Objectives. Advances in Managing COPD Patients

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1 4:45 5:30pm Advances in Managing Patients SPEAKER Nicola Hanania, MD, FCCP, FRCP, FACP Presenter Disclosure Information The following relationships exist related to this presentation: Nicola Hanania, MD, FCCP, FRCP, FACP: Contractor and research support from GSK, Mylan, BI, Sunovion, Pearl, Novartis, Pfizer; Speaking and teaching honorarium for Genentech; Honorarium as a consultant for Genentech, Novartis, Pfizer, BI, GSK, Sunovion. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Advances in Managing Patients Nicola A. Hanania, MD, MS, FCCP Associate Professor of Medicine Pulmonary and Critical Care Medicine Director, Asthma Clinical Research Center Baylor College of Medicine, Ben Taub General Hospital Houston, TX Case Presentation: Betty A Classic Scenario Betty is 52-year-old woman who smoked for about 15 years, but stopped 20 years ago. Presents with increasing shortness of breath on exertion over the past 2 years. Suffers from hypertension and osteoporosis. Reports that she used to walk 9 holes of golf with her women s group every Wednesday morning, but has needed to use a golf cart over the past year. She attributed this to getting old. Was told 3 years ago that she had a touch of asthma and was given a short-acting inhaler to use when she was symptomatic. During the past 6 months, she has gone to the emergency department three times for acute bronchitis. Spirometry shows a post-bronchodilator FEV 1 of 62% predicted and an FEV 1 /FVC of 58%. Objectives Discuss the Impact of Review the pathophysiology of Outline guidelines recommendations for assessment of Discuss non-pharmacologic and pharmacologic management strategies of GOLD: Global Initiative for Chronic Obstructive Lung Disease GOLD definition of 1 Common, preventable, treatable partially reversible Characterized by persistent airflow limitation Usually progressive and disabling Associated with enhanced chronic inflammatory response in airways/lung to noxious particles or gases is heterogeneous 2 Multiple risk factors, phenotypes, comorbidities Exacerbations and comorbidities contribute to severity 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) Goh F et al. Expert Rev RespirMed. 2013;7(6):

2 The New Look of Epidemiology Pathophysiology Diagnosis and Assessment Management : The Old Look Perception 3,4,5 is a disease of the elderly 1 is a disease of men 2 1 Tinkelman, et al. Am J Manag Care. 2003;9: Chapman KR. Clin Chest Med. 2004;25: Rennard SI. New Engl J Med. 2004;350: Kleinschmidt P. Chronic obstructive pulmonary disease and emphysema. Available at 5 Rennard SI. New Engl J Med. 2004;305: in Younger Patients and Women Is on the Rise Reality Reality: afflicts the working-age population. Reality: is also a disease of women. The Impact of in the United States In 2010, accounted for million physician office visits/y 1.5 million ED visits 699,000 hospital discharges Costly 2 Direct: $27 billion/y Indirect: $20 billion/y 3rd leading cause of death 3 4th leading cause of hospital readmissions 4 1 Mannino, et al. MMWR. 2002; 51(6 suppl):1-16. Netter illustrations used with permission from Icon Learning Systems, a division of MediMedia USA, Inc. All rights reserved. 1. Ford ES et al. Chest. 2013;144(1): Morbidity & Mortality 2012 Chart Book. pdf. 3. HeronM. Natl Vital Stat Rep. 2012;60(6): Jencks SF et al. N Engl J Med. 2009; 360: The New Look of Epidemiology Pathophysiology Diagnosis and Assessment Management Novel targets for therapy Risk Factors for Exposure to inhaled particles: Tobacco smoke (active and passive) Occupational dusts, organic and inorganic Indoor air pollution from heating and cooking with biomass in poorly ventilated dwellings Outdoor air pollution Susceptibility genes Poor lung growth and development Oxidative stress Female gender Age Respiratory infections Low socioeconomic status Poor nutrition Co-morbidities

3 : Oxidative Stress is Central to the Destruction of Pulmonary Tissue Emphysema and Small Airways Disease Contribute to Total Airflow Limitation in Cigarette Smoke Inflammatory cells (neutrophils, macrophages) Anti-Proteases 1 -anti-trypsin and secretory leukoprotease ROS inhibitor Activation of Nuclear Factor B TNF- IL-8 Neutrophil Recruitment Normal Disrupted alveolar attachments (emphysema) Mucosal inflammation, fibrosis HDAC2 Corticosteroid Resistance Mucus Secretion ROS = Reactive Oxygen Species Plasma Leak Isoprostanes Barnes PJ. N Engl J Med 2000; 343: Barnes PJ et al. Lancet 2004; 363: Bronchoconstriction Airway held open by alveolar attachments (elastin fibers) Sturton G et al. Trends Pharmacol Sci. 2008;29: ; Hogg JC et al. N Engl J Med. 2004;350: Mucus hypersecretion and inflammatory exudate Airway obstructed by: Loss of alveolar attachments Mucosal inflammation and fibrosis Luminal obstruction with inflammatory exudate and mucus Pathophysiology of The New Look of Hyperinflation, central to the pathophysiology of (ie, increased airway resistance), correlates more directly with patient-reported outcomes Hypoxemia Anxiety Tachypnea Airflow obstruction Air trapping Hyperinflation Ventilatory requirement Exacerbations Deconditioning Epidemiology Pathophysiology Diagnosis and Assessment Management Patientreported outcomes Dyspnea Activity limitation Poor health-related quality of life Cooper CB. Respir Med. 2008;20:1-10. Key Indicators for Diagnosis Consider a diagnosis of, and perform spirometry, if any of these indicators * are present in an individual >40 years of age Exertional dyspnea Chronic cough Chronic sputum production History of exposure to risk factors (eg, tobacco smoke) Spirometry is required to make the diagnosis Post-bronchodilator FEV 1 /FVC <0.70 confirms persistent airflow limitation and diagnosis *These indicators are not diagnostic in themselves, but the presence of multiple key indicators increases the probability of a diagnosis. FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated FEV 1 (% predicted at age 25 years) Natural History of Significant Drops in Lung Function Are Often Required for Patients to Become Severely Symptomatic Dyspnea, Cough Exercise Intolerance Age (years) Exacerbations Hospitalizations Systemic Effects Respiratory Failure Pulm Hypertension

4 Assessment of PT # 1 59 y FEV1: 28 % PT # 2 63 y FEV1: 33 % PT # 3 70 y FEV1: 35 % PT # 4 72 y FEV1: 34 % Patient assessment criteria* 2013 MRC: 2/4 PaO2: 70 mmhg MRC: 2/4 PaO2: 57 mmhg MRC: 3/4 PaO2: 66 mmhg MRC: 4/4 PaO2: 60 mmhg MWD: 540 mt 6MWD: 348mt 6MWD: 230 mt 6MWD: 140 mt BMI: 30 BMI: 21 BMI: 34 Heterogeneity BMI: 24 Airflow Limitation Symptoms Exacerbation Risk Spirometry for diagnosis and assessment Validated patient questionnaires (mmrc and CAT) History of exacerbations or spirometric classification *Pharmacological management of should also include an assessment of potential patient comorbidities mmrc: Modified Medical Research Council Dyspnea Scale CAT: Assessment Test 1.Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Global Strategy for Diagnosis, Management and Prevention of : Assessment of Assess symptoms Assessment of : Symptoms Grade Description of Breathlessness 0 I only get breathless with strenuous exercise 1 I get short of breath when hurrying on level ground or walking up a slight hill 2 On level ground, I walk slower than people of the same age because of breathlessness, or have to stop for breath when walking at my own pace 3 I stop for breath after walking about 100 yards or after a few minutes on level ground 4 I am too breathless to leave the house or I am breathless when dressing Modified Medical Research Council Dyspnea Score 0 1 Symptoms More Severe GOLD Website. Updated December 2011 Global Strategy for Diagnosis, Management and Prevention of : Assessment of Assess symptoms Assess degree of airflow limitation using spirometry

5 Assessment of : Lung Function Global Strategy for Diagnosis, Management and Prevention of : Assessment of In patients with post-bronchodilator FEV 1 /FVC < 0.70: Assess symptoms GOLD 1: Mild GOLD 2: Moderate GOLD 3: Severe GOLD 4: Very Severe FEV 1 > 80% predicted 50% < FEV 1 < 80% predicted 30% < FEV 1 < 50% predicted FEV 1 < 30% predicted Assess degree of airflow limitation using spirometry Assess risk of exacerbations *Based on Post-Bronchodilator FEV 1 GOLD Website. Updated December 2011 The frequent exacerbator phenotype : Parameters associated with exacerbation in year 1 (multivariate analysis) Frequent Exacerbations Drive Disease Progression Odds Ratio for 2 vs 0 Exacerbations P<0.001 Analysis by GOLD Stage showed similar results: The best predictor of future exacerbation is a history of previous exacerbations. P<0.001 P<0.001 P<0.001 P=0.002 Lower quality of life Increased inflammation Patients with frequent exacerbations Increased mortality rate Increased risk of recurrent exacerbations Exacerbation During Previous Year FEV 1 (per 100mL decrease) SGRQ score (per 4-point increase) Positive history of reflux or heartburn White Cell Count (per increase of 1000/mL) Faster disease progression Increased likelihood of hospitalization Hurst JR, et al. New Engl J Med. 2010;363: Wedzicha JA & Seemungal TA. Lancet 2007;370: ,; Donaldson GC & Wedzicha JA. Thorax 2006;61: Risk GOLD 2014: Combined Assessment (GOLD Classification of Airflow Limitation) Assessment Using Symptoms, Breathlessness, Spirometric Classification, and Risk of Exacerbations a C High risk, Less symptoms A D High risk, More symptoms B 2 or 1 leading to hospital admission 1 (not leading to hospital admission) 1 Low risk, Less symptoms Low risk, More symptoms 0 CAT < 10 CAT 10 Symptoms mmrc 0 1 mmrc 2 Breathlessness Risk (Exacerbations/Year) Global Strategy for Diagnosis, Management and Prevention of : Assessment of Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations Assess comorbidities a When assessing risk, choose the highest risk according to GOLD grade or exacerbation history.

6 Lung cancer Pulmonary hypertension Comorbidities of Anxiety, depression Cardiovascular disease Take Home Message: Assessing Comorbidities in Look for Anemia Peripheral muscle wasting and dysfunction Comorbidities Diabetes Osteoporosis Metabolic syndrome Cachexia Kao C, Hanania NA. in: Crapo J, ed. Philadelphia, PA: Current Medicine Group;2008. Peptic ulcers GI complications These comorbid conditions may influence mortality and hospitalizations; the patient should be assessed for them routinely and treated appropriately. Look for If Smoker The New Look of Goals of Management Epidemiology Pathophysiology Diagnosis and Assessment Management Airflow Limitation Symptom Burden Exacerbations Functional Limitations Improve Lung Function Slow FEV1 Decline Improve Symptoms Prevent and Manage Exacerbations Improve Health Status and Exercise Tolerance Reduce Hospital Admissions and Mortality Global Initiative for Chronic Obstructive Lung Disease (GOLD) Nonpharmacologic Therapy To Manage Patient Group Non-pharmacological Options for A Low risk, fewer symptoms B Low risk, more symptoms C High risk, fewer symptoms D High risk, more symptoms Smoking Cessation Patient Education Vaccination Description GOLD 1-2 <1 Exacerbation mmrc 0-1 or CAT <10 GOLD 1-2 <1 Exacerbation mmrc >2 or CAT >10 GOLD 3-4 >2 Exacerbations mmrc 0-1 or CAT <10 GOLD 3-4 >2 Exacerbations mmrc >2 or CAT >10 Oxygen Therapy Pulmonary Rehabilitation Surgical and Nonsurgical Alternatives Essential Smoking cessation for all patients who smoke The key intervention for smokers Can include pharmacologic treatment Pulmonary rehabilitation Recommended Physical activity Depending on local guidelines Influenza vaccination Pneumococcal vaccination Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Adapted from Global Initiative for Chronic Obstructive Lung Disease; (GOLD)

7 Exercise Training Involves the measurement of a number of physiologic variables, including maximum oxygen consumption, maximum heart rate, and maximum work performed Components of Pulmonary Rehabilitation Programs Pulmonary Rehabilitation Programs Nutrition Counseling Important determinant of symptoms, disability, and prognosis in ; a reduction in BMI is an independent risk factor for mortality in patients with Assessment and Follow-up Education Specific contributions of education to the improvements seen after pulmonary rehabilitation remain unclear Outcomes of Pulmonary Rehab in Reduces dyspnea Improves deconditioning, muscle fatigue Increases exercise capacity Improves quality of life Improves depression Reduces acute exacerbations Reduces hospitalizations. May reduce mortality Does not improve PFTs or ABGs BMI=body mass index. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated Accessed April 9, British Thoracic Society. Thorax. 2001; 56: American Thoracic Society. Am J Respir Crit Care Med. 1999;159: Guell R, et al. Chest. 2000;117: Saey D, et al. Am J Respir Crit Care Med. 2003;168: Casaburi R. Am J Respir Crit Care Med. 2003;168: Casaburi R, et al. Am J Respir Crit Care Med. 1997;155: Griffiths TL, et al. Lancet. 2000;355: Cote CG, et al. Am J Respir Crit Care Med. 2003;167:A38. Pharmacological Management of Guideline-recommended treatment Improves lung function Minimizes symptoms Improves QoL Prevents exacerbations Wide variety of options including new agents Appropriate treatment selection hinges on GOLD staging Before stepping up/modifying treatment, re-evaluate Treatment goals Clinical phenotype Comorbidities Adherence Pharmacological Agents Approved in the U.S. Short-acting β-agonists (SABA) Albuterol Pirbuterol Levalbuterol Bronchodilators Anticholinergic (SAMA) Ipratropium Long-acting β-agonists (LABA) Salmeterol Formoterol Arformoterol Indacaterol Anticholinergic (LAMA) Tiotropium Aclidinium Umeclidinium LABA +LAMA Umeclidinium +Vilanterol Theophylline Anti-Inflammatory ICS+LABA Fluticasone + Salmeterol Budesonide +Formoterol Fluticasone Fuorate +Vilanterol PDE-4 Inhibitors Roflumilast Systemic Steroids Prednisone Methylprednisolone Treatment Options Rationale for Early Treatment in The effect of treatment on lung function may be more marked in patients who are younger and in those with less severe disease 1-4 Lung function deteriorates more rapidly during the less severe, early stages of 3 LABA and LAMA are recommended initial maintenance therapy for patients who are symptomatic but at low risk of exacerbations 5 Lack of data in treatment-naïve patients with mild or moderate airflow limitation Adapted from: Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Troosters T, et al. Eur Respir J. 2010;36(1):65-73; 2 Celli B, et al. Am J Respir Crit Care Med. 2009;180(10): ; 3 Decramer M, Cooper CB. Thorax. 2010;65(9): ; 4 Morice AH, et al. Respir Med. 2010;104(11): ; 5 GOLD

8 Improving Outcomes in Early diagnosis and accurate assessment Identifying patients at risk Using appropriate diagnostic approaches, ruling out other mimickers Early treatment Implementing optimal management Reducing exposures to risk factors and triggers Non-pharmacological approaches Pharmacological treatments Incorporating self-management skills through education and collaboration with a health care team Improve adherence Inhaler Devices Available in the U.S. A large proportion (49-76%) of patients use their inhalers incorrectly GOLD guidelines recommend rechecking inhaler technique at each patient visit 1.Newman SP. Eur Respir Rev. 2005;14:96, Rice K, et al. Clin Chest Med. 2014;35(2): ; Decramer M, et al. Respir Med. 2011;105(11): Molimard M, et al. J Aerosol Med. 2003;16(3): Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease 2011 Summary continues to be a major public health problem The pathophysiology of involves chronic airway inflammation and lung destruction driven by several inflammatory cells and mediators is a heterogenous disease with multiple phenotypes Phenotypic characterization of will improve personalized approach the disease Summary Clinical approach to includes assessment of symptoms, lung function, exacerbation risk and comorbidities Several non-pharmacological and pharmacological interventions are available which should be implemented according to disease severity Multiple novel targets of therapy are being evaluated and may be available in the future