Chronic Obstructive Pulmonary Disease (COPD) KAREN ALLEN MD PULMONARY & CRITICAL CARE MEDICINE VA HOSPITAL OKC / OUHSC

Chronic Obstructive Pulmonary Disease (COPD) KAREN ALLEN MD PULMONARY & CRITICAL CARE MEDICINE VA HOSPITAL OKC / OUHSC

I have no financial disclosures

Definition COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2010 www.goldcopd.org

Epidemiology of COPD 3 rd leading cause of death in US Oklahoma Prevalence is 8.2% COPD affects 24.1 million adults in US (12%) of adult population Patients > 65 years old COPD causes 20% of hospital admission ALA MMW 2013

Concept of Susceptible Smoker Smokers lose 60ml/year of lung function Non-smokers 30ml/year lung function COPD smokers lose > 60ml/year 15-20% of smokers develop COPD

Etiology Smoking + Pollutants Pathobiology Impaired Lung Growth Accelerated Decline Lung injury Lung & Systemic Inflammation Pathology Small airways disorders and abnormalities Emphysema Systemic Effects Airflow Limitation Clinical Manifestations

Screening for COPD No professional societies recommend screening for COPD in at risk patients currently Mainly secondary to cost associated with screening in aggregate No benefit to treatment of asymptomatic patients who have evidence of COPD on spirometry only Patients do need a good history to determine if they have symptoms Agency for Healthcare Quality Research 2005 Ann of Internal Medicine 2011; 155. 179-191

Spirometry Does not measure response to treatment, better to follow symptoms No need for follow up spriometry once treatment initiated No evidence that spirometry results can be useful for patients who continue to use tobacco products Buffels Respir Med 2006 100: 2012-7 Parkes BMJ 2008; 336: 598-600 Stratelis Scan J Prim Health Care 2006; 24:133-9

Goals of Treatment Reduce long term lung function decline Prevent and treat COPD exacerbations Reduce hospitalizations Reduce mortality Relieve disabling dyspnea Improve exercise tolerance Improve quality of life ACP/ATS COPD Guidelines 2011

Tobacco Cessation #1

AECOPD Exacerbations are to COPD what myocardial infarctions are to coronary artery disease 8 billion per year in direct cost > 50 % of this is related to hospitalization for AECOPD 2/3 are associated with respiratory tract infection or air pollution 1/3 have no identifiable cause Reduce FEV 1 significantly during exacerbation any may not fully recover Chest 2015; 147(4) 883-942

Importance of preventing AECOPD Study of 351 patients with one or more AECOPD Patients with longer symptom duration Shorter interval between recovery and next exacerbation (p = 0.013) Lack of recovery of peak expiratory flow within 99 days was associated with viral symptoms at time of exacerbation Increased decline in lung function 10.8mL/year (p<0.001) AJRCC 2015 vol 192 (8) 943-50

Who is at risk? Patients with previous AECOPD Parameter HR HR (95% CI) P value Hosp. for COPD in past 12 months 2.71 (2.24-3.29) <0.001 SGRQ increase 1.08 (1.06-1.1) <0.001 FEV 1 drop by 5% 1.12 (1.09-1.16) <0.001 Age (10y) 1.29 (1.13-1.46) <0.001 Emphysema >5% CT WBC 1 X 10 9 /L 1.56 (1.23-1.97) <0.001 1.15 (1.07-1.24) <0.001 ECLIPSE Cohort Data Chest 2015; 147(4) 999-1007

Who is at risk? Patients w/o previous AECOPD Parameter HR HR (95% CI) P value SGRQ increase FEV 1 drop >5% Emphysema >5% on CT 1.08 (1.05-1.11) <0.001 1.11 (1.07-1,15) <0.001 1.71 (1.28-2.35) <0.001 O2 use 1.75 (1.30-2.35) <0.001 Age 10 y 1.24 (1.07-1.44) <0.001 Asthma 1.45 (1.17-1.79) <0.001

AECOPD Antibiotics + Steroids Steroids > 5 days showed no overall benefit no benefit to a long taper Oral steroids are equal to IV administration BIPAP for respiratory failure Chest 2007 132(6) 1741-47 JAMA 2002 162 (22) 2527-36

Management after Acute Exacerbation Mod. Severe COPD Very Severe COPD Long acting muscarinic antagonist inhaler Long acting beta agonist inhaler Placebo Long acting beta agonist and inhaled corticosteroid combination inhaler NOT ICS alone ACCP guidelines 2015

Management of Stable COPD Moderate /Severe Combination of long acting anticholinergic and long acting beta agonist OR Long acting anticholinergic monotherapy OR Long acting corticosteroid + beta agonist combo with long acting anticholinergic

GOLD guidelines for COPD Initially developed in 1997 Join effort of the National Heart, Lung, and Blood Institute and the World Health Organization Increase awareness of COPD

COPD Therapy - Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage of Disease Mild FEV 1 > 80% Moderate 50% < FEV 1 < 80% Severe 30% < FEV 1 < 50% Very Severe FEV 1 < 30% Risk factor reduction; immunizations; short-acting bronchodilator as needed One or more long-acting, scheduled bronchodilators; rehabilitation Inhaled steroid for frequent exacerbations Long-term O 2 ; surgical options

TORCH Trial 2007 Compared salmeterol + fluticasone (50/500) together and separate to placebo No difference in mortality compared to placebo Combination compared to placebo did have a reduced exacerbation rate, 1.13 vs 0.85 annual exacerbation rate (p < 0.001) Number needed to treat of 4 to prevent one exacerbation/year NEJM 2007 356 (8) 775-89

TORCH Salmeterol and fluticasone both also decreased exacerbations compared to placebo Fluticasone was associated with a higher risk of pneumonia 19.6% in combination therapy vs 12.3% in placebo ( p< 0.001) Hospitalization rates were 26% overall with a decrease of 17 % in salmeterol and combination group Number needed to treat of 32 to prevent one hospitalization per year NEJM 2007 356 (8) 775-89

UPLIFT Trial 2008 Compared tiotropium with placebo (patients were allowed to use other medications) No significant difference in FEV 1 or FVC between groups Decrease in time to exacerbation and total COPD exacerbations by 14% (p < 0.001) Decrease in respiratory failure RR 0.67 There was a decrease in mortality HR 0.87 (CI 0.76-0.99) NEJM 2008; 359(15):1543-54

POET-COPD Trial 2011 Compared salmeterol vs tiotropium Tiotropium reduced the time to exacerbation compared to salmeterol 187 vs. 145 days (HR 0.83, CI 0.77 0.90) Annual rate of mild exacerbation 0.64 vs 0.72 (p = 0.002) Annual rate of severe exacerbation 0.09 vs 0.13 (p < 0.001) NEJM 2011; 364 (12):1093-1103

Reducing Lung Function Decline Nine trials show overall the inhaled therapies do reduce lung function decline Tiotropium (-2mL/year) compared to placebo Long acting corticosteroid (-8mL/year) Long acting beta agonist (-13mL/year) Inadequate evidence to predict which patients may have decreased lung function decline with inhalers. NEJM 2008; 359:1543-54 BMJ 2000; 320:1297-303 NEJM 2000; 343: 1902-09

The oldie but goodies Tiotropium Aclidinium Ipratropium Salmeterol/fluticasone Formoterol/mometasone Formoterol/budesonide Albuterol

New Inhaler Combinations umeclidinium/vilanterol Compared to individual components alone Combo compared to UMEC showed improved FEV1 (p<0.001) Average was 60mL difference Improved SGRQ scores by 4 or more (49.3% vs 42%) Decreased COPD exacerbation (6.4% vs 8.6%) No difference in death rates Chest 2014; 145 (5) 981-991 Lancet Resp Med 2014;2(6): 472-486 Respir Med 2013;107(10) 1538-1546

New Inhaler Combinations umeclidinium/vilanterol Compare Combo to vilanterol alone Combo compared to VIL showed improved FEV1 (p < 0.001) Average was 110mL difference No significant difference in SGRQ (p=0.22) Reduced COPD exacerbations (6.1% vs 8.5%) There was a significant difference in the serious adverse events ( 3.8% vs 6.2%) Chest 2015 148(2) 397-407

UMEC/VIL vs Tiotropium There was an improvement in FEV1 in UMEC/VIL of 90mL (p< 0.001) No difference in rates of serious adverse events (4.9% vs 4.7%) No difference in SGRQ score (p=0.56) No difference in COPD exacerbations (p = 0.80) No difference in death rates (p=0.21) Chest 2015 148(2) 397-407

UMEC/VIL vs Salmeterol and fluticasone There was an improvement in FEV1 in the UMEC/VIL group (p <0.001) Average 90mL difference No difference in adverse events No difference in other study outcomes Chest 2015 148(2) 397-407

New Combo Inhaler fluticasone/vilanterol Increase in pneumonia in patients treated with combination therapy Total 8 deaths Fewer exacerbations in the combo compared to vilanterol alone (p < 0.0001) No difference in FEV 1 between groups The Lancet Resp Med 2013 vol 1 (3) 210-23

Respimat Inhaler Device New device that uses a multi-dose propellant free system Liquid inhaler with aerosol generation that creates a mist Initial use started in 2004 Int J Chron Obstruct Disease V 1 (3) 251-259

Respimat

Respimat vs Other Devices One study in NEJM showed no different in inhaler devices with tiotropium 17,000 patients No difference in death No difference in COPD exacerbation No difference in FEV 1 NEJM 2013 369(16) 1491-1501

New beta agonist olodaterol Approved for use by the FDA in 2014 Similar profile as other medications No serious adverse side effects compared to placebo

New Inhaler Combinations olodaterol/tiotropium Two studies with total of 5162 patients compare combined with individual components FEV1 improved in combo groups compared to tiotropium alone (p < 0.001) Approx- 117 ml SGRQ was improved (p < 0.05), questionable clinical significance only seen in higher dose Trend in improvement in exacerbation rate No difference in adverse events ERJ 2014

New Inhaler Combinations olodaterol/tiotropium Compared combo to olodaterol alone FEV1 was better in combo inhaler group (p < 0.001) approx. 108 ml SGRQ improved in combo group vs. olodaterol (p < 0.01), again may not be clinically sig. amt. Only showed trend in improvement in exacerbation rate No significant difference in adverse events ERJ 2014

and now, TRIPLE THERAPY Fluticasone, umeclidinum, and vilanterol together compared to other combinations FEV1 mean SGRQ score (lower is better) FEV1 @52 wk (ml) Change from baseline SGRQ score @ 52 week Change from baseline Triple Fluticasone + Vilanterol Umeclidinim + Vilanterol 1274 1177 1220 94-3 40 45 46.8 46.8-5.5-3.7-3.7 NEJM 2018 vol 378 (18)

IMPACT Trial

but, can this be done in combo? Previous trial in American Journal of Respiratory and Critical Care published in 2009 compared tiotropium alone to budesonide/formoterol Patients with FEV1 < 50% and h/o exacerbation Improved FEV1 from baseline Improved SQRG Decreased exacerbations AJRCC 2009 vol. 180 pp 741-750

Other therapies Azithromycin for frequent exacerbation 1500 patients radomized to 250 mg azithromycin vs placebo Decreased time to exacerbation 266 days vs 174 (p<0.001) Decreased exacerbation rate 1.83 vs 1.43 (p=0.01) Hearing decrements higher in azithromycin group 25% vs 20% (p= 0.04) NEJM 2011 vol. 365(8) 689-98

Other therapies Roflumilast reduces COPD exacerbation Phosphodiesterase 4 inhibitor Specific patient patients with chronic bronchitis and airflow limitation and cough/sputum Decreased exacerbations both inpatient (p= 0.009) and outpatient settings (p= 0.0001) Another study showed decreased exacerbation by 14% (p 0.026) Int J Chron Obstruct Pulm Disease 2015 10 565-76 Resp Research 2011 12:18 doi 10.1186/1465-9921-12-18

Other therapies Theophylline Narrow therapeutic window prevents significant use typically May reduce the number of exacerbations CHEST 2015 147(4) 883-893 N-acetylcysteine Recommended for patients with thick sputum as it reduces viscosity Exacerbation rate in one study was 1.16 compared to 1.49 in the placebo group More effective in GOLD II compared to III patients PANTHEON Lancet Resp Med 2014 2(3) 187-194

Outpatient Oxygen in COPD Improves survival in patients with severe resting hypoxemia Arterial PO2 (PaO2) < 55 mmhg or arterial oxygen saturation (SaO2) < 88%. PaO2 56-59 mmhg or SaO2 = 89% if there is evidence of end-organ damage. Often prescribed for patients with nocturnal or exercise-induced hypoxemia but benefits less clear

PULM REHAB Endurance / Internal Training Condition the muscles of ambulation Improve cardio-respiratory fitness Reduce breathlessness & fatigue Resistance Training Unclear optimal amount Improves muscle mass ATS Advances in Palm Rehab 2013

PULM REHAB Inspiratory Muscle Training Decreases dyspnea Improves muscle endurance Flexibility No evidence of improvement Low testosterone Replacement improves muscle mass No evidence of improved strength

Surgical Options Lung Volume Reduction Surgery (NETT TRIAL ) Patients with apical emphysema + low exercise tolerance - better survival and functional status Apical emphysema + high exercise tolerance no change in survival, better functional status Non- apical emphysema no change in survival Not ideal for homogenous emphysema NEJM 2003 348 (21) 2059-73

Best Practices Screen for Obstructive Sleep Apnea Patients will need an in lab study Monitor weight closely Vaccination (flu and pneumonia) Consider Pulm HTN if symptoms out of proportion to PFT Consider transplant in appropriate patient

Symptom Evaluation

Remember Alpha one Genetic cause of COPD ACCP guidelines recommend screening for all new diagnosis of COPD Gene allele testing or serum levels of alpha one anti-trypsin can be done Augmentation therapy may be of some benefit Genetic counseling is important AJRCC 1999 vol. 160 (5)

Minimal EvidenceTherapies High flow oxygen Home vent (noninvasive) for chronic respiratory failure

Thank you Any Questions?