COPD: Guidelines Update and

Newer Therapies
Outline
• The Problem
• Pathogenesis
• Key Clinical Concepts
– Life Prolonging vs. Symptomatic Therapy
– Spirometry - The Sixth Vital Sign
– Use of clinical practice guidelines
• COPD Exacerbations
• New Horizons
 Percent Change in Age-Adjusted Death
Rates, U.S., 1965-1998
Proportion of 1965 Rate
3.0 Coronary All Other
Stroke Other CVD COPD
Heart Causes
2.5 Disease

2.0

1.5

1.0

0.5

–59% –64% –35% +163% –7%

0
1965 - 98
 COPD in the United States
Age-Adjusted Death Rates* for COPD by State: 1995-1997

x
x
x
Deaths/100,000 Pop
Highest 46-61 (11)
High 41-45 (13)
Low 36-40 (13)
Lowest 19-35 (13)

*Morbidity and Mortality: 2000 Chart Book on Cardiovascular, Lung, and

Blood Diseases. May 2000.
 COPD - Pathogenesis
Tobacco Smoke
Host factors

Chronic Inflammation*
Anti-oxidants Anti-proteinases

Oxidative Stress Proteinases

Repair Mechanisms

*CD8+ T-lymphocytes
Emphysema Macrophages
Neutrophils
Chronic Bronchitis IL-8 and TNF
 COPD Therapy Concepts

• Life prolonging vs. symptomatic

therapies
• Spirometry - the 6th vital sign
• Use of clinical practice
guidelines
 COPD Therapy
Prolong Life Symptomatic
• Smoking Cessation • MDI Therapy
• – SA beta-2 agonists
Oxygen
– LA beta-2 agonists
• Reduce exacerbations – SA and LA Anticholinergics
• Pulmonary Rehabilitation • Theophylline
• LVRS (selected patients) • Corticosteroids (inhaled or
• Lung Transplantation oral)
• Combination Preparations
– SABA and anticholinergic
– LABA and corticosteroids
Spirometry - The Sixth Vital Sign
Indications: Symptoms or >10 pack year smoker

0
FEV1 FVC FEV1/ FVC
Normal 4.150 5.200 80 %
1 COPD 2.350 3.900 60 %

2
FEV1
Liter

3
COPD
4 FVC
FEV1

5 Normal
FVC
1 2 3 4 5 6 Seconds
 COPD Practice Guidelines
Consensus and Evidence-based Guidelines

• European Thoracic Society - 1995

• American Thoracic Society - 1995
• British Thoracic Society - 1997
• Veterans Administration - 1998, 2001
• GOLD - 2003* (http:/www.goldcopd.com)
• ACCP/ACP - 2001* (Ann Int Med 134:595,
2001)
* Evidence-based For comparisons:
Stoller JK. New Eng J Med 346:988, 2002
GOLD Workshop Report
Four Components of COPD
Management - www.goldcopd.com
1. Assess and monitor disease

2. Reduce risk factors

3. Manage stable COPD

 Education
 Pharmacologic
 Non-pharmacologic

4. Manage exacerbations
 Management of COPD
Stage 0: At Risk
Characteristics Recommended Treatment

• Risk factors •Adjust risk factors

•Chronic symptoms •Immunizations
- cough
- sputum
• No spirometric
abnormalities
 Management of COPD
Stage I: Mild COPD
Characteristics Recommended Treatment

• FEV1/FVC < 70 % • Short-acting

• FEV1 > 80 % predicted bronchodilator as
needed
• With or without
symptoms
 Management of COPD
Stage II: Moderate COPD
Characteristics Recommended Treatment

•FEV1/FVC < 70% •Treatment with one or

more long-acting
•50% < FEV1< 80% predicted
bronchodilators
•With or without symptoms
•Rehabilitation
 Management of COPD
Stage III: Severe COPD
Characteristics
•FEV1/FVC < 70%
•30% < FEV1 < 50% predicted
•With or without symptoms
Recommended Treatment
•Treatment with one or
more long-acting
bronchodilators
•Rehabilitation
•Inhaled glucocortico-
steroids if repeated
exacerbations (>3/year)
 Management of COPD
Stage IV: Very Severe COPD
Characteristics Recommended Treatment
•FEV1/FVC < 70% •Treatment with one or more long-
acting bronchodilators
•FEV1 < 30% predicted or •Inhaled glucocorticosteroids if
presence of respiratory repeated exacerbations (>3/year)
failure or right heart •Treatment of complications
•Rehabilitation
failure
•Long-term oxygen therapy if
respiratory failure
•Consider surgical options
 Bronchodilator Therapy
Some General Principles
• Inhaled therapy (with spacer) preferred
• Long-acting preparations more convenient
• Combined preparations improve effectiveness and
decrease risk of side effects
– Ipratroprium-albuterol
– Fluticasone-salmeterol
– Budesonide-formoterol
• MDI almost always as effective as nebulizers (in equal
doses)
 Effectiveness of
BronchodilatorTherapy?
• FEV1 does not always correlate with symptoms
– Concept of “dynamic hyperinflation” in COPD
• Quality of life issues are important
– Chronic fatigue
– Depression
– Physical immobility
– Dyspnea
 COPD - Surgical Options
• Giant Bullous Disease
– Consider bullectomy if see normal lung compression
• Lung Volume Reduction Surgery*
– FEV1 (<20% pred) plus diffuse emphysema or Dlco<20% pred
= high risk of surgical death
– Upper lobe emphysema and low exercise capacity = decreased
mortality, increased exercise and QOL
• Lung Transplantation
– FEV1<25% predicted, younger patient
– 3-5 year mortality 55%
*NETT Research Group. N Eng J Med 348:2059, 2003
 COPD Exacerbation
Definition Elements Severity

• Worsening dyspnea • Severe - all 3 elements

• Increased sputum purulence • Moderate - 2 elements
• Increase in sputum volume • Mild - 1 element plus:
• URI in past 5 days
• Fever without
apparent cause
• Increased wheezing or
cough
• Increase (+20%) of
respiratory rate or
heart rate
Modified from Anthonisen et al. Ann Int Med 106:196, 1987
 COPD Exacerbations
Effect on Quality of Life

Frequency Number
SGRQ Symptoms Activities Impacts
(per year) (patients)

0-2
32 48.9 53.2 67.7 36.3
Infrequent

3-8
38 64.1 77.0 80.9 50.4
Frequent

Mean = 3 Total =70 0.0005 0.0005 0.001 0.002

Seemungal et al. AJRCCM 157:1418, 1998

COPD Exacerbation
Effects on Lung Function Decline
• 109 pts (mean FEV1 = 1.0 L
over 4 years
• Frequent exacerbators:
Infrequent
Frequent – faster decline in PEFR and
FEV1
– more chronic symptoms
(dyspnea, wheeze)
– no differences in PaO2 or
PaCO2

Conclusion:
Frequent exacerbations
accelerate decline in lung
function
Donaldson et al. Thorax 57:847, 2002
 COPD Exacerbation
Pathophysiology - Current Hypothesis

Chronic Inflammation
Viral Unknown
Infection 20%
25%

Bacterial Air
Infection Acute Pollution
50% 5%
Inflammation

Exacerbation
 Therapy of COPD Exacerbation
Guidelines

Variable ACCP-ACP GOLD

Diagnostic CXR for admissions CXR, EKG, ABG,
sputum culture, lytes, cbc
Bronchodilators Ipratroprium, add B2 B2 agonist, add
agonist. No ipratroprium. Yes
methylxanthine methylxanthine
Delivery system None preferred Not discussed

Antibiotics Yes, in selected (severe). Yes, with purulence, Rx

Duration unclear local sensitivities
Ann Int Med 134:595, 2001 http:/www.goldcopd.com
 Therapy of COPD Exacerbation
Guidelines

Variable ACCP-ACP GOLD

Steroids Yes, for up to two Yes, oral or IV for 10-14 days
weeks

Oxygen Yes Yes - target PaO2 60 torr or Sat of

90% with ABG check

Chest PT No Maybe - for atelectasis or sputum

control

Mucokinetics No Not discussed

Ann Int Med 134:595, 2001 http:/www.goldcopd.com

Therapy of COPD Exacerbation
Guidelines

Variable ACCP-ACP GOLD

Mechanical Yes - use NIPPV in Yes if ≥2 of:
severe exacerbation Severe dyspnea,
Ventilation access. muscle or
paradox, pH <7.35 and
PCO2 >45, RR>25
Other LMWH, fluids, diet

Ann Int Med 134:595, 2001 http:/www.goldcopd.com

COPD Therapy - New Horizons
• Newer anti-inflammatory agents
– Matrix metalloproteinase inhibitors
– Specific phosphodiesterase (PDE4) inhibitors
• Cilomilast
• Rofumilast
• Piklanilast
• Anabolic steroids
• Repair agents
– Retinoic acid
• Long-acting anti-muscarinic agents
– tiotropium
 Tiotropium
Specific M1 and M3 Muscarinic Blockade

• 470 patients - stable COPD

• 3 month, randomized, double
blind, once daily tiotropium
vs. placebo
Conclusions:

Increased FEV1 and FVC

No tachyphylaxis
Decreased rescue albuterol
Decreased wheezing, SOB
Dry mouth in 9.3%

Casaburi et al. CHEST 118:1294, 2000

 Tiatroprium
Specific M1 and M3 Muscarinic Blockade

• 1207 patients, double

blind, randomized trial,
• qd tiotropium vs. bid
salmeterol vs. placebo
Conclusions: Tiotropium
Fewer exacerbations
Increased time to first exacerbation
Fewer admissions
Increased QOL

Brusasco et al. Thorax 58:399:2003

Lung Volumes in Obstructive Disease

TLC
Room to
Breathe
TLC
Volume

FRC
Room to
Breathe

FRC
RV

RV

Normal COPD
Tiotropium Exercise Trial: Difference from Placebo
with Tiotropium for Resting Pulmonary Function
Day 21 Day 42
600 *
400
Difference from placebo

* *
200

-200
*
-400

-600 *
*
-800
FEV FVC IC FRC RV TLC
1
<0.05 versus placebo

O’Donnell et al. In press, 2004

O’Donnell et all ERJ 2004 (in press).
 Chronic Obstructive Pulmonary
Disease
Take Home Points
• Effective vs. symptomatic therapies
• Spirometry is useful and under-utilized
• Clinical pathways are helpful and cost effective
• Role of surgery has been clarified
• Significance of frequent exacerbations
• Several new and promising avenues of therapy on the
horizon