Nicola A. Hanania, MD, MS, FCCP, FERSAssociate Professor of Medicine

Pulmonary and Critical Care MedicineDirector, Airways Clinical Research Center

Implementing GOLD COPD Guidelines

Disclosure Information

▪ Advisor/ Consultant:

- Roche/ Genentech, AstraZeneca, GSK, BI, Sunovion, Novartis, Mylan, Sanofi/Regeneron

▪ Research grant support (to institution):

- NHLBI, ALA

- GSK, BI, Roche/Genentech, Sunovion, Mylan, AstraZeneca

– Common, preventable, treatable—partially reversible

– Characterized by persistent airflow limitation

– Usually progressive and disabling

– Associated with enhanced chronic inflammatory response in airways/lung to noxious particles or gases

COPD is heterogeneous2

– Multiple risk factors, phenotypes, comorbidities

– Exacerbations and comorbidities contribute to severity

1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). www.goldcopd.org.

2. Goh F, et al. Expert Rev Respir Med. 2013;7(6):593-605.

GOLD: Global Initiative for Chronic Obstructive Lung Disease

Burden of COPD in the US

• 1 in 5 Americans has COPD

• 16 million people are diagnosed

• Total costs from hospitalization

and absenteeism estimated at

$36 Billion

▪ COPD exacerbations account

for >70% of total costs

▪ ≈13 million office visits/y due to

exacerbations

▪ Disproportionately affects

individuals of lower

socioeconomic status

Ford, et al. Chest 2013;144:305Ford, et al. Chest 2013;143:1395

COPD is Underdiagnosed

▪ Roughly half of those in the US with COPD are undiagnosed

~15 million Americans

Haroon, et al. Int J COPD 2015;10(1):1711

COPD National Action Plan

• The first-ever blueprint for a multi-

faceted, unified fight against the

disease.

• Developed at the request of

Congress with input from the broad

COPD community.

• Provides a comprehensive

framework for action by those

affected by the disease and those

who care about reducing its burden.

#COPDActionPlan

What do we know now?Factors that Influence Disease Progression

▪ Exposure to inhaled particles:

- Tobacco smoke (active and passive)

- Occupational dusts, organic and inorganic

- Indoor air pollution from heating and cooking with biomass in poorly ventilated dwellings

- Outdoor air pollution

▪ Susceptibility genes

- A1AD

- CHRNA3/CHRNA5/IREB2 region on chromosome 15

- HHIP, and FAM13A

▪ Oxidative stress

▪ Female gender

▪ Age

▪ Respiratory infections

▪ Low socioeconomic status

▪ Poor nutrition

▪ Poor lung growth and development

Early-Life Origins of COPD

FD Martinez, N Engl J Med 2016;375:871-8.M.J. McGeachie et al. N Engl J Med 2016;374:1842-52.

Factors associated with reduced lung growth:• Lower baseline FEV1• Smaller bronchodilator response• AHR at baseline• Male sex

Inflammatory and Cellular Mechanisms in COPD due to Cigarette Smoking

Chung KF, et al. Eur Respir J. 2008;31:1334-56.

Oxidative Stress is Central to the Destruction of Pulmonary Tissue

Barnes PJ. Clin Chest Med 35 (2014) 71–86

Auto

COPD is a Multicomponent Disease

►Loss of alveolar attachments

►Loss of elastic recoil

►Increased smooth musclecontraction

Airflowlimitation

Airwayinflammation

►Increased numbers ofinflammatory cells/activation:► CD8+ T-lymphocytes► Monocytes/

macrophages► Neutrophils► Mast cells

►Elevated inflammatorymediators: IL-8, TNF-,LTB-4, and oxidants

►Protease/anti-proteaseimbalance

Mucociliarydysfunction

►Mucus hypersecretion

►Reduced mucociliarytransport

►Mucosal damage

Structuralchanges

►Goblet cell hyperplasia/metaplasia

►Mucous gland hypertrophy

►Increased smooth muscle mass

►Airway fibrosis

►Alveolar destruction

Systemiccomponent

►Poor nutritionalstatus

►Reduced BMI

►Impaired skeletalmuscle

► Weakness

► Wasting

SYMPTOMSRISK

FACTORS

Consider COPD in patients with any symptoms and history of

exposure to risk factors

SYMPTOMSPersistent shortness of breath

Chronic cough

Chronic sputum production

Wheezing

RISK FACTORSTobacco smoke

Indoor/outdoor air pollution

Occupational pollutants

Family history

Age >40 y

Spirometry is required to make diagnosis

Postbronchodilator FEV1/FVC <.70 confirms presence of persistent airflow limitation*

*Postbronchodilator FEV1/FVC measured 10-15 min after 2-4 puffs of a short-acting bronchodilator

FEV1, forced expired volume in 1 second; FVC, forced vital capacity

Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. www.goldcopd.org.

COPD Diagnosis

2017 - Assessment of COPD

The goals of COPD assessment are to determine disease severity, its impact on patient health status, and the risk of future events (eg,

exacerbations, hospital admissions, death) in order to guide therapy

Symptoms

Degree of airflow limitation (using spirometry)

Risk of exacerbations (estimated by history of COPD exacerbations)

Comorbidities

http://goldcopd.org/gold-reports/.

GOLD Staging System:Spirometry

Global Initiative for Chronic Obstructive Lung Disease (GOLD). GOLD COPD web site. http://www.goldcopd.org/uploads/users/files/GOLD_Report_2015_Apr2.pdf. Accessed June 18, 2015.

Postbronchodilator FEV1/FVC <.70 • Confirms presence of persistent airflow limitation

• Supports diagnosis of COPD

GOLD Grade 4

GOLD Grade 1

GOLD Grade 2

GOLD Grade 3

• Mild• FEV1 ≥80% predicted

• Moderate• 50% ≤FEV1 <80%

predicted

• Severe• 30% ≤FEV1 <50% predicted

• Very severe• FEV1 <30% predicted

Assessment of COPD: Symptoms

GOLD Website. http://www.goldcopd.com.

Symptoms

Mo

re Severe

0 1 2 3 4

Modified Medical Research Council Dyspnea Score

Grade Description of Breathlessness

0 I only get breathless with strenuous exercise

1 I get short of breath when hurrying on level ground or walking up a slight hill

2 On level ground, I walk slower than people of the same age because of

breathlessness, or have to stop for breath when walking at my own pace

3 I stop for breath after walking about 100 yards or after a few minutes on

level ground

4 I am too breathless to leave the house or I am breathless when dressing

COPD Assessment Test (CAT)

Assessment of Exacerbation Risk

COPD exacerbations are defined as an acute worsening of respiratory symptoms that result in additional therapy.

▪ Classified as:▪ Mild (treated with SABDs only)▪ Moderate (treated with SABDs plus antibiotics

and/or oral corticosteroids) or ▪ Severe (patient requires hospitalization or visits

the emergency room). Severe exacerbations may also be associated with acute respiratory failure.

Frequent Exacerbations Drive Disease Progression

Wedzicha JA & Seemungal TA. Lancet 2007;370:786-796.,;

Donaldson GC & Wedzicha JA. Thorax 2006;61:164-168.

Patients with frequent exacerbations

Increased risk of recurrent exacerbations

Increased inflammation

Lower quality of life Increased mortality rate

Increased likelihood of hospitalization

Faster disease progression

2017 GOLD Assessment Tool

From the Global Strategy for the Diagnosis, Management and Prevention of COPD,Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available at: http://goldcopd.org.

Spirometricallyconfirmed diagnosis

Assessment of airflow

limitation

Assessment of symptoms/risk of

exacerbations

Post-bronchodilatorFEV1/FVC < 0.7

Exacerbation history

FEV1

(% predicted)

GOLD 1 ≥ 80

GOLD 2 50-79

GOLD 3 30-49

GOLD 4 < 30

≥ 2 or ≥ 1 leading to hospital admission

0 or 1(not leadingto hospitaladmission)

C D

A B

mMRC 0-1CAT < 10

mMRC ≥ 2CAT ≥ 10

Symptoms

Cardiovascular

disease

Lung cancer

Anxiety, depression

Peripheral muscle

wasting and dysfunction

Osteoporosis

Cachexia

Peptic ulcers

GI complications

Anemia

Pulmonary hypertension

Diabetes

Metabolic syndrome

Comorbidities of COPD

Kao C, Hanania NA. in: Crapo J, ed. Philadelphia, PA: Current Medicine Group;2008.

Exploring the Links Between COPD and Its Comorbidities

• Smoking and lifestyle factors

• Genetic susceptibility

Risk Factors

• Chronic airway infection

• Acute exacerbations

COPD

• Airway and systemic inflammation

• Lung hyperinflation and endothelial dysfunction

• Oxidative stress

Mechanisms

• Ischemic heart disease

• Stroke and heart failure

• Hypertension and diabetes

• Muscle weakness and osteoporotic fractures

• Depression

Comorbidities

• Worse symptoms

• Worse health status

• Reduced activity

• Reduced survival

Outcomes

Patel AR, Hurst JR. Expert Rev Respir Med. 2011;5(5):647-662.

Hyperinflation

Emphysema

predominant

Cardiac disease

Osteoporosis

Deconditioned

Undernourished

Airway

predominant

Pulmonary

fibrosis Frequent

Exacerbator

Hypoxemia

Hypercapnia

The Challenge: COPD is a Heterogenous Disease

Why Phenotype COPD Patients?

• Enhances our understanding of the

disease process, treatment and outcomes

• Allows for classification of patients into

distinct therapeutic and prognostic

subgroups

• Allows for enrichment of clinical trial

population

• Improves outcomes

A phenotype relates to “a single or combination of attributes

that describe differences between individuals”

Phenotypic Dimensions

PhysiologicalAirflow limitationRapid declinerBD-responsivenessHyperresponsivenessGas exchange: PaO2, PaCO2, DLCOExercise toleranceHyperinflationPulmonary hypertension

ClinicalChronic bronchitisAsthma/COPD overlapExacerbationsDyspneaHRQoLICS-responsiveNon-smokers

Systemic effects/ComorbiditiesNutritional statusSkeletal (respiratory and peripheral) musclesExercise capacityCardiovascular disorders

Local and Systemic inflammationLocal inflammation: inflammatory markers or cells in sputum or lung tissueSystemic inflammation: inflammatory markers or cells in blood or serumProteolysisOxidative stressVascular remodeling

Radiologic/StructuralEmphysema

Chronic bronchitisBronchiectasis

Fibrosis

COPD Phenotypes

Chen X et al. Front. Med. 2013;7(4):425-432. Oga T et al. Chest. 2005;128:62-69. Westwood M et al. Respir Res. 2011;12:40.

Disease attributes that describe the diverse symptoms and outcomes of patients

Systemic Inflammation

Chronic HypoxemiaFrequent Exacerbations

Chronic Respiratory Failure

Exercise/ Activity Intolerance/

Hyperinflation

ComorbiditiesCardiac, Nutritional

COPD

Chronic Cough and Sputum

Symptom BurdenRadiologic

Airway (CB, bronchiectasis), Emphysema

Asthma COPD Overlap Syndrome (ACOS)

Clinical Course of COPD

Cooper CB. Respir Med. 2008;20:1-10.

Hyperinflation, central to the pathophysiology of COPD (ie, increased airway

resistance), correlates more directly with patient-reported outcomes

COPD

Airflow obstruction Exacerbations

DeconditioningAnxiety

Hypoxemia

Tachypnea Ventilatory requirement

Activity limitationDyspnea

Air trapping

Hyperinflation

Poor health-related quality of life

Patient-reported outcomes

Goals of Management

Airflow Limitation

Symptom Burden

Exacerbations

Functional Limitations

Improve Lung FunctionSlow FEV1 Decline

Improve Symptoms

Prevent and Manage Exacerbations

Improve Health Status and Exercise Tolerance

Reduce Hospital Admissions and Mortality

Adapted from Global Initiative for Chronic Obstructive Lung Disease; (GOLD) 2015. www.goldcopd.org.

Management Strategies Need to Address the Disease at Multiple Levels

Agusti A, Vestbo J. AJRCCM 2011;184:507-513.

Management Need to Address Multiple Disease Components and

Individualize Management Approach

.Gibson PG et al. The Lancet 2010; 376: 803-813

Pharmacological Management of COPD▪ Guideline-recommended COPD treatment

–Improves lung function

–Minimizes symptoms

–Improves QoL

–Prevents exacerbations

▪ Wide variety of options including new agents

–Appropriate treatment selection hinges on GOLD staging

–Before stepping up/modifying treatment, re-evaluate

▪ Treatment goals

▪ Clinical phenotype

▪ Comorbidities

▪ Adherence

Benefit–risk Balance Should be Tailored to Individual Patient Characteristics

Woodruff PG, et al. Lancet 2015; 385: 1789‒98

Individual presentation and underlying mechanisms

• Mortality

• Disease progression

• Lung function

• Symptoms:cough,sputum production, and dyspnea

• Exercise tolerance

• Exacerbations

• Disability

• Health status and quality of life

Expected benefits

Individualization of

treatment choices in

COPD

Individual risk factors and comorbidities

• Pneumonia• Tuberculosis• Skin bruising• Osteoporosis or fractures• Muscle dysfunction• Nutritional impairment• Cataract• Diabetes• Tremor• Cardiovascular events• Neuropsychological events• Gastrointestinal symptoms

Expected risks

Present COPD

pharmacological

treatments

LABA;

LAMA;

LABA + LAMA;

LABA + ICS;

LABA + LAMA +

ICS;

LABA +

roflumilast;

LAMA +

roflumilast

Current Therapeutic Options for COPD

Bronchodilators

Beta2-agonists

Short-acting beta2-agonists (SABA)

Long-acting beta2-agonists (LABA)

Anticholinergics

Short-acting anticholinergics SAMA)

Long-acting anticholinergics (LAMA)

Methylxanthines

Combinations in one inhalerSABA / SAMALABA / LAMA

LABA / ICSICS/LABA/LAMA

Anti-inflammatory agents

Corticosteroids

Inhaled corticosteroids (ICS)

Systemic corticosteroids

Phosphodiesterase-4 inhibitors

Anti-oxidant agentsN-acetylcysteine

MucolyticsCarbocysteine N-acetylcysteine

2017 COPD Management

GOLD 2017 PHARMACOLOGIC TREATMENT ALGORITHM

From the Global Strategy for the Diagnosis, Management and Prevention of COPD,Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available at: http://goldcopd.org.

Other Pharmacologic Treatments

Sims MW. Chest. 2011;140:781-788.

Inhaler Devices

Pressurized Metered

Dose Inhalers

Dry Powder Inhalers

Slow Mist Inhalers

Jet Nebulizers

High-Efficiency Vibrating

Mesh Nebulizer

Issues of Inhaler Devices▪ No single inhaler will satisfy the needs of all patients

28-68% of patients do not use inhalers correctly

A sub-optimal technique can result in decreased lung delivery and potentially reduced

efficacy3

▪ The proliferation of inhalation devices in the market can

result in confusion for clinicians, nurses, respiratory

therapists and patients1

Each available device require specific inhalation techniques1

▪ Studies have demonstrated lack of knowledge in the use of

devices by healthcare professionals2

39-67% of HCPs are unable to adequately perform or describe inhalation techniques4

▪ Physicians need to select the right inhaler for each patient

knowing each product’s characteristics is key41. Anna Murphy, SIMPLE 2013

2. Baverstock et al. Thorax, 2010;65:A117-A118

3. Labiris et al. Br J Clin Pharmacol, 2003;56,588–599

4. Lewis RM, Fink JB. Resp Crit Care Clin North Am 2001;7:277-301

Emerging Therapies in COPD Management

▪ Novel therapies

✓Novel formulations of existing medications

✓Drugs used in treatment of comorbidities that may be useful in COPD

✓Novel targets for pharmacologic therapy

Novel Formulations of Existing Medications

• Novel Bronchodilators

‒Ultra LABAs

‒Ultra LAMAs

‒LABA/LAMA combinations

‒LABA/ICS combinations

‒Nebulized bronchodilators and combination therapies

‒MABAs

Cazzola M, et al. Pharmacol Rev. 2012;64:450-504.

LABA: long acting beta-2 agonists; LAMA: long acting muscarinic antagonist;

ICS; inhaled corticosteroid; MABA: bifunctional muscarinic beta-2 agonist

Drugs Used in Treatment of Comorbidities That May Be Useful in COPD

▪ Statins

▪ ACE Inhibitors

▪ Beta-blockers

▪ Peroxisome proliferator-activated receptor (PPAR) agonists

▪Macrolides

▪Mucolytic and Antioxidant Agents

Proportion of Participants Free from Acute Exacerbations of COPD

Albert RK et al. N Engl J Med 2011;365:689-698

N = 558 azithromycin

N = 559 placebo

Simvastatin for the Preventionof Exacerbations COPD

Criner GJ et al. N Engl J Med 2014;370:2201-10.

The Effect of N-acetylcysteine on COPD Exacerbations

Jin-Ping Zheng J-P et al. Lancet Respir Med 2014; 2: 187–94

Anti proteases: Neutrophil elastase

MMP9 inhibitors

Smoking CessationNicotine antagonists

Vaccination

Antioxidants

InflammosomeInhibitors

Reversal of Steroid Resistance

Antibiotics Phagocytosis

ChemokineAntagonists

PDE inhibitorsEpigenetic modulators

Mediator Antagonists (TNF , IL-17 , IL5, IL-13 antibodies)

Kinase inhibitors

Mucoregulators:EGFR inhibitors

Regeneration:Stem Cell

Retinoic Acid

Antifibrotic:Targeting TGFβPPR agonists

Barnes PJ. Nature Rev Drug Discovery 2013; 12: 543-549

Non-pharmacological Options for COPD

Adapted from Global Initiative for Chronic Obstructive Lung Disease; (GOLD) 2017.

www.goldcopd.org.

Patient GroupA

Low risk, fewer symptoms

BLow risk,

more symptoms

CHigh risk,

fewer symptoms

DHigh risk, more

symptoms

Description

<1 ExacerbationmMRC 0-1 or CAT <10

<1 ExacerbationmMRC >2 or CAT >10

>2 ExacerbationsmMRC 0-1 or CAT <10

>2 ExacerbationsmMRC >2 or CAT >10

Essential

Smoking cessation for all patients who smoke• The key intervention for smokers• Can include pharmacologic treatment

Pulmonary rehabilitation

Recommended Physical activity

Dependingon local guidelines

Influenza vaccinationPneumococcal vaccination

Defining Pulmonary Rehabilitation: Official ATS/ERS Statement

“Pulmonary rehabilitation is a comprehensive intervention based on a thorough patient assessment followed by patient tailored therapies that include, but are not limited to, exercise training, education, and behavior change, designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviors.”

Spruit MA, et al. Am J Respir Crit Care Med. 2013;188(8):e13-64.

ATS = American Thoracic Society; ERS = European Respiratory Society

Components of Pulmonary Rehabilitation Programs

Pulmonary Rehabilitation Programs

Exercise TrainingInvolves the measurement

of a number of physiologic

variables, including maximum

oxygen consumption, maximum

heart rate, and maximum

work performed

Nutrition CounselingImportant determinant of

symptoms, disability, and

prognosis in COPD; a reduction

in BMI is an independent risk

factor for mortality in

patients with COPD

EducationSpecific contributions of

education to the improvements

seen after pulmonary

rehabilitation remain unclear

Assessment and Follow-up

BMI=body mass index.Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention

of Chronic Obstructive Pulmonary Disease. Updated 2009. http://www.goldcopd.org. Accessed April 9, 2010.

1British Thoracic Society. Thorax. 2001; 56:827-34. 2American Thoracic Society. Am J Respir Crit Care Med.

1999;159:1666-82. 3Guell R, et al. Chest. 2000;117:976-83. 4Saey D, et al. Am J Respir Crit Care Med.

2003;168:425-30. 5Casaburi R. Am J Respir Crit Care Med. 2003;168:409-10. 6Casaburi R, et al. Am J Respir

Crit Care Med. 1997;155:1541-51. 7Griffiths TL, et al. Lancet. 2000;355:362-8. 8Cote CG, et al. Am J Respir Crit

Care Med. 2003;167:A38.

Outcomes of Pulmonary Rehab in COPD

▪ Reduces dyspnea

▪ Improves deconditioning, muscle fatigue

▪ Increases exercise capacity

▪ Improves quality of life

▪ Improves depression

▪ Reduces acute exacerbations

▪ Reduces hospitalizations

▪ May reduce mortality

▪ Does not improve PFTs or ABGs

Monitoring and Follow-up

© 2017 Global Initiative for Chronic Obstructive Lung Disease

In order to adjust therapy appropriately as the disease progresses, each follow-up visit should include a discussion of the current therapeutic regimen.

Monitoring should focus on:

► Dosages of prescribed medications.

► Adherence to the regimen.

► Inhaler technique.

► Effectiveness of the current regime.

► Side effects.

Treatment modifications should be recommended.

Strategies to Ensure Adherence

Patient Education:Key Educational Messages for COPD

• Basic facts about COPD• Contrast normal and COPD airways

• Roles of medications and potential adverse events• Long-term maintenance and quick-relief

medications

• Relevant environmental triggers and reducing exposures

• Building an action plan: when and how to take rescue actions

• Skills• Inhalers, nebulizers, spacers, symptoms, and

early warning signs

Non-Pharmacologic Treatment - Summary

Oxygen Therapy

1. Barach AL. JAMA 1922; 79:693-992. Levine BE et al. Ann Intern Med 1967;66: 639 – 503. Report of the Medical Research Council Working Party . Lancet . 1981 ; 1 ( 8222 ): 681 - 686 .4. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med . 1980; 93( 3): 391- 398.

▪ Introduced by Joseph Priestly (English scientist and clergyman) in 1774

▪ Alvan Barach pioneered the use of oxygen therapy in COPD. 1

▪ First systematic studies on the physiologic and clinical benefit of LTOT were reported in 1967 (Denver). 2

▪ Long-term benefit confirmed in hypoxemic patients the MRC and NOTT. 3,4

▪ LOTT study: No effect of oxygen therapy in patients with moderate or exercise-induced hypoxemia

Oxygen therapy/ NIV

Long-term oxygen therapy is indicated for stable patients who have:► PaO2 at or below 55 mmHg or SaO2 at or below 88%, with or

without hypercapnia confirmed twice over a three week period; or PaO2 between 55 mmHg and 60 mmHg, or SaO2 of 88%, if there is evidence of pulmonary hypertension, peripheral edema suggesting congestive cardiac failure, or polycythemia (hematocrit > 55%).

National Emphysema Treatment Trial

N Engl J Med 2003;348:2059-73.Proc Am Thorac Soc. 2008 May 1; 5(4): 393–405.

Bronchoscopic Approaches to LVRFl

ow

re

gula

tio

nTi

ssu

e c

om

pre

ssio

n

Zephyr-Endobronchial Valves

(EBV)

Intrabronchial Valves (IBV)

RePneu - Lung volume reduction

coil (LVRC)

AeriSeal -Polymeric Lung

Sealant

InterVapor -Bronchoscopic Thermal Vapor Ablation (BTVA)

PulmonX

Spiration

Aeris

Uptake

PneumRx

One-way valve leads to atelectasis.

One-way valve leads to atelectasis.

Coil reduces lung volume by coilingand compressing disease tissue.

Tissue sealant flows into alveolarcompartment, polymerizes and sealstarget area.

Heated water vapor produces thermalreaction with localized inflammation followed by fibrosis.

Interventional Therapy in Stable COPD

COPD: The Past, the Present and the Future

▪ Significant advancement in our knowledge over the last 300

years

▪ COPD is a heterogenous disease:

▪ Multiple inflammatory pathways involved

▪ Clinical and radiologic phenotypes are already identifiable.

Pathobiological phenotypes /endotypes will emerge.

▪ Assessment of COPD should address symptoms, risk of

exacerbations, comorbidities in addition to lung function

▪ Unmet needs with existing interventions

▪ Multiple novel targets of therapy are being evaluated and may

be available in the future