Management of COPD Updates and Evidence Providence Alaska Medical Center PGY1 Pharmacy Practice Residents Ann-Chee Cheng, PharmD Kaite Kammers, PharmD http://www.fpnotebook.com/_media/lungxsgraybb962.gif
Disclosures All presenters of this activity have no financial relationships relevant to this activity
Objectives 1. Describe the updated recommendations in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 Global Strategy for the Diagnosis, Management and Prevention of COPD 2. Compare and contrast therapies for management of COPD based on evidence from recent clinical trials 3. Develop a management plan for COPD using 2017 GOLD guidelines
Pre-Test 1. Which inhaled medication is no longer a preferred agent in the management of COPD? 2. Which inhaled medication(s) is now emphasized/ preferred in all ABCD severity groups? 3. What class of medications was added to step-up therapy for an exacerbation in a group D patient? 4. What are goals of treatment for improving inhaler technique? 5. Based on results from the FLAME study, which combination of inhaled medications lengthened time between exacerbations? 6. What did the results of the WISDOM study show in relation to withdrawing ICS from patients on triple therapy? 7. What population(s) was shown to benefit most from adding roflumilast to maintenance therapy? 8. What should be assessed in regard to medication use in all patients prior to escalating therapy in COPD?
COPD Death Rates in the United States Thun MJ, Carter BD, Feskanich D, et al. 50-year trends in smoking-related mortality in the United States. N Engl J Med. 2013;368(4):351-64.
Revisions to the GOLD Guidelines Updated the definition of COPD Separated GOLD category from COPD severity group Added long-acting muscarinic antagonist (LAMA) and long-acting beta2 agonist (LABA) to mild COPD patients Removed inhaled corticosteroids (ICS) as preferred agents in the group C and D Added azithromycin and erythromycin as alternative agents Emphasized inhaler technique teaching Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2017. www.goldcopd.org.
Definition of COPD Common, preventable, and treatable pulmonary disease Persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities Usually caused by interaction of significant exposure to noxious particles gases and specific host factors Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2017. www.goldcopd.org.
Question 1: Which of the following GOLD grades and severity groups are appropriate for a 65- year old with COPD Assessment Test (CAT) score of 28 today, not COPD exacerbations in the past year and forced expiratory volume in 1 second (FEV1) of 29% of the predicted value 1 month ago? A. GOLD grade 4, group B B. GOLD grade 4, group D C. GOLD grade 1, group A D. GOLD grade 1, group C
Severity of Airflow Limitation - GOLD Grades Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2017. www.goldcopd.org.
2016 GOLD Guidelines Severity Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2016. www.goldcopd.org.
2017 GOLD Guidelines Severity Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2017. www.goldcopd.org.
COPD Assessment based on GOLD 2017 1. Use Spirometry to diagnose COPD and assess airflow limitation (GOLD grade) 2. Use CAT or mmrc to assess COPD symptom severity 3. Determine exacerbation risk: a. Number of COPD exacerbations in past 12 months b. Number of COPD-related hospitalizations in the past year
Question 2: Which of the following types of medications are currently recommended for a 45-year old with one COPD-related hospitalization in the past year, a CAT score of 28 and a FEV1 49% and the predicted value with no airway reversibility who is using an albuterol metered-dose inhaler (MDI) 90 mcg 2 puffs 3-4 times/ day for COPD symptoms? A. Tiotropium/ Olodaterol B. Budesonide/ Formoterol C. Fluticasone/ Umeclidinium/Vilanterol D. Ipratropium/ Albuterol
2016 GOLD: Initial Medications Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2016. www.goldcopd.org.
2017 GOLD: Initial Medications Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2017. www.goldcopd.org.
Question 3: Which of the following step-up options is recommended for a 75-year old woman with GOLD grade 4, group D COPD currently taking ICS/LABA and a LAMA? She is adherent to her inhalers and is able to use them correctly. She is on 2L of oxygen/ 24 hours. She continues to have a CAT score of 30 and a COPD exacerbation every other month. Despite quitting smoking 1 year ago, she is losing weight and complains of feeling depressed. A. Azithromycin B. Roflumilast C. Theophylline D. Prednisone
Step-up / Alternative Medications 2016 LAMA and/or LABA and/or ICS combinations SAMA + SABA Theophylline Roflumilast + LAMA Roflumilast + LABA ICS + LABA + roflumilast 2017 LAMA and/or LABA combination LABA + ICS LAMA + LABA + ICS Step-up: Roflumilast Azithromycin Erythromycin Other: ICS withdrawal? Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2017. www.goldcopd.org.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2017. www.goldcopd.org.
Azithromycin and Erythromycin Decreased exacerbations when used for 6-12 months No significant decrease in hospitalizations or overall mortality Increased side-effects Unknowns: Optimal dosing Duration of therapy (no data past 12 months) Subpopulations with the most benefit Ni W, Shao X, Cai X, et al. Prophylactic use of macrolide antibiotics for the prevention of chronic obstructive pulmonary disease exacerbation: a meta-analysis. PLoS ONE. 2015;10(3):e0121257.
ICS Withdrawal Mixed data on if w/d increases lung function and/or decreases exacerbations Background use of LAMA or LABA may minimize effect Modest decrease in FEV1 (~ 40mL) Magnussen H, Disse B, Rodriguez-roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285-94. Watz H, Tetzlaff K, Wouters EF, et al. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med. 2016;4(5):390-8.
Triple Inhaled Therapy LABA + LAMA + ICS = triple inhaled therapy Fluticasone furoate + umeclidinium + vilanterol 100 mcg/62.5 mcg/ 25 mcg (Trelegy Ellipta ) daily -- approved September 2017 Add LAMA to existing LABA/ICS regimen improves lung function and patient reported exacerbations Single study found no benefit of adding ICS to LABA/LAMA combination More evidence needed if triple inhaled therapy is more beneficial than LABA/LAMA alone Brusselle G, Price D, Gruffydd-jones K, et al. The inevitable drift to triple therapy in COPD: an analysis of prescribing pathways in the UK. Int J Chron Obstruct Pulmon Dis. 2015;10:2207-17. Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146(8):545-55.
Question 4: A 55-year old with COPD returns to clinic with questions about the proper use of his Respimat inhaler. Which of the following techniques is correct for the use of this inhaler? A. Priming the inhaler before the first use B. Opening the cap and then twisting the base C. Placing the mouthpiece 2 finger spaces away from the mouth D. Inhaling use a quick and steady breath
Critical Errors with Inhalers Van der palen J, Thomas M, Chrystyn H, et al. A randomised open-label cross-over study of inhaler errors, preference and time to achieve correct inhaler use in patients with COPD or asthma: comparison of ELLIPTA with other inhaler devices. NPJ Prim Care Respir Med. 2016;26:16079.
Question 5: A COPD patient reports a history of intolerance to propellants in inhalers. Which of the following inhalation delivery systems uses a propellant? A. Metered-dose inhaler B. Dry powder inhaler C. Jet nebulizer D. Propellants are no longer used inhalation devices
Goals of Treatment with Inhaler Emphasis Reduce risk Reduce symptoms Personalized Inhaler improvement: Facilitate drug deliver Reduce frequency Minimize number of inhalers Still the same drug classes. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2017. www.goldcopd.org.
Procalcitonin Procalcitonin guided antibiotics associated with decreased antibiotic exposure without affecting clinical outcomes (Evidence: Low- Moderate) Specific for bacterial infections Rule out patients who may not benefit from antibiotics during exacerbations Christ-crain M, Jaccard-stolz D, Bingisser R, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet. 2004;363(9409):600-7. Schuetz P, Christ-crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA. 2009;302(10):1059-66.
Recently Published Evidence FULFIL - 2017 FLAME - 2016 WISDOM - 2014 RE 2 SPOND - 2016 Tie-COPD - 2017
Question 6: How are COPD exacerbations classified per GOLD guidelines? Mild Moderate Severe True or False: FEV1 is a good marker to determine likelihood of exacerbation risk
Question 6: How are COPD exacerbations classified per GOLD guidelines? Mild - can be treated with short acting bronchodilators (SABD) Moderate - treated with SABD + antibiotics + PO corticosteroids Severe - requires hospitalization or ER visit True or False: FEV 1 is a good marker to determine likelihood of exacerbation risk - False
FULFIL Study - 2017 Study comparing once a day triple agent therapy in a single inhaler with two agent twice a day therapy in a single inhaler for those at high risk of exacerbations 24 week randomized control trial double blind and double dummy Fluticasone 100 mcg + Umeclidinium 62.5 mcg + Vilanterol 25 mcg (ICS + LAMA + LABA) once daily VS Budesonide 400 mcg + Formoterol 12 mcg (ICS + LABA) twice daily Lipson DA, Barnacle H, Birk R, et al. FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2017;196(4):438-446.
FULFIL Study Population n = 1810 64 year old males (74%) Current or past average 39 pack year smoking history Average FEV 1 = 49% predicted (~ GOLD 3) About 65% experienced > 1 moderate or severe exacerbation in the previous year Lipson DA, Barnacle H, Birk R, et al. FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2017;196(4):438-446.
FULFIL Design & Results Outcomes ITT LAMA + LABA + ICS LABA + ICS P value Primary Mean change in FEV 1 from baseline Mean change in SGRQ from baseline + 142 ml - 29 ml <0.001-6.6 units - 4.3 units <0.001 Secondary Rate of mild, moderate & severe exacerbations Addition of LAMA to LABA + ICS therapy reduced rate by 35% ADE Pneumonia 20/911 (2.2%) 7/899 (0.8%) Lipson DA, Barnacle H, Birk R, et al. FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2017;196(4):438-446.
Mean Change in FEV1 from Baseline Baseline Lipson DA, Barnacle H, Birk R, et al. FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2017;196(4):438-446.
FULFIL Study Discussion Contributes to current evidence that has already shown adding LAMA to LABA + ICS results in improvement in lung function and QoL This product likely provides benefit in regards to patient adherence Funded by GSK, makers of Trelegy Ellipta TM inhaler Did not report pre-enrollment COPD maintenance regimens Improvement of FEV 1 has questionable clinical significance Frith PA, et al. Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomized controlled trial. Thorax 2015; 70(6): 519-27. Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet. 2016;388(10048):963-73.
FLAME Study - 2016 A study comparing exacerbation rate for dual long acting bronchodilator therapy with the standard of care (LABA + ICS) for those with severe COPD 52 week RCT double blind, double dummy, non-inferiority trial (HR margin 15%) Indacaterol 110 mcg + Glycopyrronium 50 mcg (LAMA + LABA) once daily VS Salmeterol 50 mcg + Fluticasone 500 mcg (LABA + ICS) twice daily Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016;
FLAME Study Population n = 3362 ~ 65 year old males (76%) Generally diagnosed COPD for 7.3 yrs and Group D at time of study (74.8%) Average FEV 1 = 44.1% predicted Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016;
FLAME Design & Methods Outcomes ITT LAMA + LABA LABA + ICS Rate ratio Primary Annual rate of any exacerbation 3.59 4.03 0.89 (11% lower) p = 0.003 LAMA + LABA was non-inferior to LABA + ICS for decreasing annual rate of any COPD exacerbation Secondary Time to 1st exacerbation of any severity Annual rate mod/severe exacerbation Time to 1st mod/severe exacerbation 71 days 51 days 0.84 (16% lower) p < 0.001 0.98 1.19% 0.83 (17% lower) p < 0.001 127 days 87 days 0.78 (22% lower) p < 0.001 Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016;
FLAME Results Favors LABA + LAMA Favors LABA + ICS Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016;
FLAME Discussion LAMA + LABA is not inferior to LABA + ICS in reducing rate of exacerbations Demonstrated that LAMA + LABA combination also lengthened time between exacerbations compared to the standard of therapy Study was not powered to assess impact of the two treatment groups on severe exacerbations Some of the LABA + LAMA group recieved ICS prior to enrollment
Available LABA + LAMA agents Brand Generic Dose FDA approval Bevespi TM Aerosphere MDI Glycopyrrolate + formoterol 2 puffs BID 2016 Utibron TM Neohaler Glycopyrrolate + indacaterol 1 capsule BID 2015 Stioltio TM Respimat MDI Tiotropium + olodaterol 2 puffs QD 2015 Anoro TM Ellipta DPI Umeclidinium + vilanterol 1 puff QD 2013 Duaklir TM Genuair DPI Aclidinium + formoterol 1 puff BID Seeking 2018
Question 7: A 62 yo woman with GOLD stage 2 and is being discharged today for her 3rd COPD exacerbation this year. The doctor was planning to continue her home Symbicort TM and Spiriva TM. PMH: CAD, T2DM, osteoporosis and reports variable adherence to inhalers What medication change (if any) would you recommend to optimize therapy? A. Change to Umeclidinium + vilanterol (Anoro Ellipta TM ) B. Discontinue Spiriva TM C. No changes, she is on optimum therapy D. Add Roflumilast
WISDOM Study - 2014 Assess the impact of ICS withdrawal from triple therapy on COPD exacerbations 52 week double blind, parallel group non-inferiority study (hazard ratio margin 1.2) Tiotropium 18 mcg QD + Salmeterol 50 mcg BID + Fluticasone 500 mcg BID Triple Therapy x 6 weeks Continue triple therapy VS Withdraw Fluticasone 500 mcg BID in 3 steps over 12 weeks Magnussen H, Disse B, Rodriguez-roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285-94.
WISDOM Study Population n = 2485 64 year old males (82.5%) Mainly caucasian Average COPD diagnosis for 7.87 years with FEV 1 < 50% (99.3%) Average FEV 1 (34.2% predicted) Magnussen H, Disse B, Rodriguez-roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285-94.
WISDOM Results Magnussen H, Disse B, Rodriguez-roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285-94.
WISDOM Results Magnussen H, Disse B, Rodriguez-roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285-94.
WISDOM Results Primary endpoint Withdrawing ICS from triple therapy was not inferior to continuing therapy when evaluating time to first moderate to severe exacerbation Hazard ratio 1.06 (CI: 0.94-1.19) Secondary endpoints Time to first severe exacerbation hazard ratio 1.2 At 18 weeks the trough FEV 1 was greater (38 ml) than those on triple therapy No significant differences were noted for dyspnea or minor health status Safety Incidence of pneumonia was similar between the groups Magnussen H, Disse B, Rodriguez-roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285-94.
WISDOM Discussion Shows ICS may not be needed in all COPD patients and can be safely withdrawn without resulting in an increase in exacerbations Only specific populations likely continue to confer benefit from ICS ie: Asthma - COPD Overlap Syndrome (ACOS) Generalizability was limited since population was mostly male and Caucasian High dose ICS used (500 mcg BID) Magnussen H, Disse B, Rodriguez-roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285-94.
RE 2 SPOND Study - 2016 The REACT study showed roflumilast is an effective add-on agent to decrease moderate or severe exacerbations and hospitalizations. RE 2 SPOND builds on REACT to determine which subgroup benefits most from roflumilast 52 week, multicenter, phase 4, RCT, double blind, placebo controlled Any ICS + LABA + LAMA for > 3 months Roflumilast 500 mcg once daily x 52 weeks VS Placebo x 52 weeks Martinez FJ, Rabe KF, Sethi S, et al. Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial. Am J Respir Crit Care Med. 2016;194(5):559-67.
RE 2 SPOND Population n = 2352 53% used ICS + LABA and remaining also had LAMA 64 year old males (85%) Mostly caucasian (80%) ~ 2.4 exacerbations/hospitalizations in the past year FEV 1 = 33% predicted ~ 52.5 pack year smoking history Martinez FJ, Rabe KF, Sethi S, et al. Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial. Am J Respir Crit Care Med. 2016;194(5):559-67.
RE 2 SPOND Design and Results Outcomes Roflumilast Placebo RR (p-value) Primary Annual mod/severe exacerbation rate 1.17 1.27 0.92 p = 0.163 Did not achieve primary endpoint but shows trend that favors roflumilast Secondary Mean time to first exacerbation 319 days 286 days 0.9 p =0.323 Subgroup analysis Annual mod/severe exacerbation rate for those with hx >3 exacerbations/yr Annual mod/severe exacerbation rate for those with > 1 severe exacerbations/yr 1.59 2.62 0.61 p = 0.03 1.23 1.63 0.77 p = 0.01 Martinez FJ, Rabe KF, Sethi S, et al. Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial. Am J Respir Crit Care Med. 2016;194(5):559-67.
RE 2 SPOND Discussion Those with > 3 exacerbations a year and those with > 1 severe exacerbation in a year are the two populations that are most likely to benefit from roflumilast Limited ICS doses used in the study Maximum dose: fluticasone 250 mcg/salmeterol 50 mcg 1 BID Baseline population potentially were not on optimal therapy 47% were on concurrent LAMA (expected 60%)
Tie-COPD Study - 2017 Study to evaluating use of long term LAMA in mild to moderate COPD patients who have minimal symptoms 2 year, multicenter, RCT, double blinded, phase 4 trial Tiotropium 18 mcg (LAMA) once daily VS Placebo Zhou Y, Zhong NS, Li X, et al. Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease. N Engl J Med. 2017;377(10):923-935.
Tie-COPD Population n = 841 Study subjects recruited from mainland China 64 year old males (85%) GOLD stage 1-2 ~ 52.5 pack year smoking history FEV 1 = 78% predicted Mean CAT score 7.1 Zhou Y, Zhong NS, Li X, et al. Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease. N Engl J Med. 2017;377(10):923-935.
Tie-COPD Design & Results Outcomes LAMA Placebo P value Primary Secondary Mean change in FEV 1 from baseline before SABD Mean change in FEV 1 from baseline after SABD Number of any exacerbation or hospitalization per pt/yr Number of moderate/severe exacerbation per pt/yr 38 ml 53 ml 0.06 29 ml 51 ml 0.006 0.27 0.5 <0.001 0.2 0.38 <0.001 Zhou Y, Zhong NS, Li X, et al. Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease. N Engl J Med. 2017;377(10):923-935.
Tie-COPD Discussion Roughly 70% of those with COPD have mild or minimal symptoms and the majority do not receive maintenance treatment Provides evidence supporting benefit of early initiation of LABA Initiation of LAMA showed slower decline in FEV 1 for those very early in the disease progression (GOLD 1 and 2) Generalizability of the study is limited given that the majority of the study population were Chinese Zhou Y, Zhong NS, Li X, et al. Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease. N Engl J Med. 2017;377(10):923-935. Mapel DW, Dalal AA, Blanchette CM, Petersen H, Ferguson GT. Severity of COPD at initial spirometry-confirmed diagnosis: data from medical charts and administrative claims. Int J Chron Obstruct Pulmon Dis. 2011;6:573-81.
Post-Test 1. Which inhaled medication is no longer a preferred agent in the management of COPD? 2. Which inhaled medication(s) is now emphasized/ preferred in all ABCD severity groups? 3. What class of medications was added to step-up therapy for an exacerbation in a group D patient? 4. What are goals of treatment for improving inhaler technique? 5. Based on results from the FLAME study, which combination of inhaled medications lengthened time between exacerbations? 6. What did the results of the WISDOM study show in relation to withdrawing ICS from patients on triple therapy? 7. What population(s) was shown to benefit most from adding roflumilast to maintenance therapy? 8. What should be assessed in regard to medication use in all patients prior to escalating therapy in COPD?
Clinical Pearls Select appropriate inhaler device based on patient inspiratory flow rate Deterioration of inhaler technique over time, review administration technique with patients Dual bronchodilator (LABA + LAMA) is a the new strategy for managing COPD ICS therapy reserved for those at highest risk for exacerbations Roflumilast added to ICS + LABA ( +/- LAMA) therapy can reduce the rate of moderate or severe exacerbations
https://images-cdn.9gag.com/photo/ad0xpmn_700b.jpg Questions?