Transcript Document

CTS: Clinical Assessment of COPD
Questions to ask:
 Do you cough regularly?
 Do you cough up phlegm regularly?
 Do even simple chores make you short of breath?
 Do you wheeze at night or when you exert yourself?
 Do you catch frequent colds that persist longer than most
other individuals’ around you?
Carry out spirometry testing
Treatment goals:
Smoking cessation
Vaccination to prevent exacerbations
Regular physical activity
Bronchodilator therapy
Adapted from Can Respir J January/February 2008;15(suppl A).
CTS: Potential Prevention Strategies for AECOPD
 Smoking cessation
 Vaccinations:
Influenza (annually)
Pneumococcal vaccine (every five to 10 years)
 Self-management education
 Regular therapy with ICS/LABA combination (for moderate to
severe COPD with ≥1 AECOPD on average per year)
 Oral corticosteroid therapy for AECOPD
 Pulmonary rehabilitation
Adapted from Can Respir J January/February 2008;15(suppl A).
CTS: Comprehensive Approach to
COPD/AECOPD Management
Surgery
Oxygen
Inhaled corticosteroids/LABA
Pulmonary rehabilitation
Long-acting bronchodilator(s)
PRN short-acting bronchodilator(s)
Smoking cessation/exercise/self-management/education
Lung function
impairment
Very severe
Mild
MRC dyspnea
scale
II
Early diagnosis
(spirometry) +
prevention
V
Prevent/Rx AECOPD
Adapted from Can Respir J January/February 2008;15(suppl A).
Follow-up
End-of-life care
CTS: Recommendations for Optimal COPD Therapy
Increasing Disability and Lung Function Impairment
Mild
Moderate
Infrequent AECOPD
(an average of
<1 per year)
SABA prn
persistent
disability
LAAC + SABA prn
or
LABA + SABD prn
LAAC or LABA + SABA prn
persistent disability
LAAC + LABA + SABA prn
Severe
Frequent AECOPD
(≥1 per year)
LAAC + ICS/LABA + SABA prn
persistent disability
LAAC + ICS/LABA + SABA prn
±
persistent disability
Theophylline
LAAC+ICS/LABA* +SABA prn
*Refers to the lower-dose ICS/LABA.
Adapted from Can Respir J January/February 2008;15(suppl A).
Clinical Differences Between Asthma and COPD
Asthma
COPD
Age of onset
Usually under 40 years
Usually over 40 years
Smoking history
Not casual
Usually >10 pack-years
Sputum production
Infrequent
Often
Allergies
Often
Infrequent
Disease course
Stable (with exacerbations)
Progressive worsening (with exacerbations)
Spirometry
Often normalizes
May improve but never normalizes
Clinical symptoms
Intermittent and variable
Persistent
Adapted from Can Respir J January/February 2008;15(suppl A).
MRC Dyspnea Scale
Grade
Description
1
Not troubled by breathlessness except with strenuous exercise
2
Troubled by shortness of breath when hurrying on the level or
walking up a slight hill
3
Walks slower than people of the same age on the level because
of breathlessness or has to stop for breath when walking at own
pace on the level
4
Stops for breath after walking about 90 m or after a few minutes
on the level
5
Too breathless to leave the house or breathless when dressing
or undressing
Adapted from Can Respir J January/February 2008;15(suppl A).
COPD Is Projected to Be the Third
Biggest Cause of Mortality by 2020
2020
1990
Ischaemic heart disease
1st
Ischemic heart disease
Cardiovascular disease
2nd
Cardiovascular disease
Lower respiratory infection
3rd
COPD
Diarrheal disease
4th
Lower respiratory infection
Perinatal disorders
5th
Lung cancer
COPD
6th
Road traffic accident
Tuberculosis
7th
Tuberculosis
Measles
8th
Stomach cancer
Road traffic accident
9th
10th
HIV
Lung cancer
Adapted from Murray CJ, Lopez AD. Lancet 1997;349:1498-504.
Suicide
Inflammation Plays a Central Role in the
Pathogenesis and Pathology of COPD
Cigarette smoke
(and other irritants)
Genetic susceptibility
Lung Inflammation
• Inflammatory cells
• Inflammatory mediators
• Oxidative stress
• Proteases
COPD pathology
Obstructive
bronchiolitis
Mucus
hypersecretion
Alveolar
wall destruction
Adapted from Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, 2006.
Available at http://www.goldcopd.com/
Amplification of Inflammation in COPD
Bacteria Viruses
Inflammation
++++
+++
++
 Inflammatory cells
 Cytokines
 Mediators
 Proteases
+
0
Non-smokers Normal smokers
Adapted from Barnes PJ. Personal Communication.
Mild COPD
Severe COPD
Exacerbation
Complementary Effect of ICS/LABA
on COPD Inflammation
CD8+ T-lymphocytes
0
–20
–40
–60
-44.67
(-90.9 to 1.6)
-53.4
(-96 to -9)
–80
-98.05
(-143.1 to -53.0)
–100
–120
–140
–160
20
10
0
-2.32
(-32.5 to 27.8)
–10
–20
-29.36
(-57.8 to -0.9)
-31.68
(-61.1 to -2.3)
–50
–60
–70
4
0.87
(3.9 to 5.6)
2
0
–2
-3.1
(-8.0 to 1.8)
–4
–6
-3.97
(-9 to 1.1)
–8
40
Treatment difference (95% CI)
Treatment difference (95% CI)
CD68+ macrophages
30
–40
6
–10
40
–30
Eosinophils
8
Treatment difference (95% CI)
Treatment difference (95% CI)
20
Neutrophils
30
20
18.21
(4.8 to 31.6)
10
0
-4.57
(-17.6 to 8.5)
–10
–20
-22.78
(-35.4 to -10.2)
–30
–40
SFC-FP
SFC-P
FP-P
SFC-FP
SFC-FP=salmeterol/fluticasone DPI vs. fluticasone DPI
SFC-P=salmeterol/fluticasone DPI vs. placebo; FP-P=fluticasone DPI vs. placebo
Adapted from Bourbeau et al. Thorax 2007;Epub.
SFC-P
FP-P
Exacerbations Drive Morbidity and Mortality
COPD exacerbations lead to:
Decline in lung function1
Increased symptoms
(breathlessness)2
Worsening health status3
Increased risk
of hospitalization4
4,5
Increased risk of mortality
1. Donaldson et al. Thorax 2002;57:847-52.
2 Donaldson et al. Eur Respir J 2003;22:931-6.
3. Seemungal et al. Am J Respir Crit Care Med 1998;157:1418-22.
4. Groenewegen et al. Chest 2003;124:459-67.
5. Soler-Cataluna et al. Thorax 2005;60:925-31.
Patients Under-report COPD Exacerbations
Unreported exacerbations
Reported exacerbations
Exacerbations (%)
100
80
40.1
49.5
60
40
20
59.9
50.5
0
Seemungal et al.1
(n=184)1
Wilkinson et al.2
(n=1099)2
1. Seemungal et al. Am J Respir Crit Care Med 1998;157:1418-22.
2. Wilkinson et al. Am J Respir Crit Care Med 2004;169:1298-303.
Pulmonary Function Testing: COPD
GOLD Guidelines
Adapted from GOLD (December 2007).
What do COPD patients with a history of
exacerbations want from their therapy?
Quicker symptom relief
55
Longer intervals between flare-ups
40
Fewer side effects
36
Better ability to cope with daily chores
27
Lower costs of treatment
27
Better doses
23
0
10
20
30
40
Patients (%)
Results from 1100 interviews in five EU countries and the USA
Adapted from Miravitlles et al. Respir Med 2007;101:453-60.
50
60
Frequent Exacerbations Lead to
Declining Lung Function
0.95
Frequent exacerbations
Infrequent exacerbations
FEV1 (l)
0.90
0.85
0.80
0.75
0
1
2
Time (years)
Frequent: >median 2.92 exacerbations/year
Infrequent: ≤median 2.92 exacerbations/year
FEV1: forced expiratory volume in 1 second
Adapted from Donaldson et al. Thorax 2002;57:847-52.
3
4
Increased Frequency of Exacerbations
Increases the Risk of Mortality in COPD
0 exacerbations
1–2 exacerbations
≥3 exacerbations
1.0
Survival probability
0.8
P<0.0002
0.6
P<0.0001
P=0.069
0.4
0.2
0
0
10
20
30
40
Time (months)
Adapted from Soler-Cataluna et al. Thorax 2005;60:925-31.
50
60
Prolonged Time to First Exacerbation
Bud/form
Formoterol
Budesonide
Placebo
Fraction of patients without an
exacerbation during the study
1.0
0.9
0.8
178 days
0.7
254 days
0.6
0.5
0.4
96 days
154 days
0.3
0
0
40
80
120
160
200
240
280
320
360
400
Time in study (days)
P<0.05 Busesonide/formoterol (bud/form) vs. all other groups (log-rank test)
Budesonide/formoterol prolonged time to first exacerbation by 100 days vs. LABA alone
Adapted from Calverley et al. Eur Respir J 2003;22:912-9.
Therapy at Each Stage of COPD
I: Mild
II: Moderate
III: Severe
IV: Very Severe
 FEV1/FVC < 70%
 FEV1/FVC <70%
 FEV1/FVC <70%
 FEV1 ≥80% predicted
 50% ≤FEV1 <80%
predicted
 FEV1/FVC <70%
 30% ≤FEV1 <50%
predicted
 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
FVC = forced vital capacity
Adapted from Global Initiative for Chronic Obstructive Lung Disease
(GOLD) Guidelines, 2006. Available from http://www.goldcopd.com/
oxygen if chronic
respiratory failure
Consider surgical
treatments
Improvements in Health Status by ICS/LABA
Combinations vs. Placebo
–8
–7
∆ Health status
–6
–5
Clinically
meaningful
improvement
–4
–3
–2
–1
0
Budesonide/
formoterol1
Budesonide/
formoterol2
Salmeterol/
fluticasone
DPI3
Salmeterol/
fluticasone
DPI4
*Measured by using the St. Georges Respiratory Questionnaire, a validated tool for measuring health status in COPD
1. Calverley et al. Eur Respir J 2003;22:912-9
2. Szafranski et al. Eur Respir J 2003;21:74-81.
3. Calverley et al. Lancet 2003;361:449-56.
4. Calverley et al. N Engl J Med 2007;356:775-89.
ICS/LABA Improves Hospitalization-free
Survival in a Cohort Study
Risk of rehospitalization or death vs.
reference patients (%)
ICS/LABA
ICS
LABA
0
–5
–10
-10%
–15
-16%
–20
–25
–30
–35
–40
–45
-41%
P<0.05 ICS/LABA vs. ICS or LABA
Retrospective cohort analysis of COPD-related rehospitalization or death within one year of first
hospitalization in 3636 COPD patients receiving ICS and/or LABA compared with 627 reference
patients receiving SABA alone
Adapted from Soriano et al. Am J Respir Med 2003;2:67-74.
ICS/LABA Improves Overall Survival
in a Cohort Study
Survival function estimate*
1.00
ICS/LABA
LABA
ICS
SABA
0.95
0.90
0.85
66% lower
relative risk for
all-cause
mortality
0.80
Hazard ratio: 0.34*
(95% CI, 0.21-0.56)
P<0.001
0.75
0.70
0
200
400
600
800
Survival (days)
*Adjusted
1000
for age, gender, ICS treatment, LABA treatment, ICS plus LABA treatment,
asthma diagnosis, measures of COPD severity at baseline, measures of asthma
severity at baseline, hospitalization for respiratory illnesses, and both inpatient and
outpatient Charlson–Deyo scores; n=1685
Adapted from Mapel et al. Respir Med 2006;100:595-609.
1200
Improved Survival with Budesonide +/– Formoterol
Compared to Bronchodilator Treatment Alone
Proportion of patients who died
0.10
Budesonide
Non-budesonide
0.08
Log-rank test: P=0.0365
Cox regression: hazard ratio, 0.564; P=0.0391
0.06
34/917
0.04
22/917
0.02
0
0
40
80
120
160
200
240
Time in study (days)
Adapted from Calverley et al. COPDV 2006.
280
320
360
400
Budesonide/formoterol: Maintained Improvement in
Lung Function vs. LABA Alone
Bud/form
Formoterol
Budesonide
Placebo
104
Mean FEV1 (% of baseline)
102
100
98
96
94
92
90
88
86
84
82
80
–0.5 0
1
2
3
4
5
6
7
8
Time from randomization (months)
P<0.001 Budesonide/formoterol (bud/form) vs. placebo and budesonide
P=0.002 Budesonide/formoterol vs. formoterol; P<0.001 formoterol vs. placebo
Calverley et al. Eur Respir J 2003;22:912-9.
9
10
11 12
Reduced Rate of Exacerbations Requiring
Medical Intervention vs. LABA Alone
+3%
0
3
–5
–10
–12%
–15
–20
–25
*
–30

2.1
2
1
0
–24%
Bud/form
Number needed to treat
Rate of exacerbations/patient/year
5
Budesonide/
formoterol vs.
formoterol
Budesonide Formoterol
Treating 100 patients with COPD (GOLD stage III–IV) with budesonide/formoterol
instead of formoterol alone may prevent 47 exacerbations in one year
*P<0.05 vs. placebo;
P=0.015 budesonide/formoterol (bud/form) vs. formoterol
Adapted from Calverley et al. Eur Respir J 2003;22:912-9.
Lower Health Status Predicts Mortality
Lower SGRQ total score (≤60)
Higher SGRQ total score (>60)
100
Survival (%)
75
P=0.0002
50
25
0
0
200
400
Observation time (days)
600
SGRQ=St. George’s Respiratory Questionnaire
Higher health status=SGRQ total score ≤60; lower health status=SGRQ total score >60
Adapted from Gudmundsson et al. Respir Res 2006;7:109.
800
Mortality Stratified by
Median Baseline SGRQ Total Score
Budesonide
Non-budesonide
Proportion of patients who died
0.10
0.08
SGRQ total score >50
0.06
0.04
SGRG total score >50
SGRQ total score ≤50
SGRQ total score ≤50
0.02
0
0
40
80
120
160
200
240
Time in study (days)
Stratified by SGRQ total score, median 50-unit cut-off
Adapted from Calverley et al. COPDV 2006.
280
320
360
400
Impact of Smoking Cessation
Programmes on Mortality
Proportion of patients with
no event
1.00
Special intervention group
Usual care group
0.95
0.90
15%
0.85
0.80
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
Time since LHS baseline (years)

All-cause 14.5-year survival from the Lung Health Study (LHS)
Adapted from Anthonisen et al. Ann Intern Med 2005;142:233-9.
COPD hospitalization-free survival
probability
ICS Improve Hospitalization-free Survival
in a Cohort Study
1.0
ICS
No ICS
0.9
Hazard ratio: 0.74
(95% CI, 0.71-0.78)
0.8
0.7
26% lower relative risk
for all-cause mortality
and repeat
hospitalization
0.6
0
0
2
4
6
8
10
Time after discharge (months)
Adapted from Sin et al. Am J Respir Crit Care Med 2001;164:580-4.
12
14
ISEEC Study: ICS Improve Survival
1.00
ICS
Placebo
27% lower
relative
risk for
All-cause
mortality
Survival probability
0.95
0.90
Hazard ratio: 0.73*
(95% CI, 0.55-0.96)
P=0.039
0.85
0.80
0
1
2
3
Follow-up (years)
ISEEC=Inhaled Steroids Effects Evaluation in COPD
*Stratified by individual trials and adjusted for age, gender, baseline post-bronchodilator
FEV1 (% predicted normal), baseline smoking status and body mass index; n=5085
Adapted from Sin et al. Thorax 2005;60:992-7.
4
EUROSCOP Study Design
Run-in
Randomization*
Treatment
Budesonide 400 µg b.i.d. (n=634)
Placebo (n=643)
Month
–6



0
12
24
36
Primary end point: change over time in FEV1
Patients: aged 30-65 years, current smokers (smoking history of
≥5 pack-years), FEV1 50-100% predicted normal, FEV1/VC <70%
*Patients who continued to smoke after two three-month smoking cessation programmes
and were ≥75% compliant with the recommended treatment regimens were randomized.
VC=vital capacity
Adapted from Pauwels et al. N Engl J Med 1999;340:1948-53.
TORCH: Further Evidence that ICS/LABA Can
Reduce Mortality in COPD
Run-in Randomization
Treatment
Follow-up
Salmeterol/fluticasone DPI 50/500 µg b.i.d.
Fluticasone DPI 500 µg b.i.d.
Salmeterol DPI 50 µg b.i.d.
Placebo
Salbutamol available as reliever medication to all patients
Month
–0.5
0

12
24
Primary end point: all-cause mortality over three years
Adapted from: Vestbo et al. Eur Respir J 2004;24:206-10.
Calverley et al. N Engl J Med 2007;356:775-89.
36 36.5
TORCH: All-cause Mortality at Three Years
Salmeterol/fluticasone DPI (12.6% mortality rate)
Placebo (15.2% mortality rate)
18
Probability of death (%)
16
14
12
HR 0.825, P=0.052
17.5% risk reduction
2.6% absolute reduction
10
8
6
4
2
0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
Time to death (weeks)
Number of patients alive:
Placebo
1524
Salmeterol/
fluticasone DPI 1533
1464
1399
1293
1487
1426
1339
Vertical bars represent standard errors
Adapted from Calverley et al. N Engl J Med 2007;356:775-89.
Health Related QOL Over 3 Years - TORCH
P<0.001 SAL/FP vs. Placebo over 3 years
P<0.001 SAL/FP vs. SAL over 3 years
P=0.017 SAL/FP vs. FP over 3 years
2
1
0
Improvement
Adjusted mean change in
SGRQ total score
3
-1
-2
-3
-4
-5
0
24
48
72
96
120
156
Week
Placebo
SAL
FP
Vertical bars represent standard errors
Adapted from Calverley et al. N Engl J Med 2007;356:775-89.
SAL/FP 500/50
Improvements in Post Bronchodilator FEV1
with SAL/FP 500/50 over 3 years - TORCH
P< 0.001 SAL/FP vs. Placebo over 3 years
P< 0.001 SAL/FP vs. SAL and FP over 3 years
Adjusted Mean Change FEV1 (mL)
100
Rate of
decline (mL /yr)
Placebo
SAL
FP
SAL/FP
500/50
-55
-42
-42
-39
P-value vs.
placebo
50
0.003 0.003
0
-50
-100
-150
0
24
Placebo
48
72
96
Time (Weeks)
SAL
FP
Adapted from Calverley et al. N Engl J Med 2007; 356: 775-89.
120
156
SAL/FP 500/50
<0.001
Rationale for TORCH: ICS with LABA
Probability of survival
1.0
Survival was significantly higher at
year 3 in patients receiving SAL/FP than in
the reference group
0.9
0.8
1045
0.7
SAL + FP
0.6
FP
SAL
Reference (no ICS or LABA)
3620
0
0
6
12
18
Follow-up (months)
SAL/FP=salmeterol/fluticasone
Adapted from Soriano et al. Eur Respir J 2002;20(4):819-25.
24
30
36