can we offer copd patients better life?

Can We offer COPD Patients better life?

ครรชิ�ต ปิ�ยะเวชิว�ร ตน์�แผน์กโรคปิอดและเวชิบำ��บำ ดว�กฤต

รพ.พระมงก�ฎเกล �24 พ.ค . 51

หั วข้ อบำรรย�ย

• สถ�น์ก�รณ์�ข้อง COPD ใน์ปิ'จจ�บำ น์

• คว�มร) พ*+น์ฐ�น์เก-.ยวก บำ COPD

• ก�รด)แลร กษ�ผ) ปิ0วย COPD ที่-.ม-อ�ก�รก��เร�บำ

• ก�รด)แลผ) ปิ0วย COPD ข้ณ์ะปิกต�

• ก�รศึ3กษ�ข้น์�ดใหัญ่5ล5�ส�ดเก-.ยวก บำผ) ปิ0วย COPD

World’s Top Ten Killers: WHOWorld’s Top Ten Killers: WHO

6

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

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.

COPDCOPD3.7%3.7%

AsthmaAsthma 10%10%

Chiangmai INNER CITY Population COPD Prevalence 2004

( n=553/66,000)

Chaicharn Pothirat et al. Chiangmai Lung Health Study 2004Chaicharn Pothirat et al. Chiangmai Lung Health Study 2004

0%

Smokers11.2%11.2%

Non-smokers

0.55%

Pack-yearsPack-years and diseasesand diseases

0.00%

9.30%12.70%

23%

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

Chaicharn P et al. WAM 2004Chaicharn P et al. WAM 2004

0 5-15 15-30 30-70 pack-yrs

Chronic smokers of Chiang Daw elderly club

0/108 7/75 14/110 47/224

Chiang Daw COPD in population

The prevalence of COPD The prevalence of COPD among at risk among at risk smokerssmokers

2121//185185 ( (11.411.4%)%)


6.67%

3.98%

0.00%

1.00%

2.00%

3.00%

4.00%

5.00%

6.00%

7.00%

Female Male

OR=1.71OR=1.71(0.69-4.25)(0.69-4.25)

Mean pack-yrs 24.7 26.3

52.7

30.4

5.410.7

0

10

20

30

40

50

60

0 1-2/yr 3-4/yr >4 /yr


N=209N=209

Frequency of Hospitalized Exacerbation

during the past year

Healthcare Resource Burden1 yr hospitalization May 2003-2004(n=271 episodes)

M:F 44.6%:55.4%Age 70.33 + 9.33 yr

Cause of admission AECOPD 153 (56.5%) CAP 39(14.4%) Others 29(29.3%) LOSLOS 11.7 11.7++9.57 d 9.57 d MV useMV use 218/271(80.4%) 218/271(80.4%) MV duration 7.6(1-44) dDirect hospital cost(bill)(n265) 52,229.8 (1,122-352,500)

Universal coverage 149(55%) goverment insurance 91(33.6%)Dead /expected dead 71(26.2%)Dead /expected dead 71(26.2%)

Chaicharn Pothirat et al. Economic impact study of COPD2004

N 153 39LOS 10.25+8.6 16.92+13.14 0.004Hosp charge * 41217+ 39,385 94,884 + 87,315 0.004Dead 17.7 41.0 0.002

Healthcare Resource Burden

1 yr hospitalization study May2003-2004

AECOPD COPD pneumonia AECOPD COPD pneumonia p-valuep-value

* Cost-to-Charge ratio > 0.80* Cost-to-Charge ratio > 0.80

Chaicharn Pothirat et al. Economic impact study of COPD2004


• สถ�น์ก�รณ์�ข้อง COPD ใน์ปิ'จจ�บำ น์• คว�มร) พ*+น์ฐ�น์เก-.ยวก บำ COPD

• ก�รด)แลร กษ�ผ) ปิ0วย COPD ที่-.ม-อ�ก�รก��เร�บำ• ก�รด)แลผ) ปิ0วย COPD ข้ณ์ะปิกต�• ก�รศึ3กษ�ข้น์�ดใหัญ่5ล5�ส�ดเก-.ยวก บำผ) ปิ0วย COPD

Definition of COPD 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.

16

Risk Factors for COPD

NutritionNutrition

InfectionsInfections

Socio-economic Socio-economic statusstatus

Aging PopulationsAging Populations

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

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 55 (severe COPD)

30 40 50 60 70 80 900

20

40

60

80

20

100

Loss of connective tissue support results in dynamic

airway collapse

Mucus hyper-secretion

Increased mucus viscosity

Reduced mucociliary transport

Mucosal damage

Muco-ciliary Dysfunction

Pathophysiological features of COPD

Mucociliarydysfunction

Airwayinflammation

Systemiccomponent

Structuralchanges

Airflowlimitation

หัลอดลมข้องผ) ปิ0วยที่-.ไม5ใชิ5 COPD

หัลอดลมข้องผ) ปิ0วย COPD

Healthy H. influenzae

Mucociliary dysfunction

Increased numbers / activation:

NeutrophilsMacrophagesCD8+

Elevated: IL-8, TNF-α, LTB4

Protease/anti-protease imbalance

Mucosal edema

Airway Inflammation



Airwayinflammation

Systemiccomponent

Structuralchanges

Airflowlimitation


Airwayobstruction

Smooth muscle contraction

Increased cholinergic tone

Bronchial hyperreactivity?

Loss of elastic recoil

Normal COPD

Systemic Component



Airwayinflammation

Systemiccomponent

Structuralchanges

Airflowlimitation

Respiratory system

Target organs

Systemic inflammation

Cardiac risk factors* in COPD patients

*adjusted for age, sex, BMI, smoking status, race and comorbidity*adjusted for age, sex, BMI, smoking status, race and comorbidity(Data are mean +/- SEM)(Data are mean +/- SEM)

Sin D and Man P. Circulation 2003

33

44

55

66

77

Neutrophils (10Neutrophils (1033/µL)/µL)

400400

200200

250250

300300

350350

Platelets (10Platelets (1033/µL)/µL)

400400

250250

300300

350350

Fibrinogen (mg/dL)Fibrinogen (mg/dL)

2.52.5

00

0.50.5

11

1.51.5

22

CRP (mg/dL)CRP (mg/dL)

STAGE 3- 4STAGE 3- 4STAGE 2STAGE 2STAGE 1STAGE 1NORMALNORMALCOPD severityCOPD severity

COPD patientHealthy control

Skeletal muscle apoptosis in COPD

Agustí AGN et al. Eur Respir J 2000

Prevalence of osteoporosis in COPD

Bolton. Am J Respir Crit Care Med 2004

55

3111

32

49

48

13 2041

0%

20%

40%

60%

80%

100%

No bone loss Osteopenia Osteoporosis

FEV1<50% predn=46

FEV1>50% predn=35

Healthy subjectsn=38

Pe

rce

nta

ge

of s

ubj

ect

gro

up

Osteoporosis in COPD

55

32

12

32

50

47

50

13 18

4150

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

No bone loss Osteopenia Osteoporosis

Low BMIlow FFMI

n=16

Normal BMIlow FFMI

n=17

Normal BMINormal FFMI

n=44

Healthysubjects

n=38

Pe

rce

nta

ge

of s

ubj

ect

gro

up

Bolton. Am J Respir Crit Care Med 2004

32

GOLD: Definition of COPD Exacerbations

“An event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.”

NICE: Definition of COPD Exacerbations• An exacerbation is a sustained worsening of

the patient’s symptoms from his or her usual stable state that is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour. The change in these symptoms often necessitates a change in medication

Disease progress vs Exacerbation

Progression

Exacerbation

COPD: Progressive Disease อา

การ/

lu

ng

fu

ncti

on

ระยะเวลา

Normal daily activity

Acute exacerbation

Outcome of COPD exacerbations

Seneff et al. JAMA 1995Murata et al. Ann Emerg Med 1991

Adams et al. Chest 2000Patil et al. Arch Intern Med 2003

2.5%-10%2.5%-10%(within 5 days)(within 5 days)

Hospital mortalityHospital mortalityIn hospitalized In hospitalized

patientspatients

22%-32%22%-32%(within 14 days)(within 14 days)

Relapse (repeat ER visit)Relapse (repeat ER visit)In ER patientsIn ER patients

24%24%(within 1 year)(within 1 year)

Hospital mortalityHospital mortalityIn ICU patientsIn ICU patients

13%-33%13%-33%(within 14 days)(within 14 days)

Treatment failure rateTreatment failure rateIn outpatientsIn outpatients

Percent of patients

COPD Exacerbations

• 43% of patients hospitalized for a COPD exacerbation died within one year (USA)1

• The in-hospital mortality rate of patients with a COPD exacerbation was 11% (USA)

• 25% of men and 38% of women will die within one year after having an initial recognized MI2

• The in-hospital acute MI mortality rate was 9.4% in 1999 (USA)

Myocardial Infarction

Exacerbations: Outcomes

38

ก�รด)แลร กษ�ผ) ปิ0วย COPD ที่-.ม-อ�ก�รก��เร�บำ

ส�เหัต�ส��ค ญ่ที่-.ที่��ใหั ผ) ปิ0วย COPD ม-อ�ก�รก��เร�บำค*อก�รต�ดเชิ*+อใน์ที่�งเด�น์หั�ยใจและมลภ�วะที่�งอ�ก�ศึ แต5 ผ) ปิ0วยปิระม�ณ์หัน์3.งใน์ส�มตรวจไม5พบำส�เหัต�ข้องก�รที่-.ม- อ�ก�รก��เร�บำ (Evidence B)

ผ) ปิ0วย COPD ที่-.ม-อ�ก�รก��เร�บำและอ�ก�รหัร*ออ�ก�รแสดงเข้ �ได ก บำก�รต�ดเชิ*+อที่�งเด�น์หั�ยใจเชิ5น์เสมหัะข้ น์ เข้-ยว อ�จได ปิระโยชิน์�จ�กก�รร กษ�ด วยย�ปิฏิ�ชิ-วน์ะ

(Evidence B)

ส�เหัต�ที่-.ที่��ใหั ผ) ปิ0วย COPD ม-อ�ก�รก��เร�บำ

• ก�รต�ดเชิ*+อ:– Rhinoviruses (common

cold)– Influenza– Parainfluenza– Coronavirus– Adenovirus– Respiratory Syncitial virus– C. pneumoniae– H. influenza– S. pneumoniae– M. catarrhalis– Staph. Aureus– P. aeruginosa

• มลภ�วะที่�งอ�ก�ศึ:– Nitrogen dioxide– Particulates– Sulphur dioxide– Ozone

• 30% ไม5พบำส�เหัต�

ก�รว�น์�จฉั ยแยกโรค• Pneumonia• Pneumothorax• Heart failure• Pulmonary embolism• Upper airway obstruction• Aspiration• Pleural effusion

41


ย�ส)ดข้ย�ยหัลอดลมโดยเฉัพ�ะ inhaled

β2-agonists และก�รใหั steroids ชิน์�ดร บำปิระที่�น์ ม-ปิระโยชิน์�ใน์ก�รร กษ�ผ) ปิ0วย

COPD ที่-.ม-อ�ก�รก��เร�บำ(Evidence A)


ก�รใชิ เคร*.องชิ5วยหั�ยใจชิน์�ดไม5ต องใส5ที่5อชิ5วยหั�ยใจใน์ผ) ปิ0วยที่-.ม-อ�ก�รก��เร�บำ จะที่��ใหั respiratory acidosis ด-ข้3+น์,

pH ใน์เล*อดเพ�.มข้3+น์, ลดอ ตร�ก�รใส5ที่5อชิ5วยหั�ยใจ, ลดอ ตร�ก�รหั�ยใจ, ลดอ�ก�รเหัน์*.อย, ลดระยะเวล�ก�รอย)5ใน์โรงพย�บำ�ล, และอ ตร�ก�รเส-ยชิ-ว�ตลดลง

(Evidence A)

ก�รด)แลร กษ�เบำ*+องต น์ที่-.หั องฉั�กเฉั�น์• ปิระเม�น์คว�มร�น์แรง (อ�ก�ร , ABG, CXR)

• ใหั ก�รบำ��บำ ดด วยออกซิ�เจน์โดยใหั ระด บำ SpO2 อย)5ใน์ชิ5วง 90-94%

• ใหั ย�ส)ดข้ย�ยหัลอดลม– เพ�.มข้น์�ดและคว�มถ-.จ�กที่-.ผ) ปิ0วยเคยได ร บำ– ใหั β2-agonist ร5วมก บำ anticholinergics

• ใหั ย�สเต-ยรอยด�ชิน์�ดร บำปิระที่�น์หัร*อชิน์�ดฉั-ดเข้ �หัลอดเล*อดด��

• พ�จ�รณ์�ใชิ NIV• ปิระเม�น์ผ) ปิ0วยเปิ;น์ระยะ

ผ) ปิ0วยที่-.ควรร บำไว ร กษ�ใน์โรงพย�บำ�ล• ผ) ปิ0วยที่-.อ�ย�ม�ก• ผ) ปิ0วยที่-.อย)5บำ �น์ต�มล��พ งหัร*อก�รเด�น์ที่�งล��บำ�ก• ผ) ปิ0วยที่-.ม-โรคร5วมเชิ5น์ CAD, CRF, cirrhosis• ผ) ปิ0วยที่-.ม-อ�ก�รก��เร�บำบำ5อย• ผ) ปิ0วยที่-.ม-อ�ก�รร�น์แรง• ผ) ปิ0วยที่-.ม-ก�รร) ส3กต วเปิล-.ยน์แปิลง• ตรวจร5�งก�ยพบำอ�ก�รแสดงที่-.เก�ดข้3+น์ใหัม5เชิ5น์ cyanosis,

peripheral edema• ม-ก�รเต น์ข้องหั วใจผ�ดปิกต�ที่-.เก�ดข้3+น์ใหัม5• ไม5แน์5ใจใน์ก�รว�น์�จฉั ย• ผ) ปิ0วยที่-.ไม5ตอบำสน์องต5อก�รร กษ�เบำ*+องต น์

ผ) ปิ0วยร�ยใดที่-.ควรใส5เคร*.องชิ5วยหั�ยใจชิน์�ดผ5�น์ที่5อชิ5วยหั�ยใจ

• ผ) ปิ0วยหัย�ดหั�ยใจ• ผ) ปิ0วยที่-.ไม5ตอบำสน์องต5อก�รใชิ NIV• อ�ก�รหัอบำเหัน์*.อยม�ก , อ ตร�ก�รหั�ยใจ > 35,

abdominal paradox

• pH < 7.25 หัร*อ PaCO2 > 60 mmHg • ม-ระด บำออกซิ�เจน์ใน์เล*อดต�.�และไม5ตอบำสน์องต5อ

ก�รบำ��บำ ดด วยออกซิ�เจน์• ม-ภ�วะแที่รกซิ อน์อ*.น์ๆ

47

ก�รด)แลร กษ�ผ) ปิ0วย COPD ข้ณ์ะที่-.อ�ก�รคงที่-.

ก�รร กษ�ผ) ปิ0วย COPD พ�จ�รณ์�ต�มอ�ก�รเพ*.อใหั ผ) ปิ0วยม-ค�ณ์ภ�พชิ-ว�ตที่-.ด-

ก�รใหั ค��แน์ะน์��ผ) ปิ0วยรวมถ3งก�รใหั ค��ปิร3กษ�ใน์ก�รเล�กบำ�หัร-.เปิ;น์ส�.งส��ค ญ่ที่-.ส�ด (Evidence A)

ย งไม5ม-ย�ใดที่-.จะเปิล-.ยน์แปิลงก�รเส*.อมสมรรถภ�พปิอดข้องผ) ปิ0วยได ใน์ระยะย�ว (Evidence A). แต5ย�จะที่��ใหั ผ) ปิ0วยม-อ�ก�รลดลงรวมถ3งลดภ�วะแที่รกซิ อน์ต5�งๆจ�ก COPD ได

48

ย�ข้ย�ยหัลอดลมเปิ;น์ปิ'จจ ยหัล กใน์ก�รลดอ�ก�รข้องผ) ปิ0วย COPD (Evidence A). อ�จใหั ใน์เม*.อม-อ�ก�รหัร*อใหั แบำบำสม�.�เสมอข้3+น์ก บำผ) ปิ0วยแต5ละร�ย

ย�ข้ย�ยหัลอลมหัล กๆได แก5 ß2-agonists,

anticholinergics, และ methylxanthines อ�จใหั ชิน์�ดเด-ยวหัร*อหัล�ยชิน์�ด ร5วมก น์ (Evidence A).

ก�รใหั ย�ข้ย�ยหัลอดลมชิน์�ดออกฤที่ธิ์�>ย�วอย5�งสม�.�เสมอ จะ ได ผลก�รร กษ�ที่-.ด-และสะดวกกว5�ก�รใชิ ย�ข้ย�ยหัลอดลม ชิน์�ดออกฤที่ธิ์�>ส +น์ (Evidence A).

ก�รด)แลร กษ�ผ) ปิ0วย COPD ข้ณ์ะที่-.อ�ก�รคงที่-.ย�ข้ย�ยหัลอดลม

49

ก�รใหั ย�สเต-ยรอยด�ชิน์�ดส)ดร5วมก บำย�ข้ย�ยหัลอดลมม-ปิระโยชิน์�ใน์ผ) ปิ0วย COPD ที่-. FEV1 < 50% predicted (Stage III: Severe COPD หัร*อ Stage IV: Very Severe COPD) ที่-.ม-อ�ก�รก��เร�บำบำ5อย (Evidence A).

ก�รใหั ย�สเต-ยรอยด�ส)ดร5วมก บำ long acting β2-

agonist ชิน์�ดออกฤที่ธิ์�>ย�วที่-.อย)5ใน์หัลอดเด-ยวก น์ได ผลด-กว5�ก�รใหั ย�สองชิน์�ดแยกหัลอดก น์ (Evidence A).

ควรหัล-กเล-.ยงก�รใหั สเต-ยรอยด�ชิน์�ดร บำปิระที่�น์ใน์ระยะย�วเน์*.อง (Evidence A).

ก�รด)แลร กษ�ผ) ปิ0วย COPD ข้ณ์ะที่-.อ�ก�รคงที่-.ย�สเต-ยรอยด�ชิน์�ดส)ด

50

แน์ะน์��ใหั influenza ว คซิ-น์ใน์ผ) ปิ0วย COPD ที่�กร�ยเน์*.องจ�กส�ม�รถลดคว�มร�น์แรงข้องโรคได

(Evidence A)

แน์ะน์��ใหั Pneumococcal polysaccharide vaccine ใน์ผ) ปิ0วย COPD ที่-.ม-อ�ย�ต +งแต5 65 ปิ?ข้3+น์ไปิ หัร*อผ) ปิ0วย COPD ที่-.ม-อ�ย�น์ อยกว5� 65 ที่-.ม-ค5� FEV1 < 40% predicted (Evidence B)

ก�รด)แลร กษ�ผ) ปิ0วย COPD ข้ณ์ะที่-.อ�ก�รคงที่-.ว คซิ-น์

Influenza Vaccination in Thailand Phunsup Wongsurakiat et al. Economic Evaluation of Phunsup Wongsurakiat et al. Economic Evaluation of Influenza Vaccination in Thai COPD patients. J Med Influenza Vaccination in Thai COPD patients. J Med Assoc Thai 2003;86:497-508Assoc Thai 2003;86:497-508

• RCT, 125 COPD patients, 62 received RCT, 125 COPD patients, 62 received vaccination, 63 received placebo ( mild, vaccination, 63 received placebo ( mild, moderate, severe)moderate, severe)

• Influenza-related ARI was 27% in placebo and Influenza-related ARI was 27% in placebo and 6.4% in treatment group (RR=0.24, vaccination 6.4% in treatment group (RR=0.24, vaccination effectiveness=76%)effectiveness=76%)

• More effective in patients with severe More effective in patients with severe diseasedisease

• Cost effectiveness in all group of COPD patientsCost effectiveness in all group of COPD patients

52

Antibiotics: ใชิ เฉัพ�ะผ) ปิ0วย COPD ที่-.ม-อ�ก�รก��เร�บำจ�กก�รต�ดเชิ*+อ

Antioxidant agents: ก�รใหั n-acetylcysteine ไม5ลดคว�มถ-.ใน์ก�รก��เร�บำข้อง COPD ยกเว น์ใน์ผ) ปิ0วยที่-.ไม5ได ร บำย�สเต-ยรอยด�ชิน์�ดส)ด

Mucolytic agents, Antitussives, Vasodilators: ไม5แน์ะน์��ใหั ใน์ผ) ปิ0วยที่-.ม-อ�ก�รคงที่-.

ก�รด)แลร กษ�ผ) ปิ0วย COPD ข้ณ์ะที่-.อ�ก�รคงที่-.ย�อ*.น์ๆ

53

Rehabilitation: ผ) ปิ0วย COPD ที่�กร�ยได ปิระโยชิน์�จ�กก�รออกก��ล ง จะที่��ใหั ผ) ปิ0วยม-อ�ก�รน์ อยลงและค�ณ์ภ�พชิ-ว�ตโดยรวมด-ข้3+น์(Evidence A)

Oxygen Therapy: ก�รใหั ก�รบำ��บำ ดด วยออกซิ�เจน์ระยะย�ว (> 15 ชิ .วโมงต5อว น์) ใน์ผ) ปิ0วยที่-.ม-ข้ อบำ5งชิ-+ส�ม�รถลดอ ตร�ก�รเส-ยชิ-ว�ตได (Evidence A)

ก�รด)แลร กษ�ผ) ปิ0วย COPD ข้ณ์ะที่-.อ�ก�รคงที่-.ก�รร กษ�อ*.น์น์อกเหัน์*อจ�กก�รใชิ ย�

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 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

TOwards a Revolution in COPD Health-

the TORCH trial

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)

Calverley et al. NEJM 2007

Worldwide participation in TORCH

42 countries

TORCH: main objectives

• Primary objective

– The effect of SFC 50/500 μg vs placebo on all-cause mortality over 3 years in patients with moderate-to-severe COPD

• Secondary objectives

– The effect of SFC 50/500 μg on the rate of moderate and severe exacerbations

– The effect of SFC 50/500 μg on health status (SGRQ)

Calverley et al. NEJM 2007SGRQ = St. George’s Respiratory Questionnaire

Study population: inclusion criteria

• Established history of COPD (ERS definition)

• Aged 40–80 years inclusive

• Smoking history ≥ 10 pack years

• Reversibility < 10% in predicted FEV1

• FEV1 < 60% predicted (pre-bronchodilator)

• FEV1/FVC ratio ≤ 70%

• Able to use Diskus/AccuhalerERS = European Respiratory SocietyFVC = Forced Vital Capacity

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

Demographics

Age 65 (8)Males 76%Current smokers

43%Pack years 49 (27)% pred baseline FEV1 (post bronc) 44 (13)

% pred reversibility 3.7 (3.7)≥1 exacerbations in previous year 57%

ITT N=6112

Mean (sd)


Premature study drug discontinuation

SALM FP048

12162024283236404448

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

Probability of withdrawal (%)

Placebo

1524152115341533

Numberat risk

1141124012471296

1005109311121164

884986971

1042

Time to withdrawal from study medication (weeks)

SFC

Statistical comparisons: SALM/FP, SAL & FP vs placebo p < 0.001; SALM/FP vs SAL p = 0.048; SALM/FP vs FP p = 0.01Vertical bars are standard errors Calverley et al. NEJM 2007

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 in context

• What are the implications of the primary result?

– Statisticians agree that p < 0.05 is an arbitrary cut off and similar conclusions should be drawn from p values of 0.055 and 0.0451

• How does the reduction in mortality in TORCH compare with other studies?

– Smoking cessation in COPD2

– Non-invasive ventilation in respiratory failure3

– Statins in cardiovascular disease4

– ACE inhibitors in vascular disease5

1. Altman 1991; 2. Anthonisen et al. Ann Intern Med 2005 3. Peter et al. Crit Care Med 2002; 4. Wilt et al. Arch Intern Med 2004

5. Flather et al. Lancet 2000

Impact of smoking cessation programme on mortality

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

Anthonisen et al. Ann Intern Med 2005

1.00

0.95

0.90

0.85

0.80

Proportion of patients with no event

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Time since LHS baseline (years)

Special intervention group

Usual care group

15%15%

Effect of statins on all-cause mortality in patients with coronary heart disease

• Meta-analysis of 17 trials

• N = 40974

• Mean/median follow up 0.3–6.1 years

• Relative Risk Reduction = 16%

• Absolute Risk Reduction = 1.8%

Wilt et al. Arch Intern Med 2004

Effect of ACE inhibitors in patients with left-ventricular dysfunction

• Analysis of 2 trials: SOLVD treatment and prevention

• Enalapril compared with placebo

• N = 6797

• Mean follow up 39 months

• 22.5% deaths on ACE-I vs 24.8% placebo

• Odd ratio 0.87

• Absolute Risk Reduction = 2.3%Flather et al. Lancet 2000

Secondary and other efficacy endpoints

Efficacy endpoints

• Mortality benefits are important, but may be of less relevance if other endpoints are not met

• Key goals of COPD management include:

– Exacerbations

– Quality of Life

– Lung function

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


Rate of exacerbations requiring systemic corticosteroids over three

years

*p < 0.001 vs placebo; †p < 0.001 vs SALM; ‡p = 0.017 vs FP

0.64*0.52*


0.46*†‡

43% reduction0.80

0

0.2

0.4

0.6

0.8

1

1.2

Placebo SALM FP SFC

Treatment


Exacerbations requiring hospitalisation over three years

*p = 0.016 vs placebo; †p = 0.028 vs placebo


0.19

0.16* 0.170.16†

0

0.05

0.1

0.15

0.2

0.25

Placebo SALM FP SFC

Treatment

HO Pop Source Figure: 7.3.004

73

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††


Post-bronchodilator FEV1

Adjusted mean change FEV1 (mL)

0 24 48 72 96 120 156Time (weeks)

–150

–100

–50

0

50

100

Placebo SALM FP

**

*†

SFC

1524152115341533

1248131713461375

Number ofsubjects

1128121812301281

1049112711571180

979105410781139

906101210061073

819934908975

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

Summary of efficacy results

• SFC improved survival in COPD

• This was supported by

– Significantly fewer exacerbations compared with components or placebo

– Significantly fewer hospitalisations compared with placebo

– Significant improvements in health status superior to components and placebo

– Significant improvements in lung function superior to components and placebo

1. Calverley et al. NEJM 2007

2. Jones et al. Chest 2006

INSPIRE

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

Methods• Inclusion criteria

– Aged 40-80 years

– Smoking history of ≥10 pack-years

– Clinical history of COPD exacerbations

– Post bronchodilator FEV1 <50% predicted

– Reversibility to 400μg salbutamol ≤10% of predicted FEV1

– MMRC score ≥ 2

• Exclusion – Any respiratory disorders other than COPD

– Requirement for long-term oxygen therapy (≥ 12 hours/

day)

MMRC = Modified medical research council dyspnoea scale


2 week

Run-in

2-years treatment

Oral prednisolone 30mg/day +

inhaled salmeterol

50μg b.d.

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

SFC 50/500μg 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 Wedzicha JA, et al. AJRCCM 2008;177:19-

26

Outcome Measurements

•Primary efficacy endpoint– The rate of health care utilization (HCU)

exacerbations

•Secondary Endpoints– Health status (SGRQ)

– Post-dose FEV1

– Study withdrawal rate

– All cause mortality (efficacy & safety endpoint)


SGRQ = St. George’s Respiratory Questionnaire

Patient characteristics

Wedzicha JA, et al. AJRCCM 2008;177:19-26 * Baseline following treatment intensification period

Time to withdrawal on treatment in SFC and TIO

Cox Hazard Ratio 95% CI p-valueTIO vs SFC 1.29 (1.08 – 1.54) 0.005

Probability of withdrawal prior to wk 104 SFC 34.5% TIO 41.7%

Numberat Risk

0 13 26 39 52 65 78 91 104

0

4

8

12

16

20

24

28

32

36

40

44P

rob

abili

ty o

f w

ithd

raw

ing

(%)

Time to withdrawal (weeks)

Treatment

SFC 50/500

TIO 18

More subjects withdrew from the TIO arm


Rate of exacerbations (mean no./year)

VariableSFC

50/500(n=658)

TIO 18(n=665)

Rate Ratio (95% CI)

P value

HCU 1.28 1.32 0.97 (0.84 to

1.12)

0.656

Requiring oral corticosteroids

0.69 0.85 0.81 (0.67 to

0.99)

0.039

Requiring antibiotics

0.97 0.82 1.19 (1.02 to

1.38)

0.028

Wedzicha JA, et al. AJRCCM 2008;177:19-26HCU = Health care utilization

Quality of Life (Total SGRQ score over 2 years)


The total SGRQ was significantly lower in the SFC group compared with the tiotropium group, although this difference did not reach the minimum clinically importance difference


Health status: Total SGRQ score

SGRQ – number of patients (%) with a change from baseline ≥ 4 units

SFC(N=658)

TIO(N=665)

Odds ratio(SFC vs

TIO)

95% CI p-value

Week 32 211 (35%) 190 (30%)

1.24 1.01, 1.54

0.045

Week 56 194 (32%) 180 (29%)

1.29 1.04, 1.60

0.021

Week 80 198 (33%) 171 (27%)

1.34 1.08, 1.67

0.008

Week 104 193 (32%) 169 (27%)

1.29 1.04, 1.60

0.021


The proportion of patients achieving a clinically significant improvement

in SGRQ was greater in the SFC group than in the Tio group


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

Numberat Risk

0 13 26 39 52 65 78 91 104

0

1

2

3

4

5

6

7

Pro

bab

ility

of

deat

h (%

)

Time to death (Weeks)

Treatment

SFC

TIO

52% risk reductionp=0.012


Hazard Ratio 95% CI p-value

SFC vs TIO 0.48 (0.27, 0.85) 0.012

Summary of events associated with death*, n (%)

Events (grouped by body system)

SFC 50/500 (n = 658)

TIO 18 (n = 665)

Cardiac disorders

Respiratory, thoracic and mediastinal

disorders

Neoplasms benign, malignant and

unspecified

General disorders & administration site

conditions

Infections and infestations

Nervous system disorders

Vascular disorders

Gastrointestinal disorders

Hepatobiliary disorders

9 (1)

5 (<1)

2 (<1)

5 (<1)

4 (<1)

1 (<1)

2 (<1)

0

1 (<1)

19 (3)

6 (<1)

7 (1)

2 (<1)

0

2 (<1)

0

1 (<1)

0Wedzicha JA, et al. AJRCCM 2008;177:19-26* Deaths can be associated with more than one adverse event

Top 5 most commonly reported AEs that began during

treatment, n (%) SFC 50/500

(n = 658)

TIO 18

(n = 665)

All events

COPD

Nasopharyngitis

Headache

Pneumonia*

Pharyngolaryngeal pain

435 (66)

122 (19)

115 (17)

48 (7)

50 (8)

34 (5)

414 (62)

104 (16)

98 (15)

60 (9)

24 (4)

26 (4)

*Includes events of pneumonia, lobar pneumonia and bronchopneumonia


Pneumonia

• The diagnosis of pneumonia was based on

clinical judgement, with radiologic confirmation

not necessarily obtained even in episodes

reported as lobar or bronchopneumonia

• The number of reported pneumonias that

overlapped with an exacerbation treated with

antiobiotics was

– 55% in the SFC group

– 48% in the TIO group


The other episodes were not given antibiotic treatment despite the report of pneumonia

Overall Study Conclusions• INSPIRE is the first large-scale trial to evaluate the impact

of two different treatment approaches-bronchodilation with

a long-acting inhaled anticholinergic agent or the

combination of bronchodilation using an LABA and

antiinflammatory therapy with an ICS-on COPD

eaxcerbations over 2-year period

• We found We found no differences in the overall rate of no differences in the overall rate of

exacerbationsexacerbations between treatment group between treatment group

• SFC treatment was associated with better health status,

fewer patient withdrawals, and a lower mortality rate than

occurred during tiotropium therapyWedzicha JA, et al. AJRCCM 2008;177:19-26

Summary

• COPD เปิ;น์โรคที่-.ย งไม5ม-ย�ใดๆร กษ�ใหั หั�ยข้�ดหัร*อชิะลอก�รด��เน์�น์ข้องโรคได น์อกจ�กก�รเล�กบำ�หัร-.

• ก�รร กษ�ปิระกอบำไปิด วยก�รใหั คว�มร) แก5ผ) ปิ0วย ก�รใหั ย� ว คซิ-น์และก�รบำ��บำ ดต5�งๆ

• ก�รก��เร�บำข้องโรคที่��ใหั ค�ณ์ภ�พชิ-ว�ตแย5ลง สมรรถภ�พปิอดลดลงและอ�ย�ข้ ยข้องผ) ปิ0วยส +น์ลง

• ก�รใหั long acting β2-agonist ร5วมก บำย�สเต-ยรอยด�ชิน์�ดส)ดส�ม�รถลดอ�ก�ร ลดก�รก��เร�บำ ลดก�รเส*.อมข้องสมรรถภ�พปิอด และอ�จก�รเส-ยชิ-ว�ตข้องผ) ปิ0วย COPD ได

can we offer copd patients better life?

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