taem10: how to help copd patients feel better and

Apichart Khanichap MD.Department of Medicine, Faculty of Medicine, Thammasat University

www.themegallery.com

Definition of COPD

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.

COPD is a preventable and treatable disease with some

significant extrapulmonary effects that may contribute to the

severity in individual patients

GOLD 2008

Future trend of COPD:Development of mortality worldwide

Diseases 1990 Diseases 20201. Coronary disease 1. Coronary disease

2. Stroke 2. Stroke

3. Pneumonia 3. COPD

4. Diarrhea 4. Pneumonia

5. Infant mortality 5. Lung cancer

6. COPD 6. Traffic accident

7. TB 7. TB

8. Measles 8. Stomach cancer

9. Traffic accident 9. HIV/AIDS

10. Lung cancer 10. Suicide

Murray CJL, Lopez AD. Lancet. 1997;349;1269-76.

Prevalence of COPD: geographical variation

Global 3.9%1

Europe 4–6%2

United States 3.6%3,4

Latin America ~15% of adults over 40 years5

Asia Pacific 6.3%6

1. Murray et al. Science 1996. 2. European White Lung Book, 2003. 3. American Lung Association Report, 2005. 4. U.S Census Bureau. www.census.gov (accessed February 2006). 5. Hallal et al. Poster presented at ATS 2005. 6. Chan-Yeung et al. Int J Tuberc Lung Dis 2004.

Worldwide burden of COPD: Asia-Pacific

1. Ko FW et al. Int J Tuberc Lung Dis 2008; 12: 713–717.

Asia-Pacific study area

Ove

rall

pre

vale

nce

of

CO

PD

(%

)

0

2

4

6

8

10

12

Japan Hong Kong China Thailand Taiwan

Prevalence assessed using the International Classification of Disease

Prevalence assessed by community surveys utilising spirometry

• Relieve symptoms • Prevent disease progression• Improve exercise tolerance• Improve health status• Prevent and treat complications• Prevent and treat exacerbations• Reduce mortality• Prevent and minimize side effects from treatment

GOALS of COPD MANAGEMENTVARYING EMPHASIS WITH DIFFERING SEVERITY

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

Spencer et al. Thorax 2003

Health status changes following an exacerbation

3030

3535

4040

4545

5050

5555

6060

4 Weeks 12 Weeks 26 Weeks

6565

No Further No Further ExacerbationExacerbation

Baseline*

Further Further ExacerbationExacerbationWithin 6 Within 6 monthsmonthsS

GR

Q S

core

SG

RQ

Sco

re

*at presentation with acute exacerbation

Company name


Therapy at Each Stage of COPD*

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

FEV1/FVC < 0.7

FEV1 80% predicted

FEV1/FVC < 0.7

50% ≤ FEV1 < 80% predicted

FEV1/FVC < 0.7

30% ≤ FEV1 < 50% predicted

FEV1/FVC < 0.7

FEV1 <30% predicted or

FEV1 < 50% predicted plus chronic respiratory failure

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 failureConsider surgical treatments

* Postbronchodilator FEV1 is recommended for the diagnosis and assessment of severity of COPD GOLD 2008

COPD: a multi-component airway disease

Mucociliarydysfunction

Airwayinflammation

Airflowlimitation

Systemiccomponent

Structuralchanges

COPD is a Disease Characterised by Inflammation

Reproduced from The Lancet, Vol 364, Barnes PJ & Hansel TT, "Prospects for new drugs for chronic obstructive pulmonary disease", pp985-96. Copyright © 2004, with permission from Elsevier.

Cigarette Smoke

Epithelial Cells

CD8+ Tc Cell

Emphysema

Proteases

Mucus Hypersecretion

Macrophage/Dendritic Cell

NeutrophilMonocyte

Fibroblast

Obstructive Bronchiolitis

Fibrosis

Inflammation and Airway Destruction

Normal COPD

Reproduced from The Lancet, Vol 364, Hogg JC. "Pathophysiology of airflow limitation in chronic obstructive pulmonary disease", pp709-721. Copyright © 2004, with permission from Elsevier.

15

Volume of Airway Wall Tissue Correlates Significantly with Disease Progression

Hogg et al. New Engl J Med. 2004;350:2645-2653.Copyright © 2004 Massachusetts Medical Society. All rights reserved.

0 20 40 60 80 100 120

0.25

0.20

0.15

0.10

0.05

0

GOLDStage 4

FEV1

V:S

A (

mm

)

GOLDStage 3

GOLDStage 2

GOLDStages 0 and 1

Inflammation in COPD occurs even in the early stages

Hogg et al. N Engl J Med 2004

0

20

40

60

80

100

Neutrophils Macrophages Eosinophils CD4 cells CD8 cells

Air

wa

ys

wit

h m

ea

su

rab

le c

ell

s (

%)

GOLD Stage 0 GOLD Stage 1 GOLD Stage 2 & 3 GOLD Stage 4

Anti-inflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease

End of double-blind phase

= Sputum = Biopsy

Run-In Seretide 50/500μg bd

RandomisationScreen

Week:

Placebo bd

-4 0 4 8 12 13-1

*

* Any previous ICS/OCS withdrawal 4 weeks

Barnes et al. Am J Respir Crit Care Med 2006

Summary - absolute changes in biopsy endpoints

-500

-300

0

100

SA

LM

/FP

50/

500

– p

lace

bo

(ce

lls/m

m2 )

-100

-400

-200

CD8p=0.015 *

CD68p=0.255 *

TNF-p=0.003

Mast cellsp=0.083

IFN-p=0.026

*p-value has been adjusted for multiplicity(Data are median, 95% CI)

Ch

ang

e f

avo

urs

SA

LM

/FP

Ch

ang

e f

avo

urs

p

lac

ebo


Sputum: neutrophil differential count

* Adjusted for multiplicity (p=0.01 unadjusted)

0

74

76

78

80

82

84

86

Placebo (n = 60) Seretide (n = 51)

Sp

utu

m n

eutr

op

hil

dif

fere

nti

al c

ou

nts

(%

)

Baseline Week 13 Week 8 Baseline Week 13 Week 8

p = 0.04*



Adjusted mean changes from baseline in prebronchodilator FEV1

Barnes NC et al. AJRCCM 2006

00 1 2 3 4 5 6 7 8 9 10 11 12 13

Weeks

- 0.1

- 0.05

0

0.1

0.2

0.05

0.15

Adj

uste

d m

ean

chan

ge (

L)

Placebo

SALM/FP

*

* * *

* p < 0.001

173 ml

What do COPD patients die from?

Mannino. Respir Med 2006

0% 20% 40% 60% 80% 100%

GOLD 2/3/4

GOLD 1

No COPD

COPD ASCVD Lung Cancer Pneum/Inf Other

ASCVD=atherosclerotic cardiovascular disease

5.4 COPD deaths per 1,000 patient years



Effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in COPD

Placebo (n=39) Fluticasone (n=85)

Fluticasone/salmeterol (n=88)

P value

CRP (mg/L)

-0.145(-1.923 to 1.732)

-0.168(-1.385 to 0.691)

0.074 (-1.205 to 2.674)

0.537

IL-6 (pg/ml)

-0.2 (-1.3 to 0.5)

0.1(-0.6 to 0.9)

0.2(-0.5 to 1.1)

0.120

SP-D (ng/ml)

-1.9 (9.8 to 15.2)

-7.3(-22.8 to -1.1)

-12.3(-28.4 to 0.4)

0.002+*

+ p=0.016 comparison placebo and fluticasone* p= 0.002 comparison placebo and fluticasone/salmeterol

Sin DD, et al. Am J Respir Crit Care Med 2008;177:1207-1214

Circulating SP-D levels related to changes in FEV 1 in COPD

Sin DD, et al. Am J Respir Crit Care Med 2008;177:1207-1214

Circulating SP-D levels related to changes in health status scores in COPD

Change in circulating SPD in quintiles (median values in ng\ml for each quintile)

Test for trend p=0.002

Improved health status

Ch

ang

e in

to

tal S

GR

Q s

core

1

(-39.2)

2

(-19.6)

3

(-8.8)

4

(-1.1)

5

(17.9)4.0

2.0

0.0

-2.0

-4.0

-6.0

-8.0 Sin DD et al. Am J Respir Crit Care Med 2008;

177: 1207–1214.

Survival by lung function impairment

Years

121086420

Su

rviv

al1.0

0.9

0.8

0.7

0.6GOLD 3 or 4

GOLD 2

GOLD 0

Normal

Restricted

GOLD 1

Mannino et al. Respir Med 2006

Survival by respiratory symptoms

Mannino et al. Respir Med 2006

0 2 4 6 8 10 12

Follow up in years

Su

rviv

al

1.0

.9

.8

.7

.6

.5

Gold stage 3 or 4

No Symptoms

Symptoms

N Engl J Med 2004;350:1005

TOwards a Revolution in COPD Health – the TORCH trial

TORCH FEB 07

SFC 50/500 µg bd (N=1533)

TORCH: study design

SAL 50 µg bd (N=1521)

Placebo (N= 1524)3-year study duration

2 week run-in

FP 500 µg bd (N=1534)

Vestbo et al. Eur Respir J 2004; Calverley et al. NEJM 2007

TORCH FEB 07

SALM FP

All-cause mortality at 3 years

Vertical bars are standard errors

18

16

14

12

10

8

6

4

2

0

Time to death (weeks)

Probability of death (%)

1524153315211534

1464148714811487

1399142614171409

1293133913161288

Placebo SFC

Numberalive

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Calverley et al. NEJM 2007

TORCH FEB 07

Primary analysis: all-cause mortality at 3 years

Vertical bars are standard errors

15241533

14641487

13991426

12931339

Numberalive

0

2

4

6

8

10

12

14

16

18

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

Probability of death (%)

SFC 12.6%Placebo 15.2%

HR 0.825, p=0.05217.5% risk reduction

2.6% absolute reduction


TORCH FEB 07

Rate of moderate and severe exacerbations over three years

*p < 0.001 vs placebo; †p = 0.002 vs SALM; ‡p = 0.024 vs FP

Mean number of exacerbations/year

1.13

0.97*0.93*

0.85*†‡

25% reduction

0

0.2

0.4

0.6

0.8

1

1.2

Placebo SALM FP SFC

Treatment


TORCH FEB 07

SGRQ total score

–5

–4

–3

–2

–1

0

1

2

3

0 24 48 72 96 120 156

Adjusted mean change SGRQ total score (units)

Time (weeks)

Placebo

SALM*

FP†

*p = 0.057 vs placebo; †p < 0.001 vs placebo; ††p < 0.001 vs placebo, SALM and FP; vertical bars are standard errors

Number ofsubjects

1149114811551133

854906942941

781844848873

726807807814

675723751773

635701686731

569634629681

SFC††


AgeAge 40-50 40-50 50-55 50-55 55-60 55-60 60-7060-70

Courtesy of D. O’Donnell.Adapted from Fletcher CM, Peto R. BMJ 1977

FEV 1 (

%) R

elat

ive

to A

ge 2

5

Age (years)

Death

Disability

Symptoms

Not SusceptibleSusceptibleSmokers

Stopped smokingat 45 (mild COPD)

Stopped smokingat 65 (severe COPD)

30 40 50 60 70 80 900

20

40

60

80

20

100

1350

1300

1250

1200

1150

1100

SFC slows the rate of decline of lung function over 3 years (TORCH)

Celli BR et al. Am J Respir Crit Care Med 2008; 178: 332–338.

FE

V1 (

mL

)

0 24 48 72 96 120 156Weeks

-39 mL/yr

-42 mL/yr

-55 mL/yr

-42 mL/yr

PlaceboSALMFPSFC

SFC versus placebo: 16 ml/year, p<0.001Salmeterol versus placebo: 13 ml/year, p=0.003FP versus placebo: 13 ml/year, p=0.003

Age and rates of decline in FEV1

•Celli BR et al. Am J Respir Crit Care Med 2008; 178: 332–338

% Predicted FEV1 and rates of decline in FEV1

Rate of FEV1 decline (ml/yr)

•Celli BR et al. Am J Respir Crit Care Med 2008; 178: 332–338

Exacerbations occur even in patients with FEV1 ≥ 50% predicted

O’Reilly et al. COPD4 2004

Number of exacerbations vs. FEV1 % predicted

0

20

40

60

80

100

120

0 5 10 15 20 25

Number of exacerbations

FE

V1

% p

red

icte

d (

L)

<50% predicted

>=50% predicted

TORCH : Exacerbation rate(patients with FEV1> 50% pred)

Jone P. presented in APSR 2008

UPLIFT study design

1. Decramer M et al. J COPD 2004; 1: 303–312.

All study medications delivered via HandiHaler® device.*Patients permitted to use all previously prescribed respiratory medications. No restrictions for medications prescribed for exacerbations.

†Active smokers advised to discontinue smoking and offered a smoking cessation program.

37 countries, 475 investigational sites

Every 6 MonthsSpriometrySGRQReview Patient Diary

End of StudySpriometrySGRQReview Patient Diary

Tiotropium 18 mcg QD + concomitant respiratory medications*

Placebo QD + concomitant respiratory medications*

Ipratropium

30 days

4 years

R

Screening†

SpriometryRandomisationSpriometrySGRQ Review Patient Diary

Day 30SpriometrySGRQ

n = 5993

Study design: TORCH vs UPLIFTDesign TORCH UPLIFT

Patients (n) 6,112 5,993

Design – 3 years

– 6184 patients (four arms, twice-daily dosing)

– Salmeterol 50 mcg

– Fluticasone 500 mcg

– Fluticasone 500 mcg/salmeterol 50 mcg

– Placebo

– 4 years

– 5993 patients (two arms, once-daily dosing)

– TIO 18 mcg

– Placebo

Primary endpoint All-cause mortality (placebo vs SFC) Rate of lung function decline

SGRQ Score 49 ± 17 46 ± 17

Baseline & predicted post-bronchodilator FEV1

~44% ~47%

Concomitant medication – ICS: 0%

– LABA: 0%

– Long-term OCS: 0%

– Theophylline permitted

– ICS: ~75%

– LABA: ~70%

– Theophylline: ~35%

Withdrawals – SFC: 34%

– Placebo: 44%

– Analysis including withdrawals

– Tiotropium: 36%

– Placebo: 45%

– Analysis including withdrawals

1. Tashkin D. Am J Med 2006; 119: S63–72. 2. Calverley PMA et al. N Eng J Med 2007; 356: 775-789.

UPLIFT: endpoints

• Co-primary Endpoints

• Yearly rate of decline in the morning pre-dose FEV1 from day 30 (steady state) until completion of double-blind treatment

• Yearly rate of decline in post-bronchodilator FEV1 from day 30 until completion of double-blind treatment.

• Secondary Endpoints• Adverse events• Exacerbations• Hospitalisations due to exacerbations• Spirometric other than co-primaries• St George’s Respiratory Questionnaire• Mortality at 1470 days (all-cause and lower respiratory)

1. Tashkin DP et al. N Engl J Med 2008; 359: 1543–54.

Co-primary UPLIFT endpoint: yearly rate of decline in pre-dose FEV1

• Rate of decline in mean FEV1 before and after bronchodilation beginning on day 30


1.50

1.40

1.30

1.20

1.10

1.00

0.00

FE

V1

(litr

es)

01 6 12 18 24 30 36 42 48

MonthDay 30

* ** * * * * *

** * * * * * * * *

Tiotropium (n=2516)

Placebo (n=2374)

Tiotropium (n=2494)

Placebo (n=2363)

Before bronchodilation

After bronchodilation

p=0.95

p=0.21

CRM: Concomitant respiratory medication

UPLIFT: Post bronchodilator FEV1 decline (ITT population)

Placebo Tiotropium

p=0.21

1. Tashkin DP et al. N Engl J Med 2008; 359: (Online Suppl.).

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

F

EV

1 d

ecli

ne

(ml/

yr)

UPLIFT: rate of decline in health-related quality of life (SGRQ)


Imp

rove

me

nt

SG

RQ

To

tal S

core

(u

nit

s)

Placebo(n=2337)

Tiotropium(n=2478)

0

35

40

45

50

p=0.78

0 6 12 18 24 30 36 42 48

Month

CRM: Concomitant respiratory medication

HR 0.86(95%CI 0.81, 0.91)

14%14%

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Exacerbations

Nu

mb

er p

er y

ear

Placebo

Tiotropium

UPLIFT: COPD exacerbations

1. Tashkin DP et al. N Engl J Med 2008; 359: (Online Suppl.).

UPLIFT: all-cause mortality


Years

20

15

10

5

0

Pro

bab

ilit

y o

f d

eath

fro

m

any

cau

se (

%)

0 1 2 3 4

Hazard ratio, 0.89(95% Cl, 0.79-1.02)

Tiotropium

Placebo

p<0.09

Mortality at 1470 days: Predefined secondary analysis

UPLIFT and TORCH: Mortality

Tiotropium Placebo Hazard Ratio (HR)

N (%) N (%) HR 95% CI P-value

ITT 1470 days 446 (14.9) 495 (16.9) 0.89 0.79-1.02 0.086

ITT 1440 days 430 (14.4) 491 (16.3) 0.87 0.76-0.99 0.034

On-treatment 381 (12.8) 411 (13.7) 0.84 0.73-0.97 0.016

SFC Placebo Hazard Ratio (HR)

N (%) N (%) HR 95% CI P-value

Log-rank adjusted 193 (12.6) 231 (15.2) 0.825 0.68-1.00 0.052

Cox proportional 193 (10.3) 231 (12.6) 0.811 0.67-0.98 0.03

UPLIFT1

TORCH2

1. Tashkin DP et al. N Engl J Med 2008; 359: 1543–54. 2. Calverley PMA et al. N Engl J Med 2007; 356: 775–789

INSPIRE

Wedzicha JA, et al. AJRCCM 2008;177:19-26

2 week

Run-in

2-years treatment

Oral prednisolone 30mg/day +

inhaled salmeterol

50g b.d.

Tiotropium bromide 18g o.d. via Handihaler (n=665)

SFC 50/500g b.d. via Accuhaler (n=658)

A 2 year multicenter, randomized, double-blind, double

dummy controlled trial

Study design

Discontinued all existing

COPD maintenance medications



Rate of HCU exacerbations

All Cause Mortality

SFC 50/500 TIO 18

Number of deaths*

p-value

21 (3%) 38 (6%)

0.032

Hazard Ratio 95% CI p-value

SFC vs TIO 0.48 (0.27 to 0.85) 0.012

Time to death on treatment from Cox’s proportional hazards model**

* Includes all patients for whom mortality was known during the study

** Time to death on treatment excludes 7 deaths (3 SFC, 4 TIO) which occurred > 2 weeks after treatment cessation



Time to death on treatment in SFC and TIO

52% risk reductionp=0.012

All cause mortality


Pneumonia reported


*Includes events of pneumonia, lobar pneumonia and bronchopneumonia

COPD treatment: Overview

Tiotropium SFC

Reduces inflammation1,2 X

Reduces breathlessness1,2

Reduces exacerbations1,2

Slows the rate of decline in lung function1,2 X

Improves and sustains quality of life1,2

Potential to improve survival1,2

1. Calverley PMA et al. N Engl J Med 2007; 356: 775–789. 2. Wedzicha JA et al. Am J Crit Care Med 2008; 177: 19–26.

SFC treats symptoms and disease progression1

Conclusion COPD treatment paradigm has change from symptomatic to

prevention

Anti-inflammatory therapy with salmeterol/fluticasone

– Reduces exacerbation

– Maintains improvement in health status

– Slows loss of FEV1

– Reduces mortality

Salmeterol/fluticasone are also seen in milder patients

– Without frequent exacerbations

– FEV1 50-60% predicted (GOLD stage II)

taem10: how to help copd patients feel better and

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