1. “How your approach in COPD might change in 2012”
INTRODUCTION
GOLD 2007
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION

2. Definition of COPD (GOLD 2012)
Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is
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.
Comorbidities and exacerbations contribute to the overall severity in individual patients.

3. COPD: epidemiology
Bousquet J. et al, Eur Respir J 2010; 36:

4. COPD: epidemiology US / Europe: smoking cigarettes cigars
Asia / Africa:
cooking and heating
biomass fuel

5. COPD: the third biggest killer by 2020
1990
2020
Ischemic heart disease
CVD disease
Lower respiratory infection
Diarrhoeal disease
Perinatal disorders
COPD
Tuberculosis
Measles
Road traffic accident
Lung cancer
3rd
6th
Stomach cancer
HIV
Suicide
As part of the Global Burden of Disease Study, Murray and Lopez1 projected future mortality rates based on the most common causes of death in The top 10 most important causes of death are presented in this slide. The majority of these leading causes of deaths are projected to remain stable or decline.
Notably, COPD is expected to rise from the sixth biggest killer in 1990 to the third in Of the top 10 leading causes of death in 1990, only deaths caused by COPD, lung cancer and road traffic accidents are projected to rise.
Reference
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997;349:1498–504.
Murray & Lopez, Lancet 1997.

6. INFLAMMATION AIRFLOW LIMITATION Small airways disease
Bronchiolitis
Emphysema
Small airways disease
Airway inflammation
Airway remodeling
Parenchymal destruction
Loss of alveolar attachments
Decrease of elastic recoil
AIRFLOW LIMITATION
GOLD 2001

7. indoor/outdoor pollution SPIROMETRY IS REQUIRED
Diagnosis of COPD
EXPOSURE TO RISK
FACTORS
SYMPTOMS
cough
tobacco
sputum
occupation
dyspnea
indoor/outdoor pollution è
: FEV1/FVC < 70%
Post bronchodilatation!
SPIROMETRY IS REQUIRED
TO MAKE DIAGNOSIS

8. “How your approach in COPD might change in 2012”
INTRODUCTION
GOLD 2007
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION

9. Previous GOLD guidelines Therapy at Each Stage of COPD
I: Mild
II: Moderate
III: Severe
IV: Very Severe
FEV1/FVC < 70%
FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure
FEV1/FVC < 70%
30% < FEV1 < 50% predicted
FEV1/FVC < 70%
50% < FEV1 < 80%
predicted
FEV1/FVC < 70%
FEV1 > 80%
predicted
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation
Add inhaled glucocorticosteroids if repeated exacerbations
Add long term oxygen if chronic respiratory failure. Consider surgical treatments
Report GOLD 2009 (Updated)

10. “How your approach in COPD might change in 2012”
INTRODUCTION
GOLD 2007
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION

11. Breathless walking on level ground
Health status, FEV1 and GOLD stage: Staging by FEV1 neglects patient outcomes
Lung function measurements do not reflect the impact of COPD 20 40 60 80
100 10 30 50 70 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 completely reflect the impact of COPD. The St George’s Respiratory Questionnaire (SGRQ) is considered to be a good tool for measuring the overall impact of COPD on patients’ health. However, as this slide shows, the correlation between FEV1 and health status measured using the SGRQ is weak, with a correlation coefficient of only − In addition, the utility of the SGRQ in everyday practice is limited because it is a 76-item questionnaire and requires a computer to score it.2 These problems resulted in an attempt to develop a new COPD assessment questionnaire.
1. Jones PW. Thorax 2001;56:880–887.
2. Jones PW et al. Am Rev Respir Dis 1992;145:1321–1327.
Jones P. Thorax 2001;56: 11

12. Medical Research Council (mMRC) Dyspnea Score
Dyspnea was defined as a score of 2 or higher on mMRC scale
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

13. 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:

14. COPD Assessment Test (CAT)✗ 1 2 4 3 5 22
Jones P. et al, ERJ 2009; 34:
Scoring range 0–40

15. Impact of COPD on daily life
CAT score
Light
Moderate
Important
Very important 10 20 30 40

16. CAT: correlation with SGRQ
P<0.0001
Jones P. et al, ERJ 2009; 34:

17. “How your approach in COPD might change in 2012”
INTRODUCTION
GOLD 2007
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION

18. HEED study: Health related quality of life in European COPD patients
A large cross-sectional observational study to evaluate health status in patients with COPD in primary care.
COPD patients:
Age: years
COPD: all severities
Current or ex-smokers with a smoking history of ≥ 10 pack-years
7 Countries: Belgium, France, Germany, Italy, the Netherlands, Spain and UK.
Real Life
Jones P. et al, Resp Medicine 2011.

19. European COPD Quality of Life Survey
Total: n = 1.787
Jones P. et al, Resp Medicine 2011.

20. European COPD Quality of Life Survey: SGRQ
Jones P. et al, Resp Medicine 2011.

21. European COPD Quality of Life Survey: CAT
Jones P., Brusselle G. et al, ERJ 2011.

22. European COPD Quality of Life Survey: CAT correlation with SGRQ
HEED EU patients: r = 0.84, p<0.001
r=0.80* *
P<0.0001
Jones P., Brusselle G. et al, ERJ 2011.
*Jones PW et al. Eur Respir J 2009

23. “How your approach in COPD might change in 2012”
INTRODUCTION
GOLD 2007
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION

24. ECLIPSE study: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints

25. The ECLIPSE Study: Objectives of this 3-yrs observational study
To define clinically relevant COPD subtypes in individuals with GOLD stage II–IV COPD
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: 25

26. ECLIPSE: Study Design 46 Centres;12 Countries Analysis
GOLD stage II (FEV1 50–80% pred.)
GOLD stage IV (FEV1 <30% pred.)
GOLD stage III (FEV1 30–50% pred.)
2180 COPD subjects**
343 smoking controls
223 non-smoking controls
566 control subjects**
Planned Recruitment
Months
Analysis
FSFV*
Dec
LSLV*
Feb
46 Centres;12 Countries
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
Year 1 and 3 Visits captured:
Chest computed tomography
Year 3 visit captured:
Depression; Fatigue
Vestbo J, et al. Eur Respir J. 2008;31:

27. Definition of COPD exacerbation according to GOLD guidelines
An exacerbation of COPD is:
“an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day- to-day variations and leads to a change in medication.” 27

28. The ‘frequent exacerbator phenotype’: ECLIPSE
Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Disease
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:
Hurst JR, et al. N Engl J Med. 2010;363:

29. The ‘frequent exacerbator phenotype’: ECLIPSE: Introduction
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: 29

30. What are the predictors of exacerbation frequency?
The ‘frequent exacerbator phenotype’: ECLIPSE Frequency/Severity of Exacerbations by GOLD stage (1)
p<0.01
Exacerbations are more frequent and more severe with increasing COPD severity
What are the predictors of exacerbation frequency?
THIS SLIDE CONTAINS 3 BUILDS
Hospitalised for exacerbation in yr 1
Frequent exacerbations (2 or more)
ECLIPSE 1 year data
Hurst et al. N Engl J Med 2010

31. The ‘frequent exacerbator phenotype’: ECLIPSE: Stability of the Exacerbator Phenotype
71% of Frequent Exacerbators in Year 1 and Year 2 were Frequent Exacerbators in Year 3
THIS SLIDE CONTAINS 7 BUILDS
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: 31

32. Conclusions (1)
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
“Airflow limitation alone does not provide an accurate measure of disease severity or activity”
New GOLD guidelines must include other parameters: QoL, symptoms and exacerbation rate
Si l'obstruction bronchique était significativement lié à l'essoufflement, l'état de santé, 6MWD et nombre d'exacerbations, il y avait un chevauchement considérable entre les stades du GOLD, confirment l’hétérogéinicité de la BPCO et les faibles corrélations.
Peu de bronchiectasies.
Les donnés sur la distribution en fonction du BODE index n’a pas été présentée.
Agusti A, et al. Resp Res. 2010;11:122 32 32

33. Exacerbation rate must be integrated in GOLD guidelines
Conclusions (2)
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
Stable over time (3 yrs)
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

34. “How your approach in COPD might change in 2012”
INTRODUCTION
GOLD 2007
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION

35. Approaches of COPD treatment according to GOLD guidelines
Timeline
Unidimensional approach
Multidimensional approach
GOLD 2001
GOLD 2012
1) Risk:
FEV1
Rate of exacerbations
2) Symptoms:
CAT score,
mMRC scale 35

36. Management of COPD according to Symptoms, Spirometric classification and Future Risk of Exacerbations 4
(C)
(D)
≥ 2 3
(GOLD Classification of Airflow Limitation)
Spirometry
(Exacerbation history)
Risk 2 1
(A)
(B) 1
mMRC < 2
CAT < 10
mMRC ≥ 2
CAT ≥ 10
Symptoms
(mMRC or CAT score)

37. Combined Assessment of COPD
Assess symptoms first
If mMRC 0-1 or CAT < 10:
Less Symptoms (A or C)
If mMRC > 2 or CAT > 10:
More Symptoms (B or D)
(C)
(D)
(A)
(B)
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
Symptoms
(mMRC or CAT score))

38. Combined Assessment of COPD
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) 4
(C)
(D)
> 2 3
(GOLD Classification of Airflow Limitation)
Risk
(Exacerbation history)
Risk 2 1
(A)
(B) 1
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
Symptoms
(mMRC or CAT score))

39. The four COPD patient groups according to GOLD 2012 (summary)
When assessing risk, choose the highest risk according to GOLD grade or exacerbation history
Patient
Characteristic
Spirometric
Classification
Exacerbations per year
mMRC
CAT A
Low Risk
Less Symptoms
GOLD 1-2
≤ 1
0-1
< 10 B
More Symptoms
>2
≥ 10 C
High Risk
GOLD 3-4 D

40. Management of COPD according to Symptoms, Spirometric classification and Future Risk of Exacerbations
ICS + LABA or LAAC
2) LAAC + LABA
ICS + LABA or LAAC
ICS + LABA + LAAC 4
≥ 2 3
(GOLD Classification of Airflow Limitation)
Spirometry
(Exacerbation history)
Risk 2
1)LAAC or LABA
2) LAAC + LABA 1
SAAC prn or
SAAB prn 1
mMRC < 2
CAT < 10
mMRC ≥ 2
CAT ≥ 10
Symptoms
(mMRC or CAT score)

41. “How your approach in COPD might change in 2012”
INTRODUCTION
GOLD 2007
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION

42. TORCH: Post-bronchodilator FEV1
Adjusted mean change FEV1 (mL)
–150
–100
–50 50
100 *†
SFC
SALM FP *
Placebo
Descriptive statistics of actual FEV1 and change from baseline FEV1 were reported for baseline and all subsequent visits and at withdrawal.
Change from baseline FEV1 was compared between treatment groups using a repeated measures analysis. Treatment group was fitted as the explanatory variable, and smoking status, age, gender, baseline FEV1, region, visit, baseline FEV1 by visit and treatment by visit were fitted as covariates.
Supportive analyses were also performed at each visit. The ANCOVA fitted change in FEV1 as the response variable, treatment group as the predictor variable and also adjusted for smoking status, age, gender, region and baseline FEV1.
The adjusted mean change in post-bronchodilator FEV1 averaged over the 3-year treatment period was calculated for each treatment group:
–62 mL for placebo
–21 mL for SALM
–15 mL for FP
29 mL for SFC.
Average treatment differences were:
92 mL for SFC vs placebo (p < 0.001)
50 mL for SFC vs SALM (p < 0.001)
44 mL for SFC vs FP (p < 0.001)
42 mL for SALM vs placebo (p < 0.001)
47 mL for FP vs placebo (p < 0.001)
In all cases, SFC significantly increased post-bronchodilator FEV1 compared with the other treatment arms. The true treatment effect may be larger, since there was differential drop out with placebo patients more likely to drop out, therefore this is likely to produce a conservative treatment effect of SFC.
Reference
Calverley PMA, Anderson JA, Celli B. for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. NEJM 2007; 356(8): & Online Supplement 24 48 72 96
120
156
Time (weeks)
*p < vs placebo; †p < vs SALM and FP
Calverley et al. NEJM 2007 42

43. TORCH: SFC significantly reduces exacerbations over 3 years
0.2
0.4
0.6
0.8
1.0
1.2
Placebo
Annualised exacerbation rate
Salmeterol FP
SFC
25% (p<0.001)
1.13
0.97
0.93
0.85
Treatment effect
p-value
SFC vs placebo
25%
<0.001
SFC vs salmeterol
12%
0.002
SFC vs FP 9%
0.02
Calverley N Eng J Med 2007

44. Annualised exacerbation rate
TORCH: SFC reduces rate of exacerbations requiring systemic corticosteroids over 3 years
–0.05
0.15
0.35
0.55
0.75
0.95
1.15
Placebo
Salmeterol FP
SFC
43% (p<0.001)
0.80
0.64
0.52
0.46
Annualised exacerbation rate
Moderate and severe
p-value
Treatment effect
SFC vs placebo
43%
<0.001
SFC vs salmeterol
29%
<0.001
SFC vs FP
13%
0.02
Calverley N Eng J Med 2007

45. Annualised exacerbation rate
TORCH: SFC reduces the rate of severe exacerbations requiring hospitalisation over 3 years
0.05
0.10
0.15
0.20
SFC FP
Salmeterol
Placebo
17% (p=0.03)
0.19
0.16
0.17
Annualised exacerbation rate
p-value
Treatment effect
SFC vs placebo
17%
0.03
SFC vs salmeterol
–2%
0.79
SFC vs FP 5%
0.56
Calverley N Eng J Med 2007

46. SFC reduces dyspnea
691 COPD (mean FEV1: 41%) with mMRC≥2 - results at 24 weeks
* p<0.05
Mahler DA et al AJRCCM 2002

47. “How your approach in COPD might change in 2012”
INTRODUCTION
GOLD 2007
CAT (COPD Assessment Test)
HEED study
ECLIPSE study
GOLD 2012
POSITION OF COMBINATION THERAPY
CONCLUSION

48. Take home message
COPD is highly heterogeneous (HEED and ECLIPSE)
Former management of COPD (GOLD 2007):
Unidimensional approach: spirometry: FEV1 (FEV1/FVC):
 Diagnosis
New management of COPD (GOLD 2012):
Multidimensional approach: FEV1; mMRC, CAT and exacerbations
 Diagnosis (and phenotyping)
 Prognosis
 Monitoring
Aim: Optimal Management and Treatment
ICS/LABA combination is effective in COPD patient groups C and D

49. Questions? 49