COPD Management - Utamahoshas.moh.gov.my/v4/attachments/article/68/CME-090409-COPD... · COPD Management Mohammed Fauzi Abdul ... •Epidemiology and pathophysiology ... Therapy at

COPD Management

Mohammed Fauzi Abdul RaniKulliyyah of MedicineInternational Islamic University MalaysiaKuantan, Pahang, Malaysia

Key Messages

Key Messages in 2008 Update

Key Message

Comorbidities Associated with COPD

Key Message

Key Message

COPD is Different from Asthma

Key Message

Identify Patients with Possible COPD

Key Message

Key Message

Assessing Disability in COPD

Comprehensive Management of COPD

Key Message

Smoking Cessation

Smoking Cessation – Physician’s Role

Key Message

Key Message

Vaccinations

Key Message

Optimal Pharmacotherapy

Key Message

Oral Corticosteroids

Key Message

Benefits of Pulmonary Rehabilitation

AECOPD: Prevention Strategies

AECOPD: Definition

AECOPD: Bronchodilators

AECOPD: Corticosteroids

AECOPD: Antibiotics

Key Message

End of Life Care in COPD

Reducing Mortality in COPD

Long Term Oxygen Therapy: Survival

Key Message

Classification by Impairment of Lung Function

COPD Diagnosis: Spirometry

COPD Classification by Symptoms and Disability

Classification of Disease Severity in COPD

Comprehensive Management of COPD

Comprehensive Management of COPD (Perceived Situation in Canada)

Bronchodilators: Summary of the Evidence

Bronchodilators: Summary of the Evidence

Bronchodilators: Summary of the

Evidence

Theophyllines: Summary of Evidence -

Pros

Theophyllines: Summary of Evidence -

Cons

Combination ICS/LABA: Summary of the

Evidence

Inhaled Corticosteroids

Inhaled Corticosteroids

Key Message

Time Course of AECOPD Recovery

AECOPD: Management

Pulmonary Rehabilitation

Pulmonary Rehabilitation

Who to Reefer to Pulmonary

Rehabilitation

Long Term Oxygen Therapy (LTOT): Sleep

Long Term Oxygen Therapy (LTOT):

Exercise and Dyspnea

Long Term Oxygen Therapy (LTOT):

Exercise and Dyspnea

AECOPD: Noninvasive Ventilation (NIV)

Lung Volume Reduction Surgery (LVRS)

Lung Volume Reduction Surgery (LVRS)

End of Life Care in COPD

•Epidemiology and pathophysiology

•Disease modification

•Review some earlier data

•Background and rationale of UPLIFT

•Results of GOLD stage

•First-line therapy for COPD

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

0

0.5

1.0

1.5

2.0

2.5

3.0

Proportion of 1965 Rate

0.0

0.5

1.0

1.5

2.0

2.5

3.0

1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998

–59% –64% –35% +163% –7%

CoronaryHeart

Disease

Stroke Other CVD COPD All OtherCauses

Source: NHLBI/NIH/DHHS

Ischemic heart disease

Cerebrovascular disease

Lower resp infection

Diarrheal disease

Perinatal disorders

COPDTuberculosis

Measles

Road traffic accidents

Lung cancer

Stomach Cancer

HIV

Suicide

6th

3rd

Murray & Lopez. Lancet 1997

Future Mortality Worldwide

1990 2020

Noxious particles

and gases

Lung inflammation

Host factors

COPD pathology

ProteinasesOxidative stress

Anti-proteinasesAnti-oxidants

Repair mechanisms

Pathogenesis of COPD

Smooth muscle

contraction

Increased

cholinergic tone

Bronchial

hyper-reactivity

Loss of elastic

recoil

Dynamic

hyper-inflation

Airflow

limitationSystemic

component

Structural

changes

Muco-ciliary

dysfunction

Airway

inflammation

Consequences of

Airflow Limitation

Dyspnea

Exercise

Tolerance

Consequences of Airflow Limitation in

COPD

Exacerbations

Airflow Limitation, Lung

Hyperinflation, Gas Trapping

Decline in

Lung

Function

Deterioration

in Health Status

Premature Mortality

Inactivity

Deconditioning

(a) Centrilobular (centriacinar) emphysema (b) Panacinar emphysema

(c) barium sulfate precipitation

Mortality comparisons across diseases

COPD Myocardial Infarction

3

50

35

69

0 20 40 60 80

No Shock

Shock

Moderate

Severe

%

Swedish Registry 2008, GUSTO-1 Trial 2007







Ability to modify the course of COPD

provides a compelling rationale for

early intervention

Stopped at 45

Stopped at 65

100

75

50

25

0

25 50 75

Death

Disability

Age (years)

Never smoked or

not susceptible

to smoke

Smoked regularly

and susceptible

to smoke

Decline of FEV1 with Age

and Smoking History

Fletcher C. BMJ 1977;1:1645-1648

Sustained smoking cessation modifies

the course of COPD

2.0

2.1

2.2

2.3

2.4

2.5

2.6

2.7

2.8

2.9

3.0

0 1 2 3 4 5 6 7 8 9 10 11Year of Follow-up

Me

an

FE

V1 (

Lit

ers

)

Sustained quitters

Intermittent quitters

Continuous smokers

Anthonisen et al. AJRCCM 2002; 166:675-9

30 ml/y

60 ml/y

Prevention of COPD Progression:

Smoking Cessation%

of

pati

en

ts w

ith

an

FE

V1

<60%

at

the e

nd

of

11 Y

ears

Smokers

Sustained quitters

Anthonisen et al. Am J Respir Crit Care Med. 2002;166:675-679 (A).

0

5

10

15

20

25

30

35

40

Schematic illustration of effects of an

intervention on disease progression

Time

Mark

er

of

Dis

ea

se S

tatu

s

Intervention

Time

Mark

er

of

Dis

ea

se S

tatu

s

Intervention

Time

Mark

er

of

Dis

ea

se S

tatu

s

Intervention

Time

Mark

er

of

Dis

ea

se S

tatu

s

Intervention

A B

C D

Halpin D & Tashkin DP. Respir Med 2009 (in press)

N=5887P

red

icte

d F

EV

1 (

%)

Annual Visits

Quitters

Smokers

1516

3804

1207

3264

1067

2864

972

2526

910

2298

Adapted from Anthonisen et al. JAMA.

1994;272:1497-1505.

NIH Lung Health Study: 1986-1994

82

80

78

76

74

72

BL 1 2 3 4 5

Schematic illustration of effects of an

intervention on disease progression

Time

Mark

er

of

Dis

ea

se S

tatu

s

Intervention

Time

Mark

er

of

Dis

ea

se S

tatu

s

Intervention

Time

Mark

er

of

Dis

ea

se S

tatu

s

Intervention

Time

Mark

er

of

Dis

ea

se S

tatu

s

Intervention

A B

C D

Halpin D & Tashkin DP. Respir Med 2009 (in press)

Can pharmacotherapy modify the

course of COPD?

Lung function

declineRate of change with age in

the post-bronchodilator

FEV1

ICS Alone Do Not Modify COPD Natural History

30

50

70

CCLS EUROSCOP ISOLDE LHS2

Placebo

ICS

As summarized by MacNee

and Calverley, Thorax

2003;58:261-5.

CCLS = Copenhagen City Lung Study

Lancet 1999;353:1819-23

EUROSCOPE = European Respiratory Society Study of COPD

N Engl J Med 1999;340:1948-53

ISOLDE = Inhaled Steroids in Obstructive Lung Disease

BMJ 2000;320:1297-1303.

LHS2 = Lung Health Study 2

N Engl J Med 2000;343:1902-9

Values represent

mean annual declines

in FEV1, ml

Lack of Effect of ICS on FEV1 Decline Soriano

et al. Chest 2007; 131:682-9

Data from 7

RCTs: LHS II

(1057)

CCLS (239)

ISOLDE (520)

EUROSCOP

(1029)

TRISTAN (515)

Szafranski (248)

Calverley 2 (303)

Total N = 3911

Adjusted means & rate of decline in post-BD FEV1 over 3

yrs for SFC, SAL, FP and Placebo treatment

Celli et al. AJRCCM 2008, 332-8

Random

coefficient

model

*p<0.003

Trough FEV1 Day 8–Day 344

Tro

ugh F

EV

1(L

)

* p= 0.005 tiotropium vs placebo (mean regression slopes)

0.9

1

1.1

1.2

8 344Day

Tiotropium (n = 518)

Placebo (n = 328)

1

-12.4 mL/year *

-58.0 mL/year

Anzueto, Tashkin & Kesten Pulm Pharm Ther 2005;18:75-81

Annual rate of change in patient-

centered outcomes

Decline in health status ( SGRQ total score)

in ISOLDE trial (fluticasone vs. placebo)

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

Means

calculated

from analyses

of covariance

Decline in health status ( SGRQ total score)

in ISOLDE trial (fluticasone vs. placebo)

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

Weighted

regressions

from random

coefficients

(mixed) model

adjusting for

differences in

no. of

observations

and for

baseline

covariates

(SGRQ score,

age, sex &

smoking

Change in SGRQ over 3 yrs for each treatment Calverley

et al. NEJM 2007; 356:775-89

No differences in

slope after 1 yr

Frequency of exacerbations and

exacerbation-related hospitalizations

Impact of Exacerbations of COPD

•Impair health-related quality of life

•Increase the risk of hospitalization

•Increase mortality risk

•? Contribute to the progression of COPD

AECB Reduction With ICS Is Seen in

Patients With More Severe COPD

P=.02.

Sin et al. JAMA. 2003;290:2301-2312.

Incr

easi

ng E

ffic

acy

of

Inh

ale

d C

ort

icost

eroid

s

Log

Rel

ati

ve

Ris

k o

f E

xace

rbati

on

0.0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

-0.7

-0.8

0.91.01.11.21.31.4 1.

5

1.61.71.81.92.02.12.22.32.4FEV1/L

Bourbeau

Paggiaro

Vestbo

Van der ValkBurge

Weir

Mortality

Mortality by Cause and Smoking Status:

Results of the LHS up to 14 Years

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

Rate

of

Death

per

1000

Pers

on

-Years

Cause of Death

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0CHD CVD Lung

Cancer

Other

Cancer

Respiratory

Disease

Other Unknown

Sustained quitters

Intermittent quitters

Continuing smokers

Probability of all-cause mortality

over 3 yrs: SFC vs placebo

Calverley et al. NEJM 2007; 356:775-89

Deaths231 (15.2%) Plac

193 (12.6%) SFC

875 Total

p=0.052

17.5%

RRR 2.6%

ARR

N needed to

treat to

prevent 1

death/3 yrs

= 39







Muscarinic (cholinergic) receptors

M1-receptors enhance

the cholinergic reflex

M2-receptors inhibit

acetylcholine release

M3-receptors mediate

bronchoconstriction and

mucus secretion

M4 and M5-receptors not

detected in the lung

FEV1 Improved With Long-Acting Anticholinergic

Bronchodilators Over 24 Hours

Tiotropium: Pulmonary Function – Day 42

(post-dose)

Tiotropium: Operating Lung Volumes

During Exercise

Reduction of Dynamic Hyperinflation With Tiotropium

Tiotropium: Exercise Endurance time

Dyspnoea Improves With

Long-Term Tiotropium Therapy

Health Related Quality of Life Improves With

Tiotropium vs Placebo, Ipratropium, or LABA

Exacerbation in COPD Patients

Decreased by Tiotropium

Reduction in Hospitalizations by Tiotropium

vs Placebo, Ipratropium, and LABA

IV: Very SevereIII: SevereII: ModerateI: 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

Active reduction of risk factor(s); influenza vaccination

Short-acting bronchodilator (when needed)

Add regular treatment with one or more long-acting bronchodilators

Add pulmonary rehabilitation

Add inhaled corticosteroid if repeated exacerbations

Add LTOT if chronic respiratory failure

Consider surgical treatments







Effect of Tiotropium on FEV1

Trough FEV1 Day 8–Day 344

Tro

ugh F

EV

1(L

)

* p= 0.005 tiotropium vs placebo (mean regression slopes)

0.9

1

1.1

1.2

8 344Day

Tiotropium (n = 518)

Placebo (n = 328)

1

-12.4 mL/year *

-58.0 mL/year

Anzueto, Tashkin & Kesten Pulm Pharm Ther 2005;18:75-81

UPLIFT® trial

(Understanding Potential Long-term Impacts on

Function with Tiotropium)

Tashkin DP et al. N Engl J Med 2008 Oct 9; 359:1543-1554

Hypothesis Underlying UPLIFT

Tiotropium modifies the natural course

of the disease in COPD

More specifically, it:

•improves lung function and reduces rate of decline

•improves health status and reduces rate of decline

•reduces exacerbations/hospitalizations

•reduces mortality

UPLIFT

Objective: Assess whether tiotropium 18 µg once daily is associated with a decrease in the rate of decline of FEV1

over time in patients with COPD

Design: Randomized, double-blind, placebo-controlled, parallel-group, multi-national study

Treatment duration: 4 years

Sample size: 5,993 patients (450 centers, 37 countries)

Treatment: Patients randomized 1:1 to receive:– tiotropium (18 µg) or

–placebo once daily

PLUS usual care – except inhaled anticholinergics

Planned Outcomes

Primary Endpoints:

• Rate of decline of FEV1 (trough and peak) over time in patients

with COPD (measured with standardized spirometry)

Secondary Endpoints:

• St. George’s Respiratory Questionnaire

• Exacerbations: mild (Rx at home); mod (visit with health care

provider, incl. ER); severe (hospitalization)

• Hospitalizations due to exacerbations

• Mortality (respiratory and all-cause)

Treatment period

4 years (48 month)

Study Design

Run in

2 weeks 30 days follow-up

Placebo qd

Tiotropium qd

Stop: Tiotropium qd

Start: Ipratropium qid

Spirometry

Screening

Spirometry

+ SGRQ

Spirometry Spirometry

+ SGRQ

Day 1

Randomization Day 30Every 6

months

Spirometry

+ SGRQ

4 years

End of trialEnd of

follow up

Spirometry

Vital status

Offer: 4-week smoking

cessation program

All previously prescribed respiratory

medications and adaptation to medical needs

(except inhaled anticholinergics)

Baseline Characteristics

Characteristic Tiotropium(n = 2986)

Control(n = 3006)

Male (%) 75 74

Age (yrs)* 65 ± 8 65 ± 9

Body Mass Index* 26 ± 5 26 ± 5

Smoking status

Current smoker (%) 29 30

Smoking history (pack-yrs)* 49 ± 28 48 ± 28

GOLD stage (II / III / IV) (%) 46 / 44 / 8 45 / 44 / 9

SGRQ total score (units)* 46 ± 17 46 ± 17

*Mean ± SD

Baseline Spirometry

Pre-Bronchodilator Post-Bronchodilator

Tiotropium(n = 2986)

Control(n = 3006)

Tiotropium(n = 2986)

Control(n = 3006)

FEV1 (L) 1.10 ± 0.40 1.09 ± 0.40 1.33 ± 0.44 1.32 ± 0.44

FEV1 (% predicted) 40 ± 12 39 ± 12 48 ± 13 47 ± 13

FVC (L) 2.63 ± 0.81 2.63 ± 0.83 3.09 ± 0.86 3.09 ± 0.90

FEV1/FVC 42 ± 11 42 ± 11 44 ± 11 43 ± 11

SVC 2.80 ± 0.82 2.80 ± 0.83 3.21 ± 0.88 3.20 ± 0.90

Mean ± SD







Baseline and On Treatment+ Respiratory

Medications

Medication (% of patients)

Tiotropium

(n = 2986)

Control

(n = 3006)

Baseline Baseline

Any respiratory medication 93 93

Short-acting anticholinergic 45 44

Short-acting beta-agonist 69 68

Long-acting beta-agonist* 60 60

Inhaled steroid* 62 62

Theophylline 23 23

Systemic steroids 8 8

Mucolytics 7 7

Leukotriene receptor antagonists 3 3

Supplemental O2 2 2

*Used alone or in combination

Baseline and On Treatment+ Respiratory

Medications

Medication (% of patients)

Tiotropium

(n = 2986)

Control

(n = 3006)

Baseline On Treatment + Baseline On Treatment +

Any respiratory medication 93 96 93 94

Short-acting anticholinergic 45 17 44 17

Short-acting beta-agonist 69 81 68 79

Long-acting beta-agonist* 60 72 60 72

Inhaled steroid* 62 74 62 74

Theophylline 23 35 23 35

Systemic steroids 8 53 8 55

Mucolytics 7 27 7 27

Leukotriene receptor antagonists 3 5 3 5

Supplemental O2 2 12 2 12

+ At any time during treatment

including short-term treatment of exacerbations


UPLIFT

Pulmonary Function

Pre- and Post-bronchodilator FEV1

Mean values at each time point

1.00

1.10

1.20

1.30

1.40

1.50

FE

V1 (

L)

Tiotropium Control

Day 30

(steady state)

0

6 12 18 24 30 36 42 480 1

Month

* * **

** * *

*

Pre-Bronch FEV1

= 87 – 103 mL

(n=2494)

(n=2363)

*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements.

Baseline trough FEV1 (observed mean) = 1.116 (trough), 1.347 (peak). Patients with ≥3 acceptable PFTs after day 30 were included in the analysis.

Pre- and Post-bronchodilator FEV1

Mean values at each time point

1.00

1.10

1.20

1.30

1.40

1.50

FE

V1 (

L)

Tiotropium Control

*

Day 30

(steady state)

**

**

**

**

0

6 12 18 24 30 36 42 480 1

Month

* * **

** * *

*

Post-Bronch FEV1

= 47 – 65 mL

Pre-Bronch FEV1

= 87 – 103 mL

(n=2516)

(n=2374)

(n=2494)

(n=2363)

*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements.

Baseline trough FEV1 (observed mean) = 1.116 (trough), 1.347 (peak). Patients with ≥3 acceptable PFTs after day 30 were included in the analysis.

Rate of Decline in FEV1

*Unadjusted p-value

Mean slope from day 30 until completion of double-blind treatment

Tiotropium (mL/yr) Control (mL/yr) ∆ Tio - Con 95% CI P-value*

n Mean (SE) n Mean (SE) Mean (SE)

Pre-bronch 2557 30 (1) 2413 30 (1) 0 (2) -4, 4 0.95

Post-bronch 2554 40 (1) 2410 42 (1) 2 (2) -6, 2 0.20

– treated set with ≥3 post-randomization measurements

Annual Decline in Post-Bronchodilator

FEV1 in Major Long-Term COPD Trials

Study (Duration)(order: year of

publication)

Current

smokers

Baseline

FEV1 %

predicted

Study drug

Annual decline in FEV1

(mL/year)

Study drugPlacebo

onlyPlacebo*+

EUROSCOP (3 years) 100% ~ 79% Budesonide 57 69 -

ISOLDE (3 years) 36 – 39% ~ 50% Fluticasone 50 59 -

LHS II (3.3 years) 90% ~ 68% Triamcinolone 44 47 -

BRONCUS (3 years) 41- 51% ~ 57% NAC 54 47 -

TORCH (3 years)

post hoc analysis43% ~ 48% S/F/SFC 42/42/39 55 -

UPLIFT (3 years) 30% ~ 47% Tiotropium 37 - 42

UPLIFT (4 years) 30% ~ 47% Tiotropium 40 - 42

* All respiratory medications permitted throughout the trial, other than inhaled anticholinergics

Tiotropium (mL/yr) Control (mL/yr) P-value

n Mean (SE) n Mean (SE)

Pre-bronch 789 33 (2) 767 38 (3) 0.085

Post-bronch 787 40 (3) 764 47 (3) 0.048

Mean slope from day 30 until completion of double-blind treatment

Rate of Decline in FEV1

No Baseline LABA or ICS

– treated set with ≥3 post-randomization measurements

Post-bronchodilator FEV1 ON (mL/yr) OFF (mL/yr)

Tiotropium (n=2557) 40 (2) 39 (3)

Control (n=2417) 40 (2) 49 (3)

P-value 0.93 0.008

Pre-bronchodilator FEV1 ON (mL/yr) OFF (mL/yr)

Tiotropium (n=2561) 29 (2) 33 (3)

Control (n=2422) 28 (2) 39 (3)

P-value 0.52 0.13

Advantage: Use all data points, results interpretable, off ICS/LABA patients

comparable to TORCH

Model of Slopes According to

Time On or Off ICS/LABA

GOLD Stage II Lung Function

Decline in FEV1 in various GOLD stages:The data from the placebo arms in long term trials

0

20

40

60

80

UPLIFT

stage II

49

69

47

EUROSCOP

LHSII

Stage I

UPLIFT IV

23

Stage IV

UPLIFT III

38

Stage III

De

clin

e in

FE

V1

(m

L / y

r)

47

ISOLDE (II-III)

TORCH (II:35%)

(III-IV: 65%)

5955

Stage II or II&III

BRONCUS

(II:75%)

E2

0

20

40

60

8069

47

EUROSCOP

LHSII

UPLIFT

stage II

49 47

ISOLDE (II-III)

TORCH (II:35%)

(III-IV: 65%)

5955

UPLIFT III UPLIFT IV

38

23

Stage I Stage II or II&III Stage IVStage III

De

clin

e in

FE

V1

(m

L / y

r)

~60ml/yr

~50 ml/yr

~40 ml/yr

~20 ml/yr

BRONCUS

(II:75%)

Decline in FEV1 in various GOLD stages:The data from the placebo arms in long term trials

E3

Improvement in FEV1 decline as a

function of severity of COPD

30

80

0

50

100

50 60 75

I

II

III

IV

FE

V1

(% p

red

icte

d)

Age (years)

Intervention at early stage

Intervention at advanced stage

Intervention at severe stage

GOLD Stage

E4

2027 Withdrew during screening

or failed to meet entry criteria

3254 GOLD Stage III/IV

424 Discontinued study med

• 235 Adverse event

• 117 Consent withdrawn

• 20 Protocol non-compliance

• 37 Lost to follow-up

• 15 Other

470 Discontinued study med

• 241 Adverse event

• 158 Consent withdrawn

• 31 Protocol non-compliance

• 27 Lost to follow-up

• 13 Other

2739 GOLD Stage II

Randomized

8020 Assessed for eligibility

885 Completed study960 Completed study

1384 received tiotropium 1355 received placebo

Disposition

Dropouts: Stage II ~31% 35%

All Stages 37% 44%

DemographicsCharacteristic Tiotropium

(n = 1384)

Control

(n = 1355)

Male (%) 72 72

Age (yrs) 65 ± 9 64 ± 9

FEV1 (Liters) Pre 1.36 ± 0.37 1.36 ± 0.35

Post 1.63 ± 0.37 1.64 ± 0.36

FEV1 (% predicted) Pre 49 ± 8 33* 49 ± 8 33

Post 59 ± 6 40 59 ± 6 40

Body Mass Index 27 ± 5 27 ± 5

Smoking status

Current smoker (%) 31 29 35 26

Smoking history

(pack-yrs)

48 ± 28 51 47 ± 27 49

Duration of COPD (yrs) 10 ± 8 9 ± 7

SGRQ total score (units) 42 ± 17 48 42 ± 17 48

LABA* (%) 56 60 55 60

ICS* (%) 59 62 57 62

Combination LABA/ICS (%) 45 44

Anticholinergics † (%) 39 45 38 44


† Includes short- or long-acting anticholinergics *Values in yellow refer to GOLD stage III

1.20

1.40

1.60

1.80

FE

V1 (

L)

Tiotropium Control

*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Estimated means are adjusted for

baseline measurements. Month 0 values are observed means. Patients with ≥3 acceptable PFTs after day 30 were

included in the analysis.

Tiotropium: Month 0 n = 1196, Month 48 n = 923; Control: Month 0 n = 1140, Month 48 n = 853

*

Day 30

(steady state)

** *

** *

**

0

6 12 18 24 30 36 42 480 1

Month

* * **

* * * **

Post-Bronch FEV1 Tio vs. control =

52 – 82 mL

Pre-Bronch FEV1 Tio vs. control =

100 – 119 mL

GOLD Stage IILung Function – FEV1

87-103 ml*

47-65 ml*

* Tio vs. control in GOLD II-IV

Marc Decramer et al

Lancet August 2009

*P<0.0001 vs. control

†P<0.05 vs. control

2.50

2.70

2.90

3.10

3.30

FV

C (

L)

Tiotropium Control

* * * * ** *

* *

Pre-Bronch FVC

= 170 - 204 mL

Post-Bronch FVC

= 32 - 65 mL

Day 30

(steady state)

0

6 12 18 24 30 36 42 480 1

Month

* **

** †

†

†

*n=2516

n=2374

n=2494

n=2363

Pre- and Post-bronchodilator FVCMean values at each time point – GOLD Stage II

Marc Decramer et al Lancet August 2009

Rate of decline in postbronchodilator FEV1 in relation to

disease severity and tiotropium treatment

P=0.08 for subgroup by treatment interaction

III IV

GOLD stage

0

10

20

30

40

50

60

II

Rate

of

declin

e i

n F

EV

1(m

L/y

ear)

n=1158

∆=6 (3)

P=0.02

Tiotropium Control

∆=0 (3)

P=0.87

∆=-9 (7)

P=0.24

n=1218 n=1031n=1104 n=194 n=185

Tashkin DP et al. UPLIFT Study Investigators. N Engl J Med 2008;359:1543-54

GOLD Stage Tiotropium (mL/yr) Control (mL/yr) ∆ Tio - Con P-value

n Mean (SE) n Mean (SE) Mean (SE)

II 1218 43 (2) 1158 49 (2) 6 (3) 0.02

III 1104 39 (2) 1031 38 (2) 0 (3) 0.87

IV 194 32 (5) 185 23 (5) -9 (7) 0.24

Post-bronchodilator FEV1

P-value for subgroup by treatment interaction = 0.07

Rate of Decline in FEV1 by

GOLD Stage

Marc Decramer et al Lancet August 2009

UPLIFT

SGRQ

SGRQ Total ScoreMean values at each time point

35

40

45

50

SG

RQ

To

tal

Sc

ore

(U

nit

s) Tiotropium (n = 2478) Control (n = 2337)

0

6 12 18 24 30 36 42 480

Month

* **

** *

**

Imp

rovem

en

t

SGRQ Total

Score

= 2.3 – 3.3 units

*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline

SGRQ Total Score (observed mean) = 45.028. Patients with ≥2 acceptable SGRQ Total Scores after month 6 were included in the analysis.

35

40

45

50

SG

RQ

To

tal S

co

re (

Un

its

)

Tiotropium Control

0

6 12 18 24 30 36 42 480

Month

**

** * * *

*

*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Estimated means are adjusted for baseline

measurements. Month 0 values are observed means. Patients with ≥2 acceptable SGRQ Total Scores after Month 6 were

included in the analysis. Tiotropium: Month 0 n = 1179, Month 48 n = 906; Control: Month 0 n = 1117, Month 48 n = 833

Difference: 2.9 – 3.9 units (p<0.001 at all time points)

SGRQ Total Score: GOLD Stage IIIm

pro

vem

en

t

Marc Decramer et al

Lancet August 2009

UPLIFT

Exacerbations

Probability of COPD Exacerbation

0

20

40

60

80

0 6 12 18 24 30 36 42 48

Pro

ba

bilit

y o

f e

xa

ce

rba

tio

n (

%)

Hazard ratio = 0.86,

(95% CI, 0.81, 0.91)

p < 0.0001 (log-rank test)

Month

Tiotropium Control

14% risk reduction

Time to 1st exacerbation, median months (95% CI)

by GOLD Stage

Tiotropium

n = 1384

Control

n = 1355Ratio (95% CI) P-value

GOLD II 23.1 (21.0, 26.3) 17.5 (15.9, 19.7) 0.82 (0.75, 0.90)* <0.0001*

GOLD III 13.2 (11.5, 14.6) 9.8 (8.8, 11.3) 0.87 (0.79, 0.95)* <0.0021*

*Hazard ratio (control vs. tiotropium) and p-value were estimated using Cox regression with treatment, GOLD stage, and

treatment by GOLD stage interaction as covariates.

Randomized patients taking ≥1 dose of study medication were included in the analysis.

# Exacerbations/pt yr (95% CI) by GOLD

Stage

Tiotropium

n = 1384

Control

n = 1355Ratio (95% CI) P-value

GOLD II 0.56 (0.52, 0.60) 0.70 (0.65, 0.75) 0.80 (0.72, 0.88)† <0.0001†

GOLD III 0.85 (0.80, 0.90) 0.97 (0.91, 1.03) 0.88 (0.80, 0.95)† <0.0025†


treatment by GOLD stage interaction as covariates. †Ratio (tiotropium/control) and p-value were estimated using the Poisson with Pearson overdispersion model adjusting for

treatment exposure.


Probability of COPD Exacerbation Leading to

Hospitalization

0

10

20

30

40

0 6 12 18 24 30 36 42 48

Pro

ba

bilit

y o

f e

xa

ce

rba

tio

n le

ad

ing

to h

os

pit

aliza

tio

n (

%)

Month

Hazard ratio = 0.86,

(95% CI, 0.78, 0.95)

p=0.002 (log-rank test)

Tiotropium Control

14% risk reduction

GOLD Stage II: Hospitalizations

Tiotropium

n = 1384

Control

n = 1355

Ratio (95% CI) P-value

Time to first

hospitalization (month)

NE NE 0.74 (0.62, 0.88)* <0.001*

# hospitalizations/pt yr

mean (95% CI)

0.08 (0.07, 0.09) 0.10 (0.08, 0.12) 0.80 (0.63, 1.03)† 0.082†

*Hazard ratio (control vs. tiotropium) and p-value were estimated using Cox regression with treatment, GOLD stage, and treatment by GOLD stage

interaction as covariates. †Ratio (tiotropium/control) and p-value were estimated using the Poisson with Pearson overdispersion model adjusting for treatment exposure.


UPLIFT

Mortality

Fatal Events: Definitions

•On-treatment

–1st to last day of treatment + 30 days

•Vital status (VS)

– 4 years follow-up (day 1440) – VS 95% complete

– 4 years + 30 days follow-up (day 1470) – VS 75%

complete

•Cause of death

– investigator

– mortality adjudication committee

Probability of Death from Any Cause

On-Treatment

Tiotropium

Control

0 6 12 24 30 36 42 4818

Hazard ratio = 0.84

95% CI: (0.73, 0.97)

P = 0.016 (log-rank test)

20

15

10

5

0

Pro

ba

bil

ity o

f d

ea

th f

rom

an

y c

au

se

[%

]

Months

Tiotropium

Control

0 6 12 24 30 36 42 4818

Hazard ratio = 0.87

95% CI: (0.76, 0.99)


20

15

10

5

0

Pro

ba

bil

ity o

f d

ea

th f

rom

an

y c

au

se

[%

]

Months

Probability of Death from Any CauseOn-Treatment + Vital Status – Day 1440

Tiotropium

Control

0 6 12 24 30 36 42 4818

Hazard ratio = 0.89

95% CI: (0.79, 1.02)


20

15

10

5

0

Pro

ba

bil

ity o

f d

ea

th f

rom

an

y c

au

se

[%

]

Months

Probability of Death from Any CauseOn-Treatment + Vital Status – Day 1470

GOLD Stage II: Mortality

Tiotropium

N (%)

Control

N (%)

Hazard Ratio*

(95% CI)

P-value*

Total treated

(GOLD Stage II)

1384 1355

On-treatment

All cause mortality 117 (8.5) 130 (9.6) 0.85 (0.66, 1.09)

0.84 (0.73, 0.97)

0.19

Including vital status (until day 1470)

All cause mortality 134 (9.7)

445 (14.9)

148 (10.9)

496 (16.5)

0.88 (0.69, 1.11)

0.89 (0.79, 1.02)

0.26

0.09


treatment by GOLD stage interaction as covariates. Observations were censored at 1470 days.

Copenhagen City Heart Study

Epidemiologic, prospective

study

started: 1976-1978; N= 14 223

mortality at 31/12/2000

On death certificates

Death: 51% of subjects

The rate of death was related to

Gold stages

Death of respiratory causes

stage 1: 7.7%

stage 2: 12.9%

stage 3: 28.2%

stage 4: 26.0%

Gold 1

Gold 3

Gold 2

Gold 4

Jensen HH. ERJ 2006

Mortality in various GOLD stagesThe Copenhagen City Heart Study

Epidemiologic, prospective

study

started: 1976-1978; N= 14 223

mortality at 31/12/2000

On death certificatesDeath: 51% of subjects

The rate of death was related to

Gold stages

Death of respiratory causes

stage 1: 7.7%

stage 2: 12.9%

stage 3: 28.2%

stage 4: 26.0%

Gold 1

Gold 3

Gold 2

Gold 4

Jensen HH. ERJ 2006

In the UPLIFT study, where almost half of the patients were of GOLD stage II, it is not an easy task to show a significant improvement in mortality

Copenhagen City Heart Study

Other Subgroup

Analyses

FEV1 decline within various subgroups

•No differences within subgroups

–Gender, smoking status, BMI

–Reversibility at baseline

–Use of anticholinergics at baseline

–Race, region

•Subgroup difference

–Not receiving LABA or ICS

–GOLD Stage II patients

–? Age

Conclusions

•No changes in the rate of decline in lung function

over 4 years with tiotropium but:

– maintenance of improved lung function and HRQoL over 4

years

– reduced risk of exacerbations & exacerbation-related

hospitalizations

– improved overall survival

Conclusions (continued)

•These benefits were at least equally apparent in

patients with moderate COPD as in those with more

severe disease

•In addition, the annual rate of decline in the post-

bronchodilator FEV1 was modestly but significantly

reduced in GOLD stage II patients.

•These findings provide a rational basis for earlier

treatment in patients with COPD.







IV: Very SevereIII: SevereII: ModerateI: 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

Active reduction of risk factor(s); influenza vaccination

Short-acting bronchodilator (when needed)

Add regular treatment with one or more long-acting bronchodilators

Add pulmonary rehabilitation

Add inhaled corticosteroid if repeated exacerbations

Add LTOT if chronic respiratory failure

Consider surgical treatments

Tiotropium is beneficial as early as GOLD stage II(bronchial obstruction, exacerbations, quality of life)

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