Transcript New insights in the immunology of COPD

“How your approach in COPD might
change in 2012”
INTRODUCTION
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION
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GOLD 2007
Definition of COPD (GOLD 2012)
– characterized by persistant airflow limitation:
not fully reversible
usually progressive
– associated with an enhanced chronic inflammatory
response in the airways and the lungs to noxious
particles or gases.
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Chronic obstructive pulmonary disease (COPD), a
common preventable and treatable disease, is
Comorbidities and exacerbations contribute to the
overall severity in individual patients.
www.goldcopd.org
COPD: epidemiology
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Bousquet J. et al, Eur Respir J 2010; 36: 995-1001.
COPD: epidemiology
Asia / Africa:
cooking and heating
– biomass fuel
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US / Europe:
smoking
– cigarettes
– cigars
COPD: the third biggest killer by 2020
Ischemic heart disease
CVD disease
Lower respiratory infection
Diarrhoeal disease
Perinatal disorders
COPD
6th
Tuberculosis
Measles
Road traffic accident
Lung cancer
Murray & Lopez, Lancet 1997.
2020
3rd
Stomach cancer
HIV
Suicide
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1990
INFLAMMATION
Small airways disease
Airway inflammation
Airway remodeling
Parenchymal destruction
Loss of alveolar attachments
Decrease of elastic recoil
AIRFLOW LIMITATION
www.goldcopd.org
GOLD
2001
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Emphysema
Bronchiolitis
Diagnosis of COPD

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EXPOSURE TO RISK
FACTORS
tobacco
occupation
indoor/outdoor pollution
SYMPTOMS
cough
sputum
dyspnea
: FEV1/FVC < 70%
Post bronchodilatation!
SPIROMETRY IS REQUIRED
TO MAKE DIAGNOSIS
www.goldcopd.org
“How your approach in COPD might
change in 2012”
INTRODUCTION
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION
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GOLD 2007
Previous GOLD guidelines
Therapy at Each Stage of COPD
I: Mild
 FEV1 > 80%
III: Severe
 FEV1/FVC < 70%
 FEV1/FVC < 70%
 50% < FEV1 < 80%
 30% < FEV1 < 50%
predicted
predicted
IV: Very Severe
 FEV1/FVC < 70%
 FEV1 < 30% predicted
or FEV1 < 50%
predicted plus chronic
respiratory failure
predicted
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
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 FEV1/FVC < 70%
II: Moderate
Add regular treatment with one or more long-acting
bronchodilators (when needed); Add rehabilitation
Add inhaled glucocorticosteroids if repeated
exacerbations
Add long term oxygen
www.goldcopd.org
Report GOLD 2009 (Updated)
if chronic respiratory
failure. Consider
surgical treatments
“How your approach in COPD might
change in 2012”
INTRODUCTION
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION
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GOLD 2007
Health status, FEV1 and GOLD stage:
Staging by FEV1 neglects patient outcomes
Lung function measurements do not reflect the impact of COPD
Stage 3
Stage 2
80
SGRQ
score
Breathless
walking on
level
ground
60
40
20
Upper limit
of normal
0
r=–0.23
P<0.0001
10
20
30
40
50
60
FEV1 (% predicted)
Jones P. Thorax 2001;56:880-887.
70
80
90
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Stage 4
100
Medical Research Council (mMRC)
Dyspnea Score
Dyspnea was defined as a score of 2 or higher on mMRC scale
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100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Mild
Moderate
mMRC 4
mMRC 3
mMRC2
Severe
mMRC1
Very Severe
mMRC 0
Airflow limitation:
(FEV1)
mMRC 4: I am to breathless to leave the house…; mMRC 3: I stop for breath after walking about 100 yards…; mMRC 2: I walk
slower than other people…; mMRC 1: Short of breath when hurrying; mMRC 0: Breathless with strenuous exercise
Adapted from Jones P. et al, ERJ 2011; 34: 29-35
Aims of the COPD Assessment Test (CAT)
a patient-completed questionnaire
a short, simple and reliable test:
To improve the assessment of COPD
patients
To grade the impact of COPD on health
status.
Jones P. et al, ERJ 2009; 34: 648-654.
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CAT:
COPD Assessment Test (CAT)
✗
✗
✗
1
1
2
4
3
4
2
✗
5
22
Jones P. et al, ERJ 2009; 34: 648-654.
Scoring range 0–40
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✗
✗
✗
✗
Impact of COPD on daily life
CAT score
10
Moderate
20
Important
Very important
30
40
www.CATestonline.org
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Light
CAT: correlation with SGRQ
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r-=0.80
P<0.0001
Jones P. et al, ERJ 2009; 34: 648-654.
“How your approach in COPD might
change in 2012”
INTRODUCTION
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION
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GOLD 2007
HEED study: Health related quality
of life in European COPD patients
COPD patients:
– Age: 40-80 years
– COPD: all severities
– Current or ex-smokers with a smoking history of ≥ 10 packyears
7 Countries: Belgium, France, Germany, Italy, the
Netherlands, Spain and UK.
Jones P. et al, Resp Medicine 2011.
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A large cross-sectional observational study to evaluate
health status in patients with COPD in primary care.
European COPD Quality of Life Survey
Jones P. et al, Resp Medicine 2011.
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Total: n = 1.787
European COPD Quality of Life Survey: SGRQ
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Jones P. et al, Resp Medicine 2011.
European COPD Quality of Life Survey: CAT
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Jones P., Brusselle G. et al, ERJ 2011.
European COPD Quality of Life Survey:
CAT correlation with SGRQ
HEED EU patients: r = 0.84, p<0.001
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r=0.80* *
P<0.0001
Jones P., Brusselle G. et al, ERJ 2011.
*Jones PW et al. Eur Respir J 2009
“How your approach in COPD might
change in 2012”
INTRODUCTION
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION
GSK slidekit for distribution –BE/SFC/0005/12
GOLD 2007
Evaluation of COPD Longitudinally
to Identify Predictive Surrogate
Endpoints
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ECLIPSE study:
The ECLIPSE Study:
Objectives of this 3-yrs observational study
To define the parameters that predict
disease progression over 3 years in the
clinically relevant COPD subtypes
To acquire data on known clinical
biomarkers in order to identify those that
correlate with clinically relevant COPD
subtypes
To identify novel genetic factors and/or
biomarkers that correlate with clinically
relevant COPD subtypes and with markers
of disease progression
Vestbo J, et al. Eur Respir J. 2008;31:869-873
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To define clinically relevant COPD
subtypes in individuals with GOLD stage
II–IV COPD
ECLIPSE: Study Design
46 Centres;12 Countries
FSFV*
Dec 19 2005
0
3
6
12
Months
18
24
30
LSLV*
Feb 19 2010
36
30
36
Analysis
GOLD stage III (FEV1 30–50% pred.)
GOLD stage IV (FEV1 <30% pred.)
343 smoking controls
566 control
subjects**
Planned
Recruitment
2180 COPD
subjects**
GOLD stage II (FEV1 50–80% pred.)
223 non-smoking controls
0
3
6
12
18
Each visit captured:
Lung Function; Impulse Oscillometry; Exhaled CO, Resting
Oxygen Saturation; Blood samples; Exacerbation assessment
Annual visits captured:
Pulmonary plethysmography; Body composition; Fat-free mass;
Exercise capacity; Induced sputum; Health status
(SGRQ,BODE); Dyspnoea
24
Year 1 and 3 Visits captured:
• Chest computed tomography
Year 3 visit captured:
• Depression; Fatigue
Vestbo J, et al. Eur Respir J. 2008;31:869-873.
Definition of COPD exacerbation
according to GOLD guidelines
“an acute event characterized by a
worsening of the patient’s respiratory
symptoms that is beyond normal dayto-day variations and leads to a
change in medication.”
www.goldcopd.org
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An exacerbation of COPD is:
The ‘frequent exacerbator
phenotype’: ECLIPSE
John R. Hurst, Jørgen Vestbo, Antonio
Anzueto, Nicholas Locantore, Hana
Mϋllerova, Ruth Tal-Singer, Bruce
Miller, David A. Lomas, Alvar Agusti,
William MacNee, Peter Calverley,
Stephen Rennard, Emiel F.M. Wouters
and Jadwiga A. Wedzicha
New England Journal of
Medicine
2010;363:1128-38
Hurst JR, et al. N Engl J Med. 2010;363:1128-38.
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Susceptibility to Exacerbation in
Chronic Obstructive Pulmonary
Disease
The ‘frequent exacerbator phenotype’:
ECLIPSE: Introduction
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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
Is the most reliable predictor of exacerbations in an individual
patient a history of prior exacerbations?
Hurst JR, et al. N Engl J Med. 2010;363:1128-38
29
The ‘frequent exacerbator phenotype’: ECLIPSE
Frequency/Severity of Exacerbations by GOLD stage (1)
Exacerbations are more frequent and more severe with increasing
COPD severity
What are the predictors of exacerbation frequency?
Hospitalised for exacerbation in yr 1
ECLIPSE 1 year data
Frequent exacerbations (2 or more)
Hurst et al. N Engl J Med 2010
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p<0.01
The ‘frequent exacerbator phenotype’:
ECLIPSE: Stability of the Exacerbator Phenotype
74% of patients having no exacerbations in Years 1 and Year 2
had no exacerbations in Year 3
ECLIPSE 3 year data
Hurst JR, et al. N Engl J Med. 2010;363:1128-38.
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71% of Frequent Exacerbators in Year 1 and Year 2 were
Frequent Exacerbators in Year 3
Conclusions (1)
Agusti A, et al. Resp Res. 2010;11:122
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ECLIPSE and HEED confirm
– Disease severity (breathlessness, exercise capacity,
exacerbations, health status degradation) increases with
“Airflowstage
limitation alone does not provide an accurate measure of
GOLD
disease severity or activity”
– FEV1 poorly related with other parameters
– COPD is highly heterogeneous
– Within GOLD stage there is substantial variation in:
Breathlessness
Exercise
capacity
New
GOLD
guidelines must include other
Exacerbation
frequency
parameters:
QoL,
symptoms and exacerbation
Health status
rate
32
Conclusions (2)
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ECLIPSE confirms
Exacerbations become more frequent and more severe
as COPD severity increases
Frequent exacerbator is an independent disease
phenotype
Exacerbation in prior year is the best predictor of occurrence of
– That can be identified
by patient self-report about
exacerbation
Exacerbation
rate must be integrated in GOLD guidelines
previous
exacerbations
– Stable over time (3 yrs)
– Patients with moderate COPD may be frequent
exacerbators (22%)
“How your approach in COPD might
change in 2012”
INTRODUCTION
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION
GSK slidekit for distribution –BE/SFC/0005/12
GOLD 2007
Approaches of COPD treatment
according to GOLD guidelines
Unidimensional approach
GOLD 2001
Multidimensional approach
GOLD 2012
1) Risk:
FEV1
Rate of exacerbations
2) Symptoms:
CAT score,
mMRC scale
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Timeline
(C)
(D)
≥2
3
2
1
(A)
(B)
1
(Exacerbation history)
4
Risk
(GOLD Classification of Airflow Limitation)
Spirometry
Management of COPD according to Symptoms,
Spirometric classification and Future Risk of Exacerbations
0
mMRC < 2
CAT < 10
mMRC ≥ 2
CAT ≥ 10
Symptoms
(mMRC or CAT score)
www.goldcopd.org
Combined Assessment of COPD
(C)
(D)
(A)
(B)
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
If mMRC 0-1 or CAT < 10:
Less Symptoms (A or C)
If mMRC > 2 or CAT > 10:
More Symptoms (B or D)
Symptoms
(mMRC or CAT score))
www.goldcopd.org
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Assess symptoms first
3
(C)
(D)
>2
2
(A)
(B)
1
0
1
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
(Exacerbation history)
4
Risk
(GOLD Classification of Airflow Limitation)
Assess risk of exacerbations next
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)
Symptoms
(mMRC or CAT score))
www.goldcopd.org
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Risk
Combined Assessment of COPD
The four COPD patient groups according to
GOLD 2012 (summary)
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
www.goldcopd.org
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When assessing risk, choose the highest risk according to GOLD
grade or exacerbation history
3
2
SAAC prn
or
1
1)LAAC or
LABA
SAAB prn
2) LAAC +
LABA
mMRC < 2
CAT < 10
mMRC ≥ 2
CAT ≥ 10
≥2
1
(Exacerbation history)
4
1) ICS + LABA 1) ICS + LABA
or LAAC
or LAAC
2) LAAC +
2) ICS + LABA
LABA
+ LAAC
Risk
(GOLD Classification of Airflow Limitation)
Spirometry
Management of COPD according to Symptoms,
Spirometric classification and Future Risk of Exacerbations
0
Symptoms
(mMRC or CAT score)
www.goldcopd.org
“How your approach in COPD might
change in 2012”
INTRODUCTION
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION
GSK slidekit for distribution –BE/SFC/0005/12
GOLD 2007
TORCH: Post-bronchodilator FEV1
100
50
0
*†
–50
*
*
–100
Placebo
–150
0
24
SALM
48
FP
72
96
Time (weeks)
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Adjusted mean change FEV1 (mL)
SFC
120
156
*p < 0.001 vs placebo; †p < 0.001 vs SALM and FP
Calverley et al. NEJM 2007
TORCH: SFC significantly reduces
exacerbations over 3 years
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25% (p<0.001)
Annualised exacerbation rate
1.2
SFC vs placebo
SFC vs salmeterol
SFC vs FP
1.0
1.13
0.97
0.8
0.93
0.85
0.6
0.4
0.2
0
Placebo
Salmeterol
FP
SFC
Treatment effect
p-value
25%
12%
9%
<0.001
0.002
0.02
Calverley N Eng J Med 2007
1.15
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Annualised exacerbation rate
TORCH: SFC reduces rate of exacerbations
requiring systemic corticosteroids over 3 years
43% (p<0.001)
0.95
0.75
0.80
0.55
0.64
0.35
0.52
0.46
0.15
–0.05
Placebo
SFC vs placebo
SFC vs salmeterol
SFC vs FP
Salmeterol
Treatment effect
43%
29%
13%
FP
SFC
p-value
<0.001
<0.001
0.02
Calverley N Eng J Med 2007
17% (p=0.03)
0.20
0.19
0.15
0.16
0.17
0.16
Salmeterol
FP
SFC
0.10
0.05
0
Placebo
SFC vs placebo
SFC vs salmeterol
SFC vs FP
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Annualised exacerbation rate
TORCH: SFC reduces the rate of severe exacerbations
requiring hospitalisation over 3 years
Treatment effect
p-value
17%
–2%
5%
0.03
0.79
0.56
Calverley N Eng J Med 2007
“How your approach in COPD might
change in 2012”
INTRODUCTION
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION
GSK slidekit for distribution –BE/SFC/0005/12
GOLD 2007
Take home message
COPD is highly heterogeneous (HEED and ECLIPSE)
Unidimensional approach: spirometry: FEV1 (FEV1/FVC):
 Diagnosis
New management of COPD (GOLD 2012):
Multidimensional approach: FEV1; mMRC, CAT and exacerbations
 Diagnosis (and phenotyping)
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Former management of COPD (GOLD 2007):
 Prognosis
 Monitoring
Aim: Optimal Management and Treatment
 ICS/LABA combination is effective in COPD patient groups C and D
Questions?
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