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12:45 1:3 pm Improving Outcomes in COPD SPEAKER Michael Campos, MD Presenter Disclosure Information The following relationships exist related to this presentation: Michael Campos, MD: No financial relationships to disclose. 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. COPD knowledge: Why Is it Important in Primary Care? COPD PATIENT SURVEY Physician primarily responsible for their COPD care: General practitioner 62% Pulmonologist 3% COPD PHYSICIAN SURVEY % of COPD patients in their practice: Primary care 12% Pulmonologists 3% % Aware of any professional guidelines for the and management of COPD: Primary care 54% Pulmonologists 94% Barr RG et al. Am J Med. 25 Dec;118(12):1415 Discuss epidemiology: Improving Review pathophysiology Discuss comorbidities and Identify prognostic factors Review pharmacologic and nonpharmacologic Implement management strategies for Discuss epidemiology: Improving Review pathophysiology Discuss comorbidities and Identify prognostic factors Review pharmacologic and nonpharmacologic Implement management strategies for The Cost of COPD - 21 Total burden of COPDattributable costs: $36 billion Total national medical costs attributable to COPD: $32.1 billion Total absenteeism costs: $3.9 billion (an estimated 16.4 million lost work days) Payers: 18% private insurance 51% Medicare 25% Medicaid National medical costs are projected to increase from $32.1 billion in 21 to $49. billion in 22 Ford ES et al. CHEST 215; 147(1) : 31-45

Overall Health Care Costs Are Higher in Patients With COPD Mean Health Care Cost per Person (US dollars) 3 25 2 15 1 5 5888 2498 1927 COPD cohort (n=837) Other health-care-related costs* Outpatient costs Hospitalization costs 272 3436 969 Comparison cohort (n=837) *Included emergency room visits, physician visits, and pharmacy costs. Each comparator was based on the mean of 3 controls from a data set including 25,11 patients. Menzin J et al. Respir Med. 28;12:1248-1256. COPD, US 27-29, MEN 12 % of US men population 1 8 6 4 2 COPD Prevalence increases with age 18-24 25-44 45-54 55-64 65-74 75-84 85+ Age Groups NCHS Data Brief No. 63 June 211 CDC/NCHS, Health Data Interactive and National Health Interview Survey If... Spirometry Is Essential for Diagnosing COPD Chronic symptoms = cough, sputum, and/or shortness of breath And... Exposure to risk factors = tobacco, occupational irritants, and/or indoor/outdoor pollution Then... Spirometry* to confirm COPD FEV 1 /FVC <.7 FEV 1 determines staging ACP, ACCP, ATS, and ERS Clinical Practice Guideline Recommendation 1: Spirometry should be obtained to diagnose airflow obstruction in patients with respiratory symptoms (Grade: strong recommendation) Spirometry should not be used to screen for airflow obstruction in individuals without respiratory symptoms (Grade: strong recommendation) Spirometry should not be used to monitor disease status or response to treatment after COPD. *Additional testing: chest x-ray, echocardiogram, arterial blood gas, sputum analysis, computed tomography (CT) scan. Global Initiative for Chronic Obstructive Lung Disease. http://www.goldcopd.com Ann Int Med 211 (155)3:179-191 Onset Triggers Differentiating COPD and Asthma Different Diseases Asthma Early in life (often childhood) Allergens COPD Mid-life Cigarette smoke, occupational pollutants Symptoms Variable Slowly progressive Airflow limitation Largely reversible Partially reversible Clinical features Episodic wheeze, chest Chronic dyspnea, cough, sputum, tightness, cough, dyspnea wheeze Inflammatory Pathology Other PFT features Primarily eosinophils (lung, peripheral blood, sputum) Airway remodeling; no lung destruction Normal D L CO Primarily neutrophils Airway remodeling and lung destruction Reduced D L CO, static hyperinflation Imaging No emphysema Emphysema Discuss epidemiology: Improving Review pathophysiology Discuss comorbidities and Identify prognostic factors Review pharmacologic and nonpharmacologic Implement management strategies for Global Initiative for Chronic Obstructive Lung Disease. Global strategy for, management, and prevention of chronic obstructive pulmonary disease. Updated 211. http://www.goldcopd.com/guidelineitem.asp?l1=2&l2=1&intid=989.

Lung Function Decline in COPD Expiratory Airflow Limitation Air Trapping 1 8 Non-smoker Hyperinflation Decreased Exercise Capacity Reduced Activity FEV 1 (%) 6 4 2 Symptoms Disability Death Susceptible smoker The vicious cycle of COPD Dyspnea Physical Deconditioning 2 3 4 5 6 7 8 9 Age (years) Fletcher C, Peto R. Br Med J. 1977;1:1645-1648. Poor Health-Related Quality of Life Co-morbidity and prognosis Discuss epidemiology: Improving Review pathophysiology Discuss comorbidities and Identify prognostic factors Review pharmacologic and nonpharmacologic Implement management strategies for Death within 5 years Predict death within 5 yrs by modified GOLD category and the presence of no ( ), one ( ), two ( ) or three ( ) comorbid diseases (diabetes, hypertension or cardiovascular disease). Mannino et al, ERJ 28 COPD: an independent risk factor for CV Disease Fibrinogen and COPD For each 1% reduction of FEV 1, cardiovascular mortality increases by 28% Presence of COPD increases the odds of having CVD by 2-3 times which was independent of other risk factors A 2.27-fold increased risk of MI was seen 1 to 5 days after COPD exacerbation Associated with reduced lung function and disease progression independent of smoking status. Dahl M et al. Am J Respir Crit Care Med 21; 164 (6): 18-11 Predict future risk of moderate and severe exacerbations and hospitalizations from COPD Groenewegen KH et al. Chest 28; 133 (2): 35-7 Engstrom G et al. Thorax 29; 64 (3): 211-5 Not easily modifiable with medications Likely to be the first COPD biomarker presented to the FDA for qualification in the drug approval process. Rosenberg & Kalhan. Translac Res 212;159:228 237 Finkelstein J. Chronic. Int. J COPD 29; 4: 337-49 Soriano J., et al. Chest 21; 137: 333-34 Donaldson G. et al. Chest 21; 137(5):191 197

Heterogeneity in Disease Progression: FEV 1 Decline FEV 1 (%) 1 8 6 4 2 Symptoms Disability Death Smoker 2 3 4 5 6 7 8 9 Age (years) Non-smoker Fletcher C, Peto R. Br Med J. 1977;1:1645-1648. Discuss epidemiology: Improving Review pathophysiology Discuss comorbidities and Identify prognostic factors Review pharmacologic and nonpharmacologic Implement management strategies for Recommendations for Evaluating Patients with COPD Discuss epidemiology: Improving Review pathophysiology Discuss comorbidities and Identify prognostic factors Review pharmacologic and nonpharmacologic Implement management strategies for 1. Spirometry before and after bronchodilator 2. Imaging (CXR) 3. Examination of the sputum 4. Comorbidity assessment 5. Evaluate need for oxygen 6. Determine exacerbation phenotype 7. Functional status 8. Composite score 9. Test for AAT Deficiency Alpha-1 Antitrypsin Deficiency 1-2% of all COPD and unexplained liver cirrhosis Smoking is the most important factor for an Alpha to develop COPD Recommendations to test all COPD patients regardless of smoking, age, race, emphysema pattern AAT levels, phenotype or genotype Genotypes: MM: normal MZ: carrier ZZ: severely deficient Am J Resp Crit Care Med 23; 168(818-9) Pharmacologic Options for COPD Short-acting bronchodilators Anticolinergics (SAAC) Beta-agonists (SABA) Long acting bronchodilators Anticolinergics or long-acting muscarinic antagonists (LAMA) Beta-agonists (LABA) Inhaled Corticosteroids (ICS) PDE-4 inhibitors Inhaled bronchodilators are preferred over oral Long-acting bronchodilators are preferred over short-acting ICS never as monotherapy. Add to high risk patients with long-acting BD No chronic oral steroids

NEW LAMAs Tiotropium Glycopyrronium Umeclidinium Aclidinium TD-428 CHF 547 QAT37 BEA-218BR Trospium Dexpirronium AZD8683 PF-3715455 or PF-3635659 New LABAs Salmeterol Formoterol Indacaterol Vilanterol Olodaterol Abediterol (LAS-1977) AZD3199 PF-61355 LABA + ICS: Improvement in lung function LABA + ICS: Improvement in lung function Budesonide/formoterol FEV 1 (ml) PLA SAL 5 FLU/SAL 25/5 (17%) 2 15 (9%) 1 5 (1%) -5 Endpoint 2 4 6 8 12 16 2 24 (last evaluable FEV 1) Time (weeks) * Mean FEV 1 % of baseline 14 12 1 98 96 94 92 9 88 86 84 82 8 Formoterol Budesonide Placebo 1 2 3 4 5 6 7 8 9 1 11 12 Months since randomization Hanania et al. Chest. 23;124:834-843. Calverley PM, et al. Eur Respir J. 23;22:912-919 LABA + ICS: Improvement in dyspnea LABA + ICS: Decrease exacerbations 2 Mean TDI focal score 3. 2.5 2. 1.5 1..5 Placebo SAL FP 5 µg FSC 5/5 µg +.4 +.9 +1.3 +2.1 Mean exacerbations per year 1.6 1.2.8.4 2 4 6 8 12 16 2 24 Time (weeks) P SAL FP FSC End point Placebo Formoterol Budesonide Formoterol + Budesonide FSC=fluticasone propionate + salmeterol combination. Mahler DA, et al. Am J Respir Crit Care Med. 22;166:184-191. Szafranski W, et al. Eur Respir J. 23;21:74-81.

LABA + ICS formulations LABA + LAMA: Improvement in lung function Salmeterol + Fluticasone Formoterol + Budesonide (Formoterol + mometasone) Vilanterol + Fluticasone Formoterol + ciclesonide Indacaterol + mometasone Indacaterol + QAE-397 GS-4242 (novel mutual prodrug of salmeterol and desisobutrylciclesonide) FEV 1 (L) 1.5 1.4 1.3 1.2 1.1 1..9 2 4 6 8 1 12 14 16 18 2 22 24 9 AM 3 PM 9 PM 3 AM 9 AM Time (hours) Tiotropium qd + formoterol qd Tiotropium qd + formoterol bid Tiotropium qd + placebo bid 24-hour base van Noord JA et al. Chest 26;129:59-17 LAMA + LABA Patients May Respond to Long-term Bronchodilator Therapy, Regardless of Initial Reversibility Status Umeclidinium/ vilanterol Olodaterol/ tiotropium Indacaterol/ glycopyrronium Formoterol/aclidinium Formoterol/glycopyrrolate FEV 1 (liters) 1.4 1.3 1.2 1.1 Day 1 Day 344 1.5 Placebo Tiotropium 1.4 Placebo Tiotropium 1.3 FEV 1 (liters) 1.2 1.1 * * 1. 1. -6-5 3 6 12 18 Time (minutes) Responders n=921. *P<.1 vs placebo at all time points following drug administration. Tashkin D, Kesten S. Chest. 23;123:1441-1449. -6-5 3 6 12 18 Time (minutes) Poor Responders Long-Term Oxygen Therapy Pulmonary Rehabilitation Oxygen therapy decreases mortality in patients that qualify At least > 16h a day Indications: po2 < 55 mmhg at rest po2 < 59 if PHTN, cor pulmonale or polycythemia (Htc > 55%) Desaturation on exertion ACP, ACCP, ATS, and ERS recommend that clinicians should prescribe continuous oxygen therapy in patients with COPD who have severe resting hypoxemia (PaO2 55 mm Hg or SpO2 88%) (Grade: strong recommendation, moderate-quality evidence). A comprehensive PR program includes: exercise training optimal medical management oxygen supplementation (when required) psychosocial support nutrition counseling Education To be effective at least eight weeks is mandatory; the longer the duration, the better the results Ann Int Med 211 (155)3:179-191

Benefits of Pulmonary Rehabilitation Lung Volume Reduction Surgery Improves Exercise performance Health-related QOL Self-management Psychosocial states Participation in daily life Self-efficacy Survival Reduced: Secondary comorbiditie (i.e. cardiac dysfunction) Dyspnea Severity of symptoms Health care costs Exacerbations/hospitaliza tions Psychological dysfunction For patients with poor functional capacity after rehabilitation and upper lobe emphysema Pulmonary Rehabilitation: Joint ACCP/AACVPR Evidence-Based Clinical Practice Guidelines. Chest. 27 May;131(5 Suppl):4S-42S Epidemiology: Improving Understanding pathophysiology Understanding comorbidities and Understanding prognostic factors Understanding pharmacologic and non-pharmacologic Management of acute exacerbations and preventing When to give antibiotics?: Assessing sputum color More reliable when assess in the lab compared with patient verbal report (correlation with cultures and inflammatory markers) One small trial did not show difference in therapeutic failure (9% vs 1%) Non-invasive positive pressure ventilation Discharge Criteria 14 RCT show benefit of NPPV as first line intervention as an adjunct therapy to usual medical care in all suitable patients for the management of respiratory failure secondary to an acute exacerbation of COPD Improves gas exchange Reduces hospital mortality Decreases intubation rate Decreases hospital stay Indications: Respiratory acidosis Severe dyspnea w respiratory fatigue Ram FS et al. Cochrane Database Syst Rev 24;(3):CD414 Able to use long-acting bronchodilators Require use of short-acting BD no more frequently than every 4 hours Able to walk across room Clinical stability for 12-24h Patient or caregiver fully understands correct use of medications F/U and home care arrangements completed Patient or family confident that patient can manage succesfully at home

COPD: Readmissions and Medicare Approximately 2% of patients hospitalized for COPD exacerbations in the United States will be readmitted within 3 days. The Centers for Medicare and Medicaid Services has recently proposed to revise the Hospital Readmissions Reduction Program to financially penalize hospitals with high all-cause 3-day rehospitalization rates after a hospitalization for COPD exacerbation on or after October 1, 214 Reported Predictors for 3-d COPD Depression Socioeconomic status Heart disease Male sex Nursing home residence Age Cor pulmonale lower quality of life Hypoproteinemia elevated PCO2 Anemia Prior hospitalization longer hospital length of stay higher number of comorbidities need for long-term oxygen treatment worse lung function marital status serum Mg and CRP Poor follow-up Ohar JA. Ann Am Thorac Soc 215: 12 (9): 1259 126 Pulmonary Rehabilitation After COPD Exacerbations Preventing exacerbations in COPD: Azithromycin Immediately or up to three weeks after initiation of exacerbation treatment. Cochrane review of 6 studies (241 patients): Decrease in : OR.13 (95% CI.4 to.35) with a NNT of 3 (95% CI 2 to 4) f/u 8 months Decrease in mortality: OR.29 (95% CI.1 to.84) a NNT of 6 (95% CI 5 to 3) f/u 26 months Improved HRQOL: SGRQ difference of 11 units; CRQ difference of 1.8 units 1 year RCT of 1142 subjects: 57 azithromycin 25 mg daily 572 placebo Funded by NIH Azithromycin: Decreased frequency of exacerbations (1.48 vs 1.83 per patient-year). HR for acute exacerbation per patient-year:.73 Puhan M et al. Cochrane Database Syst Rev. 29 Jan 21 Improved quality of life Decrease colonization with selected respiratory pathogens, but also an increase in colonization with macrolide-resistant organisms More hearing decrements (25% vs. 2%, P=.4). Albert R et al. NEJM 211;365:689-98 End-of-Life Issues and COPD Survey of 376 patients. 14.6% reported having end-of-life discussions. These subjects were: more likely to rate their quality of care as the best imaginable (OR, 2.7;95% CI, 1.5-4.9) a More likely to be very satisfied with their medical care (OR, 1.98; 95% CI, 1.1-3.55) Perceptions about COPD among Primary Care A survey by Yawn et al. among 284 PCPs and NPs/PAs about COPD in primary care revealed that: 78% believe COPD was a disease of men 61% said that COPD usually started age 6 Only 15% believe that COPD treatments are useful in relieving symptoms Only 3% thought pulmonary rehab was beneficial Leung et al. CHEST 212; 142(1):128 133 Yawn et al, Int Journal COPD. 28; 3(2): 311-317