Managing COPD --- Recent Advance

蔡熒煌長庚醫院胸腔暨重症科長庚大學呼吸照護學系

Revised 2006

Definition of COPD

• Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients.

• Its pulmonary component is characterized by airflow limitation that is not fully reversible.

• The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.

Airflowlimitation

=Driving pressure (parenchyma)

Resistance (small airways)

COPD: Linking Structure with Function

Hogg JC et al., NEJM 2004;350:2645-2653

The Nature of Small-Airway Obstruction in Chronic Obstructive Pulmonary Disease

0.000 20 40 60 80 100 120

0.25

0.20

0.15

0.10

0.05

GOLDstage 4

GOLDstage 3

GOLDstage 2

GOLD stages0 and 1

V:S

A (

mm

)

FEV1

• Unequal lung compliances and airway resistances of lung units leads to a wide distribution of RC-constants

• Asynchronously emptying results in a changing gas concentration at the mouth

• Contributes to air trapping

Mechanisms of Uneven Ventilation in COPD

Alveolar macrophage

Neutrophil

Alveolar wall Alveolar wall destructiondestruction

Mucus Mucus hypersecretionhypersecretion

Cytokines (IL-8)

Mediators (LTB4)

CD8CD8+ +

lymphocytelymphocyte

ProteasesProteases

Noxious agent

Sensitizingagent

AirwayAirwaythickeningthickening

CD4CD4++

lymphocytelymphocyteMast cell

Eosinophil Histamine

Mediators (LTD4)

Cytokines (IL-4, IL-5, IL-13)

Inflammatory Inflammatory mediatorsmediators

AirwayAirwayhyperreactivityhyperreactivity

Pathophysiology of COPD and Asthma Pathophysiology of COPD and Asthma

AsthmaCOPD

EpithelialEpithelialsheddingshedding

Barnes PJ (1999; 2000)

Clinical Course of COPD: Disease Progression

Poor Health-Related Quality of Life

COPDCOPD

Expiratory Flow LimitationAir Trapping

Hyperinflation

InactivityDeconditioning

Breathlessness

Reduced Exercise Capacity

Disability Disease progression Death

Exacerbations

age 40-50 50-55 55-60 60-70

0 2,000 4,000 6,000 8,000 10,000 12,000

Trachea, bronchusand lung cancers

Lower respiratoryinfections

COPD

Cerebrovasculardisease

Ischaemic heartdisease

Five leading causes of death by the year 2020

Of the six leading causes of death in the United States, only COPD has been increasing steadily since 1970.

Source: Jemal A. et al. JAMA 2005

Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

Proportion of 1965 Rate Proportion of 1965 Rate

1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998

–59%–59% –64%–64% –35%–35% +163%+163% –7%–7%

CoronaryHeart

Disease

CoronaryHeart

Disease

StrokeStroke Other CVDOther CVD COPDCOPD All OtherCauses

All OtherCauses

COPD Mortality by Gender,U.S., 1980-2000

COPD Mortality by Gender,U.S., 1980-2000

0

10

20

30

40

50

60

70

1980 1985 1990 1995 2000

Men

Women

0

10

20

30

40

50

60

70

1980 1985 1990 1995 2000

Men

Women

Num

ber

Death

s x

100

0N

um

ber

Death

s x

100

0

Trend of Mortality of Chronic Airway Obstruction

－ Related Diseases in 21 Years in Taiwan

0.6

15.115.8

7.1

ICD-9496

ICD-9490-493( A 323 )

19811982 1984 1986 1988 1990 1992 1994 1996 1998 2000

2

4

6

8

10

12

14

16

18

20

22

16.4

22.2

ICD-9490-493, 496

ICD-9 A323:ICD-9 490 Bronchitis, not specified as acute or chronic 491 Chronic bronchitis 492 Emphysema 493 Asthma

ICD-9 496 Chronic airways obstruction, not elsewhere classified

Mo

rta

lity

rate

pe

r 1

00,0

00

慢阻肺病患門診就醫狀況

0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

3,000,000

3,500,000

4,000,000

1998 1999 2000 2001 2002 2003 2004 2005

COPD門診人數 COPD就醫人次 COPD醫療費用

慢阻肺病患住院治療

0

50,000

100,000

150,000

200,000

250,000

1998 1999 2000 2001 2002 2003 2004 2005

COPD住院人數 COPD住院人次 COPD住院費用 （萬）

Medical Cost --- COPD vs. Asthma

0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

1998 1999 2000 2001 2002 2003 2004 2005

COPD OPD Asthma OPDCOPD Admission Asthma Admission

Data from BNHI Taiwan : * 1,000 NT

Medical Cost and COPD Severity

• There is a striking direct relationship between the severity of COPD and the cost of care, and the distribution of costs changes as the disease progresses.

• The hospitalization and ambulatory oxygen costs soar as COPD severity increases

Key Indicators for Considering a COPD Diagnosis

• Consider COPD and perform spirometry if any of these indicators are present in an individual over age 40. These indicators are not diagnostic by themselves, but the presence of multiple key indicators increases the probability of a diagnosis of COPD. Spirometry is needed to establish a diagnosis of COPD.

Key Indicators for Considering a COPD Diagnosis

• Dyspnea that is: – Progressive (worsens over time).– Usually worse with exercise.– Persistent (present every day).– Described by the patient as an “increased effort to breathe,”

“heaviness,” “air hunger,” or “gasping.”

• Chronic cough: May be intermittent and may be unproductive.

• Chronic sputum production: Any pattern of chronic sputum production may indicate COPD.

• • History of exposure to risk factors:– Tobacco smoke (including popular local preparations).– Occupational dusts and chemicals.– Smoke from home cooking and heating fuel.

Risk Factors for COPD

NutritionNutrition

InfectionsInfections

Socio-economic Socio-economic statusstatus

Aging PopulationsAging Populations

SYMPTOMScoughcough

sputumsputum

dyspneadyspnea

EXPOSURE TO RISKFACTORS

tobaccotobacco

occupationoccupation

indoor/outdoor pollutionindoor/outdoor pollution

SPIROMETRYSPIROMETRY

Diagnosis of COPDDiagnosis of COPD

Airway Patency is Fundamental

• Spirometry is the gold standard for the diagnosis and assessment of COPD

• Measuring post-bronchodilator FEV1 is essential for the classification of severity of COPD

Spirometry

Diagnosis of COPD in practice (II)Diagnosis of COPD in practice (II)Diagnosis of COPD in practice (II)Diagnosis of COPD in practice (II)

For the diagnosis and assessment of COPD, spirometry is the gold standard

Healthcare workers involved in the diagnosis and management of COPD patients should have access to spirometry

Spirometry should be undertaken whenever respiratory problems are suspected

GOLD workshop report 2001

Spirometer

Spirometry: Normal and COPDSpirometry: Normal and COPD

FEV1 FVC FEV1/FVC

Normal 4.15 5.2 80%

COPD 2.35 3.9 60%

Time (S)

0 1 2 3 4 5 6

0

1

2

3

4

5

FEV1 (l)

FEV1

FEV1

FVC

FVCNormal

COPD

Adapted from GOLD workshop report 2001

Diagnosis of COPD

• Existing COPD prevalence data show remarkable variation due to differences in survey methods, diagnostic criteria, and analytic approaches

• Survey methods can include:– Self-report of a doctor diagnosis of COPD or

equivalent condition

– Spirometry with or without a bronchodilator

– Questionnaires that ask about the presence of respiratory symptoms

COPD is Under-appreciated and Under-diagnosed

Example from Japan:

NICE Survey of COPD prevalence

NICE study population was comprised of 2343 Japanese subjects aged ≥ 40 years.

Carried out in several regions of Japan using standardized methods

COPD Prevalence Rate (adjusted)* in Population 40 years

COPD Prevalence Rate (adjusted)* in Population 40 years

*Adjusted for age, sex, cluster**8.5-10.9% depending on criteria

Study

Fukuchi et al. Respirology 2004;9:458-65

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

0.3%0.3%

8.5%**8.5%**

5.3 vs 0.2M COPD patients in Japan ≥40 years5.3 vs 0.2M COPD patients in Japan ≥40 years

MHW Survey

COPD Prevalence Survey (NICE) in

Japan

COPD Prevalence Survey (NICE) in

Japan

91%

9%

UndiagnosedDiagnosed

Had prior diagnosis

Did not have prior diagnosis:Fukuchi et al. Respirology 2004;9:458-65

Prevalence of GOLD Stage 1+ COPD1, Guangzhou, ChinaPrevalence of GOLD Stage 1+ COPD1, Guangzhou, China

1 FEV1/FVC<0.70, post BD

MEN15.3%

WOMEN7.6%

• The Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO) examined the prevalence of post-bronchodilator airflow limitation (Stage I: Mild COPD and higher) among persons over age 40 in five major Latin American cities each in a different country – Brazil, Chile, Mexico, Uruguay, and Venezuela

四十歲以上成年人

抽煙或吸入污染接觸者

Is it Inevitably All Downhill ?

How we can change the clinical course of COPD?

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

Therapy at Each Stage of COPDTherapy 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 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

The Fletcher-Curve

Smoking Cessation Slows Lung Function Decline in Mild COPD: The Lung Health Study at 11 Years

Anthonisen NR et al. Am J Respir Crit Care Med. 2002:166:675-9. Calverley PMA and Walker P. Lancet 2003;362:1053-1061

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

Sustained quitters Intermittent quitters Continuous smokers

Smoking Cessation Slows Lung Function Decline in Mild COPD: The Lung Health Study at 11 Years

Anthonisen NR et al. Am J Respir Crit Care Med. 2002:166:675-9. Calverley PMA and Walker P. Lancet 2003;362:1053-1061

Effect of Smoking Cessation on Cause of Mortality

Anthonisen et al. Ann Intern Med. 2005;142:233-239

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

Cause of Death

Special InterventionUsual Care

Rat

e of

Dea

th p

er 1

000

Per

son

-Yea

rs

CHD CVD LungCancer

OtherCancer

Respiratory Disease

Other Unknown

Bronchodilators in Stable COPD

• Bronchodilator medications are central to symptom management in COPD.

• Inhaled therapy is preferred.

• The choice between Beta2-agonist, anticholinergic, theophylline or combination therapy depends on availability and individual response in terms of symptoms relief and side effects.

Inhalation Medication

• Short acting beta-2 agonist (SABA)– Rescue use

• Long acting beta-2 agonist (LABA)

• Long acting anticholinergic agent

• Steroid

• Combination of steroid and LABA

吸入劑型藥物之吸入道具Metered-Dose Inhalers (MDI)

Nebulizer Dry Powder Inhalers (DPI)

C h a n g e fro m B a s e lin e in T ro u g h F E VC h a n g e fro m B a s e lin e in T ro u g h F E V 11 O v e r O v e r 1 Y e a r (V e rs u s1 Y e a r (V e rs u s Ip ra tro p iu m )Ip ra tro p iu m )

P < 0 .0 0 0 1 a t a ll t im e p o in ts

Δ T -I=1 6 0 m L

V in c k e n W e t a l. E u r R e s p ir J (2 0 0 2 )

-1 0 0

-5 0

0

5 0

1 0 0

1 5 0

2 0 0

ΔT

rou

gh

FE

V1

(mL

)

T io tro p iu m (n = 3 2 9 )

8 5 0 9 2 1 8 2 2 7 3 3 6 4

Ip ra tro p iu m (n = 1 6 1 )

T e s t d a y

0 .95

1 .00

1 .05

1 .10

1 .15

1 .20

1 .25

1 .30

1 .35

M ean FE VM ean FE V 1 1 O ver 6 M onths in C om bined O ver 6 M onths in C om bined S alm etero l T ria lsS alm etero l T ria ls

Δ T-S=70 m L †

*P <0.0001; †P<0.001 B rusasco V et a l. Thorax (2003)

T io trop ium (n=386)

Salm etero l (n=388)

P lacebo (n=362)

D ay 1 D ay 169

Tim e after adm in istration (m inutes)

-60 -10 30 60 120 180

Δ T-P=210 m L*

FE

V1

(L)

Randomization andStart of Oral Steroid Trial

373372

222

246

269

241288

298

174

216

194

235

168

141

ISOLDE: Lack of effect of ICS on FEV1 decline

-3 0 3 12 24 36

1.50

1.40

1.30

1.20

Start of Double-BlindTreatment

FP MDI 500 mcg b.i.d. (n=376)Placebo b.i.d. (n=375)

FEV1

(L)

Time (months)

Burge et al. BMJ. 2000; 320:1297-1303.

2003 Canadian COPD Guidelines

Effects of Inhaled Steroids:Long Term Placebo-Controlled Studies

Efficacy Variables

ISOLDE EUROSCOPE Copenhagen Lung Health Study

Primary:

FEV1 No effect No effect No effect No effect

Secondary:

Symptoms

Exacerb.

Q of L

MD visits

NR

25%

less NR

NR

NR

NR

NR

No effect

No effect

NR

NR

~dyspnea

NR

No effect

MD visits

Bronchial responsive-ness

NR NR NR Reduced

NR = not reported

Exacerbations Drive Morbidity and Mortality

1. Donaldson et al. Thorax 2002;57(10):847–522. Donaldson et al. ERJ 2003;22:931–936 3. Seemungal et al. Am J Respir Crit Care Med 1998;157:1418–1422 4. Groenewegen et al. Chest 2003;124(2):459–675. Soler-Cataluna, et al. Thorax 2005;60:925-931

COPD exacerbations lead to: Decline in lung function1

Increased symptoms

(breathlessness)2

Increased risk of hospitalisation4

Increased risk of mortality4,5

Worsening quality of life3

A downward spiral

The clinical course of COPD: consequences of exacerbations

Air trappingExpiratory flow limitation

Breathlessness

Inactivity

Poor health-related quality of life

Hyperinflation

Deconditioning

COPDCOPD

Disability Disease progression Death

Reduced exercise capacity

Exacerbations

Exacerbations

Increased mortality with exacerbationhospitalizations

Increased health resource

utilization and direct costs

Reduced health-relatedquality of life

Accelerateddeclinein FEV1

COPDCOPD

Natural History of COPDLu

ng F

unct

ion

Time (Years)

Exacerbation

Exacerbation

Exacerbation

Never smoked

Smoker

Fletcher C. Br Med J. 1977;1:1645-1648

Severe exacerbations and mortality in COPD

COPD (N=304, FEV1=46% pred.)

Exacerbations vs. Mortality (N=116)

No exacerb. (N=163)

1-2 exacerb. requiring hospital

admission (N=60)

3 exacerb. (N=36)

5 yrs

JJ Soler-Cataluna et al., Thorax 60:925, 2005

Soler-Cataluña et al. Thorax 2005;60:925

304 men with COPD classified according to number of exacerbations in first year

No exacerbations

2 exacerbations

3 exacerbations

p < 0.0001

p < 0.0002

p = 0.069

Prognosis after Exacerbations

6,748

102,876

73,876

13,276

5,366

51,578

42,117

10,385

1,178

3,193

16,277

11,012

Emergency visits

ICU management

Non-ICU hospitalization

Maintenance medications

Comparison of annual direct medical cost in different Severity of COPD patients (Chiang CH. VGH-Taipei, 2003)

Moderate (n= 54)

Severe (n= 54)

Very Severe (n= 54)

Acute Exacerbation Prevention

• ICS

• LABA

• Anti cholinergic

• Combination

Inhaled CorticosteroidsRegular use of high dose inhaled corticosteroids alone

should only be considered when patients with moderate to severe COPD have recurrence of acute

exacerbations.

The only evidence of a significant effect with inhaled corticosteroids is in reducing the rate of exacerbation

(Alsaeedi 2002).

(Level of Evidence: 1 A)Can Respir J 2003; 10(Suppl A): 11A-33A.

2003 Canadian COPD Guidelines

Relative Risk of Exacerbations in COPD Patients Treated With ICS: A Meta-analysis

0 0.5 1.0 1.5 2.0 2.5 3.0

Relative Risk

Reference

Vestbo et al. 1999

Bourbeau et al. 1998

Burge et al. 2000

Lung Health Study, 2000

Weir et al. 1999

Paggiaro et al. 1998

Overall

Alsaeedi et al. Am J Med. 2002;113:59-65

Overall relative risk = 0.7095% CI = 0.58 to 0.84

Favors ICS Favors Placebo

Overall relative risk = 0.7995% CI = 0.69 to 0.90

Relative Risk of Exacerbations in COPD Patients Treated With LABA: A Meta-analysis

0 0.5 1.0 1.5 2.0 2.5 3.0

Relative Risk

Reference

Wadbo et al. 2002

Van Noord et al. 2000

Chapman et al. 2002

Rossi et al. 2002

Dahl et al. 2001

Aalbers al. 2002

Overall

Sin et al JAMA 2003;290: 2301–2312

Favors LABA Favors Placebo

Salmeterol/fluticasone in COPDModerate/severe exacerbations

Placebo

SALM 50µg bd

FP 500µg bd

SALM/FP 50/500µg bd

* p<0.002 vs placebo# p=0.059 vs SALMBaseline: FEV1 <50% predicted

0

0.5

1.0E

xace

rbat

ion

rat

e

**

* #

Moderate/severe exacerbationsrequiring OCS

Calverley et al. Lancet 2003;361:449-456

Rate of severe exacerbationsvs placebo (%)

*p<0.05 vs placebo

–30

–20

–10

0

p=0.043 Symbicort vs formoterol*

5

*

–30

–20

–10

0

p=0.015 Symbicort vs formoterol

*p<0.05 vs placebo

Bud/Form BudesonideFormoterolBud/Form BudesonideFormoterol

Budesonide/formoterol (Bud/Form) in COPD

Rate of severe exacerbationsSzafranski Calverley

W Szafranksi et al., ERJ 2003;21:74-81

PM Calverley et al., ERJ 2003;22:912-919

ICS and LABAs improve symptoms and lung function via different mechanisms

Inflammation

Increased neutrophils andCD8+ lymphocytes

Elevated IL–8, TNF

Protease/anti-proteaseimbalance

Structural changes

Alveolar destruction

Collagen deposition

Glandular hypertrophy

Airway fibrosis

Symptoms

FEV1

Exacerbations

Inhaled corticosteroidsreduce

LABAs inhibit

Smooth muscle contraction

Increased cholinergic tone

Loss of elastic recoil

Sensory nerve activation

Airway constriction

Veterans Administration – Exacerbation Trial

Exacerbations/patient-year

0

0.4

0.8

1.2

Placebo Tiotropium

Exacerbation days/patient-year

0

5

10

15

20

Placebo Tiotropium

P=0.003 P<0.001

1.05 12.616.00.85

19% reduction21% reduction

Niewoehner et al. Ann Intern Med. 2005;143:317

Niewoehner et al. Ann Intern Med. 2005;143:317

Risk of a New Exacerbation

0.4

0.3

0.2

0.1

0.0

Pro

bab

ility

of

Exa

cerb

atio

n

0 30 60 90 120 150 180Study Days

20 %

Patients at risk, nTiotropium group 838 788 743 690 658 514Placebo 832 772 709 663 619 454

Placebo group

Tiotropium groupP=0.028

Effect of Current Drugs on Exacerbation Frequency of COPD

-50

-40

-20

-10

0

10

-30

-2

-17 -20

Per

cen

tag

e ch

ang

e(v

ersu

s p

lace

bo

)

-24 -25-28

Szafranski Brusasco TRISTAN Szafranski TRISTAN Brusasco

Formoterol Salmeterol Salmeterol Formoterol/budesonide

Salmeterol/Fluticasone

Tiotropium

COPD: Defining the Clinical Course and Implications of Therapeutic Interventions

• Changing the Clinical Course

– Prevent the PFT decline

• Smoking cessation

• pharmacotherapy

• Pulmonary rehabilitation

– Prevent of exacerbations

– Impact on survive

• Systemic co morbidity

COPD and Systemic Disorders

• COPD involves several systemic features, particularly in severe disease,

• Increased concentrations of inflammatory mediators, including TNF-, IL-6, and oxygen-derived free radicals, may mediate some of these systemic effects.

• There is an increase in the risk of cardiovascular diseases, which is correlated with an increase in C-reactive protein (CRP)21.

COPD and Systemic Disorders

• Data from the Netherlands show that up to 25% of the population 65 years and older suffer from two comorbid conditions and up to 17% have three.

• COPD and lung cancer. Whether this association is due to common risk factors (e.g., smoking), involvement of susceptibility genes, or impaired clearance of carcinogens is not clear.

COPD and Co-Morbidities

• COPD patients are at increased risk: • Myocardial infarction, angina

• Osteoporosis

• Respiratory infection

• Depression

• Diabetes

• COPD and lung cancer

New 0: At Risk I. Mild II. Moderate III. Severe IV. Very severe

Character-istics

•Chronic symptoms•Exposures to risk factors•Normal spirometry

•FEV1/FVC<70%•FEV1>80%•With or without symptoms

•FEV1/FVC<70%•50%>FEV1<80%•With or without symptoms

•FEV1/FVC<70%•30%>FEV1<50%•With or without symptoms

•FEV1/FVC<70%•FEV1<30% or presence of chronic respiratory failure or right heart failure

Avoidance of risk factor(s); influenza vaccination

Add short-acting bronchodilator when needed

Add regular treatment with one or more long-acting bronchodilatorsAdd rehabilitation

Add inhaled glucocorticosteroids if repeated exacerbations

Add long-term oxygen if chronic respiratory failureConsider surgical treatments

GOLD: COPD Pharmacotherapy

NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. April 2001 (Updated 2003).

"Mild" COPD – causes of death

0

10

20

30

40

50

COPD cardiovascular Lung carcinoma

other

[%]

EUROSCOP (n = 18/1277) LUNG HEALTH (n = 149/5887) Postma et al. (n = 22/81)

(n = number of deaths/total number)

25 % – 39 %

R. A. Pauwels et al., NEJM 1999; 340:1948–1953.; N. R. Anthonisen et al., JAMA 1994; 272:1497–1505;D. S. Postma et al., ARRD 1986; 134:276–280.

COPD and systemic inflammationMeta-analysis

COPD studies (n=14)

Markers of systemic

inflammation

WQ Gan et al., Thorax 59:574, 2004

CRP

COPD and myocardial infarctionPotential role of systemic inflammation

NHANES III survey

(n=6,629)

Cardiac infarction

injury score

spirometry

CRP

0

2

8

severe obstruct.

*

High CRP+severe obstruct.*

High CRP

6

4

*FEV1/FVC < 0.70, FEV1 < 50

% pred.

DD Sin & SFP Man, Circulation 107:1514, 2003

COPD and systemic inflammationInfluence of fluticasone on CRP

COPD (n=41, FEV1=55% pred.)

FP 500µg b.i.d

Pred. 30 mg/d

DD Sin et al., AJRCCM 170:760, 2004

ICS >>

placebo

FP 500µg b.i.d.

FP 1000µg b.i.d.

CRP

COPD and systemic inflammationInfluence of fluticasone on CRP

DD Sin et al., AJRCCM 170:760, 2004-80

-60

-40

-20

Ch

ang

e in

CR

P f

rom

ra

nd

om

izat

ion

[%

]-4 -2 0 2 4 6 8 10 12 14 16 18

weeks

Placebo

FP

Pred.

ICS>>

RC

T

FP 500µg b.i.d. FP 1000µg b.i.d.

Budesonide protects against cardio-ischaemic events in mild - moderate COPD [EUROSCOP]

COPD patients

Budesonide

400 µg bid(n=634)

Placebo(n=643)3 years

Cardio-ischaemicevents

Löfdahl et al., ERS 2005Ove

rall

Angina

pecto

ris

Myo

card

ial

infa

rctio

n

Coronar

y

arte

ry

disord

er

Myo

card

ial

isch

aem

ia

5

10

15

20

25

30

35[n]

Budesonide

Placebo

ICS and mortality in COPDPooled analysis of 7 trials

(N=5085)

DD Sin et al., Thorax 60:992, 2005

6,000 patients randomized: placebo, F, F/S and S for 3 years

Outcome = mortality

Vertical bars are standard errors

024681012141618

0 12 24 36 48 60 72 84 96 108 120 132 144 156Time to death (weeks)

Probability of death (%)

Placebo SFC

-17.5%

NNT = 39

Primary Analysis --- all-cause mortality at 3 years

Cause of Death on Treatment (adjudicated by CEC)

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

Cardio-vascular

Pulmonary Cancer Other Unknown

Death

s (%

)

Placebo SFC

age 40-50 50-55 55-60 60-70

age 40-50 50-55 55-60 60-70

84

COPD Comorbidities

Comorbid heterogeneity Common cause

Heart failure Lung cancer

Complicating Pneumonia

Coincidential Diabetes mellitus Arthritis hip/knee Depression

85

PATIENT – DISEASE ANOMALY

COPD – The Disease

• Airflow obstruction

• Function decline

• Continuous treatment

• Lifestyle

• Regular follow-up

• ‘Management plan’

• Compliance

• Effects, safety treatment

Patient with COPD

• Social isolation

• Unhealthy environment

• Poverty

• Poor self-efficacy

• Multiple health problems

• Disruptive life conditions

• Trust & support

• Safety line

What do we mean by ‘changing the course of the disease’?

Photos courtesy David Halpin MD