Copd: Guidelines Update And Newer Therapies

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

Heart Disease

Stroke

Other CVD

COPD

All Other Causes

2.0 1.5 1.0 0.5 0

–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

Proteinases

Repair Mechanisms

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

FEV 1

Normal COPD

1

Liter

2

FVC

FEV 1/ FVC

4.150

5.200

80 %

2.350

3.900

60 %

FEV 1

3

COPD 4

FEV 1

Normal

5 1

2

3

FVC

FVC 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

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

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 •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

SGRQ

Symptoms

Activities

Impacts

0-2 Infrequent

32

48.9

53.2

67.7

36.3

3-8 Frequent

38

64.1

77.0

80.9

50.4

Mean = 3

Total =70

0.0005

0.0005

0.001

0.002

(patients)

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

Unknown 20%

25%

Bacterial Infection 50%

Acute Inflammation

Exacerbation

Air Pollution 5%

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

None preferred

Not discussed

Antibiotics

Yes, in selected (severe). Duration unclear

Yes, with purulence, Rx 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 weeks

Yes, oral or IV for 10-14 days

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

Ann Int Med 134:595, 2001

Not discussed

http:/www.goldcopd.com

Therapy of COPD Exacerbation Guidelines

Variable Mechanical Ventilation

ACCP-ACP Yes - use NIPPV in severe exacerbation

Other

GOLD Yes if ≥2 of: Severe dyspnea, access. muscle or paradox, pH <7.35 and PCO2 >45, RR>25 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 Casaburi et al. CHEST 118:1294, 2000 in 9.3%

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

Volume

TLC Room to Breathe

TLC

FRC

Room to Breathe

FRC

RV

RV

Normal

COPD

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

Difference from placebo

600 400

Day 42

* *

*

200 0 -200

*

-400

*

-600

*

-800 FEV

1

FVC

IC

FRC

RV

TLC

<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