COPD: MANAGEMENT OF STABLE DISEASE AND EXACERBATIONS Dennis E. Doherty, M.D. Professor of Medicine Chief, Division of Pulmonary and Critical Care Medicine Co-chairman, National Lung Health Education Program University of Kentucky Medical Center Lexington Veterans Administration Medical Center OBJECTIVES • Historical Perspective • Mechanisms of Airflow Obstruction • Treatment Modalities MECHANISMS OF AIRFLOW OBSTRUCTION IN COPD PERIPHERAL ADRENERGIC ACTIONS Alpha Smooth Muscle Bronchoconstriction Urinary Retention Beta2 Bronchodilation Uterine Relaxation Tachycardia Arrhythmias Heart Skeletal Muscle Vascular Beta1 Tremor Hypertension Dilatation MECHANISMS OF BRONCHODILATION BETA2-ADRENERGIC AGENTS Beta2-selective Adrenergic Agents Adenylyl Cyclase ATP cAMP cAMP BRONCHODILATION Drawing by Dennis E. Doherty, MD MECHANISMS OF AIRWAY OBSTRUCTION PATHWAYS OF ATOPIC ASTHMA Vagus Nerve Mast Cell Antibody Mediator Airway Smooth Muscle Cell Antigen Classical Theory Reflex Theory Drawing by Dennis E. Doherty, MD Muscarinic Receptor Subtypes in Airways CNS Vagal Parasympathetic (X) Parasympathetic Nerves M 2 RECEPTORS Inhibit Ach Release Acetylcholine Acetylcholine M 3 RECEPTORS AIRWAY SMOOTH MUSCLE CELLS MUCUS GLANDS Drawing by Dennis E. Doherty, MD Drawing by Dennis E. Doherty, MD MECHANISMS OF BRONCHODILATION ANTICHOLINERGIC AGENTS CHOLINERGIC M Ipratropium Bromide Atropine Increased Cyclic GMP Calcium X M3 AcetylCholine (ACh) CHOLINERGIC RECEPTOR Calcium Decreased Smooth Muscle Constriction and Mucus Gland Secretion Drawing by Dennis E. Doherty, MD DISTRIBUTION OF CHOLINERGIC AND ADRENERGIC RECEPTORS Parasympathetic Sympathetic Treatment of COPD CHRONIC BRONCHITIS EMPHYSEMA AIRFLOW OBSTRUCTION ASTHMA 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) Diagnose Reduce Risk Reduce Symptoms Reduce Complications Spirometry Education Smoking cessation Education Immunize Reduce other exposures Education Bronchodilators Consider inhaled steroids Pulmonary rehabilitation Education Consider oxygen Treat exacerbations STEPWISE TREATMENT OF COPD BASED ON SEVERITY (GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276) • Avoid Risks • Vaccinate Stage 0: At Risk • Normal spirometry 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 HEALTH EDUCATION PROGRAM (NLHEP) A new national healthcare initiative aimed at the diagnosis of early stages of COPD and related disorders. • TEST YOUR LUNGS • KNOW YOUR NUMBERS www.nlhep.org OFFICE SPIROMETERS Treatment of COPD CHRONIC BRONCHITIS EMPHYSEMA AIRFLOW OBSTRUCTION ASTHMA American Thoracic Society. Am J Respir Crit Care Med. 1995. OBJECTIVES FOR INTERVENTIONS IN 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 (GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276) Bronchodilation is first-line pharmacologic therapy in COPD 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 . % Change in mean FEV1 Test Day 85 Albuterol (N=165) 30 Ipratroprium (N=176) 25 20 15 10 5 0 0 1 2 3 4 5 6 7 8 Hours After Test Dose Chest 105:1411, 1994 LONG-ACTING INHALED BETA AGONISTS • • Duration: Bronchodilation lasts for up to 12 hours Peak action: Fomoterol (30 min), onset within 5 min Salmeterol (1-2hr), not indicated for exacerbations • Most helpful: • ? Of cost-benefit compared to short-acting beta-agonists – Non-compliant patients (less frequent dosing) – Nocturnal component of COPD SALMETEROL IN COPD (Mahler et al, Chest 115:957, 1999) Change from Baseline FEV1 Placebo Salmeterol Ipratopium 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 Long-Acting Anticholinergic - Tiotropium Change in FEV1: Six Month Study Tiotropium (n = 202) Day 169 Placebo (n = 179) 1.35 1.30 FEV1 (L) 1.25 1.20 1.15 1.10 1.05 1.00 0.95 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 Time after administration (h) P < 0.001 for tiotropium vs placebo (DonohueJF, Chest 2002;122:47-55 ) Change in FEV1: Tiotropium vs Salmeterol vs Placebo Tiotropium (n = 202) Salmeterol (n = 203) Day 169 Placebo (n = 179) 1.35 1.30 FEV1 (L) 1.25 1.20 1.15 1.10 1.05 1.00 0.95 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 Time after administration (h) P < 0.001 for tiotropium vs placebo P < 0.05 for tiotropium vs salmeterol (DonohueJF, Chest 2002;122:47-55 ) Change in FEV1: Tiotropium vs Salmeterol vs Placebo Day 1 Tiotropium (n = 202) Day 169 Salmeterol (n = 203) Placebo (n = 179) 1.35 1.30 FEV1 (L) 1.25 1.20 1.15 1.10 1.05 1.00 0.95 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 Time after administration (h) P < 0.001 for tiotropium vs placebo on all test days post-treatment P < 0.05 for tiotropium vs salmeterol on all test days except day 1 (DonohueJF, Chest 2002;122:47-55 ) Binding and Dissociation Human Muscarinic Receptors in CHO Cells M1 M2 M3 Apparent KD (nM) Ipratropium Tiotropium 0.43 0.54 0.69 0.27 0.12 0.33 Dissociation Half-Life (hours) [3H]-Ipratropium [3H]-Tiotropium KD = dissociation constant 0.11 0.035 0.26 14.6 3.6 34.7 Disse B et al. Life Sci 1993 Combination Therapy in COPD CHRONIC BRONCHITIS EMPHYSEMA AIRFLOW OBSTRUCTION ASTHMA American Thoracic Society. Am J Respir Crit Care Med. 1995. Bronchodilating Effects of Combined Therapy With Clinical Dosages of Ipratropium Bromide and Salbutamol for Stable COPD: Comparison With Ipratropium Bromide Alone Akihiko Ikeda, MD, Koicht Nishimura IPRATROPIUM BROMIDE AND SALBUTAMOL FEV1 (% change) 50 80 mcg ipratropium + 400 mcg salbutamol 40 mcg ipratropium + 200 mcg salbutamol 80 mcg ipratropium 40 mcg ipratropium Placebo 40 30 20 10 0 0 1 2 3 4 5 Time After Test Dose (h) 6 7 Ikeda A, et al. Chest. 1996;109:294. 8 Ipratropium and Albuterol per MDI is More Effective than Either Agent Alone . Test Day 85 40 % Change in mean FEV1 Albuterol (N=165) 35 Ipratroprium (N=176) Ipratroprium + Albuterol (N=173) 30 25 20 15 10 5 0 0 1 2 3 4 5 6 7 8 Hours After Test Dose Chest 105:1411, 1994 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 Anticholinergic and a Long-Acting Beta-2 Agonist FEV1 (% Pred.) 12.5 Salmeterol 50 µg + ipratropium 40 µg Salmeterol 50 µg Placebo 10 7.5 5 2.5 0 -2.5 -5 0 0.5 1 2 3 4 5 6 7 Time (hours) van Noord JA et al. Eur Respir J 2000;15:878-885 8 9 10 11 12 OBJECTIVES FOR INTERVENTIONS IN THE CHRONIC MANAGEMENT OF COPD • • • • • • • • 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 FREQUENCY OF EXACERBATIONS 20 % of Patients With Exacerbations 10 0 Albuterol Friedman M, et al. Chest. 1999;115:635-641. Ipratropium Ipratropium + Albuterol COST OF HOSPITALIZATION FOR EXACERBATION Acquisition cost of primary pulmonary drug Albuterol Acquisition cost of drugs added during exacerbations Ipratropium Hospitalization cost Ipratropium + Albuterol 0 50 100 150 Friedman M, et al. Chest. 1999;115:635-641. 200 250 300 350 400 450 500 PHARMACOLOGIC ARMAMENTARIUM • • • • Anticholinergics (Parasympatholytic) • • Short-acting inhaled (Ipratropium) Long-acting (Tiotropium) Beta Agonists (Sympathomimetic) • • Short-acting inhaled (numerous available) Long-acting inhaled (Salmeterol, Fomoterol) Methylxanthines (Sympathomimetic) Anti-Inflammatory • • • Oral Steroids Inhaled Steroids Other anti-inflammatory agents (data pending) Relationship Between Plasma Theophylline Concentrations and Clinical Effects Concentration Toxicity Efficacy mg/liter 5 10 20 40 60 } Minimal Optimal Gastrointestinal Upset Nervousness Arrhythmias Convulsions Liver Disease Age Formulation Heart Disease Theophylline Metabolism Infection Smoking Severity of Illness PHARMACOLOGIC ARMAMENTARIUM • • • • Anticholinergics (Parasympatholytic) • • Short-acting inhaled (Ipratropium) Long-acting (Tiotropium) Beta Agonists (Sympathomimetic) • • Short-acting inhaled (numerous available) Long-acting inhaled (Salmeterol, Fomoterol) Methylxanthines (Sympathomimetic) Anti-Inflammatory • • • Oral Steroids Inhaled Steroids Other anti-inflammatory agents (data pending) LUNG INFLAMMATION IN ASTHMA IS DIFFERENT THAN THE LUNG INFLAMMATION IN COPD • 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 GOLD Guidelines (GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276) • • 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. 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 DURING ACUTE EXACERBATIONS OF COPD Niewoehner et al NEJM 1999;340:1941 OBJECTIVES FOR INTERVENTIONS IN THE CHRONIC MANAGEMENT OF COPD • • • • • • • • 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 MONTHLY ACQUISITION COSTS FOR COPD DRUGS (AWP) (REDBOOK, 2002 Edition) No. MDIs/Month 1.2 Albuterol 1.2 Ipratropium Albuterol + Ipratropium 1.2 + 1.2 Albuterol + Ipratropium (single MDI) 1.2 1.0 Formoterol Salmeterol 1.0 Salmeterol + Albuterol 1.0 + 1.2 0 25 50 75 AWP/month (Dollars) 100 125 MONTHLY ACQUISITION COSTS FOR COPD DRUGS (AWP) (REDBOOK, 2002 Edition) No. MDIs/Month Albuterol 1.2 Ipratropium 1.2 Albuterol +Ipratropium (Single MDI) 1.2 Formoterol + Albuterol 1.0 + 1.2 Salmeterol + Albuterol 1.0 + 1.2 Beclomethasone 1.2 Fluticasone 110 1.0 Fluticasone 220 1.0 Flunisolide 1.2 Budesonide 0.6 Fluticasone 500 + Salmeterol 50 Combination 1.0 0 25 50 75 100 125 150 175 200 AWP/month (Dollars) OBJECTIVES FOR INTERVENTIONS IN THE CHRONIC MANAGEMENT OF COPD • • • • • • • • 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 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) THE NATIONAL COPD AWARENESS PANEL (NCAP) Journal of Respiratory Diseases 21:S1-21, Sept 2000 Journal of Respiratory Diseases 23:S1-52, Sept 2002 • • • • • • • • • 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) COPD Management in Primary Care NCAP- 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 6585% 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