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 2.5 2.0 1.5 1.0 0.5 0

Heart Disease

Stroke

Other CVD

COPD

All Other Causes

–59%

–64%

–35% 1965 - 98

+163%

–7%

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
Repair Mechanisms

Proteinases

Emphysema Chronic Bronchitis

*CD8+ T-lymphocytes Macrophages Neutrophils IL-8 and TNFα

COPD Therapy Concepts
• Life prolonging vs. symptomatic therapies • Spirometry - the 6th vital sign • Use of clinical practice guidelines

COPD Therapy
Prolong Life
• • • • • • Smoking Cessation Oxygen Reduce exacerbations Pulmonary Rehabilitation LVRS (selected patients) Lung Transplantation

Symptomatic
• MDI Therapy
– SA beta-2 agonists – LA beta-2 agonists – SA and LA Anticholinergics

• Theophylline • Corticosteroids (inhaled or oral) • Combination Preparations
– SABA and anticholinergic – LABA and corticosteroids

Spirometry - The Sixth Vital Sign
Indications: Symptoms or >10 pack year smoker
0 1 2 Liter 3 FEV 1 FEV 1 FVC
5.200 3.900

FEV 1/ FVC
80 % 60 %

Normal COPD

4.150 2.350

COPD
4 5 1 2 FEV 1

FVC

Normal
3 4

FVC 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
q q q

Education Pharmacologic Non-pharmacologic

1. Manage exacerbations

Management of COPD Stage 0: At Risk
Characteristics • Risk factors •Chronic symptoms - cough - sputum • No spirometric abnormalities Recommended Treatment •Adjust risk factors •Immunizations

Management of COPD Stage I: Mild COPD
Characteristics • FEV1/FVC < 70 % • FEV1 > 80 % predicted • With or without symptoms Recommended Treatment

• Short-acting
bronchodilator as needed

Management of COPD Stage II: Moderate COPD
Characteristics •FEV1/FVC < 70% •50% < FEV1< 80% predicted •With or without symptoms Recommended Treatment •Treatment with one or more long-acting bronchodilators •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 glucocorticosteroids if repeated exacerbations (>3/year)

Management of COPD Stage IV: Very Severe COPD
Characteristics •FEV1/FVC < 70% •FEV1 < 30% predicted or presence of respiratory failure or right heart failure Recommended Treatment
•Treatment with one or more longacting bronchodilators •Inhaled glucocorticosteroids if repeated exacerbations (>3/year) •Treatment of complications •Rehabilitation •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
• Worsening dyspnea • Increased sputum purulence • Increase in sputum volume

Severity
• Severe - all 3 elements • Moderate - 2 elements • 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 (per year) Number
(patients)

SGRQ

Symptoms

Activities

Impacts

0-2 Infrequent 3-8 Frequent Mean = 3

32

48.9

53.2

67.7

36.3

38

64.1

77.0

80.9

50.4

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 Infection
25%

Unknown
20%

Bacterial Infection
50%

Acute Inflammation

Air Pollution
5%

Exacerbation

Therapy of COPD Exacerbation
Guidelines

Variable
Diagnostic

ACCP-ACP
CXR for admissions

GOLD
CXR, EKG, ABG, sputum culture, lytes, cbc

Bronchodilators Ipratroprium, add B2 B2 agonist, add agonist. No methylxanthine ipratroprium. Yes methylxanthine Delivery system Antibiotics None preferred Yes, in selected (severe). Duration unclear
Ann Int Med 134:595, 2001

Not discussed Yes, with purulence, Rx local sensitivities
http:/www.goldcopd.com

Therapy of COPD Exacerbation
Guidelines

Variable
Steroids Oxygen Chest PT

ACCP-ACP
Yes, for up to two weeks Yes No

GOLD
Yes, oral or IV for 10-14 days Yes - target PaO2 60 torr or Sat of 90% with ABG check Maybe - for atelectasis or sputum control Not discussed

Mucokinetics No

Ann Int Med 134:595, 2001

http:/www.goldcopd.com

Therapy of COPD Exacerbation
Guidelines

Variable Mechanical Ventilation

ACCP-ACP
Yes - use NIPPV in severe exacerbation

GOLD
Yes if ≥2 of: Severe dyspnea, access. muscle or paradox, pH <7.35 and PCO2 >45, RR>25 LMWH, fluids, diet

Other
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%CHEST 118:1294, 2000 Casaburi et al.

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 Room to Breathe FRC

Volume

TLC

FRC RV

RV

Normal

COPD

Tiotropium Exercise Trial: Difference from Placebo with Tiotropium for Resting Pulmonary Function
Day 21 600 Day 42

* * *

Difference from placebo

400 200 0 -200 -400 -600 -800

* *

*
RV TLC

FEV
<0.05 versus placebo

1

FVC

IC

FRC

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

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