cts: clinical assessment of copd

Questions to ask: Do you cough regularly? Do you cough up phlegm regularly? Do even simple chores make you short of breath? Do you wheeze at night or when you exert yourself? Do you catch frequent colds that persist longer than most

other individuals’ around you?

Carry out spirometry testing

Treatment goals:Smoking cessation Vaccination to prevent exacerbationsRegular physical activityBronchodilator therapy

CTS: Clinical Assessment of COPD

Adapted from Can Respir J January/February 2008;15(suppl A).

CTS: Potential Prevention Strategies for AECOPD

Smoking cessation

Vaccinations: Influenza (annually) Pneumococcal vaccine (every five to 10 years)

Self-management education

Regular therapy with ICS/LABA combination (for moderate to severe COPD with ≥1 AECOPD on average per year)

Oral corticosteroid therapy for AECOPD

Pulmonary rehabilitation


II

Mild Very severe

V

Smoking cessation/exercise/self-management/education

PRN short-acting bronchodilator(s)

Long-acting bronchodilator(s)

Pulmonary rehabilitation

Inhaled corticosteroids/LABA

Oxygen

Surgery

Lung functionimpairment

MRC dyspneascale

Early diagnosis(spirometry) +

prevention

Prevent/Rx AECOPD

Follow-upEnd-of-life care

CTS: Comprehensive Approach to COPD/AECOPD Management


Mild Moderate Severe

CTS: Recommendations for Optimal COPD Therapy

Infrequent AECOPD(an average of

<1 per year)

Frequent AECOPD(≥1 per year)

SABA prn

persistentdisability

LAAC + SABA prnor

LABA + SABD prn

LAAC or LABA + SABA prn

persistent disability

LAAC + LABA + SABA prn

persistent disability

LAAC+ICS/LABA* +SABA prn

LAAC + ICS/LABA + SABA prnpersistent disability

LAAC + ICS/LABA + SABA prn±

Theophylline


*Refers to the lower-dose ICS/LABA.

Increasing Disability and Lung Function Impairment

Clinical Differences Between Asthma and COPD

Asthma COPD

Age of onset Usually under 40 years Usually over 40 years

Smoking history Not casual Usually >10 pack-years

Sputum production Infrequent Often

Allergies Often Infrequent

Disease course Stable (with exacerbations) Progressive worsening (with exacerbations)

Spirometry Often normalizes May improve but never normalizes

Clinical symptoms Intermittent and variable Persistent


Grade Description

1 Not troubled by breathlessness except with strenuous exercise

2 Troubled by shortness of breath when hurrying on the level or walking up a slight hill

3 Walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level

4 Stops for breath after walking about 90 m or after a few minutes on the level

5 Too breathless to leave the house or breathless when dressing or undressing


MRC Dyspnea Scale

COPD Is Projected to Be the Third Biggest Cause of Mortality by 2020

Adapted from Murray CJ, Lopez AD. Lancet 1997;349:1498-504.

Ischaemic heart disease

Cardiovascular disease

Lower respiratory infection

Diarrheal disease

Perinatal disorders

COPD

Tuberculosis

Measles

Road traffic accident

Lung cancer

Ischemic heart disease

Cardiovascular disease

COPD

Lower respiratory infection

Lung cancer

Road traffic accident

Tuberculosis

Stomach cancer

HIV

Suicide

1st

2nd

3rd

4th

5th

6th

7th

8th

9th

10th

1990 2020

Inflammation Plays a Central Role in the Pathogenesis and Pathology of COPD

Adapted from Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, 2006. Available at http://www.goldcopd.com/

Cigarette smoke (and other irritants)

• Inflammatory cells• Inflammatory mediators• Oxidative stress• Proteases

COPD pathologyObstructive bronchiolitis

Mucus hypersecretion

Alveolarwall destruction

Genetic susceptibility

Lung Inflammation

Amplification of Inflammation in COPD

Adapted from Barnes PJ. Personal Communication.

++++

+++

++

+

0

Infla

mm

atio

n

Normal smokersNon-smokers Mild COPD Severe COPD Exacerbation

Bacteria Viruses

Inflammatory cells Cytokines Mediators Proteases

Complementary Effect of ICS/LABA on COPD Inflammation

Adapted from Bourbeau et al. Thorax 2007;Epub.

SFC-FP=salmeterol/fluticasone DPI vs. fluticasone DPI SFC-P=salmeterol/fluticasone DPI vs. placebo; FP-P=fluticasone DPI vs. placebo

CD8+ T-lymphocytes20

0

–20

–40

–60

–80

–100

–120

–140

–160

Tre

atm

ent

dif

fere

nce

(95

% C

I)

-53.4(-96 to -9)

-98.05(-143.1 to -53.0)

-44.67(-90.9 to 1.6)

40

30

20

10

0

Tre

atm

ent

dif

fere

nce

(95

% C

I)

-29.36(-57.8 to -0.9)

-31.68(-61.1 to -2.3)

-2.32(-32.5 to 27.8)–10

–20

–30

–40

–50

–60

–70SFC-FP SFC-P FP-P

Eosinophils8

6

4

2

0

–2

–4

–6

–8

–10

Tre

atm

ent

dif

fere

nce

(95

% C

I)

0.87(3.9 to 5.6)

-3.1(-8.0 to 1.8) -3.97

(-9 to 1.1)

CD68+ macrophages Neutrophils40

30

20

10

0

–10

–20

–30

–40

Tre

atm

ent

dif

fere

nce

(95

% C

I)

-22.78(-35.4 to -10.2)

-4.57(-17.6 to 8.5)

18.21(4.8 to 31.6)

SFC-FP SFC-P FP-P

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 mortality4,5

Decline in lung function1

Worsening health status3

Patients Under-report COPD Exacerbations

1. Seemungal et al. Am J Respir Crit Care Med 1998;157:1418-22.2. Wilkinson et al. Am J Respir Crit Care Med 2004;169:1298-303.

Seemungal et al.1 (n=184)1

Wilkinson et al.2

(n=1099)2

Exa

cerb

atio

ns

(%)

50.5 59.9

49.540.1

0

20

40

60

80

100

Reported exacerbations

Unreported exacerbations

59.9

Pulmonary Function Testing: COPD

GOLD Guidelines

Adapted from GOLD (December 2007).

What do COPD patients with a history of exacerbations want from their therapy?

Adapted from Miravitlles et al. Respir Med 2007;101:453-60.

Results from 1100 interviews in five EU countries and the USA

0 10 20 30 40 50 60

Quicker symptom relief

Patients (%)

Fewer side effects 36

Lower costs of treatment 27

Better ability to cope with daily chores 27

55

Longer intervals between flare-ups 40

Better doses 23

Frequent: >median 2.92 exacerbations/yearInfrequent: ≤median 2.92 exacerbations/yearFEV1: forced expiratory volume in 1 second

Adapted from Donaldson et al. Thorax 2002;57:847-52.

Frequent Exacerbations Lead to Declining Lung Function

FE

V1

(l)

Time (years)

0.75

0.80

0.85

0.90

0.95

0 1 2 3 4

Frequent exacerbations Infrequent exacerbations

Increased Frequency of Exacerbations Increases the Risk of Mortality in COPD

Adapted from Soler-Cataluna et al. Thorax 2005;60:925-31.

Time (months)

P<0.0001

P<0.0002

P=0.069

0 10 20 30 40 50 60

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al p

rob

abili

ty

0 exacerbations1–2 exacerbations≥3 exacerbations

Prolonged Time to First Exacerbation

P<0.05 Busesonide/formoterol (bud/form) vs. all other groups (log-rank test)

Adapted from Calverley et al. Eur Respir J 2003;22:912-9.

Time in study (days)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

00 40 80 120 160 200 240 280 320 360 400

Fra

ctio

n of

pat

ient

s w

ithou

t an

exac

erba

tion

durin

g th

e st

udy

96 days 154 days

254 days

178 days

Formoterol

Budesonide

Placebo

Budesonide/formoterol prolonged time to first exacerbation by 100 days vs. LABA alone


1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

00 40 80 120 160 200 240 280 320 360 400

Fra

ctio

n of

pat

ient

s w

ithou

t an

exac

erba

tion

durin

g th

e st

udy

96 days 154 days

254 days

178 days

Placebo

Bud/form

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

Therapy at Each Stage of COPD

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 long-term oxygen if chronic respiratory failure Consider surgical treatments

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)

Adapted from Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, 2006. Available from http://www.goldcopd.com/

FVC = forced vital capacity

Improvements in Health Status by ICS/LABA Combinations vs. Placebo

*Measured by using the St. Georges Respiratory Questionnaire, a validated tool for measuring health status in COPD

1. Calverley et al. Eur Respir J 2003;22:912-9 2. Szafranski et al. Eur Respir J 2003;21:74-81.3. Calverley et al. Lancet 2003;361:449-56.4. Calverley et al. N Engl J Med 2007;356:775-89.

–8

–7

–6

–5

–4

–3

–2

–1

0

∆ H

ealth

sta

tus

Clinically meaningful improvement

Budesonide/formoterol1

Budesonide/formoterol2

Salmeterol/ fluticasone

DPI3

Salmeterol/ fluticasone

DPI4

Adapted from Soriano et al. Am J Respir Med 2003;2:67-74.

ICS/LABA Improves Hospitalization-free Survival in a Cohort Study

P<0.05 ICS/LABA vs. ICS or LABARetrospective cohort analysis of COPD-related rehospitalization or death within one year of first hospitalization in 3636 COPD patients receiving ICS and/or LABA compared with 627 reference patients receiving SABA alone

Ris

k of

reh

ospi

taliz

atio

n or

dea

th v

s.

refe

renc

e pa

tient

s (%

)

-41%

-16%

-10%

–45

–40

–35

–30

–25

–20

–15

–10

–5

0ICS/LABA ICS LABA

ICS/LABA Improves Overall Survivalin a Cohort StudyICS/LABA Improves Overall Survivalin a Cohort Study

Adapted from Mapel et al. Respir Med 2006;100:595-609.

*Adjusted for age, gender, ICS treatment, LABA treatment, ICS plus LABA treatment, asthma diagnosis, measures of COPD severity at baseline, measures of asthma severity at baseline, hospitalization for respiratory illnesses, and both inpatient and outpatient Charlson–Deyo scores; n=1685

1.00

0.95

0.90

0.85

0.80

0.75

0.70

Survival (days)

0 200 800400 600 1000 1200

Sur

viva

l fun

ctio

n es

timat

e*

Hazard ratio: 0.34*(95% CI, 0.21-0.56)P<0.001

66% lower relative risk for

all-causemortality

LABAICSSABA

ICS/LABA

Improved Survival with Budesonide +/– Formoterol Compared to Bronchodilator Treatment Alone

Adapted from Calverley et al. COPDV 2006.

0.10

0.08

0.06

0.04

0.02

00 360120 160 200 240 3202808040


Pro

port

ion

of p

atie

nts

who

die

d

400

Log-rank test: P=0.0365Cox regression: hazard ratio, 0.564; P=0.0391

22/917

34/917

BudesonideNon-budesonide

Budesonide/formoterol: Maintained Improvement in Lung Function vs. LABA Alone

Calverley et al. Eur Respir J 2003;22:912-9.

P<0.001 Budesonide/formoterol (bud/form) vs. placebo and budesonideP=0.002 Budesonide/formoterol vs. formoterol; P<0.001 formoterol vs. placebo

Time from randomization (months)

0 1 2 3 4 5 6 7 8 9 10 11 12

80

82

84

86

88

90

92

94

96

98

100

102

104

–0.5

Formoterol

Budesonide

Placebo

Bud/formM

ean

FE

V1

(% o

f ba

selin

e)

*P<0.05 vs. placebo; P=0.015 budesonide/formoterol (bud/form) vs. formoterol

Reduced Rate of Exacerbations Requiring Medical Intervention vs. LABA Alone

Adapted from Calverley et al. Eur Respir J 2003;22:912-9.

Treating 100 patients with COPD (GOLD stage III–IV) with budesonide/formoterol instead of formoterol alone may prevent 47 exacerbations in one year

–12%

Num

ber

nee

ded

to

trea

t

0

1

2

3

Budesonide/formoterol vs.

formoterol

2.1

Budesonide Formoterol

+3%

–30

–25

–20

–15

–10

–5

0

5

Rat

e o

f ex

acer

batio

ns/p

atie

nt/y

ear

–24%*

Bud/form

Lower Health Status Predicts Mortality

Adapted from Gudmundsson et al. Respir Res 2006;7:109.

SGRQ=St. George’s Respiratory QuestionnaireHigher health status=SGRQ total score ≤60; lower health status=SGRQ total score >60

0 200 400 600 800

0

25

75

100

50

Su

rviv

al (

%)

P=0.0002

Observation time (days)

Higher SGRQ total score (>60)

Lower SGRQ total score (≤60)

Mortality Stratified by Median Baseline SGRQ Total Score

Stratified by SGRQ total score, median 50-unit cut-off

Adapted from Calverley et al. COPDV 2006.

0.10

0.08

0.06

0.04

0.02

00 3603202802402001601208040


Pro

port

ion

of p

atie

nts

who

die

d

400

SGRQ total score ≤50SGRQ total score ≤50

SGRG total score >50

SGRQ total score >50

BudesonideNon-budesonide

Impact of Smoking Cessation Programmes on Mortality

Adapted from Anthonisen et al. Ann Intern Med 2005;142:233-9.

All-cause 14.5-year survival from the Lung Health Study (LHS)

1.00

0.95

0.90

0.85

0.80

Pro

port

ion

of p

atie

nts

with

no

eve

nt

0

Time since LHS baseline (years)

15%15%

Special intervention group

Usual care group

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Adapted from Sin et al. Am J Respir Crit Care Med 2001;164:580-4.

ICS Improve Hospitalization-free Survivalin a Cohort Study

CO

PD

hos

pita

lizat

ion-

free

sur

viva

l pr

obab

ility

Time after discharge (months)

1.0

0.9

0.8

0.7

0.6

0 2 4 6 8 10 120

26% lower relative risk for all-cause mortality

and repeat hospitalization

Hazard ratio: 0.74(95% CI, 0.71-0.78)

No ICS

ICS

14

ISEEC Study: ICS Improve SurvivalISEEC Study: ICS Improve Survival

Adapted from Sin et al. Thorax 2005;60:992-7.

ISEEC=Inhaled Steroids Effects Evaluation in COPD*Stratified by individual trials and adjusted for age, gender, baseline post-bronchodilator FEV1 (% predicted normal), baseline smoking status and body mass index; n=5085

1.00

0.95

0.90

0.85

0.80

0

Follow-up (years)

1 2 3 4

Sur

viva

l pro

babi

lity

Hazard ratio: 0.73*

(95% CI, 0.55-0.96)P=0.039

27% lower relative risk for

All-causemortality

Placebo

ICS

EUROSCOP Study Design

Primary end point: change over time in FEV1

Patients: aged 30-65 years, current smokers (smoking history of

≥5 pack-years), FEV1 50-100% predicted normal, FEV1/VC <70%

*Patients who continued to smoke after two three-month smoking cessation programmes and were ≥75% compliant with the recommended treatment regimens were randomized.

VC=vital capacity

Adapted from Pauwels et al. N Engl J Med 1999;340:1948-53.

Randomization* Treatment

0

Run-in

Budesonide 400 µg b.i.d. (n=634)

Placebo (n=643)

12 24 36–6 Month

TORCH: Further Evidence that ICS/LABA Can Reduce Mortality in COPD

Month

Adapted from: Vestbo et al. Eur Respir J 2004;24:206-10. Calverley et al. N Engl J Med 2007;356:775-89.

Run-in Randomization

36

Treatment

Salbutamol available as reliever medication to all patients

Fluticasone DPI 500 µg b.i.d.

Salmeterol DPI 50 µg b.i.d.

Placebo

–0.5 0 12 24 36.5

Follow-up

Salmeterol/fluticasone DPI 50/500 µg b.i.d.

Primary end point: all-cause mortality over three years

TORCH: All-cause Mortality at Three Years

Adapted from Calverley et al. N Engl J Med 2007;356:775-89.

Vertical bars represent standard errors

Placebo 1524 1464 1399 1293Salmeterol/fluticasone DPI 1533 1487 1426 1339

0

18

2

4

6

8

10

12

14

16

0 15612 24 36 48 60 72 84 96 108 120 132 144

Time to death (weeks)

Pro

bab

ility

of

deat

h (%

)

HR 0.825, P=0.05217.5% risk reduction2.6% absolute reduction

Placebo (15.2% mortality rate)

Salmeterol/fluticasone DPI (12.6% mortality rate)

Number of patients alive:

Health Related QOL Over 3 Years - TORCH

-5

-4

-3

-2

-1

0

1

2

3

0 24 48 72 96 120 156

SAL/FP 500/50SALPlacebo FP

Imp

rovem

ent

Week

Ad

just

ed m

ean

ch

ang

e in

SG

RQ

to

tal s

core

P<0.001 SAL/FP vs. SAL over 3 years

P<0.001 SAL/FP vs. Placebo over 3 years

P=0.017 SAL/FP vs. FP over 3 years

Vertical bars represent standard errors

Adapted from Calverley et al. N Engl J Med 2007;356:775-89.

-150

-100

-50

0

50

100

Adj

uste

d M

ean

Cha

nge

FE

V1 (m

L)

0 24 48 72 96 120 156

Time (Weeks)

P< 0.001 SAL/FP vs. SAL and FP over 3 years

SALPlacebo FP

P< 0.001 SAL/FP vs. Placebo over 3 years

Adapted from Calverley et al. N Engl J Med 2007; 356: 775-89.

SAL/FP 500/50

Placebo SAL FP SAL/FP 500/50

Rate of decline (mL /yr) -55 -42 -42 -39

P-value vs. placebo 0.003 0.003 <0.001

Improvements in Post Bronchodilator FEV1

with SAL/FP 500/50 over 3 years - TORCH

Rationale for TORCH: ICS with LABA

0 6 12 18 24 30 36

Probability of survival

0

1.0

FP

Reference (no ICS or LABA)

SAL + FP

0.9

0.8

0.7

0.6

Follow-up (months)

Survival was significantly higher at year 3 in patients receiving SAL/FP than in

the reference group

Adapted from Soriano et al. Eur Respir J 2002;20(4):819-25.

SAL

SAL/FP=salmeterol/fluticasone

3620

1045

cts: clinical assessment of copd

Documents