Disclosures. Update on COPD & Asthma. Update on the Management of COPD. No Pharma Disclosures. NHLBI - Asthma Clinical Research Network

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1 Update on COPD & Asthma Michael C. Peters, M.D. MAS Division of Pulmonary & Critical Care Medicine Cardiovascular Research Institute University of California San Francisco UCSF Primary Care Medicine San Francisco, CA May 26, 2017 Disclosures No Pharma Disclosures NHLBI - Asthma Clinical Research Network NHLBI Severe Asthma Research Program Update on the Management of COPD 1

2 What is COPD Disease state characterized by airflow limitation that is not fully reversible* Post-Bronchodilator FEV1/FVC <0.7 Generally caused by cigarette smoke Biomass fuels (developing world) α1-antitypsin deficiency Pollution, chronic infection Bronchiectasis, cystic fibrosis are not included in the definition Rate of Deaths per 100,000 in the USA Heart Disease Cancer Rate COPD/Chronic respiratory Year Cancer Death by Site MEN Lung 85,920 (27%) Prostate 26,120 (8%) Colorectal 26,020 (8%) Pancreas 21,450 (7%) Liver 18,280 (6%) WOMEN Lung 72,120 (26%) Breast 40,450 (14%) Colorectal 23,170 (8%) Pancreas 20,330 (7%) Ovary 14,240 (5%) American Cancer Society

3 CHRONIC Obstructive Pulmonary Disease NEED SPIROMETRY: FEV1/FVC < 0.70 Simel and Rennie Evidence-based Clinical Diagnosis McGraw Hill, 2008 CHRONIC Obstructive Pulmonary Disease NEED SPIROMETRY: FEV1/FVC < 0.70 Simel and Rennie Evidence-based Clinical Diagnosis McGraw Hill, 2008 Original Article Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function Observational study 2734 current and former smokers and controls who never smoked Examined whether current or former smokers with preserved lung function had symptoms or suffered COPD exacerbations N Engl J Med Volume 374(19): May 12,

4 Respiratory Symptoms Smokers with Normal Pulmonary Function Symptom Scores Woodruff PG et al. N Engl J Med 2016;374: Prevalence of Symptoms and Risk of Respiratory Exacerbations Woodruff PG et al. N Engl J Med 2016;374: No benefit of screening adults with no symptoms No evidence that treating asymptomatic individuals prevents future symptoms, or reduces the subsequent decline in lung function. Anthonisen et al JAMA 272: , 1994 Qaseen, Ann Int Med 155:179-91, 2011 USPTF JAMA

5 Risk GOLD Classification of Airflow Limitation Patient Category (C) (A) mmrc 0-1 CAT < 10 GOLD Criteria When assessing risk, choose the highest risk according to GOLD grade or exacerbation history (D) (B) mmrc 2 CAT 10 Symptoms (mmrc or CAT score) Characteristics 2 or 1 leading to hospital admission 1 (no hospital admission) 0 Spirometric Classification GOLD Guidelines 2015 Risk Exacerbation History Exacerbations per year mmrc A Low Risk, Less Symptoms GOLD <10 B Low Risk, More Symptoms GOLD C High Risk, Less Symptoms GOLD <10 D High Risk, More Symptoms GOLD CAT GOLD Guidelines 2015 When assessing risk, choose the highest risk according to GOLD grade or exacerbation history Risk GOLD Classification of Airflow Limitation (C) (A) mmrc 0-1 CAT < 10 (D) (B) mmrc 2 CAT 10 Symptoms (mmrc or CAT score) 2 or 1 leading to hospital admission 1 (no hospital admission) 0 Risk Exacerbation History Take HOME Treat the patient Symptoms Exacerbations Spirometry assists with diagnosis Lung Cancer Screening 5

6 Treat The Patient!!! Prevention of Acute Exacerbations Prevent Progressive Loss of Lung Function Improve Symptoms What treatment is the most effective for preventing COPD exacerbations? A) Roflumilast B) Pulmonary Rehab C) Duel LAMA + LABA D) Azithromycin Treat The Patient!!! Prevention of Acute Exacerbations Prevent Progressive Loss of Lung Function Improve Symptoms 6

7 Hospitalized Severe AECOPD and Mortality: Severity of AECOPD 1- no AECOPD 2- AECOPD ED N = 305 men with COPD x 5 years 3- AECOPD Hosp 4- AECOPD Readmit Soler-Cataluna Thorax 2005 Predictors of Acute Exacerbations of COPD Number of Exacerbations 2 vs. 0 1 vs. 0 Odds Ratio (95% CI) Odds Ratio (95% CI) Exacerbation in Prior Year 5.7 ( ) 2.2 ( ) FEV1 per 100ml decrease 1.1 ( ) 1.1 ( ) SGRC (symptom score) per 4 points 1.1 ( ) 1.1 ( ) GERD 2.1 ( ) 1.6 ( ) WBC Count 1.1 (1-1.1) 1.1 ( ) Hurst NEJM 2010 Prevention of AECOPD American College of Chest Physicians & Canadian Thoracic Society Guideline PICO (population, intervention, comparator, outcome) Literature Search Quality Assessment (AGREE II, DART) Grading Evidence (GRADEpro) Recommendations (CHEST) Criner et al. CHEST 147: ,

8 Prevention of AECOPD Recommendations Non-Pharmacologic Treatments/Vaccinations: Influenza Vaccine (Grade 1B) Pulmonary Rehab (Grade 1C) Smoking Cessation (Grade 2C) Pneumococcal Vaccine (Grade 2C) Mod-severe-very severe; recent AECOPD<4 weeks Criner et al. CHEST 147: , 2015 Figure 2. Pulmonary Rehab Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to end of follow-up). Puhan Cochrane Database 2011 Figure 2. Pulmonary Rehab Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to end of follow-up). Pulmonary Control Rehab Subject Odds Ratio Total Event ( ) Puhan Cochrane Database

9 Figure 2. Pulmonary Rehab Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to end of follow-up). Pulmonary Control Rehab Subject Odds Ratio Total Event ( ) Number Needed to Treat = 4!!!! CI 3-8 Puhan Cochrane Database 2011 Prevention of AECOPD Recommendations Maintenance Inhaled Therapy: LAMA vs PBO (Grade 1A) LABA vs PBO (Grade 1B) LAMA vs LABA (Grade 1C) COMBO Therapy vs MonoTherapy (Grade 1B,C) Criner et al. CHEST 147: , 2015 FLAME TRIAL LAMA + ICS = Good LABA + ICS = Good 9

10 FLAME TRIAL LAMA + ICS = Good LABA + ICS = Good ICS risk of Pneumonia? FLAME TRIAL LAMA + ICS = Good LABA + ICS = Good LABA + LAMA =? ICS risk of Pneumonia? FLAME TRIAL LAMA + ICS = Good LABA + ICS = Good LABA + LAMA =? LABA (indacaterol) + LAMA (glycopyrronium) QDay VS. LABA (salmeterol) + ICS (fluticasone) BID 10

11 Wedzicha JA et al. N Engl J Med 2016;374: NNT = 9 Wedzicha JA et al. N Engl J Med 2016;374: Wedzicha JA et al. N Engl J Med 2016;374: Wedzicha JA et al. N Engl J Med 2016;374:

12 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) Criner et al. CHEST 147: , 2015 NEJM 365:689-98, 2011 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,

13 Rates of Acute Exacerbations of Chronic Obstructive Pulmonary Disease per Macrolides Decrease AECOPD Person-Year, According to Study Group. NNT=15 Albert RK et al. NEJM 2011 Macrolides May Increase risk of Cardiovascular Death Ray WA et al. N Engl J Med 2012;366: Ray WA et al. NEJM 2012 Am J Respir Crit Care Med 2014; 189: Macrolides can prolong QT and QTc leading to arrhythmias, including torsades de pointes Most arrhythmias with macrolides occur in patients with underlying risk factors Incidence of arrhythmias in absence of additional risk factors is very low, perhaps 1 in 100,000. Mosholder, NEJM

14 Am J Respir Crit Care Med 2014; 189: Macrolide-associated arrhythmias can be reduced by not prescribing to patients with comorbidities of concern the majority of which can be discovered by: History ECG before initiating therapy ECG a short time after initiating therapy 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: Martinez et al. Lancet 2015 Roflumilast Ray WA et al. N Engl J Med 2012;366: Martinez et al. Lancet

15 Roflumilast Ray WA et al. N Engl J Med 2012;366: NNT=25 NNH=16 Martinez et al. Lancet 2015 Effect of Corticosteroids on Treatment Failure Rates after AE COPD Rate of Treatment Failure (%) week 2 week Placebo Month 2 week = Solumedrol 125mg q6hr x 3d, Prednisone 60mg qd x 4d, 40mg qd x 4d, 20mg qd x 4d 8 week = additional 10mg qd x 5 week, then 5 mg qd x 1 week Niewoehner et al., NEJM 340:1941, 1999 Prednisone, 40 mg/day x 5 days vs Prednisone, 40 mg/day x 14 days Leuppi et al JAMA 2013; 309:

16 Time to Reexacerbation of COPD (Intention-to-treat) (Per-Protocol) Leuppi et al. JAMA 2013;309(21): Summary Pulmonary Rehab (NNT=4) Duel Long Acting Bronchodilator Medications over ICS + LABA (NNT=9) Azithromycin prevents COPD Exacerbations (NNT=15) Potential Risk of Cardiac Arrhythmias Roflumilast offers some benefit in bronchitis patients (NNT=25), (NNH=16) 5 days of corticosteroids is the appropriate time frame Therapy Reduces Lung Decline (TORCH) Salmeterol + Fluticasone Placebo Celli et al Am J Respir Crit Care Med 178:332-38,

17 Tiotropium Reduces Lung Decline Tashkin et al NEJM 359: , 2008 Pulmonary Rehabilitation Benefits all levels of disease severity Reduces respiratory symptoms Reduces anxiety and depression Reduces medical and hospital usage Improves exercise performance Improves quality of life Is typically provided as outpatient Can be initiated as an inpatient until functional ability has improved 2015 Cochrane Review, McCarthy Update on the Management of Asthma 17

18 Definition of Asthma Obstruction that is reversible either spontaneously or with treatment; [NAEPP-EPR, 1991] Chronic inflammatory disorder (MCs, Eos, Tcells, Macs, PMNs, Epi); variable obstruction; [NAEPP-EPR2, 1997] Variable symptoms, obstruction, BHR; inflammation; interaction [NAEPP-EPR3, 2007] Definition of Asthma Chronic inflammatory disorder; many different cells; BHR; variable/reversible symptoms and obstruction; phenotypes? [GINA, 2011] Heterogeneous; Chronic airway inflammation; variable/reversible symptoms and obstruction; Different phenotypes or clusters [GINA, 2014] Epidemiology million people have asthma globally Asthma rates have been increasing in low/middle income countries (caught up) Most of the morbidity/mortality from asthma stems from the 5-10% with severe disease 18

19 Asthma Prevalence in USA Causes of Asthma Hygiene Hypothesis Exposure to Antibiotics Microbiome Genetics Obesity Environmental Influences Dogs/Cats Medications 19

20 Asthma JAMA 2017 Called patients Do you have asthma? 20

21 Called patients Do you have asthma? Spirometry Pre/Post BD Positive Asthma Confirmed Called patients Do you have asthma? Spirometry Pre/Post BD Positive Asthma Confirmed Methacholine Positive Asthma Confirmed Called patients Do you have asthma? Spirometry Pre/Post BD Positive Asthma Confirmed Methacholine Positive Asthma Confirmed Stop All Meds Positive Methacholine Asthma Confirmed 21

22 Called patients Do you have asthma? Spirometry Pre/Post BD Positive Asthma Confirmed Methacholine Positive Asthma Confirmed Methacholine Stop All Meds Positive Asthma Confirmed 12 Month Follow up Methacholine Or worse symptoms Positive Asthma Confirmed No Asthma What percentage of patients had no asthma? A) 0-10% B) 10-20% C) 30-40% D) 40-50% E) >50% Aging and Asthma Years Lost Life Years Lost Disability Global Asthma Report

23 Obesity and Asthma Obesity is an important risk factor for the development of asthma Percentage of adults with asthma who are obese CDC National Asthma Control Program 2010 EPR-3, NHLBI, 2011 Black Box Warning Data from a large placebo-controlled U.S. study that compared the safety of salmeterol or placebo added to usual asthma therapy showed a small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179)". 23

24 Original Article Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone Adolescent and adult patients >12 years with persistent asthma were randomized to ICS (fluticasone) vs ICS + LABA (salmeterol) for 26 weeks All patients had a history of a severe asthma exacerbation in the past year NEJM 2016 Primary Safety End Point (Intention-to-Treat Population). Stempel DA et al. N Engl J Med 2016;374: Summary of Safety End Points. Stempel DA et al. N Engl J Med 2016;374:

25 Asthma Phenotypes Haldar AJRCCM 2008 Fahy, NRI, 2015 Not all asthma is the same!! (Heterogeneity) (Phenotypes) 25

26 Patients ( 15 Years) Not Controlled on PRN Beta-Agonists FEV 1 : Distribution of Individual Patient Responses Patients (%) Beclomethasone (n=246) Montelukast (n=375) 5 0 < to < to -10 to 0 to 10 to 20 to 30 to <-10 <0 <10 <20 <30 <40 FEV 1 Percent Change From Baseline 40 to <50 50 Malmstrom et al. Ann Intern Med. 130: , 1999 A Large Subgroup of Mild-to-Moderate Asthma Is Persistently Noneosinophilic (NON Allergic) Asthma is a heterogeneous disease ~50% of asthmatics poor response to steroids Eosinophilic airway inflammation not ubiquitous Sputum Eosinophil Percentage (No ICS) McGrath et al (ACRN) Am J Respir Crit Care Med 185: ,

27 TH 2 Genes Overexpressed in Asthma Th2 High Th2 High Th2 High Th2 Low Th2 Low Th2 Low Woodruff et al Am J Respir CCM 180:388, 2009 Th2 Status Predicts Corticosteroid Response Woodruff et al Am J Respir CCM 180:388, 2009 N=135, prednisone x 6 months, eosinophils >300 27

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29 Type-2 Inhibitors for Severe Asthma Anti IL-5 Agents Mepolizumab (NUCALA)* Resilizumab (CINQAIR)* Anti IL-13 Agents Lebrikizumab Anti IL-4/IL-13 Dupilumab Anti TSLP AMG 157 * FDA Approved A Large Subgroup of Mild-to-Moderate Asthma Is Persistently Noneosinophilic (NON Allergic) Asthma is a heterogeneous disease ~50% of asthmatics poor response to steroids Eosinophilic airway inflammation not ubiquitous Sputum Eosinophil Percentage (No ICS) McGrath et al (ACRN) Am J Respir Crit Care Med 185: , 2012 Alternative Treatment? 29

30 Tiotropium Step-Up for Uncontrolled Asthma Peters et al. N Engl J Med 363:18, 2010 Eur Respir J; 43:343-73, 2014 Recommendations: In adults with severe asthma use sputum eos in experienced centers In severe allergic asthma therapeutic trial of omalizumab: Mepolizumab? Do not use methotrexate for asthma Do not use azithromycin for asthma Eur Respir J; 43:343-73,

31 Recommendations: Use anti-fungals for ABPA Do not use anti-fungals without ABPA Consider bronchial thermoplasty only as part of a study Eur Respir J; 43:343-73, 2014 NAEPP GUIDELINES If there is a clear and positive response for at least 3 months, a careful step down in therapy should be attempted to identify the lowest dose required to maintain control. (Evidence D) Evidence D = Panel Consensus Judgment Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report National Asthma Education and Prevention Program. J Allergy Clin Immunol Nov;120(5 Suppl):S GINA GUIDELINES Controller treatment may be stopped if the patient s asthma remains controlled on the lowest dose of controller and no recurrence of symptoms occurs for 1 year (Evidence D) Evidence D = Panel Consensus Judgment Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J Jan;31(1):

32 Is There Really A Difference Between Asthma And COPD? Pathophysiology in COPD versus Asthma COPD Loss of elastic recoil Changes in small airways Inflammation Fixed airway obstruction Asthma Inflammation Bronchial hyperresponsiveness Varying airway obstruction Inflammation in COPD versus Asthma COPD Asthma Predominant Cells Macrophages Eosinophils Neutrophils Activated Mast Cells CD-8 T-Lymphocytes CD-4 T Lymphocytes Predominant Cytokines Interleukin 8 Interleukin 4 Leukotriene B4 Interleukin 5 Tumor Necrosis Factor alpha Interleukin 13 Calverley, Barnes. AJRCCM 2000; 161:

33 COPD Asthma Overlap IN COPD Postma DS, Rabe KF. N Engl J Med 2015; 373: Asthma Summary The Cause of asthma remains unknown, but is unlikely to be fully explained by genetics Many patients with asthma diagnosis may not have asthma LABA are safe to use in asthma patients Patients respond differently to medications based upon underlying endotype/phenotype Th2-High or Allergic Asthma responds to corticosteroids New Medications are on the way for Severe Allergic Asthma 33