What s new in COPD? Apichart Khanichap MD. Department of Medicine, Faculty of Medicine, Thammasat university

What s new in COPD? Apichart Khanichap MD. Department of Medicine, Faculty of Medicine, Thammasat university

Management stable COPD Relieve symptoms Improve exercise tolerance Improve health status Prevent disease progression Prevent and treat exacerbations Reduce mortality Reduce symptoms Reduce risk

GOLD 2018: Symptoms and exacerbation risk should be assessed to determine appropriate treatment 1. Diagnose COPD and determine the severity of airflow limitation (GOLD Grade 1 4) using spirometry 2. Determine GOLD Group (A D) and subsequent appropriate pharmacological treatment by assessing symptoms and exacerbation history (including prior hospitalizations) Spirometrically confirmed diagnosis Assessment of airflow limitation Assessment of symptoms/ risk of exacerbations Exacerbation history Grade FEV 1 (% pred.) 1 80 >2 or 1 leading to hospitalization C D Post-bronchodilator FEV 1 /FVC <0.7 2 50 79 3 30 49 0 or 1 (not leading to hospital admission) A B 4 <30 CAT = COPD Assessment Test; CCQ = Clinical COPD Questionnaire; COPD = chronic obstructive pulmonary disease FEV 1 = forced expiratory volume in 1 second; GOLD = Global Initiative for Chronic Obstructive Lung Disease mmrc = modified Medical Research Council TH1701583100, 31/01/2017 mmrc 0 1 CAT <10 CCQ <1 mmrc 2+ CAT 10+ CCQ 1+

SPIROMICS : a longitudinal study of ever smokers and never smokers Ever smokers (current of former) had > 20 pack years Respiratory symptoms assessed using the COPD Assessment test (CAT) CAT scores range from 0-40; higher score denotes grater impact. GOLD uses CAT score > 10 as a symptom threshold for considering increase symptoms in choice of treatment regimens N Engl J Med 2016;374:1811-21

Smokers with symptoms despite preserved pulmonary function have COPD-like exacerbation

Symptomatic smokers with preserved pulmonary function have airway wall thickening (left) without emphysema (right)

GOLD 2018: therapeutic recommendations by GOLD Group Group C Further exacerbation(s) LAMA + LABA LAMA LABA + ICS Group D Consider roflumilast if FEV 1 <50% pred. and patient has chronic bronchitis Further exacerbation(s) Further exacerbation(s) LAMA LAMA + LABA + ICS LAMA + LABA Consider macrolide Persistent symptoms/further exacerbations LABA + ICS Group A Group B Continue, stop or try alternative class of bronchodilator LAMA + LABA Evaluate effect A bronchodilator Persistent symptoms A long-acting bronchodilator (LABA or LAMA) FEV 1 = forced expiratory volume in 1 second; GOLD = Global Initiative for Chronic Obstructive Lung Disease ICS = inhaled corticosteroid; LABA = long-acting β 2 -agonist; LAMA = long-acting muscarinic antagonist GOLD 2017 TH1701583100, 31/01/2017

Agusti A. Ann Am Thorac Soc2013;10: s125-s130

Concept of one-treatment-fitall Agusti A. Ann Am Thorac Soc2013;10: s125-s130

Oslerian diagnostic label Fails to provide optimal care in a significant number of patients Can increase clinical practice variability and enhance inappropriate prescription of some drugs (e.g ICS) Can contribute to treatment failure and high rates of hospital readmissions Inhibits research progress

Principles of precision medicine Agusti A, et al. Eur Respir J 2017;50:1701655

Precision medicine The terms precision, personalized, and individualized medicine are often used interchangeably.. Precision medicine is treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations. Jameson JL, NEJM 2015;372:2229-34

Precision medicine Goal of improving clinical outcomes for individual patients and minimizing unnecessary side effects for those less likely to have a response to a particular treatment.

Examples of precision medicine

Agusti A, et al. Eur Respir J 2017;50:1701655

Agusti A, et al. Eur Respir J 2017;50:1701655

COPD COPD is complex and heterogeneous Complex means that they have several components with nonlinear dynamic interactions Heterogeneous indicates that not all of these components are present in all patients or, in a given patient, at all time points

Main reasons to make precision medicine in COPD There is variability in the clinical presentation There is no correlation between the different variables at the patient level There are a number of relevant clinical variable associated with outcomes We do have specific therapies for specific patient types There is variability in the clinical response

Distribution of the CAT score among the different GOLD 2011 classification Lopez-Campos JL, et al. Int J COPD 2015;10:975-84

Distribution of Estimated Annual Rates of Change in FEV 1 over a 3-Year Period in COPD patients Vesbo J, et al N Engl J Med 2011;365:1184-92

Different COPD cases with similar functional impairment but different radiological expression

6MWD (Metres) Number of exacerbations mmrc score SGRQ-C Total score Weak correlation between disease outcome parameters and FEV 1 4 3 2 1 0 0 20 40 60 80 Post-Dose FEV 1 (% Pred.) Rho=-0.36 p<0.001 100 80 60 40 20 0 0 20 40 60 80 Post-Dose FEV 1 (% Pred.) Rho=-0.38 p<0.001 1000 800 600 400 200 0 0 20 40 60 80 Post-Dose FEV 1 (% Pred.) Rho=-0.34 p<0.001 7 6 5 4 3 2 1 0 0 20 40 60 80 Post-Dose FEV 1 (% Pred.) Rho=-0.21 p<0.001 Agusti et al. Respir Res 2010

Functional response to bronchodilator (Trough FEV1) Donohue JF, et al. Respir Med 2016;112:65-74

COPD phenotype Miravitlles M, et al. Arch Bronconeumol 2017 :53;324 335

2major criteria or 1major and 2minor criteria should be met.

Risk classification in Spainish guideline 2017 Miravitlles M, et al. Arch Bronconeumol 2017 :53;324 335

Management Spanish COPD Guideline 2017 Miravitlles M, et al. Arch Bronconeumol 2017 :53;324 335

Two-step Algorithm algorithm for treatment for treatment of COPD of COPD Lahousse L, et al. Eur Respir J 2017; 49: 1602200

Benefit risk balance and its individual determinants with personalised COPD treatment choices Woodruff PG, Agusti A, et al. Current concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management. Lancet. 2015 May 2;385(9979):1789-98.

Asthma-COPD overlap phenotype Clinical importance Identification Phenotype-specific management 1.Increased frequency and severity of exacerbation 2.Faster FEV 1 decline 3.Increased health care utilization 4.Increased comorbidity burden and mortality Guidelines: 2 major criteria or 1 major and 2 minor criteria Major criteria: 1.Very positive bronchodilator test result (increase in FEV 1 15% of predicted and 400 ml) 2.Sputum eosinophilia 3.Personal history of asthma Minor criteria: 1.High total IgE 2.Personal history of atopy 3.Positive bronchodilator test result (increase in FEV 1 12% of predicted and 200 ml) on 2 occasions ICS should be an essential part of management in addition to longacting bronchodilators Address atopy component as indicated

Diagnosis criteria for ACOS

Frequent exacerbator phenotype Clinical importance Identification Phenotype-specific management 1.Faster decline in lung function 2.Increased health care utilization 3.Increased mortality up to 3-fold 4.Increased risk of depressive symptoms 2 or more COPD exacerbations per year Long-acting bronchodilators Inhaled corticosteroids Anti-inflammatory treatment: macrolides, roflumilast, acetylcysteine

Upper lobe predominant emphysema phenotype Clinical importance Identification Phenotype-specific management 1.Potentially substantial symptomatic benefit with surgical LVR CT findings consistent with predominant upper lobe emphysema Consider surgical LVR

Rapid decliner phenotype Clinical importance Identification Phenotype-specific management 1.High mortality Rapid decline of lung function Relatively younger Poor nutritional status No major comorbidities Early subspecialty and lung transplant evaluation

Comorbid phenotype Clinical importance Identification Phenotype-specific management 1.Increased health care utilization 2.Poorer quality of life 3.Increased mortality risk Persistently symptomatic despite comprehensive therapy Symptoms are disproportionate with severity of airway obstruction High comorbidity burden, predominantly cardiovascular Aggressive management of comorbid disease

Physical frailty phenotype Clinical importance Identification Phenotype-specific management 1.Higher symptom burden 2.Frequent exacerbations 3.Poor functional capacity 4.Poor disease management self-efficacy Screening: 4MGS (4-meter gait speed) (<0.8 m/s), Timed Up and Go test(tugt) (>10 seconds), Program of Research to Integrate Services for the Maintenance of Autonomy(PRISMA-7) questionnaire (score 3) Diagnosis: Fried criteria, frailty deficit index Pulmonary rehabilitation

Emotional frailty phenotype Clinical importance Identification Phenotype-specific management 1.Increased health care utilization 2.Poorer quality of life 3.Poor disease management self-efficacy Depression screen PHQ-2 score >3 points Anxiety screen GAD-2 scale >3 points Fear of breathlessness: Screen with How often during the past 2 weeks did you have a feeling of fear or panic when you had difficulty getting your breath? Comprehensive pulmonary rehabilitation that includes behavioral interventions such as health coaching or cognitive therapy Pharmacological management

Eosinophil counts in stable COPD predict exacerbation risk

Sensitivity Blood eosinophils as a biomarker of eosinophilic exacerbations in COPD % blood eosinophils AUC=0.85 2% cut off 90% sensitivity & 60% specificity 1.0 0.8 0.6 0.4 Per cent blood eosinophils Serum IL-5 Serum CCL17 Serum VCAM1 Serum TNF-1B Serum C reactive protein Serum IL-6 Serum TNF-1B Serum amyloid A1 Reference Line 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1- Specificity 1.0 Bafadhel M et al. Am J Respir Crit Care Med 2011;184:662-71

Mean annual exacerbation rate (events per year during follow-up for each individual) in the COPD population by quartiles of blood eosinophils. Vedel-Krogh S, et al. AM j Respir Crit Care Med 2016;193:965-74

Risk of severe and moderate exacerbations in COPD using the cutpoints for blood eosinophils of 0.34 10 9 cells per liter and 3.3% Vedel-Krogh S, et al. AM j Respir Crit Care Med 2016;193:965-74

Risk factors of COPD exacerbation Vedel-Krogh S, et al. AM j Respir Crit Care Med 2016;193:965-74

Eosinophil and response to corticosteroid in COPD exacerbation

Blood eosinophil guided prednisolone therapy for exacerbations of COPD Data taken from the three RCTs Bafadhel M, et al. Eur Respir J 2014;44:789-791

Eosinophil and response to ICS in COPD exacerbation

ISOLDE study Fluticasone propionate monotherapy was compared with placebo in the 3-year No difference in the rate of decline FEV1 for FP versus placebo ( p=0.16) There was a significant reduction in median yearly exacerbation rate with FP versus placebo (0.99 versus 1.32 ;reduction of 25%; p=0.026) Burge PS, et al. BMJ 2000; 320: 1297 1303.

Blood eosinophils as a marker of response to ICS in COPD Eo<2% Eo>2%

TRISTAN: Study design Study participants FEV 1 25-70% pred FEV 1 /FVC ratio <0.70 10 pack years Exacerbation history Reversibility <10% Double-blind treatment period (52 weeks) n=1465 FP/Sal 500/50 µg BD FP 500 µg BD R Sal 50 µg BD Placebo BD Week -2 Week 0 Week 52 Calverley et.al. Lancet 2003; 361:449-56 ICS and LABA stopped Anti-cholinergic could continue Primary end-point Pre-bronchodilator FEV 1 Other end-points Exacerbations SGRQ Symptom scores Nocturnal awakenings

Exacerbation rate ratio by eos: TRISTAN post-hoc analysis Patients with EOS 2% have a significant reduction in exacerbations with FP, SAL or FP/SAL vs placebo Barnes et al; Am J Respir Crit Care Med 2015:191;A3975 54

INSPIRE: Study design Study participants 40-80 years At least 10 pack years History of exacerbations Post-bronchodilator FEV 1 <50% predicted <10% reversibility At least 2 on mmrc scale n=1323 R Double-blind treatment period (2 years) FP/Sal 500/50 µg BD Tiotropium 18 µg OD Week -2 Week 0 Month 24 30mg prednisolone/day Salmeterol 50 µg BD Wedzicha et.al. Am J Respir Crit Care Med 2008;177: 19-26 Primary end-point Rate of healthcare utilisation exacerbations Other end-points SGRQ Post-bronch FEV 1 Mortality

Exacerbation rate by EOS: INSPIRE post-hoc analysis Patients with EOS 2% have significantly greater exacerbation reduction with FP/Sal vs tiotropium Adapted from Barnes et al; Am J Respir Crit Care Med 2015:191;A3975

Blood Eosinohils counts, exacerbations, and response inhaled fluticasone furoate /vilanterol in COPD Pascoe S, et al. Lancet Respir Med 2015;3:435-42.

Expected excess incidence of hospitalization for COPD exacerbation and pneumonia per 100 patients treated with ICS for 1 year Suissa S. et al. Chest 2017

Single inhaler triple therapy versus ICS/LABA for COPD (TRILOGY) FEV1 mean change from baseline Singh D, et al. Lancet 2016;388:963-73

Single inhaler triple therapy versus ICS/LABA for COPD (TRILOGY) :SGRQ Singh D, et al. Lancet 2016;388:963-73

Single inhaler triple therapy versus ICS/LABA for COPD (TRILOGY) moderate and severe exacerbation Singh D, et al. Lancet 2016;388:963-73

Targeting eosinophilic inflammation in the airway Barn PJ. J Allergy Clin Immunol 2015;136:531-45

Targeting neutrophilic inflammation in the airway Barn PJ. J Allergy Clin Immunol 2015;136:531-45

Conclusions Approach to treatment according to clinical phenotypes represents a significant change in management COPD From treatment focused onto more personalised approach directed by clinical feature New studies need to incorporate subgroup analysis of response by particular phenotypes to investigate the response to therapy The results of these trials will help to personalised treatment for this complex disease

Questions