Nashat H. Rabadi,MD FCCP

1. Nashat H. Rabadi,MD FCCP Pulmonary and Critical Care Medicine Buffalo Medical Group PC Associate Clinical Professor State University of New York at Buffalo Chief of Pulmonary and Critical Care Medicine Sisters of Charity Hospital

2. Impact of COPD in the US • Affects ~20 million Americans1 • Annual cost $32.1 billion in 20022 • $18 billion in direct healthcare costs • $14.1 billion in indirect morbidity and mortality costs • The fourth leading cause of death3 • 118,744 deaths in 2001 1. Mannino et al. MMWR. 2002;51(SS-6):1-16. 2. Morbidity & Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Diseases. NHLBI, NIH; May 2002. 3. Arias et al. Natl Vital Stat Rep. 2003;52(3):1-116.

3. COPD vs Asthma: Direct Cost $18.0 Billion $9.4 Billion $2.7 † $0.8 $3.4 Direct Cost (Billions) $2.6 $7.3 $3.1 $3.7 $3.7 * No estimate available for asthma. † Physicians, clinics, and other professional services. Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Diseases. NIH, NHLBI. May 2002.

4. Leading Causes of Deaths in U.S., 1998 COPD Deaths: 124,181 (1999), 45.8 deaths/100,000 NHLBI, Morbidity and Mortality Chartbook, 2000

5. Audience Response System Question #1 The typical demographic of the COPD patient is male gender and older than 65 years of age. 1. True 2. False

6. 3.0 Coronary Heart Disease Stroke Other CVD COPD All Other Causes 2.5 2.0 1.5 Proportion of 1965 rate 1.0 0.5 –59% –64% –35% +163% –7% 0 1965-1998 1965-1998 1965-1998 1965-1998 1965-1998 Percent Change in Adjusted Death Rates, United States, 1965-1998 Global Obstructive Lung Disease (GOLD) Initiative Web site. Available at: www.goldcopd.com. Accessed April 2, 2001.

7. 90 † † 80 † † † † † † † † † † † 70 † † 60 50 Rate/1,000 Population* 40 30 Male Female Total 20 10 0 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 Year Prevalence of COPD in the US • The number of patients with COPD has increased nearly 50% from 1980 to 2000 • Since 1987, the prevalence of COPD among women has been significantly higher than that among men * Age-adjusted to 2000 US population. †Represents a statistically significant difference from rate among males. Mannino et al. MMWR. 2002;51(SS-6):1-16.

9. Physician Specialty Seen Most Often Other 2% Not Sure 5% Cardiologist 3% Allergist 1% Respiratory Specialist 22% General/Family 52% Internal Medicine 15% “COPD in America” survey conducted by Schulman, Ronca, and Bucuvalas, Inc. Feb 2001.

10. Spectrum of Disease COPD ChronicBronchitis Emphysema Mixed Disease Asthma

11. History of COPD Guidelines

12. Definition of COPD: GOLD 2003 • Clinical syndrome with symptoms including • Intermittent or persistent cough • Sputum production • Persistent and/or progressive dyspnea • History of exposure to risk factors for COPD (smoking tobacco) • Disease state characterized by airflow limitation that is not fully reversible • Usually progressive • Usually associated with an abnormal inflammatory response of the lungs to noxious particles or gases GOLD=Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at: www.goldcopd.com/revised.pdf.

13. 2004 ATS/ERS Definition of COPD

14. Risk Factors for COPD • Host factors • Genetic (eg, -1 antitrypsin deficiency) • Airway hyperresponsiveness • Lung growth • Environmental factors • Tobacco smoke • Occupational dusts and chemicals • Air pollution (outdoor and indoor) • Infections • Socioeconomic status Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at: www.goldcopd.com/revised.pdf.

15. COPD Risk: Smoking • Primary risk factor for COPD • Higher prevalence of respiratory symptoms and lung function abnormalities • Greater annual rate of decline in FEV1 • Greater COPD mortality rate than nonsmokers • Differences between cigarette smokers and nonsmokers increase in direct proportion to the quantity of smoking Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at: www.goldcopd.com/revised.pdf.

17. COPD Affects a Wide Range of Patients • It’s Not Just A Disease Of the Elderly Data from the third National Health and Nutrition Examination Survey (NHANES III) : 70% of patients with COPD are younger than age of 65

18. Differential Diagnosis of COPD • COPD must be distinguished from the following : • Asthma • Acute bronchitis • Congestive heart failure • Bronchiectasis • Tuberculosis • Obliterative bronchitis

19. CXR Changes Occur Very Latein the Course of COPD

20. CT Scan of Emphysema

21. Measurement of Airway Obstruction:Spirometry • Simple to measure • Reproducible • On average reflects functional status and prognosis • For years has been the gold standard used by the FDA and scientific community to assess outcome

22. 7 FVC = 5.8 L 6 5 4 Liters(BTPS) 3 2 1 0 0 1 2 3 4 5 6 Seconds Measurement of Forced Vital Capacity (FVC)

23. Measurement of Forced Expiratory Volume (FEV1 ) 7 6 FEV1 = 4 L 5 4 Liters(BTPS) 3 2 1 0 0 1 2 3 4 5 6 Seconds

24. FEV1: Prognostic Implications FEV1 Survival(%)  50% 1 2 3 Years Anthonisen NR et al. Am Rev Respir Dis. 1986;133:14-20.

25. COPD Risk and Smoking Cessation 100 Never smoked or not susceptible 80 Smoked and susceptible Quit Age 45 60 FEV1 (%) 40 Disability Age 65 20 Death 0 20 30 40 50 60 70 80 90 Age (years) Fletcher C, Peto R. Br Med J. 1977;1:1645-1648.

26. Audience Response System Question #2 In a patient with history of smoking and an FEV1 of < 70% of predicted increases the risk of lung cancer? 1. True 2. False

27. The Use of Spirometry in Patients With COPD

28. When Is Spirometry Recommended?

29. Pathogenesis of COPD Noxious particles and gases Inflammation Airflow Limitation Structural Changes COPD Adapted from Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report. Bethesda, Md: National Heart, Lung, and Blood Institute, National Institutes of Health; March 2001. NIH publication 2701A.

30. Pathophysiological Features of COPD Airway Obstruction StructuralChanges Inflammation Oxidative stress  Neutrophils  Macrophages  CD8+ lymphocytes  IL-8 and TNF- Protease/antiproteaseimbalance Smooth muscle contraction  Cholinergic tone Loss of elastic recoil Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis Adapted from Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report. Bethesda, Md: National Heart, Lung, and Blood Institute, National Institutes of Health; March 2001. NIH publication 2701A.

32. Effect of Bronchodilators Normal COPD Bronchodialted airway Constricted airway R ~ 1/radius4 Barnes PJ. Managing Chronic Obstructive Pulmonary Disease, 2nd ed. London: Scientific Press Limited.; 2001. Used with permission.

33. Stage 0Chronic cough/sputum; PFT WNL Stage IFEV1  80%, FEV1/FVC <70%, with/without Sx Stage IIFEV1 50%-80%, FEV1/FVC <70%, with/without Sx Stage III FEV1 30%-50%, FEV1/FVC <70%, with/without exacerbations Stage IVFEV1 < 30% or presence of respiratory failure or right-heart failure, FEV1/FVC <70% GOLD Guidelines for COPD:Stages of Severity

34. Audience Response SystemQuestion # 3 Leukotriene modifiers play an important role in the early therapy of COPD? 1. True 2. False

35. Recommended Progression of COPD Pharmacotherapy Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Updated 2003. Available at: www.goldcopd.com/revised.pdf.

36. Important Clinical Outcomesin COPD • FEV1 • Dyspnea • HRQoL • Acute Exacerbations • Mortality • Lung Volume • Exercise endurance

37. Audience Response SystemQuestion # 4 Which of the following therapies wil improve survival/mortality in patient with COPD? 1. Oxygen therapy 2. Chronic antibiotic treatment 3. Smoke cessation 4. a and c 5. a, b and c

38. Bronchodilators Short-acting albuterol, ipratropium,ipratropium/albuterol Long-acting Salmeterol , formoterol tiotropium theophylline oral 2-agonists Corticosteroids Inhaled Oral Oxygen Current Treatment Options

39. Audience Response SystemQuestion # 5 • Which of the following will decrease (slow down) the rate of decline in the FEV1 in COPD patients: • 1. Inhaled corticosteroids • 2. Long-acting bronchodilators • 3. Oxygen therapy • 4. Smoke cessation • 5. Pulmonary rehabilitation

40. Bronchodilators in COPD • Central to symptom management of COPD • Inhaled agents are preferred • Choice depends on availability, individual response and adverse effects • Long acting agents are more effective and convenient, but more expensive • Combinations may be more effective and with less adverse effects GOLD guidelines AJRCCM 2001 163:1256-76

41. Bronchodilators: Site of Action Anticholinergic M1 M2 M3 Contraction Relaxation cAMP AMP Smooth Muscle Cell -agonist Theophylline Spector SL. In: Anticholinergic Agents in the Upper and Lower Airways. New York, NY: Marcel Dekker; 1999.

42. Current Treatment Options • Bronchodilators • Short-acting • albuterol, ipratropium,ipratropium/albuterol

43. Short-Acting Bronchodilators: Albuterol • Stimulates 2-receptors on airway smooth muscle • Onset of effect: 1-3 minutes • Duration of action: 4-6 hours • Reliever/rescue medication: PRN dosing • 2:1 selectivity • Albuterol = 1,375:1 • Salmeterol = 85,000:1 • Formoterol = 400:1

44. Short-Acting Bronchodilators: Ipratropium • Nonspecific muscarinic receptor antagonist – Decreases airway smooth muscle tone • Onset of action: 20-30 minutes • Duration of action: 4-6 hours • Maintenance medication: 2-3 inhalations q.i.d. according to package insert Rennard et al. Chest. 1995;107:171S-175S.

45. Duration of Action 1.00 0.95 0.90 0.85 0.80 Salmeterol SalbutamolIpratropium Placebo Mean Increase in FEV1(L) 0 1 2 3 4 5 6 8 10 12 Time (hours) Matera MG et al. Pulmonary Pharmacol. 1995;8:267-271.

46. Short-Acting Bronchodilators in COPD Responders (%) * Time Postadministration (minutes) *% of patients demonstrating 15% or greater increase in FEV1 vs baseline. Albuterol = ipratropium < (albuterol + ipratropium).Dorinsky PM et al. Chest. 1999;115:966-971.

47. Current Treatment Options • Bronchodilators • Short-acting albuterol, ipratropium,ipratropium/albuterol • Long-acting Salmeterol / formoterol tiotropium theophylline oral 2-agonists

48. Long-Acting Bronchodilators: Salmeterol • Stimulates 2-receptors on airway smooth muscle • Onset of effect: 20-30 minutes • Duration of action: 12+ hours • Maintenance medication: 1 inhalations b.i.d. • 2:1 selectivity • Albuterol = 1,375:1 • Salmeterol = 85,000:1 • Formoterol = 400:1

49. First-Line Treatment: Salmeterol vs Ipratropium Salmeterol MDI 42 µg b.i.d. Randomized, Double-Blind,and Double-Dummy N = 411 Placebo q.i.d. Ipratropium 36 µg q.i.d. 12 Weeks *All patients received albuterol p.r.n.Mahler DA et al. Chest. 1999;115:957-965.

50. First-Line Therapy: Salmeterol vs Ipratropium All Patients Day 1 0.4 0.3 0.2 0.1 0 Day 1 Baseline Salmeterol 1.36 LIpratropium 1.18 L†Placebo 1.31 L ‡ * ‡ * * * * *  FEV1(L) * * * 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Time (hours) *P < .001 salmeterol vs baseline.†P < .05 IP vs salmeterol and placebo. ‡P < .05 salmeterol vs ipratropium. Mahler DA et al. Chest. 1999;115:957-965.