What ‘s new in COPD?¸œศ_นพ_อภิชาติ...Different COPD cases with similar...

What ‘s new in COPD?

Apichart Khanichap MD.

Department of Medicine, Faculty of Medicine, Thammasat university

Relieve symptoms

Improve exercise tolerance

Improve health status

Prevent disease progression

Prevent and treat exacerbations

Reduce mortality

Reduce

symptoms

Reduce

risk

Management stable COPD

GOLD 2018: Symptoms and exacerbation risk should

be assessed to determine appropriate treatment

Spirometrically

confirmed diagnosis

C D

A B

mMRC 0–1

CAT <10

CCQ <1

mMRC 2+

CAT 10+

CCQ 1+

>2 or ≥1

leading to

hospitalization

0 or 1

(not leading to

hospital admission)

Exacerbation

history

Grade

FEV1

(% pred.)

1 ≥80

2 50–79

3 30–49

4 <30

Post-bronchodilator

FEV1/FVC <0.7

Assessment of

airflow limitation

Assessment of symptoms/

risk of exacerbations

CAT = COPD Assessment Test; CCQ = Clinical COPD Questionnaire; COPD = chronic obstructive pulmonary disease

FEV1 = forced expiratory volume in 1 second; GOLD = Global Initiative for Chronic Obstructive Lung Disease

mMRC = modified Medical Research Council

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)

TH1701583100, 31/01/2017

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)

Group A Group B

Group C Group D

A bronchodilator

Continue, stop or

try alternative class

of bronchodilator

Evaluate

effect

A long-acting bronchodilator

(LABA or LAMA)

LAMA + LABA

Persistent

symptoms

LAMA

LAMA +

LABA

Further

exacerbation(s)

LABA + ICS

LAMA + LABA

Consider roflumilast

if FEV1 <50% pred.

and patient has

chronic bronchitis

Further

exacerbation(s)

Consider

macrolide

LAMA LABA + ICS

LAMA +

LABA + ICS

Further

exacerbation(s)

Persistent

symptoms/further

exacerbations

GOLD 2018: therapeutic recommendations by

GOLD Group

FEV1 = forced expiratory volume in 1 second; GOLD = Global Initiative for Chronic Obstructive Lung Disease

ICS = inhaled corticosteroid; LABA = long-acting β2-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-fit-all

Agusti A. Ann Am ThoracSoc2013;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

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

Lopez-Campos JL, et al. Int J COPD 2015;10:975-84

Distribution of the CAT score among the different GOLD 2011 classification

Distribution of Estimated Annual Rates of Change in FEV1over 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

Agusti et al. Respir Res 2010

Weak correlation between disease

outcome parameters and FEV1

0 20 40 60 80

0

1

2

3

4

Post-Dose FEV1 (% Pred.)

mM

RC

sc

ore

Rho=-0.36p<0.001

0

20

40

60

80

100

0 20 40 60 80

SG

RQ

-C T

ota

l s

co

re


Rho=-0.38p<0.001

0

200

400

600

800

1000

0 20 40 60 80

6M

WD

(M

etr

es

)


Rho=-0.34p<0.001

0 20 40 60 80

0

1

2

3

4

5

6

7


Nu

mb

er

of

ex

ac

erb

ati

on

s

Rho=-0.21p<0.001

Donohue JF, et al. Respir Med 2016;112:65-74

Functional response to bronchodilator (Trough FEV1)

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


Management Spanish COPD Guideline 2017


Two-step algorithm for treatment of COPD

Lahousse L, et al. Eur Respir J 2017; 49: 1602200

Algorithm for treatment of COPD

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.

Benefit–risk balance and its individual determinants with personalised COPD treatment choices

Asthma-COPD overlap phenotypeClinical importance Identification Phenotype-specific

management

1.Increased frequency and severity of exacerbation2.Faster FEV1decline3.Increased health care utilization4.Increased comorbidity burden and mortality

Guidelines: 2 major criteria or 1 major and 2 minor criteriaMajor criteria:

1.Very positive bronchodilator test result (increase in FEV1 ≥15% of predicted and ≥400 mL)2.Sputum eosinophilia3.Personal history of asthma

Minor criteria:1.High total IgE2.Personal history of atopy3.Positive bronchodilator test result (increase in FEV1 ≥12% of predicted and ≥200 mL) on ≥2 occasions

ICS should be an essential part of management in addition to long-acting bronchodilators

Address atopycomponent as indicated

Diagnosis criteria for ACOS

Frequent exacerbator phenotype

Clinical importance Identification Phenotype-specific management

1.Faster decline in lung function2.Increased health care utilization3.Increased mortality up to 3-fold4.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


1.Potentially substantial symptomatic benefit with surgical LVR

CT findings consistent with predominant upper lobe emphysema

Consider surgical LVR

Rapid decliner phenotype


1.High mortality Rapid decline of lung function

Relatively younger

Poor nutritional status

No major comorbidities

Early subspecialty and lung transplant evaluation

Comorbid phenotype


1.Increased health care utilization2.Poorer quality of life3.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


1.Higher symptom burden2.Frequent exacerbations3.Poor functional capacity4.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


1.Increased health care utilization2.Poorer quality of life3.Poor disease management self-efficacy

Depression screen PHQ-2 score >3 pointsAnxiety screen GAD-2 scale >3 pointsFear 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

% blood eosinophils AUC=0.852% cut off90% sensitivity & 60% specificity

Blood eosinophils as a biomarker of

eosinophilic exacerbations in COPD

Bafadhel M et al. Am J Respir Crit Care Med 2011;184:662-71

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.2 0.4 0.6 0.8

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

1- Specificity

Sensitiv

ity

1.0

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 × 109 cells per liter

and 3.3%


Risk factors of COPD exacerbation


Eosinophil and response to corticosteroid in COPD exacerbation

Bafadhel M, et al. Eur Respir J 2014;44:789-791

Blood eosinophil guided prednisolone therapy for exacerbations of COPD

Data taken from the three RCTs

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%

Study participants

– FEV1 25-70% pred

– FEV1/FVC ratio <0.70

– ≥10 pack years

– Exacerbation history

– Reversibility <10%

Calverley et.al. Lancet 2003; 361:449-56

Primary end-point

Pre-bronchodilator FEV1

Other end-pointsExacerbations

SGRQ

Symptom scores

Nocturnal awakenings

Double-blind treatment period (52 weeks)

Sal 50 µg BD

Placebo BD

FP 500 µg BD

R

Week 52Week 0Week -2

ICS and LABA stopped

Anti-cholinergic could continue

n=1465 FP/Sal 500/50 µg BD

TRISTAN: Study design

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

54Barnes et al; Am J Respir Crit Care Med 2015:191;A3975

Study participants

– 40-80 years

– At least 10 pack years

– History of exacerbations

– Post-bronchodilator FEV1

<50% predicted

– <10% reversibility

– At least 2 on mMRC scale

INSPIRE: Study design

Primary end-point

Rate of healthcare

utilisation exacerbations

Other end-pointsSGRQ

Post-bronch FEV1Mortality

Double-blind treatment period (2 years)

FP/Sal 500/50 µg BD

Tiotropium 18 µg OD

R

Month 24Week 0Week -2

30mg prednisolone/day

Salmeterol 50 µg BD

n=1323

Wedzicha et.al. Am J Respir Crit Care Med 2008;177: 19-26

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


Single inhaler triple therapy versus ICS/LABA for COPD (TRILOGY)

moderate and severe exacerbation


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

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