COPD Management - Utamahoshas.moh.gov.my/v4/attachments/article/68/CME-090409-COPD... · COPD...
Transcript of COPD Management - Utamahoshas.moh.gov.my/v4/attachments/article/68/CME-090409-COPD... · COPD...
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
•Epidemiology and pathophysiology
•Disease modification
•Review some earlier data
•Background and rationale of UPLIFT
•Results of GOLD stage
•First-line therapy for COPD
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
•Epidemiology and pathophysiology
•Disease modification
•Review some earlier data
•Background and rationale of UPLIFT
•Results of GOLD stage
•First-line therapy for COPD
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
•Epidemiology and pathophysiology
•Disease modification
•Review some earlier data
•Background and rationale of UPLIFT
•Results of GOLD stage
•First-line therapy for COPD
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
•Epidemiology and pathophysiology
•Disease modification
•Review some earlier data
•Background and rationale of UPLIFT
•Results of GOLD stage
•First-line therapy for COPD
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
*Used alone or in combination
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
*Used alone or in combination
† 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†
*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.
Randomized patients taking ≥1 dose of study medication were included in the analysis.
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.
Randomized patients taking ≥1 dose of study medication were included in the analysis.
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)
P = 0.034 (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
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)
P = 0.086 (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
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
*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. 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.
•Epidemiology and pathophysiology
•Disease modification
•Review some earlier data
•Background and rationale of UPLIFT
•Results of GOLD stage
•First-line therapy for 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)