COPD: MANAGEMENT OF STABLE DISEASE
AND EXACERBATIONS
Dennis E. Doherty, M.D.
Professor of Medicine
Chief, Division of Pulmonary and Critical Care Medicine
Co-chairman, National Lung Health Education Program
University of Kentucky Medical Center
Lexington Veterans Administration Medical Center
OBJECTIVES
• Historical Perspective
• Mechanisms of Airflow Obstruction
• Treatment Modalities
MECHANISMS OF AIRFLOW OBSTRUCTION
IN COPD
PERIPHERAL ADRENERGIC ACTIONS
Alpha
Smooth
Muscle
Bronchoconstriction
Urinary Retention
Beta2
Bronchodilation
Uterine Relaxation
Tachycardia
Arrhythmias
Heart
Skeletal
Muscle
Vascular
Beta1
Tremor
Hypertension
Dilatation
MECHANISMS OF BRONCHODILATION
BETA2-ADRENERGIC AGENTS
Beta2-selective
Adrenergic Agents
Adenylyl
Cyclase
ATP
cAMP
cAMP
BRONCHODILATION
Drawing by Dennis E. Doherty, MD
MECHANISMS OF AIRWAY OBSTRUCTION
PATHWAYS OF ATOPIC ASTHMA
Vagus
Nerve
Mast Cell
Antibody
Mediator
Airway Smooth
Muscle Cell

Antigen
Classical Theory

Reflex Theory
Drawing by Dennis E. Doherty, MD
Muscarinic Receptor Subtypes in Airways
CNS
Vagal Parasympathetic (X)
Parasympathetic
Nerves
M 2 RECEPTORS
Inhibit Ach Release
Acetylcholine
Acetylcholine
M 3 RECEPTORS
AIRWAY SMOOTH MUSCLE CELLS
MUCUS GLANDS
Drawing by Dennis E. Doherty, MD
Drawing by Dennis E. Doherty, MD
MECHANISMS OF BRONCHODILATION
ANTICHOLINERGIC AGENTS
CHOLINERGIC M
Ipratropium Bromide
Atropine
Increased
Cyclic GMP
Calcium
X
M3
AcetylCholine (ACh)
CHOLINERGIC
RECEPTOR
Calcium
Decreased Smooth Muscle
Constriction and
Mucus Gland Secretion
Drawing by Dennis E. Doherty, MD
DISTRIBUTION OF CHOLINERGIC AND
ADRENERGIC RECEPTORS
Parasympathetic
Sympathetic
Treatment of COPD
CHRONIC
BRONCHITIS
EMPHYSEMA
AIRFLOW
OBSTRUCTION
ASTHMA
American Thoracic Society. Am J Respir Crit Care Med. 1995.
PREVENT EMPHYSEMA
CHRONIC MANAGEMENT OF COPD
(GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276)
Diagnose
Reduce
Risk
Reduce
Symptoms
Reduce
Complications
Spirometry
Education
Smoking cessation
Education Immunize
Reduce other exposures
Education
Bronchodilators
Consider inhaled steroids
Pulmonary rehabilitation
Education
Consider oxygen
Treat exacerbations
STEPWISE TREATMENT OF COPD BASED ON SEVERITY
(GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276)
• Avoid Risks
• Vaccinate
Stage 0:
At Risk
• Normal spirometry
Stage I:
Mild COPD
• FEV1/FVC < 70%
• FEV1 > 80% predicted
• Add a short-acting bronchodilator prn
– Anticholinergic or
– Beta2-agonist
Stage IIA:
Moderate COPD
• FEV1/FVC < 70%
• IIA: 50% < FEV1 < 80%
• Add one or more short-acting
bronchodilators on a scheduled basis
(Anticholinergic + Beta2-agonist)
Stage IIB:
Moderate COPD
• FEV1/FVC < 70%
• IIB: 30% < FEV1 < 50%
• Consider trial of inhaled steroids
• Add Pulmonary Rehabilitation
Stage III:
Severe COPD
•FEV1/FVC < 70%
•FEV1 < 30%
• Evaluate for adding oxygen
• Consider surgical options
NATIONAL LUNG HEALTH
EDUCATION PROGRAM (NLHEP)
A new national healthcare
initiative aimed at the
diagnosis of early stages of
COPD and related disorders.
• TEST YOUR LUNGS
• KNOW YOUR NUMBERS
www.nlhep.org
OFFICE SPIROMETERS
Treatment of COPD
CHRONIC
BRONCHITIS
EMPHYSEMA
AIRFLOW
OBSTRUCTION
ASTHMA
American Thoracic Society. Am J Respir Crit Care Med. 1995.
OBJECTIVES FOR INTERVENTIONS
IN THE CHRONIC MANAGEMENT OF COPD
•
•
•
•
•
•
•
•
Improvement in Lung Function
Improve Quality of Life (Healthcare Status)
Relieve Symptoms
Decrease Exacerbations
Decrease Hospitalizations
Decelerate Decline in Lung Function
Increase Life Expectancy
Achieve Objectives in a Cost-Effective Manner
First Line Therapy in COPD is
Preventative
AVOID TOBACCO
GOLD Guidelines
(GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276)
Bronchodilation is first-line
pharmacologic therapy in COPD
PHARMACOLOGIC ARMAMENTARIUM
•
•
•
•
Anticholinergics (Parasympatholytic)
•
•
Short-acting inhaled (Ipratropium)
Long-acting (Tiotropium)
Beta Agonists (Sympathomimetic)
•
•
Short-acting inhaled (numerous available)
Long-acting inhaled (Salmeterol, Formoterol)
Methylxanthines (Sympathomimetic)
Anti-Inflammatory
•
•
•
Oral Steroids
Inhaled Steroids
Other anti-inflammatory agents (data pending)
ANTICHOLINERGICS AND SHORT-ACTING BETA-AGONISTS
ENHANCE FEV1 IN COPD
.
% Change in mean FEV1
Test Day 85
Albuterol (N=165)
30
Ipratroprium (N=176)
25
20
15
10
5
0
0
1
2
3
4
5
6
7
8
Hours After Test Dose
Chest 105:1411, 1994
LONG-ACTING INHALED BETA AGONISTS
•
•
Duration: Bronchodilation lasts for up to 12 hours
Peak action: Fomoterol (30 min), onset within 5 min
Salmeterol (1-2hr), not indicated for exacerbations
•
Most helpful:
•
? Of cost-benefit compared to short-acting beta-agonists
– Non-compliant patients (less frequent dosing)
– Nocturnal component of COPD
SALMETEROL IN COPD
(Mahler et al, Chest 115:957, 1999)
Change from Baseline
FEV1
Placebo
Salmeterol
Ipratopium
SALMETEROL IN COPD
(Mahler et al, Chest 115:957, 1999)
•
•
•
•
•
•
For patients ‘non-responsive’ to albuterol, (n=145, 35% ), ipratropium lead to
greater bronchodilation compared to other treatments
The mean transitional dyspnea index was significantly improved vs placebo
and not significantly different for salmeterol vs ipratropium
Ipratropium lead to a significantly improved 6 min walk vs placebo whereas
salmeterol did not
Night time dyspnea was improved with salmeterol treatment
Overall, ipratropium lead to a greater reduction in dyspnea related to activities
of daily living vs placebo or salmeterol
The incidence of total lower respiratory tract adverse events (exacerbations)
was different for salmeterol vs ipratropium, but both lead to fewer
exacerbations vs placebo
Long-Acting Anticholinergic - Tiotropium
Change in FEV1: Six Month Study
Tiotropium (n = 202)
Day 169
Placebo (n = 179)
1.35
1.30
FEV1 (L)
1.25
1.20
1.15
1.10
1.05
1.00
0.95
-1
0
1
2
3
4
5
6
7
8
9 10 11 12
Time after administration (h)
P < 0.001 for tiotropium vs placebo
(DonohueJF, Chest 2002;122:47-55 )
Change in FEV1: Tiotropium vs Salmeterol vs Placebo
Tiotropium (n = 202)
Salmeterol (n = 203)
Day 169
Placebo (n = 179)
1.35
1.30
FEV1 (L)
1.25
1.20
1.15
1.10
1.05
1.00
0.95
-1
0
1
2
3
4
5
6
7
8
9 10 11 12
Time after administration (h)
P < 0.001 for tiotropium vs placebo
P < 0.05 for tiotropium vs salmeterol
(DonohueJF, Chest 2002;122:47-55 )
Change in FEV1: Tiotropium vs Salmeterol vs Placebo
Day 1
Tiotropium (n = 202)
Day 169
Salmeterol (n = 203)
Placebo (n = 179)
1.35
1.30
FEV1 (L)
1.25
1.20
1.15
1.10
1.05
1.00
0.95
-1
0
1
2
3
4
5
6
7
8
9 10 11 12
Time after administration (h)
P < 0.001 for tiotropium vs placebo on all test days post-treatment
P < 0.05 for tiotropium vs salmeterol on all test days except day 1
(DonohueJF, Chest 2002;122:47-55 )
Binding and Dissociation
Human Muscarinic Receptors in CHO Cells
M1
M2
M3
Apparent KD (nM)
Ipratropium
Tiotropium
0.43
0.54
0.69
0.27
0.12
0.33
Dissociation Half-Life (hours)
[3H]-Ipratropium
[3H]-Tiotropium
KD = dissociation constant
0.11
0.035
0.26
14.6
3.6
34.7
Disse B et al. Life Sci 1993
Combination Therapy in COPD
CHRONIC
BRONCHITIS
EMPHYSEMA
AIRFLOW
OBSTRUCTION
ASTHMA
American Thoracic Society. Am J Respir Crit Care Med. 1995.
Bronchodilating Effects of Combined
Therapy With Clinical Dosages of
Ipratropium Bromide and Salbutamol for
Stable COPD:
Comparison With Ipratropium Bromide Alone
Akihiko Ikeda, MD, Koicht Nishimura
IPRATROPIUM BROMIDE AND SALBUTAMOL
FEV1 (% change)
50
80 mcg ipratropium + 400 mcg salbutamol
40 mcg ipratropium + 200 mcg salbutamol
80 mcg ipratropium
40 mcg ipratropium
Placebo
40
30
20
10
0
0
1
2
3
4
5
Time After Test Dose (h)
6
7
Ikeda A, et al. Chest. 1996;109:294.
8
Ipratropium and Albuterol per MDI
is More Effective than Either Agent Alone
.
Test Day 85
40
% Change in mean FEV1
Albuterol (N=165)
35
Ipratroprium (N=176)
Ipratroprium + Albuterol
(N=173)
30
25
20
15
10
5
0
0
1
2
3
4
5
6
7
8
Hours After Test Dose
Chest 105:1411, 1994
COMBINATION METERED DOSE INHALER
(Ipratropium Bromide plus Albuterol Sulfate)
•
•
•
•
Effective bronchodilation via two distinct mechanisms.
Useful in the subset of patients who require both classes of agents
to achieve maximal bronchodilation without potentiation of side
effects over either single component alone.
Useful in noncompliant (non-adherent) patients- can improve
adherence and patient satisfaction- by decreasing their time, effort,
and the number of puffs required to administer two efficacious
drugs.
Cost effective if restricted to these subsets of patients, and if the
combination inhaler is properly priced.
COMBINATION THERAPY IN COPD
•
Combination of ipratropium and long-acting beta-agonists have
been shown to lead to significantly greater bronchodilation than
that observed in response to either agent alone
– Ipratropium + Salmeterol (Van Noord, Eur Resp J 2000;15:878-885)
– Ipratropium + Formoterol (D’Urzo, Chest 2001;119:1347-1356)
•
A new generation anticholinergic agent, tiotropium bromide, which
is more selective, more potent, and has a longer duration of action
compared to ipratropium bromide is currently in development
(Litner, Am J Respir Crit Care Med 2000;161:1136-1142)
Combination Therapy with an Anticholinergic
and a Long-Acting Beta-2 Agonist
 FEV1 (% Pred.)
12.5
Salmeterol 50 µg
+ ipratropium 40 µg
Salmeterol 50 µg
Placebo
10
7.5
5
2.5
0
-2.5
-5
0
0.5
1
2
3
4
5
6
7
Time (hours)
van Noord JA et al. Eur Respir J 2000;15:878-885
8
9
10 11 12
OBJECTIVES FOR INTERVENTIONS
IN THE CHRONIC MANAGEMENT OF COPD
•
•
•
•
•
•
•
•
Improvement in Lung Function
Relieve Symptoms
Decrease Exacerbations
Decrease Hospitalizations
Improve Quality of Life (Healthcare Status)
Decelerate Decline in Lung Function
Increase Life Expectancy
Achieve Objectives in a Cost-Effective Manner
COPD EXACERBATION - DEFINITION
Acute Worsening of Respiratory Symptoms (72hr)
•
•
•
Increased Dyspnea
Increased Quantity of Sputum
Increased Purulence of Sputum
Anthonisen NR 1987 Ann Int Med 106:196-204
FREQUENCY OF EXACERBATIONS
20
% of Patients
With Exacerbations
10
0
Albuterol
Friedman M, et al. Chest. 1999;115:635-641.
Ipratropium
Ipratropium +
Albuterol
COST OF HOSPITALIZATION FOR EXACERBATION
Acquisition cost of primary
pulmonary drug
Albuterol
Acquisition cost of drugs
added during exacerbations
Ipratropium
Hospitalization cost
Ipratropium
+ Albuterol
0
50
100
150
Friedman M, et al. Chest. 1999;115:635-641.
200
250
300
350
400
450
500
PHARMACOLOGIC ARMAMENTARIUM
•
•
•
•
Anticholinergics (Parasympatholytic)
•
•
Short-acting inhaled (Ipratropium)
Long-acting (Tiotropium)
Beta Agonists (Sympathomimetic)
•
•
Short-acting inhaled (numerous available)
Long-acting inhaled (Salmeterol, Fomoterol)
Methylxanthines (Sympathomimetic)
Anti-Inflammatory
•
•
•
Oral Steroids
Inhaled Steroids
Other anti-inflammatory agents (data pending)
Relationship Between Plasma Theophylline
Concentrations and Clinical Effects
Concentration
Toxicity
Efficacy
mg/liter
5
10
20
40
60
}
Minimal
Optimal
Gastrointestinal Upset
Nervousness
Arrhythmias
Convulsions
Liver
Disease
Age
Formulation
Heart
Disease
Theophylline Metabolism
Infection
Smoking
Severity
of Illness
PHARMACOLOGIC ARMAMENTARIUM
•
•
•
•
Anticholinergics (Parasympatholytic)
•
•
Short-acting inhaled (Ipratropium)
Long-acting (Tiotropium)
Beta Agonists (Sympathomimetic)
•
•
Short-acting inhaled (numerous available)
Long-acting inhaled (Salmeterol, Fomoterol)
Methylxanthines (Sympathomimetic)
Anti-Inflammatory
•
•
•
Oral Steroids
Inhaled Steroids
Other anti-inflammatory agents (data pending)
LUNG INFLAMMATION IN ASTHMA IS DIFFERENT THAN
THE LUNG INFLAMMATION IN COPD
•
The inflammation of asthma is responsive to steroids
– Mast cells, eosinophils, TH2-like lymphocytes (CD4)
– IL-4, IL-5, IL-13, ECP, LTC4
•
The chronic inflammation in COPD is not responsive
to steroids
– Macrophages, Neutrophils, T-Lymphocytes (CD8)
– LTB4, TNF, IL-8, Chemokines
GOLD Guidelines
(GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276)
•
•
Trial of inhaled corticosteroids (6 wks – 3 mo) given
only if patient with moderate to severe COPD
(defined by spirometry) continues with significant
symptoms and frequent exacerbations (3 - 4 per yr)
despite maximal bronchodilation.
If symptoms or the frequency of exacerbations are
not improved, steroids should be discontinued.
INHALED CORTICOSTEROIDS IN COPD
•
•
Copenhagen City Heart Study (Lancet 1999;353:1819-23)
•
•
•
Mild-Moderate COPD (n=290)
Budesonide 1200-800 micrograms/day
No difference vs placebo in rate of decline in FEV1 over 3 years
EUROSCOP Trial (N Engl J Med 1999;340:1948-53)
•
•
•
•
Mild COPD (n=1277)
Budesonide 800 micrograms/day
No difference vs placebo in rate of decline in FEV1 over 3 years
Increase of 30-40ml FEV1 in treatment group early on which was
sustained throughout the study
INHALED CORTICOSTEROIDS IN COPD
•
•
Lung Health Study (N Engl J Med 2000;343:1902-1909)
•
•
•
•
•
Moderate COPD, FEV1 of 2L (n=1116)
Triamcinolone 1200 micrograms/day
No difference vs placebo in rate of decline in FEV1 over 3.5 years
Modest improvement in dyspnea and onset of severe symptoms
Increased risk of osteoporosis
ISOLDE Trial (BMJ 2000;320:1297-303)
•
•
•
•
•
Moderate to severe COPD , FEV1 of 1.5L (n=751)
Fluticasone 1000 micrograms/day
No difference vs placebo in rate of decline in FEV1 over 3 years
Increase of 100ml FEV1 in treatment group early on which was
sustained throughout the study
Exacerbations decreased by 25% in treatment group
SYSTEMIC CORTICOSTEROIDS SHOULD BE USED DURING
ACUTE EXACERBATIONS OF COPD
Two studies have shown efficacy for the use of
systemic steroids during acute COPD exacerbations
• Niewoehner DE et al, NEJM 340:1941, 1999
• Davies L et al, Lancet 354:456, 1999
Once daily Solumedrol (60 mg iv) or
Once daily Prednisone (30 - 40mg po)
Taper off in 5-7 days
CORTICOSTEROIDS DURING
ACUTE EXACERBATIONS OF COPD
Niewoehner et al NEJM 1999;340:1941
OBJECTIVES FOR INTERVENTIONS
IN THE CHRONIC MANAGEMENT OF COPD
•
•
•
•
•
•
•
•
Improvement in Lung Function
Relieve Symptoms
Decrease Exacerbations
Decrease Hospitalizations
Improve Quality of Life (Healthcare Status)
Decelerate Decline in Lung Function
Increase Life Expectancy
Achieve Objectives in a Cost-Effective Manner
MONTHLY ACQUISITION COSTS FOR COPD DRUGS (AWP)
(REDBOOK, 2002 Edition)
No. MDIs/Month
1.2
Albuterol
1.2
Ipratropium
Albuterol +
Ipratropium
1.2 + 1.2
Albuterol +
Ipratropium
(single MDI)
1.2
1.0
Formoterol
Salmeterol
1.0
Salmeterol +
Albuterol
1.0 + 1.2
0
25
50
75
AWP/month (Dollars)
100
125
MONTHLY ACQUISITION COSTS FOR COPD DRUGS (AWP)
(REDBOOK, 2002 Edition)
No. MDIs/Month
Albuterol
1.2
Ipratropium
1.2
Albuterol +Ipratropium
(Single MDI)
1.2
Formoterol + Albuterol
1.0 + 1.2
Salmeterol + Albuterol
1.0 + 1.2
Beclomethasone
1.2
Fluticasone 110
1.0
Fluticasone 220
1.0
Flunisolide
1.2
Budesonide
0.6
Fluticasone 500
+ Salmeterol 50
Combination
1.0
0
25
50
75 100 125 150 175 200
AWP/month (Dollars)
OBJECTIVES FOR INTERVENTIONS
IN THE CHRONIC MANAGEMENT OF COPD
•
•
•
•
•
•
•
•
Improvement in Lung Function
Relieve Symptoms
Decrease Exacerbations
Decrease Hospitalizations
Improve Quality of Life (Healthcare Status)
Decelerate Decline in Lung Function
Increase Life Expectancy
Achieve Objectives in a Cost-Effective Manner
MODALITIES IMPROVING SURVIVAL IN COPD
• Successful Smoke Cessation
(Behavioral Modification Required)
• Oxygen Therapy
(Minimum of 15-18 hr qd)
NON-PHARMACOLOGIC ARMAMENTARIUM
•
•
•
•
•
•
Successful Smoke Cessation
Pulmonary Rehabilitation (formal/informal)
•
•
•
•
•
Overall Education
Exercise Program (home program)
Nutrition
Vaccination
Pulmonary Hygiene (?mucolytic agents)
Antibiotics
Transplantation (Single Lung)
Oxygen, Noninvasive Ventilation
Experimental (LVRS, Anti-oxidants/Vitamins)
THE NATIONAL COPD AWARENESS PANEL (NCAP)
Journal of Respiratory Diseases 21:S1-21, Sept 2000
Journal of Respiratory Diseases 23:S1-52, Sept 2002
•
•
•
•
•
•
•
•
•
Carol Boland (Nurse Practitioner)
Dick D. Briggs (Pulmonary)
Dennis E. Doherty (Pulmonary)
Harold Hedges III (Family Medicine)
Louis Kuritzky (Family Medicine)
Ron Levine (Internal Medicine)
Kenneth Pellegrino (Family Medicine)
Alan Radin (Internal Medicine)
Steven A. Sahn (Pulmonary)
COPD Management in Primary Care
NCAP- Journal of Respiratory Diseases 23:S1-52, Sept 2002
GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276
•
•
•
Sustained Smoking Cessation
First-line Therapy is to Maximize Bronchodilation
•
•
•
Anticholinergics (short- or long-acting)
Beta-2 Agonists (short- or long-acting)
Methylxanthines
After Maximal Bronchodilation with multiple agents in
patients with severe COPD and frequent exacerbations
•
A trial of Inhaled Corticosteroids can be considered
– 6 week to 3 month trial
– Monitor Spirometry and Symptoms
– Discontinue if no improvement in that time period
VACCINNATION IN COPD
•
Pneumococcal
•
•
•
•
In all COPD Patients
Patients > 65 vaccinated more than 5 years previously should
be revaccinated, if unsure - revaccinate
Evidence for efficacy is inconclusive (some studies show a 6585% efficacy amongst high-risk populations)
Influenza
•
•
•
Administer annually unless there is a history of severe
anaphylaxis to egg protein
30-80% effective in preventing illness, complications, and death
in high-risk populations
Can be administered concurrently with pneumococcal vaccine
if administered at different sites
For more information on COPD
National Lung Health Education Program
www.nlhep.org
U.S. COPD Coalition
www.uscopd.com