Transcript 1-21 Amherst - copd disease mgmt and case

Nashat H. Rabadi,MD FCCP
Pulmonary and Critical Care Medicine
Buffalo Medical Group PC
Associate Clinical Professor
State University of New York at Buffalo
Chief of Pulmonary and Critical Care Medicine
Sisters of Charity Hospital
Impact of COPD in the US
• Affects ~20 million Americans1
• Annual cost $32.1 billion in 20022
– $18 billion in direct healthcare costs
– $14.1 billion in indirect morbidity and mortality
costs
• The fourth leading cause of death3
– 118,744 deaths in 2001
1. Mannino et al. MMWR. 2002;51(SS-6):1-16.
2. Morbidity & Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Diseases. NHLBI, NIH; May 2002.
3. Arias et al. Natl Vital Stat Rep. 2003;52(3):1-116.
COPD vs Asthma:
Direct Cost
$18.0 Billion
$9.4 Billion
$20
Nursing Home Care*
Home Health Care*
Physician Services
Hospital Care
Presciption Drugs
Direct Cost (Billions)
$18
$16
$14
$12
$2.7
$0.8
$3.4
$10
$8
$7.3
$6
$2.6
$3.1
$4
$2
$3.7
$3.7
$0
COPD
Asthma
* No estimate available for asthma.
† Physicians, clinics, and other professional services.
Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Diseases. NIH, NHLBI. May 2002.
†
Leading Causes of Deaths in U.S.,
1998
1.
2.
3.
4.
5.
Heart Disease
Cancer
CVA
COPD
Accidents
724,269
538,937
158,060
114,381
94,828
COPD Deaths: 124,181 (1999), 45.8 deaths/100,000
NHLBI, Morbidity and Mortality Chartbook, 2000
Audience Response System
Question #1
The typical demographic of the COPD patient is male gender
and older than 65 years of age.
1. True
2. False
Percent Change in Adjusted Death Rates,
United States, 1965-1998
Proportion of 1965 rate
3.0
2.5
Coronary
Heart
Disease
Stroke
Other CVD
COPD
All Other
Causes
–59%
–64%
–35%
+163%
–7%
1965-1998
1965-1998
1965-1998
2.0
1.5
1.0
0.5
0
1965-1998
1965-1998
Global Obstructive Lung Disease (GOLD) Initiative Web site. Available at: www.goldcopd.com. Accessed April 2, 2001.
Prevalence of COPD in the US
90
Rate/1,000 Population*
80
†
†
70
†
†
† †
†
†
†
†
†
†
†
†
†
60
• Since 1987, the
prevalence of COPD
among women has
been significantly
higher than that among
men
50
40
30
Male
Female
Total
20
10
0
1980
1982 1984
1986
• The number of patients
with COPD has
increased nearly 50%
from 1980 to 2000
1988 1990
1992
1994 1996
1998
2000
Year
* Age-adjusted to 2000 US population.
† Represents a statistically significant difference from rate among males.
Mannino et al. MMWR. 2002;51(SS-6):1-16.
Physician Specialty Seen Most Often
Other Not Sure
5%
Cardiologist 2%
3%
Allergist
1%
Respiratory
Specialist
22%
General/Family
52%
Internal Medicine
15%
“COPD in America” survey conducted by Schulman, Ronca, and Bucuvalas, Inc. Feb 2001.
Spectrum of Disease
Chronic
Bronchitis
Emphysema
COPD
Mixed Disease
Asthma
History of COPD Guidelines
Definition of COPD: GOLD 2003
•
•
Clinical syndrome with symptoms including
–
–
–
–
Intermittent or persistent cough
Sputum production
Persistent and/or progressive dyspnea
History of exposure to risk factors for COPD
(smoking tobacco)
Disease state characterized by airflow
limitation that is not fully reversible
– Usually progressive
– Usually associated with an abnormal inflammatory
response of the lungs to noxious particles or gases
GOLD=Global Initiative for Chronic Obstructive Lung Disease.
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at:
www.goldcopd.com/revised.pdf.
2004 ATS/ERS Definition of COPD
Risk Factors for COPD
•
Host factors
•
Environmental factors
– Genetic (eg, -1 antitrypsin deficiency)
– Airway hyperresponsiveness
– Lung growth
– Tobacco smoke
– Occupational dusts and chemicals
– Air pollution (outdoor and indoor)
– Infections
– Socioeconomic status
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003.
Available at: www.goldcopd.com/revised.pdf.
COPD Risk: Smoking
•
•
Primary risk factor for COPD
•
•
•
Greater annual rate of decline in FEV1
Higher prevalence of respiratory symptoms and
lung function abnormalities
Greater COPD mortality rate than nonsmokers
Differences between cigarette smokers and
nonsmokers increase in direct proportion to the
quantity of smoking
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at:
www.goldcopd.com/revised.pdf.
COPD Affects a Wide Range of Patients
It’s Not Just A Disease Of the Elderly
Data from the third National Health and Nutrition Examination Survey
(NHANES III) : 70% of patients with COPD are younger than age of 65
Differential Diagnosis of COPD
COPD must be distinguished from the following :
• Asthma
• Acute bronchitis
• Congestive heart failure
• Bronchiectasis
• Tuberculosis
• Obliterative bronchitis
CXR Changes Occur Very Late
in the Course of COPD
CT Scan of Emphysema
Measurement of Airway Obstruction:
Spirometry
• Simple to measure
• Reproducible
• On average reflects functional status
•
and prognosis
For years has been the gold standard used by
the FDA and scientific community to assess
outcome
Measurement of Forced Vital Capacity
(FVC)
7
FVC = 5.8 L
6
5
Liters
(BTPS)
4
3
2
1
0
0
1
2
3
Seconds
4
5
6
Measurement of Forced Expiratory
Volume (FEV1 )
7
6
FEV1 = 4 L
5
Liters
(BTPS)
4
3
2
1
0
0
1
2
3
Seconds
4
5
6
FEV1: Prognostic Implications
100
90
Survival
(%) 80
70
FEV1
Healthy Smoker
 50%
40%-49%
30%-39%
< 30%
60
1
Years
2
Anthonisen NR et al. Am Rev Respir Dis. 1986;133:14-20.
3
COPD Risk and Smoking Cessation
100
Never smoked or
not susceptible
80
Smoked and
susceptible
Quit Age 45
60
FEV1
(%)
40
Disability
20
Death
Age 65
0
20
30
40
50
60
Age (years)
Fletcher C, Peto R. Br Med J. 1977;1:1645-1648.
70
80
90
Audience Response System
Question #2
In a patient with history of smoking and an FEV1 of < 70% of
predicted increases the risk of lung cancer?
1. True
2. False
The Use of Spirometry in
Patients With COPD
When Is Spirometry Recommended?
Pathogenesis of COPD
Noxious particles
and gases
Airflow Limitation
Inflammation
Structural Changes
COPD
Adapted from Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive
Pulmonary Disease: NHLBI/WHO Workshop Report. Bethesda, Md: National Heart, Lung, and Blood Institute, National Institutes of Health; March 2001. NIH
publication 2701A.
Pathophysiological Features of COPD
Airway
Obstruction
Smooth muscle contraction
 Cholinergic tone
Loss of elastic recoil
Structural
Changes
Inflammation
Oxidative stress
 Neutrophils
Macrophages
 CD8+ lymphocytes
 IL-8 and TNF-
Protease/antiprotease
imbalance

Alveolar destruction
Collagen deposition
Glandular hypertrophy
Airway fibrosis
Adapted from Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive
Pulmonary Disease: NHLBI/WHO Workshop Report. Bethesda, Md: National Heart, Lung, and Blood Institute, National Institutes of Health; March 2001. NIH
publication 2701A.
Effect of Bronchodilators
Normal
COPD
Constricted
airway
Bronchodialted
airway
R~
1/radius4
Barnes PJ. Managing Chronic Obstructive Pulmonary Disease, 2nd ed. London: Scientific Press Limited.; 2001. Used with permission.
GOLD Guidelines for COPD:
Stages of Severity
Stage 0
Chronic cough/sputum; PFT WNL
Stage I
FEV1  80%, FEV1/FVC < 70%,
with/without Sx
Stage II
FEV1 50%-80%, FEV1/FVC < 70%, with/without Sx
Stage III FEV1 30%-50%, FEV1/FVC < 70%, with/without
exacerbations
Stage IV FEV1 < 30% or presence of respiratory failure or
right-heart failure, FEV1/FVC < 70%
Audience Response System
Question # 3
Leukotriene modifiers play an important role in the early therapy
of COPD?
1. True
2. False
Recommended Progression of
COPD Pharmacotherapy
0: At Risk
I: Mild
• Chronic symptoms
• Exposure to risk
• FEV1/FVC <70% • FEV1/FVC <70%
• FEV1 80%
• 50% FEV180%
• With or without
• With or without
•
factors
Normal spirometry
symptoms
II: Moderate III: Severe
symptoms
IV: Very Severe
• FEV1/FVC <70% • FEV1/FVC <70%
• 30% FEV1 <50% • FEV1 <30% or presence of
chronic respiratory failure or
• With or without
symptoms
right heart failure
Avoidance of risk factor(s); influenza vaccination
Add short-acting bronchodilator when needed
Add regular treatment with one or more long-acting
bronchodilators
Add rehabilitation
Add ICS if repeated exacerbations
Add long-term oxygen if
chronic respiratory failure
Consider surgical
treatments
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at:
www.goldcopd.com/revised.pdf.
Important Clinical Outcomes
in COPD
• FEV1
• Dyspnea
• HRQoL
• Acute Exacerbations
• Mortality
• Lung Volume
• Exercise endurance
Audience Response System
Question # 4
Which of the following therapies wil improve survival/mortality in
patient with COPD?
1. Oxygen therapy
2. Chronic antibiotic treatment
3. Smoke cessation
4. a and c
5. a, b and c
Current Treatment Options
• Bronchodilators
–
Short-acting
albuterol, ipratropium,
ipratropium/albuterol
–
Long-acting
Salmeterol , formoterol
tiotropium
theophylline
oral 2-agonists
•
Corticosteroids
– Inhaled
– Oral
• Oxygen
Audience Response System
Question # 5
Which of the following will decrease (slow down) the rate of
decline in the FEV1 in COPD patients:
1. Inhaled corticosteroids
2. Long-acting bronchodilators
3. Oxygen therapy
4. Smoke cessation
5. Pulmonary rehabilitation
Bronchodilators in COPD
•
•
•
•
•
Central to symptom management of COPD
Inhaled agents are preferred
Choice depends on availability, individual
response and adverse effects
Long acting agents are more effective and
convenient, but more expensive
Combinations may be more effective and with
less adverse effects
GOLD guidelines AJRCCM 2001 163:1256-76
Bronchodilators: Site of Action
Anticholinergic
M1
M2
M3
Contraction
Relaxation
cAMP
AMP
-agonist
Smooth Muscle Cell
Theophylline
Spector SL. In: Anticholinergic Agents in the Upper and Lower Airways. New York,
NY: Marcel Dekker; 1999.
Current Treatment Options
• Bronchodilators
– Short-acting
 albuterol, ipratropium,
ipratropium/albuterol
Short-Acting Bronchodilators: Albuterol
• Stimulates 2-receptors on airway smooth
•
•
•
•
muscle
Onset of effect: 1-3 minutes
Duration of action: 4-6 hours
Reliever/rescue medication: PRN dosing
2:1 selectivity
– Albuterol = 1,375:1
– Salmeterol = 85,000:1
– Formoterol = 400:1
Short-Acting Bronchodilators: Ipratropium
• Nonspecific muscarinic receptor antagonist
•
•
•
– Decreases airway smooth muscle tone
Onset of action: 20-30 minutes
Duration of action: 4-6 hours
Maintenance medication: 2-3 inhalations q.i.d.
according to package insert
Rennard et al. Chest. 1995;107:171S-175S.
Duration of Action
1.00
Salmeterol
Salbutamol
Ipratropium
Placebo
0.95
Mean
Increase
in FEV1
(L)
0.90
0.85
0.80
0
1
2
3
4
5
6
Time (hours)
Matera MG et al. Pulmonary Pharmacol. 1995;8:267-271.
8
10
12
Short-Acting Bronchodilators in COPD
100
90
80
Responders 70
(%) *
60
Albuterol
Ipratropium + albuterol
Ipratropium
50
40
0
15
30
45
60
75
90
Time Postadministration (minutes)
*% of patients demonstrating 15% or greater increase in FEV1 vs baseline.
Albuterol = ipratropium < (albuterol + ipratropium).
Dorinsky PM et al. Chest. 1999;115:966-971.
105
120
Current Treatment Options
•
Bronchodilators
– Short-acting
albuterol, ipratropium,
ipratropium/albuterol
– Long-acting
Salmeterol / formoterol
tiotropium
theophylline
oral 2-agonists
Long-Acting Bronchodilators: Salmeterol
•
•
•
•
•
Stimulates 2-receptors on airway smooth muscle
Onset of effect: 20-30 minutes
Duration of action: 12+ hours
Maintenance medication: 1 inhalations b.i.d.
2:1 selectivity
–
–
–
Albuterol = 1,375:1
Salmeterol = 85,000:1
Formoterol = 400:1
First-Line Treatment:
Salmeterol vs Ipratropium
Salmeterol MDI 42 µg b.i.d.
Randomized, Double-Blind,
and Double-Dummy
Placebo q.i.d.
N = 411
Ipratropium 36 µg q.i.d.
12 Weeks
*All patients received albuterol p.r.n.
Mahler DA et al. Chest. 1999;115:957-965.
First-Line Therapy:
Salmeterol vs Ipratropium
All Patients Day 1
Day 1 Baseline
Salmeterol 1.36 L
Ipratropium 1.18 L†
Placebo 1.31 L
0.4
0.3
 FEV1
(L)
*
*
‡
‡
*
* *
*
*
*
*
0.2
0.1
0
0
1
2
3
4
5
*P < .001 salmeterol vs baseline.
†P < .05 IP vs salmeterol and placebo.
6
7
8
Time (hours)
‡P
Mahler DA et al. Chest. 1999;115:957-965.
9
10
11
12
< .05 salmeterol vs ipratropium.
13
First-Line Therapy:
Salmeterol vs Ipratropium
All Patients Day 84
Day 1 Baseline
Salmeterol 1.36 L
Ipratropium 1.18 L†
Placebo 1.31 L
0.4
‡
0.3
*
 FEV1
(L)
*
*
‡
*
*
*
*
0.2
*
0.1
0
-0.1
0
1
2
3
4
5
*P < .001 salmeterol vs baseline.
†P < .05 IP vs salmeterol and placebo.
6
7
8
9
10 11 12
13
Time (hours)
‡P
Mahler DA et al. Chest. 1999;115:957-965.
< .05 salmeterol vs ipratropium.
Salmeterol as Add-On
Maintenance Therapy: van Noord
Salmeterol MDI 50µg b.i.d.
+ IP 40µg q.i.d.
•
•
•
•
•
N = 144
Salmeterol MDI 50µg b.i.d.
+ Placebo
2 Weeks
Placebo
12 Weeks
 10 pack - years
Age 40-75 years old
FEV1  65% > .75 L
FEV1/FVC  60%, symptomatic, poorly reversible
Continued theophylline, ICS to 2000 µg/day and FP to 1000 µg/day
van Noord JA et al. Eur Respir J. 2000;15:878-885.
Salmeterol as Add-On
Maintenance Therapy: van Noord
Single-Dose Response
12.5
Salmeterol 50 µg
+ IP 40 µg
Salmeterol 50 µg
Placebo
10
7.5

5
FEV1
2.5
(% pred.)
0
-2.5
-5
0 0.5 1
2
3
4
5
6
7
8
Time (hours)
van Noord JA et al. Eur Respir J. 2000;15:878-885.
9
10 11 12
In Vitro Muscarinic Receptor
Dissociation Half-life
Dissociation Half-life (hours)
M1
M2
M3
Ipratropium
0.11
0.035
0.26
Tiotropium
14.60
3.600
34.70
Disse et al 1999:64;457
Tiotropium: Improvement in Trough FEV1
Over 1 Year (vs Placebo)
1.20
Tiotropium
1.15
Trough
FEV1 (litre)
1.10
1.05
1.00
0.95
Placebo
0.90
8
50
92
176
260
344
Test Day
p<0.0001 at all time points
Casaburi et al. Eur Respir J. 2002; 19:209
FEV1 Over One Year (Tiotropium vs Placebo)
Day 1
Day 8
Day 92
Day 344
1.3
Tiotropium (n=518)
FEV1 (L)
1.2
1.1
1.0
Placebo (n=328)
0.9
-60
-5
30
60
Time (minutes)
120
180
Casaburi R et al. Eur Respir J (2002)
Tiotropium: Reduction in COPD
Exacerbations (vs Placebo)
p=0.045
1.2
1.0
0.95
20%
Number of
Events/PatientYear
0.8
0.76
0.6
0.4
0.2
0.0
Placebo
(n=371)
Tiotropium
(n=550)
Casaburi et al. Eur Respir J. 2002; 19:209
1-year Ipratropium-Controlled Trials
Included Patients Across Disease Severity
ipratropium
tiotropium
FEV1 Improvement on Day 1
Tiotropium vs. Ipratropium
Tiotrop (n=153)
Ipratrop (n=72)
FEV1 Improvement Sustained on Day 364
With Tiotropium vs Ipratropium
Tiotrop (n=153)
Ipratrop (n=72)
FVC Improvement Maintained Over
1 Year With Tiotropium vs Ipratropium
Tiotrop(n=153)
(n=153)
Tiotrop
Ipratrop
Ipratrp (n=72)
(n=72)
Audience Response System
Question # 6
Mechanism of dyspnea and exercise limitation in COPD patients
are due to :
1. Respiratory muscle weakness
2. Dynamic hyperinflation
3. Increased ventilatory demand
4. a. and b. only
5. a. b. and c
Current Treatment Options
• Bronchodilators
–
Short-acting
albuterol, ipratropium,
ipratropium/albuterol
–
Long-acting
Salmeterol , formoterol
tiotropium
theophylline
oral 2-agonists
•
Corticosteroids
– Inhaled
– Oral
• Oxygen
Oral Corticosteroids
•
•
Conflicting results in patients with stable COPD –
may lead to systemic side effects
Treatment of exacerbations
–
–
–
–
–
Reduced treatment failure rate
Improved subjective dyspnea
Rapid improvement in lung function and symptom scores
Reduced in-hospital days
Maximum benefit obtained during first 2 weeks
of therapy
Thompson WH et al. Am J Respir Crit Care Med. 1996;154:407-412.
Davies L et al. Lancet. 1999;354:456-460.
Niewoehner D et al. N Engl J Med. 1999;340:1941-1947.
Inhaled Corticosteroids
• Controversial, but increasing acceptance in
•
•
•
treatment of COPD
Do not modify the long-term decline in FEV1
May reduce airway inflammation associated
with COPD
May decrease frequency and severity
of exacerbations
What Is the Question?
• Do ICS slow spirometric disease progression in
subjects with mild to moderate COPD (eg,
tobacco cessation effect)?
• Do ICS effectively treat symptoms, decrease
exacerbations in symptomatic patients with
COPD?
Large Multicenter Studies
of ICS in COPD
Study
FEV1
Treatment Randomized
(% predicted) (µg/day)
Patients
Primary Outcome
ISOLDE
50
FP 1000
751
Rate of decline in FEV1
Int’l COPD
57
FP 1000
281
Total exacerbations
Copenhagen
86
BUD 800
290
Rate of decline in FEV1
EUROSCOP
77
BUD 800
912
Rate of decline in FEV1
Lung Health II
64
TAA 1200
1116
Rate of decline in FEV1
ISOLDE, Inhaled Steroids in Obstructive Lung Disease in Europe; Int’l COPD, International COPD
Study Group; Copenhagen, Copenhagen City Lung Study; EUROSCOP, European Respiratory
Society Study on Chronic Obstructive Pulmonary Disease; TAA, triamcinolone acetonide; FEV1, %
predicted FEV1 at baseline. Primary outcomes were all not significant.
Burge S. Drugs. 2001;61:1535-1544.
The ISOLDE Trial
2 months
2 weeks
3 years
4 weeks
 N = 751
Corticosteroid
withdrawal
Run-in
Oral
prednisolone
0.6 mg/kg/day
 Reversibility
FP 500 g BID via MDI
vs placebo BID via MDI
Follow-up
period
<10%
predicted
FEV1
 Mean FEV1:
V1
V2
V3
V15
Randomization
• 24% dropout rate during run-in
• 38% of “ICS withdrawal” but only 6% of “ICS naive” group with
exacerbation during run-in
Burge PS, et al. Br Med J. 2000;320:1297-1303.
Jarad NA, et al. Respir Med. 1999;93:161-166.
V16
50% at
baseline
ISOLDE: Impact of ICS on FEV1
1.50
373
372
1.45
Start of double-blind
treatment
298
269
246
FEV1
(L)
1.40
1.35
235
216
168
288
241
222
Randomization and
start of oral steroid trial
194
174
141
1.30
FP MDI (500 g BID)
Placebo
1.25
1.20 -3
0
3
6
9
12 15 18 21 24 27 30 33 36
Time (months)
• No significant difference in annual rate of decline in FEV1
• Significantly higher FEV1 in FP group than in placebo group at each time point (P = 0.001)
• Fewer withdrawals due to respiratory disease: 25% for FP vs 19% for placebo (P = 0.034)
Burge PS, et al. Br Med J. 2000;320:1297-1303.
ISOLDE: Exacerbation Frequency
1.4
Median Annual
Exacerbation Rate
1.2
1.0
25 %
1.32
0.8
0.99*
0.6
0.4
0.2
0.0
Placebo (n = 376)
*P = 0.026.
Burge PS, et al. Br Med J. 2000;320:1297-1303.
FP 500 g BID
(n = 375)
Systematic Review of Effects of ICS
in COPD: Study Selection Process
Studies evaluating inhaled corticosteroids in COPD
(n=118)
RCT of inhaled corticosteroids in COPD
(n=52)
Placebo-controlled RCT in COPD
(n=24)
Placebo-controlled RCT of inhaled corticosteroids in COPD
patients of at least 6 months’ follow-up
(n=13)
Placebo-controlled RCTs comparing the long-term
effect of inhaled corticosteroids in COPD
(n=9)
RCT = randomized controlled trial.
Adapted from Alsaeedi et al. Am J Med. 2002;113:59-65.
Relative Risk of Exacerbations in COPD
Patients Treated With ICS
Reference
Vestbo et al., 1999
Bourbeau et al., 1998
Burge et al., 2000
Lung Health Study, 2000
Weir et al., 1999
Overall relative risk = 0.70
95%CI = 0.58 to 0.84
Paggiaro et al., 1998
Overall
0
Alsaeedi et al. Am J Med. 2002;113:59-65.
0.5
1.0
1.5
2.0
Relative Risk
2.5
3.0
What Is the Question?
Q: Do ICS slow spirometric disease progression in subjects
with mild to moderate COPD (eg, tobacco cessation effect)?
A: Probably not much
Q: Do ICS effectively treat symptoms,and decrease
exacerbations in patients with COPD?
A: Yes, yes
Study Design
FP/SAL 250/50 mcg b.i.d.
p.r.n.
albuterol
Placebo
run-in
FP 250 mcg b.i.d.
Salmeterol 50 mcg b.i.d.
Placebo b.i.d.
2 weeks
24 weeks
All treatments administered via the DISKUS device.
Patients were stratified based on reversibility to albuterol.
Hanania et al. Chest. 2003;124:834-843.
Key Inclusion Criteria
•
•
•
•
Diagnosis of COPD
Age 40 years
Current or ex-smoker (20 pack-years)
Prebronchodilator FEV1 <65% predicted
– If <0.7 L, then must be >40% predicted
•
•
•
FEV1/FVC 70%
Symptoms of chronic bronchitis
Moderate dyspnea
Hanania et al. Chest. 2003;124:834-843.
Baseline Characteristics
Variable
Placebo
SAL
177
64
58%
FP
250
183
63
66%
FP/SAL
250/50
178
63
61%
No. of patients
Age (years)*
Gender (% male)
185
65
68%
FEV1 (L)*
FEV1 % predicted*
1.29
42%
1.25
42%
1.31
42%
1.25
41%
% patients reversible†
55%
55%
55%
56%
* Mean values.
† Reversible defined as 12% and 200 mL increase in FEV following 4 puffs (360 mcg) of albuterol.
1
Hanania et al. Chest. 2003;124:834-843.
Primary Efficacy Measures
• Predose FEV1
– FP/SAL vs salmeterol
– Evaluates contribution of FP
• 2-hour postdose FEV1
– FP/SAL vs FP
– Evaluates contribution of salmeterol
All treatments administered b.i.d. via the DISKUS device.
Hanania et al. Chest. 2003;124:834-843.
Improvement in Predose FEV1
Placebo
SAL
FP 250
FP/SAL 250/50
*
(17%)
†
(11%)
 FEV1 (mL)
200
150
(9%)
100
50
(1%)
0
-50
0
2
4
6
8
12
Time (weeks)
* P0.012 FP/SAL vs placebo and FP/SAL vs salmeterol.
† P<0.001 FP vs placebo.
‡ Last evaluable FEV .
1
Hanania et al. Chest. 2003;124:834-843.
16
20
24
Endpoint‡
Improvement in 2-Hour Postdose FEV1
Placebo
SAL
FP 250
FP/SAL 250/50
*
350
(27%)
 FEV1 (mL)
300
†
250
(19%)
200
(14%)
150
100
(6%)
50
0
-50
0
2
4
6
8
12
Time (weeks)
* P<0.001 FP/SAL vs placebo and FP/SAL vs FP.
† P<0.001 salmeterol vs placebo.
‡ Last evaluable FEV .
1
Hanania et al. Chest. 2003;124:834-843.
16
20
24
Endpoint‡
Improvement in Predose FEV1 Seen in
Reversible and Nonreversible Patients
Placebo
SAL
FP 250
FP/SAL
Mean Change From Baseline
at Endpoint in FEV1 (mL)
200
150
100
50
0
-50
Reversible
Nonreversible
Reversible defined as 12% and 200 mL increase in FEV1 following 4 puffs (360 mcg) of albuterol.
Baseline FEV1 values:
Reversible group: Placebo, 1.33 L; SAL, 1.24 L; FP, 1.35 L; ADVAIR 250/50, 1.28 L.
Nonreversible group: Placebo, 1.12 L; SAL, 1.15 L; FP, 1.10 L; ADVAIR 250/50, 1.11 L.
Hanania et al. Chest. 2003;124:834-843.
Data on file, GlaxoSmithKline (SFCA3007).
Improvement in 2-Hour Postdose FEV1 Seen in
Reversible and Nonreversible Patients
Placebo
SAL
FP 250
FP/SAL
Mean Change From Baseline
at Endpoint in FEV1 (mL)
350
300
250
200
150
100
50
0
Reversible
Nonreversible
Reversible defined as 12% and 200 mL increase in FEV1 following 4 puffs (360 mcg) of albuterol.
Baseline FEV1 values:
Reversible group: Placebo, 1.33 L; SAL, 1.24 L; FP, 1.35 L; ADVAIR 250/50, 1.28 L.
Nonreversible group: Placebo, 1.12 L; SAL, 1.15 L; FP, 1.10 L; ADVAIR 250/50, 1.11 L.
Hanania et al. Chest. 2003;124:834-843.
Data on file, GlaxoSmithKline (SFCA3007).
Audience Response System
Question # 7
Some patients with chronic asthma cannot be distinguished from
those with COPD with current diagnostic tests – management of
these patients should be similar to :
1. Asthma patients
2. COPD patients
Current Treatment Options
• Bronchodilators
–
Short-acting
albuterol, ipratropium,
ipratropium/albuterol
–
Long-acting
Salmeterol , formoterol
tiotropium
theophylline
oral 2-agonists
•
Corticosteroids
– Inhaled
– Oral
• Oxygen
Oxygen Therapy Trial
100
90
80
COT
70
Cumulative
Survival
(%)
60
50
MRC
O2
NOT
40
30
MRC
controls
20
10
0
0
10
20
30
40
50
60
70
COT = continuous oxygen therapy; NOT = nocturnal oxygen therapy; MRC controls =
no oxygen therapy; MRC = domiciliary oxygen therapy.
Flenley DC. Chest. 1985;87:99-103.
Pulmonary Rehabilitation: Meta-Analysis
Study
Favors
control
Favors treatment
McGavin, 1977
Cockcroft, 1981
Booker, 1984
Jones, 1985
Lake, 1990
Simpson, 1992
Weiner, 1992
Goldstein, 1994
Wijkstra, 1994
Guell, 1995
Strijbos, 1996
Overall effect
-2
-1
0
1
2
Effect Size (SD units)
Lacasse Y et al. Lancet. 1996;348:1115-1119.
3
4
Benefits of Pulmonary Rehabilitation
•
Goals
– Reduce symptoms
– Improve QoL
– Increase physical and emotional participation in everyday
activities
• Benefits
–
–
–
–
–
–
–
Improved exercise capacity
Decreased perception of breathlessness
Improved health-related QoL
Reduced hospitalization
Decreased COPD-associated anxiety and depression
Improved arm function
Increased survival
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at:
www.goldcopd.com/revised.pdf.
Other Nonpharmacologic Treatments
for COPD
• Noninvasive ventilation
• Surgical treatments
– Bullectomy
– Lung volume reduction surgery
– Lung transplantation
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003.
Available at: www.goldcopd.com/revised.pdf.
Recommended Progression of
COPD Pharmacotherapy
0: At Risk
I: Mild
• Chronic symptoms
• Exposure to risk
• FEV1/FVC <70% • FEV1/FVC <70%
• FEV1 80%
• 50% FEV180%
• With or without
• With or without
•
factors
Normal spirometry
symptoms
II: Moderate III: Severe
symptoms
IV: Very Severe
• FEV1/FVC <70% • FEV1/FVC <70%
• 30% FEV1 <50% • FEV1 <30% or presence of
chronic respiratory failure or
• With or without
symptoms
right heart failure
Avoidance of risk factor(s); influenza vaccination
Add short-acting bronchodilator when needed
Add regular treatment with one or more long-acting
bronchodilators
Add rehabilitation
Add ICS if repeated exacerbations
Add long-term oxygen if
chronic respiratory failure
Consider surgical
treatments
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at:
www.goldcopd.com/revised.pdf.
Important Clinical Outcomes
in COPD
• FEV1
• Dyspnea
• HRQoL
• Acute Exacerbations
• Mortality
• Lung Volume
• Exercise endurance
Eur Resp J 2004: 23: 932-946
Effect of Commonly Used medications on Clinical
Outcomes in COPD
FEV1 SOB HRQOL
AE
FEV1
Mortality
SABA
yes
yes
NA
NA
NA
NA
yes
Ipratrop
yes
yes
no
yes
no
NA
yes
LABA
yes
yes
yes
yes
no
NA
yes
Tiotrop
yes
yes
yes
yes
NA
NA
yes
ICS
yes
yes
yes
yes
no
NA
NA
Theo
yes
yes
yes
NA
NA
NA
yes
Eur Resp J 2004: 23: 932-946
lung vol.
RULE OF 50’s
50% Undiagnosed
50% of predicted FEV1 at time diagnosis
50% of patients are untreated
50 yrs age at time of diagnosis
50% or more are treated by PCP
50% will have a BD response
Case Study
Mr. Cavanaugh, Age 64
Mr. Cavanaugh’s Background
• Mr. Cavanaugh is a white, 64-year-old building inspector.
Physically demanding job requires extensive travel to
job sites for inspection and certification of construction
•
Smoker (about 1½ pack of cigarettes per day) since the
age of 16. Has never attempted to quit smoking
•
Presents with complaints of a chronic cough that has
gotten worse during the last 5 months, increased fatigue
and difficulty carrying out his job, and shortness of
breath when walking rapidly or climbing stairs or
ladders on construction sites
Mr. Cavanaugh’s Background (cont’d)
•
Has also experienced occasional mild dull chest
pain when walking rapidly or climbing
•
Particularly concerned that his fatigue and
shortness of breath will make it difficult or
impossible for him to continue to work
•
No other presenting symptoms
Mr. Cavanaugh’s History
• No significant childhood diseases
• Not receiving any treatment for his cough
or other pulmonary symptoms
Objective Findings: Physical Exam
Parameter
Result
Blood pressure
151/96 mm Hg
Heart rate
79 bpm
Temperature
Afebrile
Respiratory rate
12 (12–15 = normal)
Height
5'8"
Weight
197 lb
Head, eyes, ears, nose, throat
Within normal limits
Heart
No abnormalities noted
Chest
Prolonged expiratory phase, rhonchi
Audience Response System
Question 8
What Do You Suspect?
What are the most likely causes of
Mr. Cavanaugh’s symptoms?
1.
Asthma
2.
3.
4.
5.
COPD
Angina
Tuberculosis
Pulmonary infection
Diagnostic Considerations for
Mr. Cavanaugh
•
Mr. Cavanaugh has 2 classic symptoms of COPD—
cough and shortness of breath on exertion
•
His past and present use of cigarettes are sufficient for
COPD to be suspected
•
Obesity may be contributing to his exertional dyspnea
•
Mr. Cavanaugh also has hypertension and is at high risk
for development of coronary heart disease (CHD) and
associated symptoms (angina pectoris)
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003.
Available at: www.goldcopd.com/revised.pdf.
Khot UN, et al. JAMA. 2003;290:898-904.
Audience Response System:
Question 9
What Test(s) Would You Perform?
What diagnostic test(s) would you consider?
1.
Chest X-ray
2.
Electrocardiogram (ECG)
3.
Spirometry
4.
Complete blood count
5.
All of the above
Spirometry Tests
Parameter
Result
Baseline
FEV1
FVC
FEV1/FVC
2.75 liters (82% predicted)
4.08 liters (90% predicted)
67%
Assessment of
Reversibility
Postbronchodilator
FEV1
FVC
FEV1/FVC
2.82 liters (84% predicted)—2% improvement
4.31 liters (95% predicted)—5% improvement
65%
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003.
Available at: www.goldcopd.com/revised.pdf.
Audience Response System
Question 10
How Do Mr. Cavanaugh’s Findings Influence Your Diagnosis?
Mr. Cavanaugh’s symptoms could be caused by
1.
High blood pressure
2.
Coronary artery disease
3.
COPD
4.
Asthma
5.
Other noninfectious pulmonary disease
Audience Response System
Question 11
Diagnosis of Pulmonary Symptoms
Given the spirometry results for Mr. Cavanaugh,
what is the most likely cause of his pulmonary
symptoms?
1.
Cardiovascular disease
2.
Asthma
3.
Malignancy
4.
COPD
5.
Other
Spirometry Findings Confirm
Diagnosis of COPD
• Mr. Cavanaugh’s spirometry results
indicate an airflow limitation consistent
with Stage I (mild) COPD, according to
GOLD guidelines
– FEV1 80% predicted
– FEV1/FVC <70%
– With or without chronic symptoms
(cough, sputum production)
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003.
Available at: www.goldcopd.com/revised.pdf.
Recommended Progression of
COPD Pharmacotherapy
0: At Risk
I: Mild
• Chronic symptoms
• Exposure to risk
• FEV1/FVC <70% • FEV1/FVC <70%
• FEV1 80%
• 50% FEV180%
• With or without • With or without
•
factors
Normal spirometry
symptoms
II: Moderate III: Severe
symptoms
IV: Very Severe
• FEV1/FVC <70% • FEV1/FVC <70%
• 30% FEV1 <50% • FEV1 <30% or presence of
chronic respiratory failure or
• With or without
symptoms
right heart failure
Avoidance of risk factor(s); influenza vaccination
Add short-acting bronchodilator when needed
Add regular treatment with one or more long-acting
bronchodilators
Add rehabilitation
Add ICS if repeated exacerbations
Add long-term oxygen if
chronic respiratory failure
Consider surgical
treatments
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at:
www.goldcopd.com/revised.pdf.
Case Study
Ms. Kramer, Age 57
Background
•
•
•
•
Ms. Kramer is an African American, 57-year-old widow
with no children. She is a production assistant for a
television studio in a large city and presents with
shortness of breath
Ms. Kramer’s breathlessness is worsened by mildly
stressful physical activity such as walking rapidly or
climbing stairs. It also becomes much worse on smoggy
days
Ms. Kramer’s shortness of breath has begun to make it
difficult for her to carry out her duties at work and to
enjoy leisure activities (walking, gardening)
Ms. Kramer has no other presenting symptoms
Ms. Kramer’s History
•
•
•
•
•
Ms. Kramer had no significant childhood diseases, but she
has always had a problem with her weight
Up until 2 years ago, Ms. Kramer was a moderately heavy
smoker (1-2 packs of cigarettes per day). Ms. Kramer stopped
smoking in 2000 but has since gained 30 lb. The weight gain
has prompted several smoking relapses
Ms. Kramer has also had short bouts of respiratory illness
that she believes to be the flu, which have occurred twice in
the past year
Ms. Kramer has a history of type 2 diabetes, hypertension,
hypercholesterolemia, mild angina, and breast cancer
requiring lumpectomy and radiotherapy 4 years ago
Ms. Kramer believes that her ability to function at work and
desire to engage in leisure activities have both declined
markedly in the past year
Current Treatment of Ms. Kramer
•
Ms. Kramer is not receiving any treatment for
her breathlessness
•
She is currently taking
–
Amlodipine (10 mg QD) and atenolol (25 mg QD) to
control her blood pressure and treat her angina
–
–
–
Sertraline (100 mg QD) for depression and anxiety
Atorvastatin (20 mg QD) for hypercholesterolemia
Metformin (850 mg TID) for diabetes
Objective Findings: Physical Exam
Result
Parameter
Blood pressure
151/84 mm Hg
Heart rate
75 bpm
Respiratory rate
17 (elevated; 12–15 = normal)
Head, eyes, ears,
nose, throat
Within normal limits
Heart
No abnormalities noted
Chest
Increased expiratory phase
Height
5'4"
Weight
190 lb
Audience Response System
Question 12
What Do You Suspect?
What are the most probable diagnoses for Ms. Kramer?
1.
Breast cancer recurrence
2.
COPD
3.
CHD
4.
Lower respiratory tract infection
5.
Cannot differentiate between above possibilities
Diagnostic Considerations for
Ms. Kramer
•
•
•
•
•
Ms. Kramer has one of the classic symptoms of
moderate COPD—shortness of breath on mild exertion
Her smoking history is sufficient for COPD to be
suspected
The illness that she ascribes to the flu may be acute
exacerbations of COPD
Most patients seek medical attention only when they
experience dyspnea or an exacerbation
CHD must still be considered for Ms. Kramer because of
her hypertension, diabetes, and dyslipidemia
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003.
Available at: www.goldcopd.com/revised.pdf.
Spirometry Tests
Parameter
Result
Baseline
FEV1
FVC
FEV1/FVC
SaO2
1.76 liters (60% predicted)
2.88 liters (70% predicted)
61%
97% at rest; decrease to 93% after
walking on level surface for 6 minutes
Assessment of
Reversibility
Postbronchodilator
FEV1
FVC
FEV1/FVC
SaO2
1.77 liters (60% predicted): 0% improvement
2.87 liters (70% predicted): 0% improvement
61%
96% at rest; no decrease after
walking on level surface for 6 minutes
Spirometry results are consistent with a diagnosis of Stage II COPD.
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003.
Available at: www.goldcopd.com/revised.pdf.
Treatment Considerations
• Treatment for Stage II COPD
–
–
–
–
Risk factor reduction (smoking cessation)
Influenza vaccination
Short-acting bronchodilator (albuterol) PRN
Regular treatment with one or more long-acting
bronchodilators
– Consider ICS
– Rehabilitation
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003.
Available at: www.goldcopd.com/revised.pdf.
Recommended Progression of
COPD Pharmacotherapy
0: At Risk
I: Mild
• Chronic symptoms
• Exposure to risk
• FEV1/FVC <70% • FEV1/FVC <70%
• FEV1 80%
• 50% FEV180%
• With or without
• With or without
•
factors
Normal spirometry
symptoms
II: Moderate III: Severe
symptoms
IV: Very Severe
• FEV1/FVC <70% • FEV1/FVC <70%
• 30% FEV1 <50% • FEV1 <30% or presence of
chronic respiratory failure or
• With or without
symptoms
right heart failure
Avoidance of risk factor(s); influenza vaccination
Add short-acting bronchodilator when needed
Add regular treatment with one or more long-acting
bronchodilators
Add rehabilitation
Add ICS if repeated exacerbations
Add long-term oxygen if
chronic respiratory failure
Consider surgical
treatments
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at:
www.goldcopd.com/revised.pdf.