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““How your approach in COPD might How your approach in COPD might change in 2012”change in 2012”

INTRODUCTIONINTRODUCTION

GOLD 2007GOLD 2007

CAT (COPD Assessment Test)CAT (COPD Assessment Test)

HEED studyHEED study

ECLIPSE studyECLIPSE study

GOLD 2012GOLD 2012

POSITION OF COMBINATION THERAPYPOSITION OF COMBINATION THERAPY

CONCLUSIONCONCLUSION

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Definition of COPD Definition of COPD (GOLD 2012)(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.

www.goldcopd.org

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COPD: epidemiologyCOPD: epidemiology

Bousquet J. et al, Eur Respir J 2010; 36: 995-1001.

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COPD: epidemiologyCOPD: epidemiologyUS / EuropeUS / Europe: :

smokingsmoking– cigarettescigarettes– cigarscigars

Asia / AfricaAsia / Africa: :

cooking and heatingcooking and heating– biomass fuelbiomass fuel

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COPD: the third biggest killer by 2020COPD: the third biggest killer by 2020

Murray & Lopez, Lancet 1997.

Ischemic heart disease

CVD disease

Lower respiratory infection

Diarrhoeal disease

Perinatal disorders

COPD

Tuberculosis

Measles

Road traffic accident

Lung cancer

Stomach cancer

HIV

Suicide

1990 2020

3rd

6th

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Emphysema

Parenchymal destructionParenchymal destructionLoss of alveolar attachmentsLoss of alveolar attachments

Decrease of elastic recoilDecrease of elastic recoil

Small airways diseaseSmall airways diseaseAirway inflammationAirway inflammationAirway remodelingAirway remodeling

AIRFLOW LIMITATION

GOLD 2001

INFLAMMATIONINFLAMMATION

Bronchiolitis

www.goldcopd.org

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SYMPTOMS

coughcough

sputumsputumdyspneadyspnea

EXPOSURE TO RISKFACTORS

tobaccotobaccooccupationoccupation

indoor/outdoor pollutionindoor/outdoor pollution

SPIROMETRY IS REQUIREDTO MAKE DIAGNOSIS

SPIROMETRY IS REQUIREDTO MAKE DIAGNOSIS

Diagnosis of COPDDiagnosis of COPD

: FEV1/FVC < 70%Post bronchodilatation!

www.goldcopd.org

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GOLD 2007GOLD 2007




GOLD 2012GOLD 2012




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IV: Very Severe III: Severe II: Moderate I: Mild

FEV1/FVC < 70%

FEV1 > 80% predicted

FEV1/FVC < 70%

50% < FEV1 < 80% predicted

FEV1/FVC < 70%

30% < FEV1 < 50% predicted

FEV1/FVC < 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 rehabilitation

Add inhaled glucocorticosteroids if repeated exacerbations

Active reduction of risk factor(s); influenza vaccinationAdd short-acting bronchodilator (when needed)

Add long term oxygen if chronic respiratory failure. Consider surgical treatments

Report GOLD 2009 (Updated)

Previous GOLD guidelinesPrevious GOLD guidelinesTherapy at Each Stage of COPDTherapy at Each Stage of COPD

www.goldcopd.org

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GOLD 2007GOLD 2007




GOLD 2012GOLD 2012




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Health status, FEVHealth status, FEV1 1 and GOLD stage:and GOLD stage:

Staging by FEVStaging by FEV11 neglects patient outcomes 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

Breathless walking on

level ground

r =–0.23P<0.0001

Lung function measurements do not reflect the impact of COPD

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Medical Research Council (mMRC) Medical Research Council (mMRC) Dyspnea ScoreDyspnea Score

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

0%10%20%30%40%50%60%70%80%90%

100%

Mild Moderate Severe Very Severe mMRC 4 mMRC 3 mMRC2 mMRC1 mMRC 0

Adapted from Jones P. et al, ERJ 2011; 34: 29-35

Airflow limitation: (FEV1)

Dyspnea was defined as a score of 2 or higher on mMRC scale

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AimsAims of the COPD Assessment Test (CAT) of the COPD Assessment Test (CAT)

CATCAT: :

a patient-completed questionnairea patient-completed questionnaire

a short, simple and reliable test:a short, simple and reliable test:

To improve the assessment of COPD To improve the assessment of COPD patientspatients

To grade the impact of COPD on health To grade the impact of COPD on health status.status.

Jones P. et al, ERJ 2009; 34: 648-654.

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COPD Assessment Test (CAT)COPD Assessment Test (CAT)

Scoring range 0–40

✗✗✗

✗

✗✗

✗✗

1

1

2

4

3

4

2

5

22Jones P. et al, ERJ 2009; 34: 648-654.

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Impact of COPD on daily lifeImpact of COPD on daily life

40

Light

Moderate

Important

Very important

30

20

10

CAT score

www.CATestonline.org

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CAT: correlation with SGRQCAT: correlation with SGRQ

r-=0.80P<0.0001

Jones P. et al, ERJ 2009; 34: 648-654.

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GOLD 2007GOLD 2007




GOLD 2012GOLD 2012




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HEED study: Health related quality HEED study: Health related quality of life in European COPD patientsof life in European COPD patients

A large cross-sectional observational study to evaluate A large cross-sectional observational study to evaluate health status in patients with COPD health status in patients with COPD inin primary careprimary care..

COPD patients:COPD patients:– Age: 40-80 yearsAge: 40-80 years– COPD: all severitiesCOPD: all severities– Current or ex-smokers with a smoking history of Current or ex-smokers with a smoking history of ≥ 10 pack-≥ 10 pack-

yearsyears

7 Countries: Belgium, France, Germany, Italy, the 7 Countries: Belgium, France, Germany, Italy, the Netherlands, Spain and UK.Netherlands, Spain and UK.

Jones P. et al, Resp Medicine 2011.

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European COPD Quality of Life SurveyEuropean COPD Quality of Life Survey


Total: n = 1.787

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European COPD Quality of Life Survey: SGRQEuropean COPD Quality of Life Survey: SGRQ


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European COPD Quality of Life Survey: CATEuropean COPD Quality of Life Survey: CAT

Jones P., Brusselle G. et al, ERJ 2011.

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European COPD Quality of Life Survey: European COPD Quality of Life Survey: CAT correlation with SGRQCAT correlation with SGRQ

r=0.80* *P<0.0001

Jones P., Brusselle G. et al, ERJ 2011.*Jones PW et al. Eur Respir J 2009

HEED EU patients: r = 0.84, p<0.001

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GOLD 2007GOLD 2007




GOLD 2012GOLD 2012




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ECLIPSE study:

Evaluation of COPD Longitudinally to Identify Predictive Surrogate

Endpoints

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The ECLIPSE Study: Objectives of this 3-yrs observational study

Vestbo J, et al. Eur Respir J. 2008;31:869-873

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

ECLIPSE: Study DesignECLIPSE: Study Design

Vestbo J, et al. Eur Respir J. 2008;31:869-873.

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)(SGRQ,BODE); Dyspnoea

GOLD stage II (FEV1 50–80% pred.)

GOLD stage IV (FEV1 <30% pred.)

GOLD stage III (FEV1 30–50% pred.)

21

80

CO

PD

s

ub

jec

ts**

343 smoking controls

223 non-smoking controls56

6 c

on

tro

l s

ub

jec

ts**P

lan

ned

R

ecru

itm

ent

0 3 6 12 18 24 30 36

Months0 3 6 12 18 24 30 36

An

alys

is

FSFV* Dec 19 2005

LSLV* Feb 19 2010

46 Centres;12 Countries

Year 1 and 3 Visits captured:• Chest computed tomography

Year 3 visit captured: • Depression; Fatigue

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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.”

Definition of COPD exacerbationDefinition of COPD exacerbation according to GOLD guidelinesaccording to GOLD guidelines

www.goldcopd.org

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Susceptibility to Exacerbation in Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Chronic Obstructive Pulmonary

DiseaseDiseaseJohn R. Hurst, Jørgen Vestbo, Antonio John R. Hurst, Jørgen Vestbo, Antonio

Anzueto, Nicholas Locantore, Hana Anzueto, Nicholas Locantore, Hana Mϋllerova, Ruth Tal-Singer, Bruce Mϋllerova, Ruth Tal-Singer, Bruce

Miller, David A. Lomas, Alvar Agusti, Miller, David A. Lomas, Alvar Agusti, William MacNee, Peter Calverley, William MacNee, Peter Calverley,

Stephen Rennard, Emiel F.M. Wouters Stephen Rennard, Emiel F.M. Wouters and Jadwiga A. Wedzichaand Jadwiga A. Wedzicha

New England Journal of New England Journal of MedicineMedicine

2010;363:1128-382010;363:1128-38

The ‘frequent exacerbator The ‘frequent exacerbator phenotype’: ECLIPSEphenotype’: ECLIPSE

Hurst JR, et al. N Engl J Med. 2010;363:1128-38.

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BackgroundBackground– Exacerbations of COPD are a major part of the natural history of Exacerbations of COPD are a major part of the natural history of

COPD:COPD:

Accelerate decline in lung functionAccelerate decline in lung function

Reduce physical activity and QoLReduce physical activity and QoL

Increase risk of hospitalization and deathIncrease risk of hospitalization and death

Increased significantly healthcare costsIncreased significantly healthcare costs

RationaleRationale– The ECLIPSE cohort was used to test the hypothesis of a The ECLIPSE cohort was used to test the hypothesis of a

frequent exacerbation phenotypefrequent exacerbation phenotype

The ‘frequent exacerbator phenotype’: The ‘frequent exacerbator phenotype’: ECLIPSE: ECLIPSE: IntroductionIntroduction

Hurst JR, et al. N Engl J Med. 2010;363:1128-38

Is the most reliable predictor of exacerbations in an individual patient a history of prior exacerbations?

29

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The ‘frequent exacerbator phenotype’: ECLIPSEThe ‘frequent exacerbator phenotype’: ECLIPSEFrequency/Severity of Exacerbations by GOLD stage (1)Frequency/Severity of Exacerbations by GOLD stage (1)

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

Exacerbations are more frequent and more severe with increasing COPD severity

What are the predictors of exacerbation frequency?

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The ‘frequent exacerbator phenotype’: The ‘frequent exacerbator phenotype’: ECLIPSE: ECLIPSE: Stability of the Exacerbator PhenotypeStability of the Exacerbator Phenotype

74% of patients having no exacerbations in Years 1 and Year 2 had no exacerbations in Year 3

Hurst JR, et al. N Engl J Med. 2010;363:1128-38.ECLIPSE 3 year data

71% of Frequent Exacerbators in Year 1 and Year 2 were Frequent Exacerbators in Year 3

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ECLIPSE and HEED confirm ECLIPSE and HEED confirm – Disease severity (breathlessness, exercise capacity, Disease severity (breathlessness, exercise capacity,

exacerbations, health status degradation) increases with exacerbations, health status degradation) increases with GOLD stageGOLD stage

– FEV1 poorly related with other parameters FEV1 poorly related with other parameters – COPD is highly heterogeneousCOPD is highly heterogeneous– Within GOLD stage there is Within GOLD stage there is substantialsubstantial variation in: variation in:

BreathlessnessBreathlessness

Exercise capacity Exercise capacity

Exacerbation frequencyExacerbation frequency

Health statusHealth status

Conclusions (1)Conclusions (1)

Agusti A, et al. Resp Res. 2010;11:122

“Airflow limitation alone does not provide an accurate measure of disease severity or activity”

32

New GOLD guidelines must include other parameters: QoL, symptoms and exacerbation rate

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Conclusions (2) Conclusions (2)

ECLIPSE confirms ECLIPSE confirms

Exacerbations become more frequent and more severe Exacerbations become more frequent and more severe as COPD severity increasesas COPD severity increases

Frequent exacerbator is an independent disease Frequent exacerbator is an independent disease phenotypephenotype– That can be identified by patient self-report about That can be identified by patient self-report about

previous exacerbationsprevious exacerbations– Stable over time (3 yrs)Stable over time (3 yrs)– Patients with moderate COPD may be frequent Patients with moderate COPD may be frequent

exacerbators (22%)exacerbators (22%)

Exacerbation in prior year is the best predictor of occurrence of exacerbation

Exacerbation rate must be integrated in GOLD guidelines

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GOLD 2007GOLD 2007




GOLD 2012GOLD 2012




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Approaches of COPD treatment Approaches of COPD treatment according to GOLD guidelinesaccording to GOLD guidelines

TimelineUnidimensional approach Unidimensional approach Multidimensional approachMultidimensional approach

GOLD 2001 GOLD 2012

1) Risk: FEV1

Rate of exacerbations2) Symptoms:CAT score,mMRC scale

(C)

(B)(A)

(D)

Symptoms(mMRC or CAT score)

Ris

k(E

xace

rba

tion

his

tory

)

Sp

iro

met

ry(G

OLD

Cla

ssifi

catio

n of

Airf

low

Lim

itatio

n)

1

2

3

4

0

1

≥ 2

mMRC < 2CAT < 10

mMRC ≥ 2CAT ≥ 10

Management of COPD according to Symptoms, Spirometric classification and Future Risk of Exacerbations

www.goldcopd.org

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Combined Assessment of Combined Assessment of COPDCOPD

(C) (D)

(A) (B)

mMRC 0-1CAT < 10

mMRC > 2CAT > 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

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Combined Assessment of Combined Assessment of COPDCOPD

Ris

k (G

OL

D C

lass

ific

atio

n o

f A

irfl

ow

Lim

itat

ion

)

Ris

k (E

xace

rbat

ion

his

tory

)

> 2

1

0

(C) (D)

(A) (B)

mMRC 0-1CAT < 10

4

3

2

1

mMRC > 2CAT > 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

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Patient Characteristic SpirometricClassification

Exacerbations per year

mMRC CAT

ALow Risk

Less SymptomsGOLD 1-2 ≤ 1 0-1 < 10

BLow Risk

More SymptomsGOLD 1-2 ≤ 1 >2 ≥ 10

CHigh Risk

Less SymptomsGOLD 3-4 >2 0-1 < 10

DHigh Risk

More SymptomsGOLD 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 The four COPD patient groups according to GOLD 2012 (summary)GOLD 2012 (summary)

www.goldcopd.org

1) ICS + LABA or LAAC

2) LAAC + LABA

1)LAAC or LABA

2) LAAC + LABA

SAAC prn or

SAAB prn

1) ICS + LABA or LAAC

2) ICS + LABA + LAAC

Symptoms(mMRC or CAT score)

Ris

k(E

xace

rba

tion

his

tory

)

Sp

iro

met

ry(G

OLD

Cla

ssifi

catio

n of

Airf

low

Lim

itatio

n)

1

2

3

4

0

1

≥ 2

mMRC < 2CAT < 10

mMRC ≥ 2CAT ≥ 10

Management of COPD according to Symptoms, Spirometric classification and Future Risk of Exacerbations

www.goldcopd.org

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GOLD 2007GOLD 2007




GOLD 2012GOLD 2012




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TORCH: Post-bronchodilator TORCH: Post-bronchodilator FEVFEV11

Adjusted mean change FEV1 (mL)

0 24 48 72 96 120 156Time (weeks)

–150

–100

–50

0

50

100

Placebo SALM FP

**

*†

SFC

*p < 0.001 vs placebo; †p < 0.001 vs SALM and FPCalverley et al. NEJM 2007

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0.029%SFC vs FP

0.00212%SFC vs salmeterol

<0.00125%SFC vs placebo

TORCH: SFC significantly reduces TORCH: SFC significantly reduces exacerbationsexacerbations over 3 years over 3 years

p-valueTreatment effect

0

0.2

0.4

0.6

0.8

1.0

1.2

Placebo

Annualis

ed e

xace

rbati

on r

ate

Salmeterol FP SFC

25% (p<0.001)

1.13

0.97 0.930.85

Calverley N Eng J Med 2007

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0.0213%SFC vs FP

<0.00129%SFC vs salmeterol

<0.00143%SFC vs placebo


TORCH: SFC reduces rate of TORCH: SFC reduces rate of exacerbations exacerbations requiring systemic corticosteroidsrequiring systemic corticosteroids over 3 over 3

yearsyearsA

nnualis

ed e

xace

rbati

on r

ate

–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

0.520.46


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TORCH: SFC reduces the rate of severe TORCH: SFC reduces the rate of severe exacerbations exacerbations requiring hospitalisationrequiring hospitalisation over 3 years over 3 years


0.565%SFC vs FP

0.79–2%SFC vs salmeterol

0.0317%SFC vs placebo

Annualis

ed e

xace

rbati

on r

ate

0

0.05

0.10

0.15

0.20

SFCFPSalmeterolPlacebo

17% (p=0.03)

0.19

0.16 0.17 0.16


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GOLD 2007GOLD 2007




GOLD 2012GOLD 2012




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Take home message Take home message COPD is highly heterogeneous (HEED and ECLIPSE)

Former management of COPD (GOLD 2007):Former management of COPD (GOLD 2007):

Unidimensional approach: spirometry: Unidimensional approach: spirometry: FEVFEV11 (FEV (FEV11/FVC): /FVC):

DiagnosisDiagnosis

New management of COPD (GOLD 2012):New management of COPD (GOLD 2012):

Multidimensional approach: Multidimensional approach: FEVFEV11; ; mMRCmMRC, , CAT and exacerbationsCAT and exacerbations

Diagnosis (and phenotyping)Diagnosis (and phenotyping)

PrognosisPrognosis

MonitoringMonitoring

Aim: Optimal Management and Treatment Aim: Optimal Management and Treatment

ICS/LABA combination is effective in COPD patient groups C and D

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Questions?Questions?

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