Disclosures Update on COPD & Asthma • No Pharma Disclosures • NHLBI - Asthma Clinical Research Network Michael C. Peters, M.D. MAS Division of Pulmonary & Critical Care Medicine • NHLBI – Severe Asthma Research Program Cardiovascular Research Institute University of California San Francisco UCSF Primary Care Medicine San Francisco, CA October 13, 2016 What is COPD • Disease state characterized by airflow limitation that is not fully reversible* – Post-Bronchodilator FEV1/FVC <0.7 Update on the Management of COPD • Generally caused by cigarette smoke – Biomass fuels (developing world) – α 1-antitypsin deficiency – Pollution, chronic infection • Bronchiectasis, cystic fibrosis are not included in the definition 1
Rate of Deaths per 100,000 in Cancer Death by Site the USA 2005-2011 Heart Disease WOMEN Cancer MEN Lung 72,120 (26%) Lung 85,920 (27%) Rate Breast 40,450 (14%) Prostate 26,120 (8%) Colorectal 23,170 (8%) Colorectal 26,020 (8%) COPD/Chronic respiratory Pancreas 20,330 (7%) Pancreas 21,450 (7%) Ovary 14,240 (5%) Liver 18,280 (6%) 2005 2006 2007 2008 2009 2010 2011 Year American Cancer Society 2016 USPTF The USPSTF recommends annual screening for lung cancer with low-dose computed • CHRONIC Obstructive Pulmonary Disease tomography (LDCT) in adults aged 55 to 80 • NEED SPIROMETRY: FEV1/FVC < 0.70 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Simel and Rennie USPTF 2013 Evidence-based Clinical Diagnosis McGraw Hill, 2008 2
Original Article Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function • CHRONIC Obstructive Pulmonary Disease Observational study 2734 current and former smokers • NEED SPIROMETRY: FEV1/FVC < 0.70 and controls who never smoked Examined whether current or former smokers with preserved lung function had symptoms or suffered COPD exacerbations Simel and Rennie Evidence-based Clinical Diagnosis N Engl J Med McGraw Hill, 2008 Volume 374(19):1811-1821 May 12, 2016 Respiratory Symptoms Smokers with Normal Pulmonary Prevalence of Symptoms and Risk of Respiratory Function Exacerbations Symptom Scores Woodruff PG et al. N Engl J Med 2016;374:1811-1821 Woodruff PG et al. N Engl J Med 2016;374:1811-1821 3
GOLD Criteria When assessing risk, choose the highest risk GOLD Guidelines 2015 according to GOLD grade or exacerbation history GOLD Classification of Airflow Limitation 4 • No benefit of screening adults with no symptoms (C) (D) ≥ 2 or Exacerbation History ≥ 1 leading 3 to hospital admission Risk Risk • No evidence that treating asymptomatic individuals 2 1 (no hospital (A) (B) prevents future symptoms, or reduces the subsequent admission) 1 0 decline in lung function. mMRC 0-1 mMRC ≥ 2 CAT < 10 CAT ≥ 10 Symptoms (mMRC or CAT score) Anthonisen et al Patient Characteristics Spirometric Exacerbations mMRC CAT JAMA 272:1497-505, 1994 Category Classification per year Qaseen, Ann Int Med 155:179-91, 2011 A Low Risk, Less Symptoms GOLD 1-2 ≤ 1 0-1 <10 B Low Risk, More Symptoms GOLD 1-2 ≤ 1 ≥ 2 ≥ 10 USPTF JAMA 2016 C High Risk, Less Symptoms GOLD 3-4 ≥ 2 0-1 <10 D High Risk, More Symptoms GOLD 3-4 ≥ 2 ≥ 2 ≥ 10 GOLD Guidelines 2015 Take HOME When assessing risk, choose the highest risk according to GOLD grade or exacerbation history GOLD Classification of Airflow Limitation • Treat the patient 4 (C) (D) ≥ 2 or Exacerbation History – Symptoms ≥ 1 leading 3 to hospital – Exacerbations admission Risk Risk 2 1 (no hospital • Spirometry assists with diagnosis (A) (B) admission) 1 0 • Lung Cancer Screening mMRC 0-1 mMRC ≥ 2 CAT < 10 CAT ≥ 10 Symptoms (mMRC or CAT score) 4
Hospitalized Severe AECOPD and Mortality: Predictors of Acute Exacerbations of Severity of AECOPD COPD 1- no AECOPD Number of Exacerbations 2- AECOPD ED ≥ 2 vs. 0 1 vs. 0 Odds Ratio (95% CI) Odds Ratio (95% CI) Exacerbation in Prior Year 5.7 (4.5-7.3) 2.2 (1.8-2.8) FEV1 per 100ml decrease 1.1 (1.08-1.1) 1.1 (1.0-1.1) SGRC (symptom score) per 4 1.1 (1.0-1.1) 1.1 (1.0 – 1.1) points N = 305 men with COPD GERD 2.1 (1.6-2.7) 1.6 (1.2-2.1) x 5 years 3- AECOPD Hosp 4- AECOPD Readmit WBC Count 1.1 (1-1.1) 1.1 (1.0-1.1) Soler-Cataluna Thorax 2005 Hurst NEJM 2010 Prevention of AECOPD Prevention of AECOPD American College of Chest Physicians & Canadian Recommendations Thoracic Society Guideline Non-Pharmacologic Treatments/Vaccinations: • PICO (population, intervention, comparator, outcome) • Influenza Vaccine (Grade 1B) • Literature Search • Pulmonary Rehab (Grade 1C) • Smoking Cessation (Grade 2C) • Quality Assessment (AGREE II, DART) • Pneumococcal Vaccine (Grade 2C) Mod-severe-very severe; recent AECOPD<4 • Grading Evidence (GRADEpro) weeks • Recommendations (CHEST) Criner et al. CHEST 147:894-942, 2015 Criner et al. CHEST 147:894-942, 2015 5
Pulmonary Rehab Pulmonary Rehab Figure 2. Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to Figure 2. Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to end of follow-up). end of follow-up). Pulmonary Control Odds Ratio Rehab Subject 124 126 Total Event 20 51 0.22 (0.08- 0.58) Puhan Cochrane Database 2011 Puhan Cochrane Database 2011 Pulmonary Rehab Prevention of AECOPD Recommendations Figure 2. Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to end of follow-up). Maintenance Inhaled Therapy: • LAMA vs PBO (Grade 1A) • LABA vs PBO (Grade 1B) • LAMA vs LABA (Grade 1C) Pulmonary Control Odds Ratio Rehab • COMBO Therapy vs MonoTherapy (Grade Subject 124 126 1B,C) Total Event 20 51 0.22 (0.08- 0.58) Number Needed to Treat = 4!!!! CI 3-8 Criner et al. CHEST 147:894-942, 2015 Puhan Cochrane Database 2011 6
FLAME TRIAL FLAME TRIAL • LAMA + ICS = Good • LAMA + ICS = Good ICS risk of Pneumonia? • LABA + ICS = Goo • LABA + ICS = Good 7
FLAME TRIAL FLAME TRIAL • LAMA + ICS = Good • LAMA + ICS = Good ICS risk of Pneumonia? • LABA + ICS = Good • LABA + ICS = Good • LABA + LAMA = ? • LABA + LAMA = ? LABA (indacaterol) + LAMA (glycopyrronium) QDay VS. LABA (salmeterol) + ICS (fluticasone) BID NNT = 9 Wedzicha JA et al. N Engl J Med 2016;374:2222-2234 Wedzicha JA et al. N Engl J Med 2016;374:2222-2234 8
Prevention of AECOPD Recommendations Oral Therapy: • Macrolide (Grade 2A) (Frequent AECOPD despite Tx) • Systemic Corticosteroids (Grade 2B) (For AECOPD – prevent next 30 days) • Roflumilast (Grade 2A) (Chr Bronchitis, ≥ 1 AECOPD in year) • Do not use statins for AECOPD (Grade 1B) Wedzicha JA et al. N Engl J Med 2016;374:2222-2234 Criner et al. CHEST 147:894-942, 2015 Wedzicha JA et al. N Engl J Med 2016;374:2222-2234 The MACRO Study (Azithromycin 250mg/day x 1 year) • NHLBI – COPD Clinical Research Network • N = 1130 • Moderately-severe COPD FEV 1 /FVC < 70%; FEV 1 <80% • “ Exacerbation Prone ” • Primary Outcome: Time to first AECOPD NEJM 365:689-98, 2011 NEJM 365:689-98, 2011 9
Macrolides May Increase risk of Rates of Acute Exacerbations of Chronic Obstructive Pulmonary Disease per Macrolides Decrease AECOPD Person-Year, According to Study Group. Cardiovascular Death Ray WA et al. N Engl J Med 2012;366:1881-1890 NNT=15 Albert RK et al. NEJM 2011 Ray WA et al. NEJM 2012 Am J Respir Crit Care Med Am J Respir Crit Care Med 2014; 189:1173-1180 2014; 189:1173-1180 • Macrolides can prolong QT and QTc leading to “Macrolide-associated arrhythmias can be reduced by arrhythmias, including torsades de pointes not prescribing to patients with comorbidities of • Most arrhythmias with macrolides occur in concern…the majority of which can be discovered by: patients with underlying risk factors • History • Incidence of arrhythmias in absence of additional • ECG before initiating therapy risk factors is very low, perhaps 1 in 100,000. • ECG a short time after initiating therapy” Mosholder, NEJM 2013 10
Roflumilast Roflumilast • Oral Tablet • 500 ug Once Daily • Phosphodiesterase-4 Inhibitor • 1 year trial • 40 years old, >20 pack years, +COPD • FEV1% predicted<50% • Symptoms of chronic bronchitis, +cough and sputum • “Exacerbation Prone” • ICS + LABA Ray WA et al. N Engl J Med 2012;366:1881-1890 Ray WA et al. N Engl J Med 2012;366:1881-1890 Martinez et al. Lancet 2015 Martinez et al. Lancet 2015 Roflumilast Effect of Corticosteroids on Treatment Failure Rates after AE COPD Rate of Treatment Failure (%) 60 50 40 30 8 week 20 2 week Placebo 10 0 0 1 2 3 4 5 6 Month 2 week = Solumedrol 125mg q6hr x 3d, Prednisone 60mg qd x 4d, 40mg qd x 4d, 20mg qd x 4d Ray WA et al. N Engl J Med 2012;366:1881-1890 NNT=25 NNH=16 8 week = additional 10mg qd x 5 week, then 5 mg qd x 1 week Martinez et al. Lancet 2015 Niewoehner et al., NEJM 340:1941, 1999 11
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