease and an increased risk of exacerbations. However, ICS are largely overprescribed in clinical practice, and most patients are unlikely to benefit from long-term ICS therapy. Evidence from recent randomized-controlled trials supports the hypothesis that ICS can be safely and effectively discontinued in patients with stable COPD and in whom ICS therapy may not be indicated, without detrimental effects on lung function, health status, or risk of exacerbations. This article summarizes the evidence supporting the discontinuation of ICS therapy, and proposes an algorithm for the implementation of ICS withdrawal in patients with COPD in clinical practice. Given the increased risk of potentially serious adverse effects and complications with ICS therapy (including pneumonia), the use of ICS should be limited to the minority of patients in whom the treatment effects outweigh the risks.
Algorithm; Chronic obstructive pulmonary disease; Exacerbations; Inhaled corticosteroids; Lung function
Chronic obstructive pulmonary disease (COPD) is
associated with high morbidity and mortality worldwide,
] and continues to represent a significant public
health challenge. According to the Global Initiative
for Chronic Obstructive Lung Disease (GOLD)
recommendations, long-acting bronchodilators are the
mainstay of treatment in patients with COPD [
Similarly, all national guidelines for the management
of COPD in Europe recommend bronchodilators as
first-line therapy, regardless of clinical presentation or
Anti-inflammatory therapy with inhaled corticosteroids
(ICS) may be added to long-acting β2-agonists (LABAs) in
patients with moderate-to-very severe COPD and
]. The ICS/LABA combination is more effective
than either of the individual drugs alone for improving
health status and lung function and reducing
exacerbations in these patients, [
] and may also be used in the
management of patients with asthma-COPD overlap
2, 7, 8
]. However, regular ICS therapy is associated
with an increased risk of pneumonia, particularly in older
patients (aged ≥55 years) and those with severe disease, as
well an increased prevalence of oral candidiasis, skin
bruising and hoarse voice [
2, 9, 10
According to the GOLD strategy, patients with COPD
in group D (with a history of frequent exacerbations [≥2
in the past year], and a COPD Assessment Test [CAT]
score ≥ 10 or modified Medical Research Council score ≥
2) should receive first-line treatment with a
LABA/longacting muscarinic antagonist (LAMA) combination [
ICS/LABA combination therapy may be considered as
first-line therapy in patients with suspected ACO or high
blood eosinophil counts [
]. Based on these combined
risk criteria, real-life data indicate that only a minority of
patients with COPD would be potential candidates for
ICS therapy [
]. However, ICS prescribing rates
(either alone or as combination therapy) reportedly range
from 42% to 86%, regardless of COPD severity and
exacerbation risk [
]. This high ICS usage
significantly increases the risk of serious pneumonia and other
respiratory infections [
6, 19, 20
In a 2015 Spanish consensus report, it was agreed that
ICS therapy should be added to long-acting
bronchodilators in patients with frequent exacerbations and in those
with ACO phenotype, but should not be added to LABA
therapy to improve lung function [
]. The expert panel
also agreed that ICS withdrawal in patients with stable
COPD was possible, although no consensus was reached
on how, when and in whom to discontinue ICS [
Algorithms for the withdrawal of ICS in patients
switched from GOLD D to C following the new GOLD
] and for the stepwise ICS withdrawal in
patients with COPD [
] have previously been
proposed; however, complex treatment algorithms are often
difficult to adopt into clinical practice. To this end,
simplified treatment algorithms for COPD management
have been developed [
As a follow-up to the previous Spanish consensus
report on ICS use in COPD, experts in COPD
management met with the aim of developing a simplified
strategy for ICS withdrawal in patients with COPD. This
article summarizes the evidence for the discontinuation
of ICS therapy and presents a potential algorithm for the
implementation of ICS withdrawal in clinical practice.
Effects of ICS therapy in patients with COPD
ICSs are very effective as anti-inflammatory therapy in
patients with asthma. ICS therapy works by recruiting
histone deacetylase (HDAC) enzymes to inflammatory genes
that are being actively transcribed; this suppresses the
expression of inflammatory proteins and results in decreased
airway inflammation [
]. Compared with asthma, ICS
therapy is less effective when used in the management of
COPD. The diminished anti-inflammatory effects of ICSs
in COPD may be caused by decreased HDAC expression
and enzyme activity, which has been observed in the
alveolar macrophages of patients with COPD and is thought
to be mediated by oxidative stress [
Although the anti-inflammatory effects of ICS therapy
are decreased in COPD compared with asthma, decreases
in airway inflammation with ICS have been reported in
patients with COPD. In a study of patients with
moderateto-severe COPD, inhaled fluticasone/salmeterol for
13 weeks led to significant reductions in absolute biopsy
CD8+, CD4+, and CD45+ cell counts versus placebo, as well
as sputum differential neutrophil counts and sputum
]. The Groningen Leiden Universities
Corticosteroids in Obstructive Lung Disease (GLUCOLD)-1 study
has also shown significant reductions in sputum
neutrophils, macrophages, and lymphocyte counts with
fluticasone therapy over 30 months in patients with
moderate-to-severe COPD, while withdrawal of fluticasone
after 6 months led to increased bronchial CD3+, mast, and
plasma cell counts [
]. In a long-term observational
follow-up study (GLUCOLD-2), patients who discontinued
fluticasone after 30 months of treatment experienced an
increase in sputum inflammatory cells, as well as bronchial
T-lymphocytes and mast cells [
]. The GLUCOLD-2 study
also demonstrated a significant correlation between
increased sputum macrophage counts and an accelerated
rate of decline in lung function [
]. These studies
suggest that at least some patients with COPD, and
in particular those with significant airway
inflammation, may benefit from ICS therapy. However, there is
also evidence that fluticasone may not affect airway
inflammation. For example, a study of Japanese
patients with COPD showed no significant changes
from baseline in sputum neutrophils or other
inflammatory markers with salmeterol/fluticasone for
12 weeks when compared with placebo [
Eosinophilic airway inflammation, which is commonly
found in patients with asthma, also occurs in some
patients with COPD [
]. High blood and/or sputum
eosinophil counts are often associated with an increased
risk of COPD exacerbations, [
] and may be a
marker of response to ICS therapy [
Early randomized-controlled trials (RCTs) have
demonstrated the clinical benefits of inhaled fluticasone
propionate in patients with moderate-to-severe COPD [
]. In these trials, fluticasone was associated with
significantly lower rates of moderate or severe
exacerbations compared with placebo over 6 months,  or
3 years [
Subsequent studies have shown that ICS/LABA
combination therapy is more effective than ICS
alone, particularly with regard to reducing
] but has no effect on long-term survival. In
the Towards a Revolution in COPD Health
(TORCH) trial, fluticasone propionate/salmeterol was
associated with a slight reduction in mortality risk
compared with placebo, but this reduction was not
statistically significant [
]. The mortality risk also
did not significantly differ between
fluticasone/salmeterol and salmeterol alone, but was significantly
lower with the combination therapy than fluticasone
alone (p = 0.007) [
]. A subsequent analysis of data
from the TORCH study suggested that any mortality
benefit from fluticasone/salmeterol versus placebo
was more likely attributable to the salmeterol
]. In the Study to Understand Mortality
and Morbidity (SUMMIT) in patients with moderate
COPD and increased cardiovascular risk, fluticasone
furoate/vilanterol had no significant effect on
allcause mortality or cardiovascular outcomes
compared with placebo [
The beneficial effects of ICS therapy in preventing or
reducing exacerbations appear to be limited to patients
with eosinophilic inflammation. In a randomized study
of patients with COPD, a 62% mean reduction in the
frequency of severe exacerbations was observed when
COPD management was aimed at minimizing sputum
eosinophil levels compared with conventional
guidelinebased management [
]. In a post hoc analysis of two
randomized, double blind trials, the combination of
vilanterol/fluticasone furoate was shown to reduce
COPD exacerbations by 29% in patients with eosinophil
counts of ≥2% and by 10% in patients with eosinophil
counts of <2% compared with vilanterol alone [
]. In a
post hoc analysis of the Foster 48-Week Trial to Reduce
Exacerbations in COPD (FORWARD), the beneficial
effects of beclomethasone dipropionate/formoterol
fumarate (ICS/LABA) versus formoterol fumarate alone with
regard to reductions in exacerbations were most evident
in patients with peripheral blood eosinophilia (≥279.8
]. Similarly, a pooled analysis of two
12month RCTs showed that patients with >2.4% blood
eosinophils potentially achieve the greatest reductions in
exacerbations with ICS/LABA therapy versus LABA
]. An analysis of the Inhaled Steroids in
Obstructive Lung Disease in Europe (ISOLDE) trial
indicated that a baseline blood eosinophil count ≥2% was
associated with a significantly reduced rate of FEV1
decline with fluticasone propionate versus placebo (p =
0.003), while there was no difference in FEV1 decline
among those with <2% eosinophils [
However, when comparing the efficacy of ICS with that
of long-acting bronchodilators the results are usually
favorable to the latter. LAMA alone has been shown to be
as effective as ICS/LABA therapy with regard to
improvements in lung function and preventing exacerbations in
patients with COPD. In the Investigating New Standards
for Prophylaxis In Reducing Exacerbations (INSPIRE)
study of patients with severe or very severe COPD and a
history of exacerbations, the annual rate of exacerbations
showed no difference between fluticasone
propionate/salmeterol and tiotropium bromide alone, although the
incidence of pneumonia was significantly higher with
fluticasone propionate/salmeterol (p = 0.008) [
The LABA/LAMA combination
indacaterol/glycopyrronium was associated with significantly greater
improvements in lung function over 26 weeks compared with
fluticasone/salmeterol (p < 0.001) in the Efficacy and safety
of once-daily indacaterol/glycopyrronium compared with
twice-daily salmeterol–fluticasone in patients with chronic
obstructive pulmonary disease (ILLUMINATE) trial, [
and significantly reduced the rate of moderate or severe
exacerbations with a lower rate of pneumonia in A 26-week
treatment randomized, double-blind, double dummy,
parallel-group study to assess the efficacy and safety of
indacaterol/glycopyrronium (LANTERN) trial [
]. In the
Effect of indacaterol/glycopyronium vs
fluticasone/salmeterol on COPD exacerbations (FLAME) trial, the annual
rate of COPD exacerbations was also found to be
significantly (11%) lower with indacaterol/glycopyrronium than
fluticasone/salmeterol over 12 months (p = 0.003) in
patients with a previous history of at least one exacerbation. It
is important to indicate that patients with a history of
asthma and/or blood eosinophil counts >600 cells/μL were
excluded form FLAME [
Adverse effects of inhaled corticosteroids
Accumulated evidence from clinical trials indicates that
ICS therapy is associated with a high risk of pneumonia,
oral candidiasis, hoarse voice, and skin bruising [
2, 4, 5, 9,
]. The risk of pneumonia is increased in older patients
(aged ≥55 years), current smokers, and patients with a
history of exacerbations or pneumonia, a body mass index
<25 kg/m2, dyspnea, and/or severe airflow limitation [
In a meta-analysis of RCTs in patients with COPD,
inhaled fluticasone or budesonide was associated with
a significant (57%) increase in the risk of pneumonia
(p < 0.0001) . However, an observational cohort
study of patients with COPD found that the rates of
pneumonia and hospitalization were significantly
higher with fluticasone/salmeterol than budesonide/
formoterol (p < 0.001), which suggests there are
intradrug class differences in the risks of pneumonia with
ICS/LABA combination therapies [
Long-term ICS exposure may also be associated with an
increased risk of bone fractures in patients with COPD
]. A meta-analysis of RCTs and observational studies
indicated a significant (27%) increase in the risk of
fractures with fluticasone or budesonide therapy (p = 0.04)
]. Osteoporosis and COPD are also strongly correlated
due to common lifestyle risk factors (eg physical inactivity,
poor diet, and smoking), COPD-associated inflammation,
and vitamin D deficiency [
Other adverse effects associated with the use of ICS
include an increased risk of new-onset diabetes or diabetes
] cataracts, [
] and tuberculosis [
]. In a
database cohort study of patients with respiratory disease,
ICS therapy was associated with a 34% increase both in
the risk of new-onset diabetes and in the risk of diabetes
Evidence supporting ICS withdrawal in patients with
The excessive and inappropriate use of ICS in COPD
together with the increased risk of adverse effects
associated with its use makes it necessary to discontinue this
treatment in patients in which the risks overweight the
possible benefits. Withdrawal of ICS has been analyzed
in several studies.
In patients with COPD, ICS withdrawal was associated
with several clinical disadvantages in early studies
(Table 1). As part of the ISOLDE trial, [
observational study compared patients who were receiving ICS
at study entry with those who were not on ICS [
this 8-week study, ICS withdrawal was associated with
more exacerbations, indicating that patients should be
monitored carefully following abrupt ICS
]. In the Effect of discontinuation of inhaled
corticosteroids in patients with chronic obstructive
pulmonary disease (COPE) study, withdrawal of inhaled
fluticasone led to a higher risk of exacerbation and a
significant decline in quality of life [
discontinuation of fluticasone was associated with a decline in
lung function and an increase in dyspnea and mild
exacerbations in the COPD and Seretide: a Multicenter
Intervention and Characterization (COSMIC) trial, [
and a worsening of symptoms and increased risk of
exacerbations in the Withdrawal of inhaled corticosteroids
in people with COPD in primary care (WISP) trial [
However, a meta-analysis of the WISP, COPE, and
COSMIC trials indicated that ICS withdrawal was not
associated with a significant increase in the risk of
]. The definition of exacerbation differed
between these early studies and the use of other
medication was not reported [
]. A more recent and robust
meta-analysis concluded that ICS discontinuation did
not significantly increased the overall rate of COPD
exacerbations, although an increased risk of severe
exacerbations was detected [
]. The increased risk of all
types of exacerbations following ICS withdrawal
observed in early studies was most likely due to a lack of
alternative COPD medications.
Evidence from more recent RCTs and real-life studies
supports the hypothesis that the ICS therapy can be
safely withdrawn in patients with stable COPD (Table 1).
In the Withdrawal of Inhaled Steroids During Optimized
Bronchodilator Management (WISDOM) trial, in which
the safety of gradual ICS withdrawal in patients
previously on ICS/LABA/LAMA triple therapy was evaluated,
there was no significant difference in the risk of
moderate or severe COPD exacerbation over 12 months after
ICS withdrawal compared with ongoing triple therapy
]. Although a significantly greater decrease in FEV1
was observed at 18 weeks after ICS withdrawal (mean
difference 38 mL vs continued ICS; p < 0.001), [
was less than half of what is considered as the minimum
clinically important difference. A post hoc analysis of
WISDOM showed that patients who stopped ICS
experienced a similar disease course with regard to lung
function to those who continued ICS therapy [
Although deterioration of lung function was observed after
ICS withdrawal, these changes were small, not
progressive and not predictive of clinically important changes
over the duration of study follow-up [
By contrast, in the Indacaterol: Switching Non-exacerbating
Patients with Moderate COPD from Salmeterol/Fluticasone
to Indacaterol (INSTEAD) trial, there were no clinically
relevant reductions in lung function or differences in dyspnea
or health status over 26 weeks among patients who switched
to indacaterol compared with those who continued
fluticasone/salmeterol therapy [
]. The annual rate
of mild, moderate, or severe COPD exacerbations also
showed no significant difference between the groups.
The INSTEAD trial concluded that patients with
moderate airflow limitation and no history of
exacerbations can be switched from fluticasone/salmeterol
to indacaterol monotherapy without loss in treatment
In the Real-life study on the appropriateness of
treatment in moderate COPD patients (OPTIMO), the risk
of exacerbations did not significantly increase over
6 months after ICS withdrawal compared with continued
ICS/bronchodilator therapy [
]. There was also no
evidence of deterioration in COPD symptoms or lung
function over 6 months following ICS withdrawal [
Consistent with these findings, a subgroup analysis of
patients on ICS prior to study entry in the Outpatient
care with long-acting bronchodilators: COPD registry in
Germany (DACCORD) showed that ICS withdrawal was
not associated with an increase in the risk of
exacerbations or an increased risk of health status deterioration
compared with continued ICS therapy [
]. Indeed, in
the second year of follow-up in DACCORD, the annual
rate of exacerbations was lower among patients who
underwent ICS withdrawal than in those who continued
ICS therapy [
ICS withdrawal may also provide clinical benefits in
patients by reducing the risk of adverse effects, particularly
pneumonia. In a population-based cohort study, ICS
withdrawal in patients with COPD was associated with a 37%
decrease in the rate of serious pneumonia over 3 years,
with a 20% risk reduction over the first month [
note, patients who discontinued fluticasone showed
greater reductions in severe pneumonia risk than those
who discontinued budesonide [
]. These findings
indicate that the beneficial effects of ICS withdrawal may
occur soon after treatment discontinuation.
In a subanalysis of exacerbation rates by previous therapy
in the FLAME trial, among patients who had previously
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received ICS therapy (56% of patients), those who were
randomized to LABA/LAMA had a significantly lower risk of
exacerbations than those who continued ICS/LABA therapy
(risk ratio 0.88; 95% confidence interval 0.80–0.97) [
Additionally, the effect of glyCopyrronium or indacateRol
maleate and glYcopyrronium bromide fixed-dose
combination on SympToms and heALth status in patients with
moderate COPD (CRYSTAL) study of symptomatic patients
with moderate COPD previously on ICS/LABA, LABA or
LAMA therapy showed that switching to
indacaterol/glycopyrronium was associated with significant improvements in
trough FEV1 over 12 weeks [
In a subanalysis of the WISDOM study, patients with
severe or very severe COPD and a history of
exacerbations who had blood eosinophil counts of ≥4% (≥300
cells/μL) were at an increased risk of exacerbations
following ICS withdrawal compared with those with lower
eosinophil counts [
]. In fact, the risk of exacerbation
after withdrawal was significantly increased in patients
who suffered 2 or more exacerbations the previous year
and had blood eosinophil counts >300 cells/μL. In
addition, these patients experienced a mean decrease of
109 mL in FEV1 compared with the mean decrease of
43 mL for the whole population [
]. This suggests that
ICS withdrawal may have deleterious effects in a
subpopulation of patients with higher blood eosinophil
counts and frequent exacerbations.
Proposed algorithm for ICS withdrawal in patients with
The proposal for managing ICS withdrawal in patients
with COPD takes three clinical parameters into account:
a) whether or not there is a history of previous
exacerbations; b) whether FEV1 is more or less than 50%; and c)
whether the patient has criteria for ACO (which in the
Spanish guidelines includes patients with COPD and
blood eosinophil counts >300 cells/μL and/or a
postbronchodilator response of >400 mL and 15% in FEV1)
]. Based on these clinical parameters, patients with
COPD may be classified into three categories: (i)
patients in whom the risks associated with ICS withdrawal
exceed the benefits; (ii) those in whom the benefits of
ICS withdrawal are greater than the risks; and (iii) those
in whom the risks and benefits of ICS are balanced. A
summary of this patient classification and how lung
function and exacerbation history affect the benefits and
risks of ICS withdrawal is shown in Fig. 1. Taking these
categories into consideration, the decision to withdraw
or continue ICS is based on the following:
1. In patients with COPD, FEV1 > 50% and no previous
exacerbations, the benefits of ICS withdrawal exceed
risks and ICS must be withdrawn.
2. In patients with ACO and exacerbations in the
previous year, the risks associated with ICS
withdrawal exceed the benefits and ICS should not
3. Patients with FEV1 > 50% and exacerbations in the
previous year and patients with FEV1 < 50% without
exacerbations have an intermediate level of risk
associated with ICS withdrawal. The risk of
exacerbations after ICS discontinuation is low, but
dual bronchodilator therapy should be maintained to
make sure that the risk of exacerbations does not
4. Patients with FEV1 < 50% and exacerbations in the
previous year, together with patients with ACO
without exacerbations, may have an increased risk of
exacerbations after ICS withdrawal. Discontinuation
should be considered only in patients with a
significant risk of serious ICS-related adverse effects.
In these patients, ICS withdrawal may still be
possible provided that dual bronchodilator
therapy is maintained, but close follow-up is
An overview of the proposed algorithm is shown in Fig. 2.
Benefits of ICS withdrawal exceed risks
In patients with FEV1 > 50% and no exacerbations in the
previous year, the benefits of ICS withdrawal exceed the
risks and ICS therapy should be discontinued. Evidence
supporting ICS withdrawal in these patients is provided
by the OPTIMO, [
] INSTEAD, [
] and DACCORD
] studies, in which patients with mild or moderate
COPD had no changes in exacerbations, lung function,
or health status following ICS withdrawal.
Studies have also indicated that dual bronchodilator
therapy with a LABA/LAMA combination may be used
as an alternative to ICS/LABA therapy in patients with
moderate-to-severe COPD and a low risk of
exacerbations. In this group of patients, LABA/LAMA therapy
(indacaterol/glycopyrronium) was associated with
improved lung function and lower rates of exacerbation
and pneumonia compared with ICS/LABA therapy
(fluticasone/salmeterol) in the ILLUMINATE, [
] and CRYSTAL [
] studies. Therefore,
patients with an FEV1 > 50% and no exacerbations in the
previous year are candidates for ICS withdrawal,
provided that dual bronchodilator therapy is continued [
Risks associated with ICS withdrawal exceed benefits
In patients with ACO and a history of exacerbations in
the previous year, the ICS withdrawal risks are greater
than the benefits and ICS should not be discontinued.
ACO is recognized as a distinct COPD phenotype, and
relevant clinical practice guidelines provide criteria to
enable clinicians to identify patients with COPD who
have an asthma component [
]. The prevalence of
ACO among patients with COPD is thought to be up to
] although prevalence is difficult to
stimate as there is no internationally accepted definition of
A simplified algorithm for the identification of ACO
was proposed following a consensus between the
Spanish COPD and asthma guidelines [
]. In this
algorithm, the first criterion to be met is a diagnosis of
COPD (ie aged ≥35 years, ≥10 pack-year smoker or
exsmoker, and post-bronchodilator FEV1/FVC <0.7), after
which the diagnostic criteria for asthma are assessed. If
the diagnostic criteria for both COPD and asthma are
met, a diagnosis of ACO is confirmed; patients who do
not meet all of the asthma diagnostic criteria, but have a
bronchodilator response of ≥400 mL and 15% in FEV1
and/or eosinophilia of ≥300 cells/μL are also classified as
having ACO [
]. Patients with non-completely
reversible airflow obstruction but who smoked less than
10 pack-years should be considered and treated like
A post hoc analysis of the WISDOM trial identified a small
subgroup of patients with COPD with a significantly
increased risk of exacerbations after ICS withdrawal; these
patients had a history of frequent exacerbations (≥2 per year)
and high baseline eosinophil counts (≥300 or ≥400 cells/μL;
defined as ACO according to Spanish guidelines), although a
history of frequent exacerbations alone was not predictive of
ICS responsiveness in the overall study population [
these patients represented a very small proportion of the
total patient population in the WISDOM study, this category
is expected to consist of a minority of the patients with
Intermediate ICS withdrawal risk: benefit ratio
Patients with FEV1 > 50% and exacerbations in the
previous year and patients with FEV1 < 50% without
exacerbations have an intermediate risk associated with ICS
withdrawal. Patients should be individually assessed to
determine whether or not ICS therapy should be
discontinued, with the risk of ICS-related adverse effects being
taken into consideration. This recommendation is
supported by evidence from the WISDOM [
] and FLAME
] studies, in which patients with moderate, severe, or
very severe COPD and a history of exacerbations showed
no increase in the annual rate of exacerbations after
discontinuation of ICS and ongoing dual bronchodilator
therapy. In the FLAME study, the rate of pneumonia
was lower with LABA/LAMA than ICS/LABA therapy,
] and a post hoc analysis indicated that the lower rate
of exacerbations with LABA/LAMA was independent of
blood eosinophil levels [
]. Although the risk of
exacerbations may be increased in patients with FEV1 < 50%
and exacerbations in the previous year, as well as
patients with ACO without exacerbations, ICS withdrawal
needs to be considered in these patients, particularly
those with an increased risk of serious ICS-related
adverse effects. Following ICS withdrawal, these patients
should be maintained on dual bronchodilator therapy
and closely followed for exacerbations.
Method of ICS withdrawal
Based on clinical evidence, ICS therapy may be
discontinued abruptly, rather than with gradual dose reduction.
In the INSTEAD, [
] FLAME, [
] OPTIMO, [
] and DACCORD [
] studies, ICS
therapy was withdrawn abruptly with no apparent increase
in exacerbations or loss of lung function. WISDOM was
the only study in which the ICS dose was decreased in a
stepwise fashion [
]. Although ICS withdrawal was
associated with a significant decrease in FEV1 in this
study, the decline in lung function was only observed
after complete ICS discontinuation at 18 weeks and was
not progressive [
]. This suggests that the effect of
ICS withdrawal on lung function (if any) only occurs
after complete discontinuation, and there is no need to
taper the dose in most patients. It should be noted that
the LABA used in this study was salmeterol, which has a
low intrinsic efficacy and a well-known tolerance in
terms of reduction of effect over time . Particular
care should be exercised in high-risk patients with
frequent exacerbations or poor lung function receiving
high doses of ICS, and routine follow-up of patients after
ICS withdrawal is recommended.
Physicians should carefully evaluate patients and provide
individualized COPD treatment, especially when
considering the initiation of ICS therapy or the safe
discontinuation of ICS in patients on long-term therapy. Given the
limited efficacy and the potentially serious adverse effects
and complications of long-term ICS therapy, the use of
ICS should be limited to the minority of patients with
COPD in whom the treatment effects outweigh the risks,
and patients for whom safe ICS withdrawal can be
achieved should be identified.
ACO: Asthma-COPD overlap; CAT: COPD Assessment Test; COPD: Chronic
obstructive pulmonary disease; COPE: Effect of discontinuation of inhaled
corticosteroids in patients with chronic obstructive pulmonary disease;
COSMIC: COPD and Seretide: a Multicenter Intervention and Characterization;
CRYSTAL: Effect of glyCopyrronium or indacateRol maleate and
glYcopyrronium bromide fixed-dose combination on SympToms and heALth
status in patients with moderate COPD; DACCORD: Outpatient care with
long-acting bronchodilators: COPD registry in Germany; FLAME: Effect of
indacaterol glycopyronium vs fluticasone salmeterol on COPD exacerbations;
FORWARD: Foster 48-week trial to reduce exacerbations in COPD; GOLD,
Global Initiative for Chronic Obstructive Lung Disease; GLUCOLD: Groningen
Leiden Universities Corticosteroids in Obstructive Lung Disease;
HDAC: Histone deacetylase; ICS: Inhaled corticosteroids; ILLUMINATE: Efficacy
and safety of once-daily QVA149 compared with twice-daily salmeterol–
fluticasone in patients with chronic obstructive pulmonary disease;
INSPIRE: Investigating New Standards for Prophylaxis In Reducing
Exacerbations; INSTEAD: Indacaterol: Switching non-exacerbating patients
with moderate COPD from salmeterol/fluticasone to indacaterol;
ISOLDE: Inhaled Steroids in Obstructive Lung Disease in Europe; LABA:
Longacting β2-agonists; LAMA, long-acting muscarinic antagonist; LANTERN: A
26week treatment randomized, double-blind, double dummy, parallel-group
study to assess the efficacy and safety of QVA149; OPTIMO: Real-life study on
the appropriateness of treatment in moderate COPD patients;
RCT: Randomized-controlled trials; SUMMIT: Study to understand mortality
and morbidity; TORCH: Towards a revolution in COPD health;
WISDOM: Withdrawal of inhaled steroids during optimized bronchodilator
management; WISP: Withdrawal of inhaled corticosteroids in people with
COPD in primary care
The authors would like to thank Paul Karagounis, who prepared the outline
of this manuscript on behalf of Springer Healthcare, and Sarah Greig, PhD, of
Springer Healthcare Communications who prepared the first draft of this
manuscript. This medical writing assistance was funded by Novartis.
This article is a summary of a workshop held in Barcelona, Spain on February
14 2017. The workshop was supported by unrestricted grant from Novartis.
The sponsor had no role in the discussion, preparation of manuscript and
decision to submit the manuscript for publication.
Availability of data and materials
All authors participated in the round table discussions and drafted, reviewed
and approved the final version of the manuscript.
Ethics approval and consent to participate
Consent for publication
MM has received speaker fees from Boehringer Ingelheim, AstraZeneca,
Chiesi, GlaxoSmithKline, Menarini, Teva, Grifols, and Novartis, and consulting
fees from Boehringer Ingelheim, GlaxoSmithKline, Gebro Pharma, CLS
Behring, Cipla, MediImmune, Mereo Biopharma, Teva, Novartis, and Grifols;
BGC has received grants from SEPAR (Sociedad Española de Neumología y
Cirugíatorácica), Boehringer Ingelheim, and Menarini, personal fees from
AstraZeneca, Rovi, and Esteve, grants and personal fees from Novartis and
Chiesi; AA has received grants from SEPAR, Esteve, and NEUMOSUR
(Asociación de Neumología y Cirugía Torácica del Sur), and speaker fees
from Boehringer Ingelheim, AstraZeneca, Chiesi, Gebro Pharma, Grifols, MSD,
Mundipharma, Pfizer, and Novartis; MC has received personal fees from
Laboratorios Menarini, GSK, and Rovi, and grants from Boehringer Ingelheim;
Bernardino Alcázar-Navarrete has received personal fees from GSK, Gebro,
and AstraZeneca, grants, personal fees, and non-financial support from
Novartis AG and Laboratorios Menarini, and personal fees and non-financial
support from Boehringer Ingelheim and Chiesi; CG has received grants from
SVN (Sociedad Valenciana de Neumología) and Laboratorios Menarini; grants
and speaker fees from Boehringer Ingelheim, Novartis, Rovi, and Teva,
speaker fees from AstraZeneca, and grants and consulting fees from Esteve;
CE has no conflicts of interest to declare; JAT has received speaker fees from
Boehringer Ingelheim, Menarini, Teva, and Novartis, and consulting fees from
Boehringer Ingelheim, GlaxoSmithKline, and Esteve; JMRGM has received
speaker fees from Boehringer Ingelheim, AstraZeneca, Chiesi, Teva, and
Novartis, and consulting fees from Boehringer Ingelheim and Teva; JAQJ has
received speaker fees from Esteve, Teva, Gebro, and Grifols, and consulting
fees from Boehringer Ingelheim and Teva; and Adolfo Baloira has received
speaker fees from Boehringer Ingelheim, AstraZeneca, Chiesi,
GlaxoSmithKline, Esteve, Ferrer, Menarini, Teva, Grifols, and Novartis, and consulting fees
from Boehringer Ingelheim, GlaxoSmithKline, Esteve, Teva, Novartis, and
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