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Treatment of COPD What are we really doing? Questions Is all COPD created equal? Is there a “right” way to treat my patient? What are the outcomes I can expect for my treatments? Does anything affect mortality in my patients? Are there any downsides to treatments? How do I assess my patient’s prognosis? Recommended website Official guidelines Global initiative for chronic obstructive lung disease (GOLD) www.goldcopd.org Pocket guide, Iphone app Does your patient have COPD? Diagnosis of COPD SYMPTOMS shortness of breath chronic cough sputum EXPOSURE TO RISK FACTORS tobacco occupation indoor/outdoor pollution SPIROMETRY: Required to establish diagnosis © 2015 Global Initiative for Chronic Obstructive Lung Disease Spirometry refresher: FEV1; amount of air that can be exhaled in 1 second FVC total amount of air that can be exhaled in one breath Most patients should be able to exhale >70% of their vital capacity in one second. If they can’t, they have airflow obstruction and their FEV1/FVC ratio is <70% Global Strategy for Diagnosis, Management and Prevention of COPD Classification of Severity of Airflow Limitation in COPD* In patients with FEV1/FVC < 0.70: GOLD 1: Mild FEV1 > 80% predicted GOLD 2: Moderate 50% < FEV1 < 80% predicted GOLD 3: Severe 30% < FEV1 < 50% predicted GOLD 4: Very Severe FEV1 < 30% predicted *Based on Post-Bronchodilator FEV1 © 2015 Global Initiative for Chronic Obstructive Lung Disease GOLD risk stratification based on Functional status Using CAT or MRC scales Presence of dyspnea with with normal ambulation Severity of airflow obstruction Mild/moderate vs severe Number of exacerbations <2 vs >1 or needing hospitalization Global Strategy for Diagnosis, Management and Prevention of COPD Modified MRC (mMRC)Questionnaire © 2015 Global Initiative for Chronic Obstructive Lung Disease Global Strategy for Diagnosis, Management and Prevention of COPD GOLD 3 A GOLD 2 GOLD 1 ICS + LABA or and LAMA LAMA SAMA prn LABA or or SABA prn LAMA CAT < 10 mMRC 0-1 D B CAT > 10 mMRC > 2 © 2015 Global Initiative for Chronic Obstructive Lung Disease 2 or more or > 1 leading to hospital admission 1 (not leading to hospital admission) 0 Exacerbatoins C GOLD 4 ICS + LABA per yearr Manage Stable COPD: Pharmacologic Therapy RECOMMENDED FIRST CHOICE Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD When assessing risk, choose the highest risk according to GOLD grade or exacerbation history. One or more hospitalizations for COPD exacerbations should be considered high risk.) Patient Characteristic A Spirometric Classification Exacerbations per year CAT mMRC Low Risk Less Symptoms GOLD 1-2 ≤1 < 10 0-1 B Low Risk More Symptoms GOLD 1-2 ≤1 > 10 >2 C High Risk Less Symptoms GOLD 3-4 >2 < 10 0-1 D High Risk More Symptoms GOLD 3-4 >2 > 10 © 2015 Global Initiative for Chronic Obstructive Lung Disease >2 Modified Stepwise Approach to Treatment MILD MODERATE SEVERE VERY SEVERE FEV1>80% FEv1 50-79% FEV1 30-49% FEV1<30% or failure Smoking cessation; Reduce risk factors; Vaccination Pulmonary Rehab based on functional status O2 Surgery Short acting bronchodilators PRN if respiratory symptoms Long acting bronchodilators ICS, if freq. exac (≥ 2/yr.) Azithromycin/roflumilast/NAC Available Drugs SABA Albuterol Levalbuterol LABA Salmeterol Formoterol Beta-2 agonists SAMA Arformoterol Olodaterol Vilanterol Ipratropium Antimuscarinics LAMA Tiotropium Aclidinium Umeclidinium Budesonide Fluticasone Mometasone Roflumilast Theophylline azithromycin ICS PDEI BUT, ALL COPD IS NOT CREATED EQUAL! Obstructive Diseases Asthma: functional dx Emphysema: anatomic dx Reversible airflow obstruction Inflammation prominent Permanent obstruction Destruction of the respiratory bronchioles and alveoli Chronic Bronchitis: symptomatic dx Sputum production 3 months/year for 2 years Asthma/COPD overlap syndrome Chronic bronchitis emphysema ACOS asthma Asthma/COPD overlap syndrome (ACOS) Adults > 40, usually smokers May have a h/o childhood asthma Often have marked variability in symptoms Partial reversibility of airflow obstruction on bronchodilator testing Very little hard data about how to treat this specific group of patients Patients with improvement in FEV1>10% excluded from most studies ICS should probably be used earlier WILL TREATING MY PATIENT ACCORDING TO GUIDELINES AFFECT OUTCOME? GOLD statement None of the existing medications for COPD have been shown to modify the long-term decline in lung function that is the hallmark of this disease (Evidence A). Therefore, pharmacotherapy for COPD is used to decrease symptoms and/or complications. http://www.goldcopd.org Therapeutic outcomes: What really makes a difference Smoking cessation: all patients should be encouraged to quit Pharmacologic aids improve success Oxygen therapy in patients with daytime hypoxemia Benefit of oxygen therapy in patients with exercise desaturation is not known Oxygen therapy COT Cumulative Survival (%) NOT MRC O2 MRC controls • PaO2 < 55 or • PaO2 = 56-59 with evidence of pulmonary hypertension, polycythemia or cor pulmonale Months Flenley DC. Chest. 1985;87:99-103 Smoking and COPD Males Females Former smokers 30 ml/year 22 ml/year Current smokers 66 ml/year 54 ml/year Anthonisen NR, et.al. Am J Respir Crit Care Med 166:675-9, 2002. Inhaled steroids in COPD Possible Benefits Improvement in lung function Decrease in exacerbations Improvement in quality of life Decrease in lung cancer Possible drawbacks Increased pneumonia Cost Cataracts Osteoporosis Do inhaled corticosteroids improve pulmonary function in COPD? change in lung function ISOLDE trial Randomized double blind placebo controlled study in 751 pts with moderate to severe COPD (FEV1 50% pred) over 3 year period Excluded pts with >10% change in FEV1 post BD Included smokers and non-smokers 2 week run in trial with oral prednisone Treated with fluticasone 500 mcg bid vs placebo 43% withdrew from ICS and 53% from placebo groups, most commonly for exacerbations ISOLDE trial Change in lung function No change in rate of decline between ICS and placebo Pts treated with ICS had higher FEV1 throughout the study (average of 30cc) All patients deteriorated when ICS were withdrawn during run-in phase Response to oral prednisone didn’t predict response to ICS Change in FEV1 No Caption Found Burge, P S et al. BMJ 2000;320:1297-1303 Copyright ©2000 BMJ Publishing Group Ltd. TORCH Trial 6112 pts with moderate to severe COPD Current or former smokers < 10% response to BD Followed for 3 years 44% pts withdrew from placebo, 34% from tx groups NEJM Randomized to: 2007;356:775 Fluticasone 500 mcg bid alone Salmeterol alone Fluticasone plus salmeterol combination Placebo Change in FEV1 TORCH Trial All therapy arms had an improvement in first 6 months. Adjusted mean change in FEV1 over 3 years (liters): - .062 placebo - .021 Salmeterol - .015 Fluticasone +.029 Sal/Flu All treatment groups statistically better than the next group, though changes are modest No difference in rate of decline between the groups. Change in FEV1 TORCH trial TORCH study Mortality data TORCH Study Causes of death 35% pulmonary causes 27% cardiovascular causes 21% cancer If ICS don’t dramatically increase pulmonary function or survival, what about quality of life? ISOLDE trial; fluticasone in moderatesevere COPD SGRQ data Questionnaire designed to specifically evaluate health status in respiratory disease Increase in score with worsened health status Change of > 4 points is considered significant Placebo pts in ISOLDE trial worsened at a faster rate than treated pts (3.2 vs 2.0 points/yr p=.004) ? Is this clinically significant Change in health status No Caption Found ISOLDE trial Burge, P S et al. BMJ 2000;320:1297-1303 Copyright ©2000 BMJ Publishing Group Ltd. TORCH study change in health status SGRQ NEJM 2007;356:775 Change in quality of life in pts with severe COPD and recurrent exacerbations 42% SFC vs 30% SAL had improvement of > 4pts AJRCCM 2007;175:144 OK, so what can ICS really do? TORCH study Exacerbations Yearly exacerbation rate 0.85 combination therapy vs 1.13 placebo. 25% reduction corresponds to NTT of 4 pts to prevent 1 exacerbation/yr Combination treatment group exacerbation rate lower than all other groups Hospitalization rates lower in combination and salmeterol groups than in placebo (0.16 vs 0.19) NTT is 32 to prevent 1 hospitalization/yr Time to recurrent exacerbation AJRCCM 2007;17544 ICS and exacerbations Meta-analysis Ann Fam Med 2006;4:253 WHY DO WE CARE ABOUT EXACERBATIONS? COPD Exacerbations : Mortality 1016 pts with severe COPD exacerbation 60 (PaCO2 > 50 mm Hg) 49% 50 Mortality (%) 43% 40 33% 30 20% 20 11% 10 0 Hospital stay 60 days 180 days 1 year 2 years Connors AF Jr et al. Am J Respir Crit Care Med. 1996;154:959-67 COPD exacerbations: Survival Probability of surviving 1.0 0.8 No exacerbation 0.6 p<0.001 1–2 exacerbations 0.4 p=0.07 3–4 exacerbations 0.2 0.0 0 10 20 30 40 Time (months) Soler-Cataluña JJ et al. Thorax. 2005;64:925-31 50 60 p<0.0001 Lung cancer and ICS Cohort study of 10,500 veterans with COPD Median f/u time 4 years 423 cases of lung cancer 20% had been prescribed ICS, only 5% adherent (517 pts) Risk adjusted for smoking status, age, comorbidity, other cancers and BD AJRCCM canister use 2007;175:712 Lung cancer and Triamcinolone use Adjusted Hazard ratio (95% CI) Pts on < 1200 mcg/day HR 1.13 (0.67-1.9) Pts on > 1200 mcg/day HR 0.39 (0.160.96) Continuous per 100mcg/day HR 0.96 (0.94-1) Is there something different about the pts treated with ICS (more asthmatics?) Is there a delay in dx of lung cancer in ICS pts if they seek less medical care? Prospective randomized study would be useful, but likely not feasible OK, so what’s the down side? Effect of ICS on pneumonia incidence TORCH trial: 19% vs 13% in fluticasone containing regimens (p<.001) No prospective definition of pneumonia included Nested case control study 175,000 Canadian COPD pts also found increased risk of hospitalization for pneumonia Risk of hospitalization for pneumonia with ICS use Current ICS user Rate ratio 1.7 High dose ICS Medium dose ICS Low dose ICS Rate ratio 2.25 Rate ratio 1.63 Rate ratio 1.50 ARJCCM 2007; 176:162 Risk of cataracts with ICS Increased occurrence not seen in prospective studies Population based studies do show association May be exposure time too short Less firm if pts treated with systemic steroids are excluded Lifetime dose important May not be relevant in most COPD pts Ann fam med 2006;4:253 Risk of Osteoporosis with ICS Some decrease in bone mineral density, particularly associated with triamcinolone use Risk of fractures does not appear to be increased in prospective studies Cochrane review 2007:CD002991 ICS in COPD Drawbacks Pneumonia rate may be increased May be a dose related phenomenon Is benefit preserved with lower doses? Cost/benefit ratio is not well defined Particularly in combination with LABD Cataracts and increased fractures probably not an issue in this specific pt population Conclusions Benefits of ICS in COPD High dose ICS may improve lung function and quality of life, but effects are small Exacerbation rate appears to be reduced, particularly with more severe disease Pulmonary function may decline if ICS are abruptly withdrawn Would this have a mortality effect in larger study? Is it outweighed by pneumonia incidence? Benefit may be better in patients with bronchodilator response (ACOS) since they were excluded from studies Lung cancer rate may be reduced Prospective data are needed WHAT ABOUT ANTICHOLINERGIC (ANTIMUSCARINIC) AGENTS? Tiotropium Delays Next Exacerbation/ Hospitalization Niewoehner, D. E. et. al. Ann Intern Med 2005;143:317-326 Cardiac Risk, Ipratroprium, Tiotropium Better tolerated than beta-agonists Meta-analysis - increased CV deaths in patients on anti-muscarinics UPLIFT - 4 yr trial - decreased fatal cardiovascular event risk with Tiotropium Clinical trial safety database Tiotropium – no increased risk Celli. Am J Respir Crit Care Med. 2009;180(10):948 Celli. Chest. 2010;137(1)20 Antimuscarinic agents: conclusion They seem to reduce exacerbation rate. Likely do NOT increase cardiovascular risk May reconsider risk in patients with unstable cardiovascular disease Long acting agents (LAMAs); tiotropium, aclidinium, umeclidinium should NOT be used with atrovent Competition for receptors may reduce efficacy What about long acting beta agonists (LABA)? Beware the black box! Increased risk of death associated LABA use found only in asthmatics Do not need to be combined with inhaled steroids (ICS) in COPD patients Still, patients will ask about it, and it may be difficult to use LABAs without ICS OK; MY PATIENT IS ON 3 DIFFERENT INHALERS AND STILL MISERABLE. IS THERE ANYTHING ELSE? Theophilline Positive effects for COPD Stimulate respiratory center May improve diaphragmatic function Anti-inflammatory Negative effects for COPD Increases GERD Narrow therapeutic window Cardiac tachyarrhthmias Significant drug-drug interactions Roflumilast Unknown exact mechanism Selectively inhibits phosphodiesterase Type 4 leading to increased intracellular cAMP Decreases exacerbations in patients with chronic bronchitis Use with caution in liver disease, depression (suicide) N-acetyl cysteine (NAC) and exacerbation rates Lancet resp medicine 2014: 187 Azithromycin Randomized controlled trial of 1142 patients with COPD either on oxygen or with exacerbation during the last year had Decreased exacerbation rate NNT to prevent exacerbation 2.86 Mild improvement in QOL 43% VS 36% had improvement>4pts in SGRQ Colonization with macrolide resistant bacteria found on f/u treatment Pts with prolonged QT or hearing impairment excluded Possible worsening in hearing in treated pts Proportion of Participants Free from Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) for 1 Year, According to Study Group. Albert RK et al. N Engl J Med 2011;365:689-698. Pulmonary rehabilitation programs Decrease symptoms of dyspnea and fatigue Improve exercise tolerance and quality of life Decrease hospitalization rates Do not affect rate of decline in FEV1 The longer the program is, the more benefit Continued exercise at home afterwards increases benefit Lung volume reduction surgery (LVRS) Greatest benefit in patients with upper lobe predominant emphysema and low exercise capacity 7.9% 90 day mortality vs 1.9% control 28% had improved exercise capacity at 6 months 15% at 2 years NETT. NEJM 2003: 348:2059-73 Endobronchial valve placement Designed to cause progressive lobar collapse; non-operative lung volume reduction In selected patients improved FEV1, 6mwt and QOL at 6 months Lots of adverse events; ptx, displacement of valve, need for removal Small study ?? Ready for “prime time” Nejm 2015; 373:2325 Lung Transplant Age <=65 Maximal medical therapy Have undergone pulmonary rehab Body weight 80-120% of ideal Favorable social factors Costly 5 year mortality 50% Lung Transplant Contraindications Untreatable pulmonary infection Malignancy within last 2 years Significant dysfunction of other organs (heart) Significant chest wall/spine deformity Active smoking/drug and alcohol dependency Unresolved psychosocial problems (noncompliance) Need dedicated care giver to travel with them to transplant center HIV, Hep B, Hep C Acute Exacerbation Classification Level 1: Treatment at home Level 2: Hospitalization Clinical Factors Favoring Hospitalization HR, RR, change in BP Hypoxia/ hypercapnea Significant comorbidities Elderly Poor home support Inadequate outpatient response ER Visit in last 2 weeks Level 3: ICU/Specialized Care Acute Exacerbation Treatment Oxygen for low saturations Bronchodilators Steroids 14 day max MDI vs nebulizer IV vs Oral Improves spirometry, decreases relapse rate and length of stay No study on taper; 40 mg x5 days recommended by GOLD Education; MDI use Antibiotics Antibiotics in acute exacerbation Indicated for Increased sputum volume Increased purulence In patients who require mechanical ventilation Antibiotics and Survival Retrospective cohort of 50K COPD pts in Netherlands Median time to next exacerbation delayed More benefit in worse exacerbations Fewer treatment failures with newer Abx Roede et al. Thorax 2008: 63:968 NIPPV in Acute Exacerbations If pH<7.35, if tolerated Decreases symptoms/ LOS/ mortality Avoid in: CV instability, Uncooperative patient, ΔMS, Copious secretions, high aspiration risk, Facial abnormalities How long will my patient live? PROGNOSTICATION IN COPD BODE index for COPD survival prediction FEV1 50-64% 1 point 36-49% 2 points <35% 3 points 6MWT distance Dyspnea Need to stop on level ground: 1 point Walking 100 yards: 2 points 250-349 M 1 point Breathless with ADLs: 150-249 M 2 points 3 points < 149 M 3 points BMI <21: 1 point Bode inex; 4 year survival 0-2 points: 3-4 points: 5-6 points: 7-10 points: 80% 67% 57% 18% Summary Prevention is key Smoking cessation Vaccinations, early treatment of exacerbations Only oxygen and smoking cessation improve mortality Stepwise treatment with: Short acting bronchodilators Long acting bronchodilators Inhaled steroids To reduce symptoms and exacerbations Summary Inhaled corticosteroids may be associated with increased pneumonia risk Patients may deteriorate if ICS are withdrawn abruptly Pulmonary rehab should be used in symptomatic patients COPD exacerbations portend a poor prognosis Consider transplant or LVRS in selected patients The REAL reason dinosaurs became extinct...