copd: management of stable disease and exacerbations

COPD: MANAGEMENT OF STABLE DISEASEAND EXACERBATIONS

Dennis E. Doherty, M.D.Professor of Medicine

Chief, Division of Pulmonary and Critical Care MedicineCo-chairman, National Lung Health Education Program

University of Kentucky Medical CenterLexington Veterans Administration Medical Center

OBJECTIVES

• Historical Perspective

• Mechanisms of Airflow Obstruction

• Treatment Modalities

MECHANISMS OF AIRFLOW OBSTRUCTION IN COPD

PERIPHERAL ADRENERGIC ACTIONS

BronchoconstrictionUrinary Retention

TachycardiaArrhythmias

BronchodilationUterine Relaxation

Tremor

DilatationHypertension

SmoothMuscle

Heart

SkeletalMuscle

Vascular

Alpha Beta1 Beta2

MECHANISMS OF BRONCHODILATIONBETA2-ADRENERGIC AGENTS

BRONCHODILATION

AdenylylCyclase

cAMP cAMPATP

BRONCHODILATION

Beta2 -selectiveAdrenergic Agents

Drawing by Dennis E. Doherty, MD

MECHANISMS OF AIRWAY OBSTRUCTION

VagusNerve

Airway SmoothMuscle Cell

MediatorMast Cell

Antigen

Antibody

Classical Theory Reflex Theory

PATHWAYS OF ATOPIC ASTHMA


Muscarinic Receptor Subtypes in Airways

M 3 RECEPTORS

M 2 RECEPTORSInhibit Ach Release

Acetylcholine

Acetylcholine

AIRWAY SMOOTH MUSCLE CELLS MUCUS GLANDS

CNS Parasympathetic

Nerves


Vagal Parasympathetic (X)

.

BRONCHO- DILATATION

BRONCHO- CONSTRICTION

SYMPATHETIC (CATECHOLAMINES)

PURINERGIC(VIP, NO)

PARASYMPATHETIC (ACETYLCHOLINE) (METHACHOLINE)

DED


MECHANISMS OF BRONCHODILATIONANTICHOLINERGIC AGENTS

Increased Cyclic GMP

Calcium

Calcium

CHOLINERGICRECEPTOR

Acetyl-Choline (ACh)X

CHOLINERGIC M


Decreased Smooth Muscle Constriction andMucus Gland Secretion

Ipratropium BromideAtropine

M3

Parasympathetic Sympathetic

DISTRIBUTION OF CHOLINERGIC AND ADRENERGIC RECEPTORS

CHRONICBRONCHITIS EMPHYSEMA

ASTHMA

AIRFLOWOBSTRUCTION

Treatment of COPD

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)

DiagnoseDiagnose

Reduce Reduce RiskRisk

Smoking cessationImmunizeReduce other exposures

Reduce Reduce SymptomsSymptoms

Reduce Reduce ComplicationsComplications

BronchodilatorsConsider inhaled steroidsPulmonary rehabilitation

Consider oxygenTreat exacerbations

Spirometry

Education

Education

Education

Education

STEPWISE TREATMENT OF COPD BASED ON SEVERITY(GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276)

Stage 0:At Risk

• Normal spirometry• Avoid Risks• Vaccinate

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 HEALTHEDUCATION PROGRAM (NLHEP)

• TEST YOUR LUNGS• KNOW YOUR NUMBERS

A new national healthcare initiative aimed at the diagnosis of early stages of COPD and related disorders.

www.nlhep.org

OFFICE SPIROMETERS


ASTHMA

AIRFLOWOBSTRUCTION

Treatment of COPD


OBJECTIVES FOR INTERVENTIONSIN 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

Bronchodilation is first-line pharmacologic therapy in COPD

(GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276)

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

.

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8

Hours After Test Dose

Test Day 85

Ipratroprium (N=176)Albuterol (N=165)

Chest 105:1411, 1994

% C

hang

e in

mea

n FE

V 1

LONG-ACTING INHALED BETA AGONISTS

• Duration: Bronchodilation lasts for up to 12 hours

• Peak action: Fomoterol (30 min), onset within 5 minSalmeterol (1-2hr), not indicated for exacerbations

• Most helpful:– Non-compliant patients (less frequent dosing)– Nocturnal component of COPD

• ? Of cost-benefit compared to short-acting beta-agonists

SALMETEROL IN COPD(Mahler et al, Chest 115:957, 1999)

Cha

nge

from

Bas

elin

eFE

V 1

PlaceboSalmeterolIpratopium

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

0.95

1.00

1.05

1.10

1.15

1.20

1.25

1.30

1.35

-1 0 1 2 3 4 5 6 7 8 9 10 11 12

Time after administration (h)

Tiotropium (n = 202)

Placebo (n = 179)

Long-Acting Anticholinergic - TiotropiumChange in FEV1: Six Month Study

P < 0.001 for tiotropium vs placebo

FEV 1

(L)

(DonohueJF, Chest 2002;122:47-55 )

Day 169

0.95

1.00

1.05

1.10

1.15

1.20

1.25

1.30

1.35

-1 0 1 2 3 4 5 6 7 8 9 10 11 12


Tiotropium (n = 202)Salmeterol (n = 203)Placebo (n = 179)

Day 169

Change in FEV1: Tiotropium vs Salmeterol vs Placebo

P < 0.001 for tiotropium vs placeboP < 0.05 for tiotropium vs salmeterol

FEV 1

(L)


0.95

1.00

1.05

1.10

1.15

1.20

1.25

1.30

1.35

-1 0 1 2 3 4 5 6 7 8 9 10 11 12


Tiotropium (n = 202)Salmeterol (n = 203)Placebo (n = 179)

Day 169

Day 1

Change in FEV1: Tiotropium vs Salmeterol vs Placebo

P < 0.001 for tiotropium vs placebo on all test days post-treatmentP < 0.05 for tiotropium vs salmeterol on all test days except day 1

FEV 1

(L)


Binding and Dissociation

Disse B et al. Life Sci 1993

Apparent KD (nM)Ipratropium 0.43 0.54 0.69Tiotropium 0.27 0.12 0.33

Dissociation Half-Life (hours)[3H]-Ipratropium 0.11 0.035 0.26[3H]-Tiotropium 14.6 3.6 34.7

Human Muscarinic Receptors in CHO Cells

M1 M2 M3

KD = dissociation constant


ASTHMA

AIRFLOWOBSTRUCTION

Combination Therapy in COPD


Bronchodilating Effects of CombinedTherapy With Clinical Dosages ofIpratropium Bromide and Salbutamol forStable COPD:Comparison With Ipratropium Bromide Alone

Akihiko Ikeda, MD, Koicht Nishimura

Ikeda A, et al. Chest. 1996;109:294.

0

10

20

30

40

50 80 mcg ipratropium + 400 mcg salbutamol40 mcg ipratropium + 200 mcg salbutamol80 mcg ipratropium40 mcg ipratropiumPlacebo

FEV

1 (%

cha

nge)

0 1 2 3 4 5 6 7 8 Time After Test Dose (h)

IPRATROPIUM BROMIDE AND SALBUTAMOL

.

0

5

10

15

20

25

30

35

40

0 1 2 3 4 5 6 7 8

Hours After Test Dose

Test Day 85

Ipratroprium + Albuterol(N=173)

Ipratroprium (N=176)Albuterol (N=165)

Chest 105:1411, 1994

% C

hang

e in

mea

n FE

V1

Ipratropium and Albuterol per MDIis More Effective than Either Agent Alone

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 Anticholinergicand a Long-Acting Beta-2 Agonist

-5-2.5

02.5

57.510

12.5

0 0.5 1 2 3 4 5 6 7 8 9 10 11 12Time (hours)

FE

V 1 (%

Pre

d.)

Salmeterol 50 µg + ipratropium 40 µg Salmeterol 50 µg Placebo

van Noord JA et al. Eur Respir J 2000;15:878-885


• 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

0

10

20

Albuterol Ipratropium Ipratropium + Albuterol

% of PatientsWith Exacerbations

Friedman M, et al. Chest. 1999;115:635-641.

FREQUENCY OF EXACERBATIONS

0 50 100 150 200 250 300 350 400 450 500

Acquisition cost of primarypulmonary drug

Acquisition cost of drugsadded during exacerbations

Hospitalization cost

Albuterol

Ipratropium

Ipratropium + Albuterol

Friedman M, et al. Chest. 1999;115:635-641.

COST OF HOSPITALIZATION FOR EXACERBATION



• Beta Agonists (Sympathomimetic)• Short-acting inhaled (numerous available)• Long-acting inhaled (Salmeterol, Fomoterol)



Relationship Between Plasma Theophylline Concentrations and Clinical Effects

mg/liter

EfficacyToxicityConcentration

5

10

20

40

60

} Minimal

OptimalGastrointestinal Upset

Nervousness

ArrhythmiasConvulsions

Theophylline Metabolism

Age

Smoking

Formulation

LiverDisease

HeartDisease

Infection

Severityof Illness



• Beta Agonists (Sympathomimetic)• Short-acting inhaled (numerous available)• Long-acting inhaled (Salmeterol, Fomoterol)



• 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

LUNG INFLAMMATION IN ASTHMA IS DIFFERENT THAN THE LUNG INFLAMMATION IN COPD

GOLD Guidelines

• 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.

(GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276)

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 DURINGACUTE EXACERBATIONS OF COPD

Niewoehner et al NEJM 1999;340:1941

MONTHLY ACQUISITION COSTS FOR COPD DRUGS (AWP)(REDBOOK, 2002 Edition)

0 25 50 75 100 125

Albuterol

AWP/month (Dollars)

No. MDIs/Month

Ipratropium

Albuterol +Ipratropium

Albuterol +Ipratropium(single MDI)

Formoterol

Salmeterol

Salmeterol +Albuterol

1.2

1.2

1.2 + 1.2

1.2

1.0

1.0

1.0 + 1.2

MONTHLY ACQUISITION COSTS FOR COPD DRUGS (AWP)(REDBOOK, 2002 Edition)

0 25 50 75 100 125 150 175 200

AWP/month (Dollars)

No. MDIs/MonthAlbuterol

Ipratropium

Albuterol +Ipratropium(Single MDI)

Salmeterol + Albuterol

Formoterol + Albuterol

Beclomethasone

Fluticasone 110

Fluticasone 220

Flunisolide

Budesonide

Fluticasone 500+ Salmeterol 50

Combination

1.2

1.2

1.2

1.0 + 1.2

1.0 + 1.2

1.2

1.0

1.0

1.2

0.6

1.0

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)

• 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)

THE NATIONAL COPD AWARENESS PANEL (NCAP)Journal of Respiratory Diseases 21:S1-21, Sept 2000Journal of Respiratory Diseases 23:S1-52, Sept 2002

COPD Management in Primary CareNCAP- 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 65-

85% 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

copd: management of stable disease and exacerbations

Documents

j respir crit care med

moderate copd fev1fvc

mild copd fev1fvc

shortacting bronchodilators

inhaled salmeterol

inhaled numerous availablelong

trial of inhaled steroids

severitygold guidelines