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State of the Art: COPD in 2020Bartolome R. Celli, M.D., FCCPProfessor of MedicineHarvard Medical SchoolUniversita di Bologna Founded 1088

B. Celli DisclaimerNo stocks or ownership in any company.No Tobacco fundsAdvisory boards: GSK, B.I., Astra Zeneca, Novartis,Pulmonx, Chiesi, Menarini.Member of the Scientific and Executive Committee ofGOLD

Agenda Describe the COPD landscape in the World There are several “natural courses” to develop COPD Provide a practical approach to initiate and modify pharmacotherapyin patients with COPD. Review the tools available for patients on maximal therapy whoremain functionally impaired Conclusions

Agenda Describe the COPD landscape in the World There are several “natural courses” to develop COPD Provide a practical approach to initiate and modify pharmacotherapyin patients with COPD. Review the tools available for patients on maximal therapy whoremain functionally impaired Conclusions

Annual % change1990-2013Death municableILDInjuries

Annual % change1990-2013Death 100K personswww.GBDAccessed2/2020Percent of deaths: 5.36Annual % change - 1.01

Burden of COPDAbsolute numbers 1990 to 94199820022006201020142016Axis South AfricaGhanaMexicoUkraineWWW.GBD. Accessed July 2019 (Courtesy Dr. Sundeep Salvi)

Agenda Describe the COPD landscape in the World There are several “natural courses” to develop COPD Provide a practical approach to initiate and modify pharmacotherapyin patients with COPD. Review the tools available for patients on maximal therapy whoremain functionally impaired Conclusions

Course of Lung FunctionDeterminants of lossCurrent smokingMaleEmphysemaLow BMILower CC16 levelsHigher FEV1No yLange P et al NEJM 2015;372:2

Course of Lung FunctionDeterminants of gainLange P et al NEJM 2015;372:2

Agenda Describe the COPD landscape in the World There are several “natural courses” to develop COPD Provide a practical approach to initiate and modify pharmacotherapyin patients with COPD. Review the tools available for patients on maximal therapy whoremain functionally impaired Conclusions

Bronchodilator responsiveness in COPDPercent of patients53%30n 588125FEV1 1.1 L20151050-300-200-1000100200300FEV1 ml changeTashkin D et al ERJ 2008;31:742

Bronchodilator responsiveness in COPDFVC, but notFEV1 responseFEV1, but notFVC responseStage IIStage IIIStage IVStage IIStage IV5040% of responders% of responders50Stage III3020100403020100 15% 12% 200 mL 15% 12% 200 mLTashkin D et al ERJ 2008;31:742

TORCH: DB, R, PC, 3 year trial. 6000 patients comparing F, S, SF, POutcome: Primary: Mortality Secondary: FEV1, QoL, Exacerbations92 mldifferencefromplaceboFEV1QEXACERBAT25% reduction inexacerbationsOLSt George’sis 3.1 betterthan placeboand betterthan baselineIONCalverley P et al NEJM 2007;22:356

Pneumonia Risk in TORCHOlder than 55 yearsLower BMI 25 Kg/m2FEV1 50 % predictedPrevious exacerbationsCrim C et al ERJ 2009;34:341

UPLIFT: DB, R, PC, 4 year trial. 6000 patients. Tio vs Usual careOutcome: Primary: FEV1 decline Secondary: QoL, AE, MortalityUPLIFT110 mldifferencefrom placeboFEV1QEXACERBAT16% reduction inexacerbations IOLSt George’sis 3.3 unitsbetter thanplacebo andbetter thanbaselineONTashkin D et al NEJM 2008;359:1543

How to approach?ICS LABALABA LAMALABAPDEI 4LAMASABASAMA

Assessmentof airflowlimitationDiagnosisGradeFEV1/FVC 0.71FEV1(%pred.) 80250-79330-494 30

Assessmentof airflowlimitationDiagnosisAssessment ofsymptoms/risk ofexacerbationsExacerbation historyGradeFEV1/FVC 0.71FEV1(%pred.) 80250-79330-494 30CDABmMRC 0-1CAT 10CCQ 1mMRC 2 CAT 10 CCQ 1 2 or moreor1 or morehospitalization0 or 1(nohospitalization)

GOLD 2019: Initial Pharmacological Treatment4 INITIAL PHARMACOLOGICAL TREATMENT 2 moderateexacerbations or 1 leading tohospitalization0 or 1 moderateexacerbation(not leading tohospital admission)Group CGroup DLAMAGroup AA BronchodilatormMRC 0-1 CAT 10LAMA orLAMA LABA* orICS LABA†Group BA Long-acting Bronchodilator(LABA or LAMA)mMRC 2 CAT 10ICS inhaled corticosteroid; LABA long-acting beta2-adrenergic agonist; LAMA long-acting muscarinic antagonist.*Consider if highly symptomatic (eg, CAT 20)†Considerif eosinophils 300GOLD. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2019 Report. www.goldcopd.org. 2018 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license fromthe owner. 2017 Global Initiative for Chronic Obstructive Lung Disease20

4 GOLD 2019: FOLLOW-UP PHARMACOLOGICAL TREATMENT1. IF RESPONSE TO INITIAL TREATMENT IS APPROPRIATE, MAINTAIN IT.2. IF NOT: ü Consider the predominant treatable trait to target (dyspnea or exacerbations) Use exacerbation pathway if both exacerbations and dyspnea need to be targetedü Place patient in box corresponding to current treatment and follow indicationsü Assess response, adjust, and reviewü These recommendations do not depend on the ABCD assessment at diagnosisEXACERBATIONSDYSPNEALABA or LAMALAMA or LABA† Consider switchinginhaler devices ormolecules Investigate (and treat)other causes ofdyspnea†ICS LABAICS LAMA LABALAMA LABAConsider ifEOS 100LABA or LAMA*†ICS LABA†Consider ifEOS 100ICS LAMA LABARoflumilastFEV1 50 & ChronicbronchitisIn former smokersAzithromycin*Consider if eosinophils 300 cells/µL or 100 cells/µL 2 moderate exacerbations or 1 hospitalized exacerbation.†Consider de-escalation of ICS or switch if pneumonia, inappropriate original indication, or lack of response.GOLD. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2019 Report. www.goldcopd.org. 2018 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license fromthe owner. 2017 Global Initiative for Chronic Obstructive Lung Disease

Exacerbations predictors: Post hoc analysis of budesonide in 3 RC COPD trialsData from 3 RC trials of:B/F versus F alone whohad eosinophils measuredN 4153 patientsFEV1 1 L38% predOutcomes:ExacerbationsFEV1QoLBafadhel M et al Lancet RM 2018;6:117

Makediagnosisand graderisk factorsInitiateTherapyFEV1Symptoms (Dyspnea) eckadherenceCelli B and Wedzicha J NEJM 2019;381:1257

Makediagnosisand graderisk factorsFEV1Emphysema featuresHyperinflationEosinophils 100 cells/ µLInitiateTherapySymptoms (Dyspnea) andExacerbationsAsthmatic featuresWheezing, allergiesEosinophils 100 cells/ elli B and Wedzicha J NEJM 2019;381:1257

Makediagnosisand graderisk factorsSymptoms (Dyspnea) andExacerbationsFEV1Emphysema featuresHyperinflationEosinophils 100 cells/ ptompersistenceAsthmatic featuresWheezing, allergiesEosinophils 100 cells/ µLLAMA LABAandCheckadherenceCelli B and Wedzicha J NEJM 2019;381:1257

Makediagnosisand graderisk factorsSymptoms (Dyspnea) andExacerbationsFEV1Emphysema featuresHyperinflationEosinophils 100 cells/ kadherenceLAMASymptompersistenceLAMA LABAAsthmatic featuresWheezing, allergiesEosinophils 100 cells/ µLLABA ICSCheck for ICSside effectsIf importantdiscontinueand consideralternativesCelli B and Wedzicha J NEJM 2019;381:1257

Makediagnosisand graderisk factorsSymptoms (Dyspnea) andExacerbationsFEV1Emphysema featuresHyperinflationEosinophils 100 cells/ kadherenceLAMASymptompersistenceContinued lackof controlLAMA LABAAsthmatic featuresWheezing, allergiesEosinophils 100 cells/ µLLABA ICSFrequent and/or severeexacerbationsTriple (LAMA LABA ICS)Check for ICSside effectsIf importantdiscontinueand consideralternativesCelli B and Wedzicha J NEJM 2019;381:1257

Makediagnosisand graderisk factorsSymptoms (Dyspnea) andExacerbationsFEV1Emphysema featuresHyperinflationEosinophils 100 cells/ kadherenceLAMASymptompersistenceAsthmatic featuresWheezing, allergiesEosinophils 100 cells/ µLLAMA LABALABA ICSFrequent and/or severeexacerbationsContinued lackof controlTriple (LAMA LABA ICS)Check for ICSside effectsIf importantdiscontinueand consideralternatives(PDE4i, macrolides, NAC, Xanthines)Check for persistent eosinophiliaIf present, consider biologicalsCelli B and Wedzicha J NEJM 2019;381:1257

Agenda Describe the COPD landscape in the World There are several “natural courses” to develop COPD Provide a practical approach to initiate and modify pharmacotherapyin patients with COPD. Review the tools available for patients on maximal therapy whoremain functionally impaired Conclusions

Along with 31 RCT’s includedin the 2006 CochraneReview, the authors included34 additional RCT’s with agrand total of 3,822participants.Conclusions

Hyperinflation in a 63 year old man with mMRC dyspnea of 3FEV 1 32 %FRC 192 %DLCO 49 %

Endobronchial Valves (EBV) Zephyr (Pulmonx) silicone based mounted ina nitinol stent one wayvalve Spiration (Olympus) 6 Nitinol struts andpolyurethane umbrellashape unidirectional valve

Conclusions COPD is an important health problem worldwide Although cigarettes remain the most important cause, this is not sofor the majority of countries in the world Well applied pharmacotherapy works In patients with persistent symptoms consider rehabilitation Check for emphysema and hyperinflation for potential LVR A nihilistic approach is not justified!

“If it were not for the great variabilityamong individuals,medicine might aswell be a science and not an art”William Osler

Harvard Medical School Universitadi Bologna Founded 1088. No stocks or ownership in any company. No Tobacco funds . Review the tools available for patients on maximal therapy who remain functionally impaired Conclusions. . SABA SAMA LAMA LABA ICS LABA LABA LAMA PDEI 4 How to approach? Diagnosis Grade FEV 1 (% pred.) 1 80 2 50-79