Inhaled corticosteroids in COPD

Consultant Chest Physician
TB TEAM EXPERT – WHO
Mansoura - Egypt
www.slideshare.net/ashraf eladawy

COPD: Management
Clinical diagnosis
Spirometry
Gold Severity stage
Drugs a/t stages

SYMPTOMS
Cough
Sputum
Shortness of breath
EXPOSURE TO RISK
FACTORS
Tobacco
Occupation
Indoor/outdoor pollution
SPIROMETRY
Diagnosis of COPD


GOLD Therapy at Each Stage of COPD
• FEV1/FVC <0.70
• FEV1 ≥80%
predicted
I: Mild II: Moderate III: Severe IV: Very Severe
• FEV1/FVC <0.70
• 50% ≤FEV1 <80%
predicted
• FEV1/FVC <0.70
• 30% ≤FEV1 <50%
predicted
• FEV1/FVC <0.70
• FEV1 <30%
predicted
or FEV1 <50%
predicted plus
chronic
respiratory failure
Add regular treatment with one or more long-acting bronchodilators (when
needed):
Add pulmonary rehabilitation
Add inhaled glucocorticosteroids if repeated
exacerbations
Add long-term oxygen if
chronic respiratory failure
Consider surgical
treatments
Global Initiative for Chronic Obstructive Lung Disease (GOLD). NHLBI/WHO Workshop report. www.goldcopd.com
Active reduction of risk factor(s): influenza vaccination
Add short-acting bronchodilator (when needed PRN)

 It is well established that patients with COPD lose
lung function at a steeper rate than subjects
without COPD.
 Post-bronchodilator (FEV1) is the single most
important marker to determine severity and
treatment algorithms in COPD.
 The decline of FEV1 over time has been
traditionally used to indicate disease progression.
13

Years
FEV1(L)
2.0
2.1
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
0 1 2 3 4 5 6 7 8 9 10 11
Continuous smokers
Disease Progression in COPD
Lung Function

Limitations
 FEV1, while a crucial marker, is far from being the
only measure to comprehensively characterize
patients with COPD.
 Additional outcome measures are usually needed.
 FEV1 measurements do not always correlate with
clinically relevant outcomes such as dyspnoea,
health status, exercise capacity, or exacerbations
15

Staging by FEV1 neglects patient outcomes
Jones P. Thorax 2001;56:880-887.
0
20
40
60
80
100
10 20 30 40 50 60 70 80 90
Upper limit
of normal
SGRQ
score
Stage 4 Stage 3 Stage 2
FEV1 (% predicted)
Breathless
walking
on level
ground
r=–0.23
P<0.0001
Lung function measurements do not reflect the impact of COPD

COPD: Progressive Disease
อาการ/lungfunction
ระยะเวลา
Acute exacerbation

Frequent Exacerbations Lead to
Declining Lung Function
LungFunction
Time (Years)
Exacerbation
Exacerbation
Exacerbation
Never smoked
Smoker
Fletcher C. Br Med J. 1977

Frequent exacerbations are associated
with increased mortality
A = No exacerbations B = 1-2 exacerbations C = 3 or more exacerbations
Soler-Cataluna JJ, et al. Thorax 2005;60:925-931.
p < 0.0001
1.0
Probabilityofsurviving
0.8
0.6
0.4
0.2
0.0
0 10 20 30 40 50 60
Time (months)
A
B
C
p = 0.069
p < 0.0002

Acute exacerbation in COPD
Increased symptoms
Reduced lung function
Accelerate lung function
decline
Deteriorate quality of life
Increased economic cost
Increased mortality
Impact of
acute
exacerabations
in COPD
“an acute event characterized by
worsening of respiratory symptoms
that is beyond normal day-to-day
variations and leads to a change
in medication.”
GOLD Strategy Document 2014 (http://www.goldcopd.org/)

1. Donaldson et al. Thorax 2002;57:847-52.
2 Donaldson et al. Eur Respir J 2003;22:931-6.
3. Seemungal et al. Am J Respir Crit Care Med 1998;157:1418-22.
4. Groenewegen et al. Chest 2003;124:459-67.
5. Soler-Cataluna et al. Thorax 2005;60:925-31.
Exacerbations Drive Morbidity and Mortality
COPD exacerbations lead to:
Increased symptoms
(breathlessness)2
Increased risk
of hospitalization4
Increased risk of mortality
4,5
Decline in lung function1
Worsening health status3

 Background
– Exacerbations of COPD are a major part of the
natural history of COPD:
 Accelerate decline in lung function
 Reduce physical activity and QoL
 Increase risk of hospitalization and death
 Increased significantly healthcare costs
 Rationale
– The ECLIPSE cohort was used to test the hypothesis
of a frequent exacerbation phenotype
The ‘frequent exacerbator phenotype’:
ECLIPSE: Introduction
Hurst JR, et al. N Engl J Med. 2010;363:1128-38
22

 Background
 Rationale
23
Exacerbations are more frequent and more severe
with increasing COPD severity

Frequency/severity by GOLD Category (1)
7
18
33
22
33
47
0
10
20
30
40
50
GOLD II
(N=945)
GOLD III
(N=900)
GOLD IV
(N=293)
%ofpatients
p<0.01
Hospitalised for exacerbation in yr 1 Frequent exacerbations (2 or more)
ECLIPSE 1 year data Hurst et al. N Engl J Med 2010

 Background
 Rationale
25
Exacerbations are more frequent and more severe with
increasing COPD severity
What are the predictors of exacerbation frequency?
The most reliable predictor of exacerbations in an individual
patient a history of prior exacerbations?

Conclusions
ECLIPSE confirms
 Exacerbations become more frequent and more
severe as COPD severity increases
 Frequent exacerbator is an independent disease
phenotype
– That can be identified by patient self-report
about previous exacerbations
– Patients with moderate COPD may be frequent
exacerbators (22%)
Exacerbation in prior year is the best predictor of
occurrence of exacerbation
Exacerbation rate must be integrated in GOLD guidelines

ECLIPSE and HEED confirm
– Disease severity (breathlessness, exercise capacity,
exacerbations, health status degradation) increases with
GOLD stage
– FEV1 poorly related with other parameters
– COPD is highly heterogeneous
– Within GOLD stage there is substantial variation in:
 Breathlessness
 Exercise capacity
 Exacerbation frequency
 Health status
Agusti A, et al. Resp Res. 2010;11:122
“Airflow limitation alone does not provide an
accurate measure of disease severity or activity”
27
“
New GOLD guidelines must include other
parameters: QoL, Symptoms and
Exacerbation rate beyond FEV1 measurements
Conclusions

GOLD 2011
© 2013 Global Initiative for Chronic Obstructive Lung Disease

 Looks at 3 things:
1) FEV1
2) Symptoms
3) History of exacerbations
Revised GOLD classification

 It’s still important to know the OLD FEV1
classification system because it’s used in
the NEW GOLD classification.

In patients with FEV1/FVC <0.70
GOLD 1 Mild FEV1>80%
GOLD 2 Moderate 50%<FEV1<80%
GOLD 3 Severe 30%<FEV1<50%
GOLD 4 Very severe FEV1<30%
Grading severity of airflow
Point out that FEV1/FVC ratio used to be the only factor in the
old classification system.
In a sense, we are using the same 1-4 ratios of FEV1 as the old
system here, but it is now one of three factors in the new
classification system
Low
risk
High
Risk

Combined Assessment of COPD
Assess symptoms
Assess degree of airflow limitation using
spirometry
Assess risk of exacerbations
Assess comorbidities
COPD Assessment Test (CAT)
or
mMRC Breathlessness scale

 Modified British Medical Research Council
(mMRC) Dyspnea Questionnaire:
A 5-item measure of perceived dyspnea
Self-report on grade 0 – 5
(or)
 COPD Assessment Test (CAT):
An 8-item measure of health status impairment
in COPD
Self-report on scale 0 – 5
Assess symptoms

Grading symptoms
0-1 = less breathlessness
>2 = more breathlessness

41
Cough
Sputum
Chest tightness
Walking up hill
ADLs
Leaving the house
Sleep
Energy levels

42
Scores
11-20 medium impact
> 20 high impact

COPD Assessment Test (CAT)
Aim of the COPD Assessment
Test(CAT) is to grade the impact
of COPD on health status.

(C) (D)
(A) (B)
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
Symptoms
(mMRC or CAT score))
If mMRC 0-1 or CAT < 10:
Less Symptoms (A or C)
If mMRC > 2 or CAT > 10:
More Symptoms (B or D)
Assess symptoms first
www.goldcopd.org

 COPD Assessment Test CAT ≥10
 Modified Medical Research Council
Breathlessness scale mMRC ≥2
High Symptoms indicators
Adapted from GOLD 2014

Risk
(GOLDClassificationofAirflowLimitation)
Risk
(Exacerbationhistory)
> 2
1
0
(C) (D)
(A) (B)
mMRC 0-1
CAT < 10
4
3
2
1
mMRC > 2
CAT > 10
Symptoms
(mMRC or CAT score))
If GOLD 1 or 2 and only
0 or 1 exacerbations per
year:
Low Risk (A or B)
If GOLD 3 or 4 or two or
more exacerbations per
year:
High Risk (C or D)
Assess risk of exacerbations next
www.goldcopd.org

 Two or more exacerbations in the last
year.
 GOLD 3 or GOLD 4 categories (FEV1 < 50
% of predicted value)
High risk indicators

Global Strategy for Diagnosis, Management
and Prevention of COPD. Updated 2011
Risk
(GOLDClassificationofAirflowLimitation)
Risk
(Exacerbation
history)
> 2
1
0
(C) (D)
(A) (B)
mMRC 0-1
CAT < 10 or CCQ<1
4
3
2
1
mMRC > 2
CAT > 10 or
CCQ>1
Symptoms
A: Les symptoms, low risk
B: More symtoms, low risk
C: Less symptoms, high risk
D: More Symtoms, high risk

Patient Characteristic Spirometric
Classification
Exacerbations
per year
mMRC CAT
A
Low Risk
Less Symptoms
GOLD 1-2 ≤ 1 0-1 < 10
B
Low Risk
More Symptoms
GOLD 1-2 ≤ 1 >2 ≥ 10
C
High Risk
Less Symptoms
GOLD 3-4 >2 0-1 < 10
D
High Risk
More Symptoms
GOLD 3-4 >2 >2 ≥ 10
When assessing risk, choose the highest risk according to GOLD grade
or exacerbation history
The four COPD patient groups according
to GOLD 2011

Risk
Pre-2011 GOLD
Classification of
Airflow Limitation
Risk
Exacerbation
history
≥ 2
1
0
(C) (D)
(A) (B)
mMRC 0-1 (or) CAT < 10
4
<30%
3
30-50%
1
≥ 80%
mMRC > 2 (or) CAT > 10
Symptoms
(mMRC or CAT score)
2
50-80%

Approaches of COPD treatment according
to GOLD guidelines
Timeline
Unidimensional approach Multidimensional approach
GOLD 2001 GOLD 2011
1) Risk:
FEV1
Rate of exacerbations
2) Symptoms:
CAT score,
mMRC scale

Disease Management should now be focusing on
2 key areas
1.
Goal of COPD Management

Manage Stable COPD: Pharmacologic
Therapy
Patient Recommended 1st choice Alternative choice
Other Possible
Treatments
A
SAMA prn
or
SABA prn
LAMA
or
LABA
or
SABA & SAMA
Theophylline
B
LAMA
or
LABA
LAMA & LABA
SABA and/or SAMA
Theophylline
C
ICS + LABA
or
LAMA
LAMA & LABA or
LAMA & PDE4-inh. or
LABA & PDE4-inh.
SABA and/or SAMA
Theophylline
D
ICS + LABA
and/or
LAMA
ICS + LABA & LAMA or
ICS+LABA & PDE4-inh. or
LAMA & LABA or
LAMA & PDE4-inh.
Carbocysteine
SABA and/or SAMA
Theophylline
From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. http://www.goldcopd.org.

Treatment algorithm for patients without frequent
exacerbations

Pharmacological options for the prevention of
exacerbations in frequent exacerbators

The combination containing ICS + LABA may
be appropriate in patients at high risk of
exacerbations & recommended as first
choice in patients group C and D

ICS/LABA combination therapy
 Inhaled steroids not licensed for use in
COPD except as combination
– ICS must be used in combination with LABA
for patients with COPD
– ICS monotherapy only FDA approved for
treatment of asthma, not COPD
66

ICS and LABAs improve symptoms and lung function
via different mechanisms in COPD
Inflammation
Increased
neutrophils and
CD8+ lymphocytes
Elevated IL–8, TNF
Protease/anti-
protease
imbalance
Structural changes
Alveolar destruction
Collagen deposition
Glandular
hypertrophy
Airway fibrosis
Symptoms
 FEV1
Exacerbations
Inhaled corticosteroids
reduce
LABAs inhibit
Smooth muscle
contraction
Increased
cholinergic tone
Loss of elastic recoil
Sensory nerve
activation
Airway constriction

Corticosteroid
Corticosteroid
receptors
HSP 90
Long-acting 2-agonists
2- adrenoceptor synthesis
Increased anti-inflammatory effect Decreased acquired tolerance
Synergistic Interaction of 2-Agonists with Corticosteroid
cyclic AMP
PKA
MAPK

Aug-15
Interactions between corticosteroids
and ß2-agonists
Glucocorticoid
receptor
ß2-Adrenoceptor
Increased expression/function ß2-adrenoceptors
Corticosteroid
Anti-inflammatory effect
Effect of ß2-agonists on GR function
ß2-Agonist
Bronchodilatation
modified from Barnes P 2002

Interaction between corticosteroids &
β2-Adrenergic Receptors
70

Combination inhalers in COPD
Symbicort 320 Turbohaler and Seretide 500 Accuhaler

 Inhaled corticosteroids (ICS) are now very widely
used in high doses in the management of COPD
patients , in sharp contrast to the situation in
asthma
72

ASTHMA AND COPD
Macrophages
Neutrophils
Tc1 cells
Mast cells
Eosinophils
Th2 cells
Airway Inflammation
ASTHMA COPD
Inflammatory gene
expression
NF-κB
AP-1
Steroid sensitive Steroid resistant

 ICS are the most effective anti-inflammatory
therapy for asthma but are relatively ineffective
in COPD.
 ICS fail to suppress inflammation in COPD patients
because there is a marked reduction in histone
deacetylase-2 (HDAC) , the nuclear enzyme that
corticosteroids require to switch off activated
inflammatory genes.

 In the resting cells, DNA is wound tightly
around basic core histones.
 This conformation of chromatin structure is
described as closed and is associated with
suppression of gene expression.
Epigenetic regulation
of gene expression

 It has been recognised that histones play a
critical role in regulating the expression of
genes and determines which genes are
transcriptionally active and which ones
are suppressed (silenced).
82

Histone acetylation
Douwe Pons et al. Eur Heart J 2009;30:266-277
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2009. For permissions please email: journals.permissions@oxfordjournals.org

Histone acetylation
 Acetylation of histone tails is mediated by histone
acetyltransferases (HATs) and results in an open
modification of chromatin structure.
 It allows transcriptions factors to access the DNA
and to initiate gene transcription.
85

 Gene expression is regulated by acetylation of
histones
 Acetylation open the chromatin structure &allow
the interaction of DNA with transcription factors
(activated proinflammatory transcription factors,
such as NF-KB ) and initiate gene transcription.
91
Histone acetyltransferases
& coactivators

 These transcription factors have the ability to
interact with coactivator molecules: CREB-binding
protein (CBP), p300 and p300/CBP-associated
factor, which all have intrinsic HAT activity
 Gene transcription occurs only when the
chromatin structure is open up with unwind naked
DNA, so that the enzyme RNA polymerse II can
activate the formation of mRNA.
92
Histone acetyltransferases
& coactivators

 Conversely, gene repression is mediated
via histone deacetylases (HDACs), which
remove the acetyl groups from the histone
tails, resulting in a closed chromatin
structure.
94

 Inflammatory gene expression and immune
response is regulated by the balance
between:
1. Histone acetylation by HAT
2. Histone de-acetylation by HDAC2

 Histone acetylation by histone acetyl transferases
(HAT) activates inflammatory gene expression
 Histone de-acetylation by histone deacetylases
(HDAC) play a critical role in gene repression

 Chronic inflammation is characterised by the
increased expression of multiple inflammatory
genes that are regulated by proinflammatory
transcription factors, such as NF-KB and AP-1,
that bind to and activate coactivator molecules,
which then acetylate core histones to switch on
gene transcription
99

10
2
Molecular mechanisms whereby
corticosteroids suppress
inflammation

Molecular mechanisms of action of steroids
10
3

 The predominant effect of corticosteroids is to
switch off multiple inflammatory genes
(encoding cytokines, chemokines, adhesion
molecules, inflammatory enzymes) that have
been activated during the chronic inflammatory
process.

 Corticosteroids suppress the multiple inflammatory
genes that are activated in chronic inflammatory
diseases, such as asthma, mainly by :
1. Reversing histone acetylation of activated
inflammatory genes through binding of liganded
glucocorticoid receptors (GR) to coactivators
2. Recruitment of histone deacetylase-2 (HDAC2) to
the activated transcription complex.

 At higher concentrations , corticosteroids
have additional effects on the synthesis of
anti-inflammatory proteins
 GR homodimers interact with DNA recognition
sites to active transcription of anti-inflammatory
genes and to inhibit transcription of several
genes linked to corticosteroid side effects
(ICS suppress osteocalcin levels and may therefore
inhibit bone formation).11
1

Corticosteroids activation of anti-
inflammatory gene expression
1) GCS bind to cytoplasmic GR, which translocate to the
nucleus where they bind to GRE in the promoter region
of steroid-sensitive genes
2) GCS bind also directly or indirectly to coactivator
molecules such as CBP, pCAF, which have intrinsic HAT
activity, causing acetylation of lysines on histone H4,
which leads to activation of genes encoding anti-
inflammatory proteins,
11
3

 Several genes that are switched on by GCS have anti-
inflammatory effects, including annexin-1 (lipocortin-1),
SLPI, interleukin-10 (IL-10) and the inhibitor of NF-κB
(IκB-α).
 However, it seems unlikely that the widespread anti-
inflammatory actions of corticosteroids could be entirely
explained by increased transcription of small numbers of
anti-inflammatory genes
 High concentrations of corticosteroids are usually required
for this effect, whereas in clinical practice corticosteroids
are able to suppress inflammation at low concentrations.

1) GR-mediated transactivation of key anti-inflammatory
genes involves direct DNA binding of both GR dimers
to GC-response elements (GRE) in the promoter region
of target gene.
2) Transrepression of pro-inflammatory genes does not
require direct DNA binding of GR, but rather ‘tethering’
of GR monomers to DNA-bound pro-inflammatory
transcription factors.
11
5
Glucocorticoid (GC) effects on
inflammatory signalling.

Glucocorticoid (GC) effects on inflammatory signalling.
Mark Nixon et al. J Endocrinol 2012;212:111-127
© 2012 Society for Endocrinology

Molecular mechanisms of action of steroid

LUNG INFLAMMATION
COPD PATHOLOGY
Oxidative
stress Proteinases
Host factors
Amplifying mechanisms
Cigarette smoke
Biomass particles
Particulates
Pathogenesis of
COPD

 Oxidative stress in the presence of increased nitric oxide
production results in the formation of peroxynitrite
 Peroxynitrite impairs the activity of HDAC2. This amplifies
the inflammatory response to NF-kB activation, as
HDAC2 is now unable to reverse histone acetylation
 Peroxynitrite markedly reduces the anti-inflammatory
effect of corticosteroids

PI3K Pathway activation by
free radicals
 Oxidative stress also activates a phosphoinositide-3-
kinase (PI3K) pathway that phosphorylates (P) and
inactivates HDAC2.
 Loss of HDAC function then results in enhanced
inflammatory gene expression and blocks the anti-
inflammatory action of corticosteroids.

 Stimulation of normal and asthmatic alveolar
macrophages activates NF-κB and other
transcription factors to switch on HAT leading to
histone acetylation ...
 In COPD the increased acetylation is not due to
increased HAT activity as in asthma It is due to a
decrease in de-acetylation (HDAC2)
12
9

 Corticosteroids cross the cell membrane and bind to
glucocorticoid receptor (GR) in the cytoplasm, which
rapidly translocate to the nucleus.
 Activated GR may directly bind to CBP or to other
coactivators to inhibit their HAT activity and thus,
prevent the histone acetylation and chromatin
remodelling .
 More importantly activated GR can recruit the HDAC-
2 molecules to activated inflammatory genes, which
reverses the acetylation of activated inflammatory
genes . This mechanism can account for the clinical
efficacy of corticosteroids in asthma

CS
GR
IL-1b
TNFa
NF-kB
CBP
(HAT activity)
IIkB2
NF-kB
HDAC
IkB2
Cell wall
Nucleus
CS
GCS in sensitive asthmatics induce HDAC causing histone
deacetylation, leading to reduced inflammatory response.

 In patients with COPD and asthmatic patients who
smoke & severe asthma , HDAC2 is markedly
reduced in activity and expression
 This as a result of oxidative/nitrative stress so that
inflammation becomes resistant to the anti-
inflammatory actions of corticosteroids
13
2

 Although corticosteroids insensitivity is seen in all
stages of COPD it is most marked in the patients
with the most severe disease (GOLD stage 4),
when HDAC2 expression is reduced by more
than 95% compared to nonsmokers

Cigarette smoke
Oxidative stress
AMPLIFICATION AND STEROID RESISTANCE
NF-κB
Glucocorticoid
receptor
HDAC2
Corticosteroids
Histone
acetylation
Inflammation
Inflammatory
genes
e.g. IL-8, MMP-9

Cigarette smoke
Oxidative stress
AMPLIFICATION AND STEROID RESISTANCE
NF-κB
Histone
acetylation
Inflammatory
genes
e.g. IL-8, MMP-9
HDAC2
↑ Inflammation
Steroid
resistancePI3K-δ
Theophylline
Nortriptyline

Theophylline directly activates
histone deacetylases

 Theophylline is the only HDAC activator by far
identified , HDAC function may be restored by
low doses of theophylline
 The mechanism is not phosphodiesterase
inhibition or inhibition of receptor antagonism to
adenosine
 The mechanism is selective inhibition of the PI3K
pathway activated by oxidative stress

ICS for COPD Risks vs. Benefits
Risks Benefits
Pneumonia
Adverse events
Mortality LOS
complications
•Improvement in
Quality of Life
•Decrease
Exacerbations rate
•Improves
symptoms
•May decrease
Mortality

 Patients with COPD have a poor response to ICS in
comparison to asthma.
 High doses of ICS fail to reduce disease progression
or mortality, even when combined with a LABA , yet
it has been shown to reduce the frequency of
exacerbations.
 High doses of ICS have consistently been shown a
reduction (20–25%) in exacerbations in patients with
severe disease and this is the main clinical indication
for their use in COPD .

 According to GOLD guidelines ,ICS are indicated in
COPD patients with severe or very severe airflow
limitation (FEV1 < 50% of predicted) and/or frequent
exacerbations that are not adequately controlled by
long-acting bronchodilators (Evidence A) because
they reduce the risk of future episodes of ECOPD.
 More recently, ICS have also been recommended for
the treatment of the so-called Asthma- COPD overlap
syndrome (ACOS).
14
7

 On the contrary, ICS should never be used in mono-
therapy (i.e., alone) in COPD patients (an important
difference vs. asthma).
 There is ICS over prescription in COPD, particularly in
patients classified in GOLD groups A or B, where ICS
should not be theoretically prescribed.
 Finally, treatment with ICS has been linked to an
increased risk of pneumonia in COPD
14
8

 There is increasing evidence that high doses
of ICS may have detrimental effects on
bones and may increase the risk of
pneumonia.
14
9

 The increased risk of pneumonia was causally
attributed to ICS as the risk of pneumonia was higher
in patients receiving ICS plus LABA in comparison to
those on LABA alone.
 It has been proposed that ICS may achieve high
concentration in the lung that may increase the risk
of pneumonia due to an immunosuppressive effect.
15
0

 Studies showed that the use of fluticasone &
budesonide, in COPD patients increased the
risk of pneumonia .
15
2

TOwards a Revolution in COPD Health

What is PATHOS?
 A Retrospective Epidemiological Study to Map
Out Patients With Chronic Obstructive Pulmonary
Disease (COPD) and Describe COPD Health Care
in Real-Life Primary Care During the First Ten Years
of the 21th Century in Sweden - PATHOS
 Providing Answers To Healthcare by Observational
Studies- PATHOS

PATHOS Objectives
• To compare between the two fixed ICS/LABA
combinations:
• BUD/FORM Turbuhaler® and FLU/SAL Diskus®
as regard
 Effectiveness ( rate of exacerbations ) &
 Safety (rate of pneumonia and pneumonia
related morality)

21,361 COPD
7155
BUD/FORM
2738
FLU/SAL
9893
Fixed combinations of ICS/LABA
4421
Could not be matched & not
included in analysis
4
Could not be matched & not
included in analysis
2734
BUD/FORM
2734
FLU/SAL
PSM
Total population: 5468
Two pair-wise
matched
populations
(covering 19170 patient-
years of follow up)
31 variables
Unmatched

Study Analyses
Disease
management
evolution over
11 years
Effectiveness
of fixed
ICS/LABA
combinations
on
exacerbation
Safety
of fixed
ICS/LABA
combinations
on
pneumonia

Comparative effectiveness of
BUD/FORM Turbuhaler® and
FLU/SAL Diskus® in Propensity
Matched Patients
COPD Exacerbations
(hospitalisations, emergency visits, prescription
of oral steroids, and prescriptions of antibiotics
due to COPD).
Effectiveness
of fixed
ICS/LABA
combinations
on
exacerbation

Results
 Compared with FLU/SAL Diskus, BUD/FORM Turbuhaler
was associated with reduced risk of :
1. Exacerbations by 27 %, here presented as Rate ration
and event/100 patient/year
2. Budesonide/formoterol treated patients had 26.0%
fewer oral steroid courses
3. Budesonide/formoterol treated patients had 29.0%
fewer antibiotic courses
4. Budesonide/formoterol treated patients had reduced
risk of hospitalizations due to COPD by 29% and
21.0% lower risk for ER visits .......All highly significant16
9

Relative safety difference of
BUD/FORM Turbuhaler® and
FLU/SAL Diskus® in Propensity
Matched Patients
Pneumonia related events
(physician diagnosed)
Safety
of fixed
ICS/LABA
combinations
on
pneumonia

Pneumonia-related events
Adjusted yearly pneumonia event rates compared using Poisson regression analysis. P<0.001 for all.
CI, confidence intervals; BUD/FORM, budesonide/formoterol; FLU/SAL, fluticasone/salmeterol
1.3
4.2
7.4
11.0
0.7
2.7
4.3
6.4
0 2 4 6 8 10 12
Hospital outpatient
diagnosis
Primary care
diagnosis
Pneumonia
hospitalisations
Pneumonia
diagnoses
BUD/FORM
FLU/SAL
Rate ratio (95% CI)
1.73
(1.57, 1.90)
1.56
(1.39, 1.75)
1.75
(1.53, 2.00)
Event rate per 100 patient-years
1.74
(1.56, 1.94)
Pneumonia events in propensity matched COPD patients
BUD/FORM (n=2734) or FLU/SAL (n=2734)
AZ data on file
↑73%
↑74%
↑56%
↑75%

Multiple pneumonia events
 Multiple pneumonia events were far more common
 for patients treated with FLU/SAL than
 for BUD/FORM

Summary
 Intra-class difference between BUD/FORM
vs. SAL/FLU with regard to the risk of
exacerbations, risk of pneumonia and
pneumonia related events in the treatment
of patients with COPD.

 The PATHOS study assessed the yearly pneumonia
events as well as hospital admissions and deaths
due to pneumonia in patients with combinations of
inhaled steroid and long acting beta 2 agonists.

 The study revealed that patients taking fluticasone
and salmeterol were more likely to be admitted
with pneumonia or pneumonia-related events
compared to those on budesonide and formoterol.
17
7

Recent Data
Dransfield MT, et al. Lancet Respir Med 2013 :
Fluticasone furoate (FF)/Vilanterol (50,100,
200/25 mcg) vs. Vilaterol (VI)
More pneumonia cases
Deaths from pneumonia (n=8 vs. n=0)

182
Once-daily inhaled fluticasone furoate and vilanterol
versus vilanterol only for prevention of exacerbations
of COPD: two replicate double-blind, parallel-group,
randomised controlled trials
Mark T D
Addition of fluticasone furoate to vilanterol was
associated with a decreased rate of moderate
and severe exacerbations of COPD in patients with
a history of exacerbation, but was also associated
with an increased pneumonia risk.

Summary
 In COPD, compared with BUD/FORM, patients
treated with FLU/SAL were significantly:
– more likely to suffer with COPD exacerbations
– more likely to suffer with pneumonia,
pneumonia hospitalizations and mortality
related to pneumonia.

 The risk of patients with COPD developing
serious pneumonia is particularly elevated
and dose related with fluticasone use and
much lower with budesonide
18
6

Implications
 In the management of COPD the benefit/risk
ratio for different ICS/LABAs cannot be
considered equal.
 BUD/FORM has improved benefit/risk ratio
supported by both better efficacy and
safety.

 The current recommendations favour the use of
ICS in severe and very severe patients of COPD
having repeated episodes of exacerbations.
 However, in light of the above evidence,
clinicians should observe these patients for
occurrence of pneumonia.
18
8

 As the symptoms of early pneumonia and an
acute exacerbation are similar, hence,
pneumonia may go undiagnosed in patients
with severe COPD.
 Close observation and imaging including
repeated plain chest radiographs and computed
tomography should enable a differentiation and
appropriate management.
18
9

Inhaled corticosteroids in COPD

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