Enhancing Patient Diagnosis and Management of COPD: A Case-Based Review

September 19, 2012 Rosemont, Illinois

Educational Partner:

CME Incite, LLC

Session 3

Session 3: Enhancing Patient Diagnosis and Management of COPD: A Case-Based Review Learning Objectives 1. Prevent chronic obstructive pulmonary disorder (COPD) exacerbations by recognizing the clinical factors that put

patients at risk by improving early recognition and intervention. 2. Stratify COPD severity and develop individualized treatment plans on the basis of spirometry results. 3. Tailor both initial and maintenance therapies for COPD according to the standards set by evidence-based guidelines.

Faculty Stephen I. Rennard, MD Larson Professor of Internal Medicine University of Nebraska Medical Center Omaha, Nebraska Dr. Stephen Rennard is Larson Professor of Medicine in the Pulmonary and Critical Care Medicine Division of the Departments of Pathology and Microbiology and Genetics, Cell Biology, and Anatomy at the University of Nebraska Medical Center. He received an AB with honors in folklore and mythology from Harvard University and an MD with honors from the Baylor College of Medicine in Houston. He completed internal medicine training at Barnes Hospital, Washington University, in St. Louis, and trained in pulmonary diseases at the National Institutes of Health where he remained for seven years, conducting research in the cell biology of lung disease. Dr. Rennard currently serves on the board of directors of the COPD Foundation and the Alpha-1 Foundation. A member of the National Heart, Lung, and Blood Institute’s National Lung Health Education Program Executive Committee, he chairs the Steering Committee of SPIROMICS. Dr. Rennard is an external advisor to the Thomas Petty Aspen Lung Conference and the University of California, Davis, Pulmonary Training Grant. Dr. Rennard maintains an active program of clinical investigation in COPD and smoking cessation and conducts a program of basic research into the mechanisms of lung tissue repair and remodeling, including the role of stem cells in disease pathogenesis and repair. Fernando J. Martinez, MD, MS Professor, Department of Internal Medicine Director, Pulmonary Diagnostic Services University of Michigan Ann Arbor, Michigan Dr. Fernando Martinez is Professor of Internal Medicine, Associate Chief for Clinical Research in the Division of Pulmonary and Critical Care Medicine, Director of Pulmonary Diagnostic Services, and Co–Medical Director of Lung Transplantation at the University of Michigan Health System in Ann Arbor. After graduating from the University of Florida School of Medicine, Dr. Martinez completed his residency in internal medicine at Beth Israel Hospital in Boston, along with a fellowship in pulmonary medicine at the Boston University Pulmonary Center. His main research interests include COPD, interstitial lung disease, lung transplantation, and lung volume reduction. Dr. Martinez is currently a member of numerous societies, including the American Thoracic Society (ATS), the European Respiratory Society, the American College of Chest Physicians, and the Fleischner Society. Previously, he was chair of the Clinical Problems Assembly of the ATS and a member of the ATS committees that generated guidelines for the management of COPD and respiratory infections, and cardiopulmonary exercise testing. He is currently a member of the GOLD Executive and Science Committees. Dr. Martinez serves on a number of editorial boards, including the Journal of COPD and the American Journal of Respiratory and Critical Care Medicine. Faculty Financial Disclosure Statements The presenting faculty reports the following:

Dr Rennard serves as a speaker for the American Association for Respiratory Care; Almirall; the American College of Osteopathic Physicians; Asan Medical Center; the American Thoracic Society; the California Society of Allergy; CME Incite; the COPD Foundation; Creative Educational Concepts; Dey Pharma, LP; Duke University; Forest Laboratories; The France

Session 3

Foundation; HSC Medical Education; Information TV; the American Lung Association; Novartis Horsham Research Centre (UK); Nycomed; Otsuka America Pharmaceutical; PeerVoice; Pfizer Inc.; Shaw Science Partners, Inc.; the University of Washington; the University of Alabama Birmingham; and the Veterans Administration Sioux Falls; and is a consultant for the American Board of Internal Medicine (ABIM); Able Associates Research Group; Adelphi Research; Align2Action; Almirall/Prescott; APT Pharma/Brintnall; AstraZeneca Pharmaceuticals LP; the American Thoracic Society; Beilenson; Boehringer Ingelheim; Boehringer Ingelheim (ACCP); BoomCom!; Brintnall & Nicolini, Inc.; Capital Research; Chiesi Pharmaceuticals Inc.; Clarus Acuity Group; CMC|Complete Medical Group; ConsultComplete; COPDforum; Daiichi Sankyo; Datamonitor; Decision Resources; The Dunn Group, Inc.; Easton Associates; Equinox Pharma Limited; Forest Laboratories; Frankel Group; Fulcrum Pharma; Gerson Lehrman Group, Inc.; Globe Life Sciences; GlaxoSmithKline; Guidepoint Global, LLC; Health Advances; Hoffmann-La Roche; InforMed; Insyght Interactive, Inc.; The KOL Connection Ltd.; Leerink Swann LLC; M. Pankove; McKinsey & Company; MDRxFinancial; MedImmune, LLC; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Nycomed; Ogilvy Common Health; Oriel Therapeutics Inc.; Osterman; Pearl Therapeutics; Penn Technology Partnership; Pennside Partners, Ltd.; Pfizer Inc.; PharmaVentures; Pharmaxis Ltd.; Prescott Medical Communications; PricewaterhouseCoopers; Propagate Pharma Ltd.; Pulmonary Reviews; Pulmatrix, Inc.; J. Reckner Associates, Inc.; Recruiting Resource; Roche; Schering Corporation; Schlesinger Medical; SciMed; Smith Research; Sudler & Hennessey; Summer Street Research Partners; Talecris Biotherapeutics, Inc.; ThinkEquity LLC; United BioSource Corporation (UBC); Uptake Medical; and Vantage Point Management. Dr Martinez serves as a consultant for GlaxoSmithKline; MedImmune/AstraZeneca Pharmaceuticals LP; Merck & Company, Inc.; Forest Laboratories; Takeda/Nycomed/Forest; Bayer; Ikaria, Inc.; Actelion Pharmaceuticals US, Inc.; Pfizer Inc.; Pearl Therapeutics; Carden Jennings Publishing; JK Associates, Inc.; Prescott Medical Communications; Sudler & Hennessey; and the University of Virginia; receives honoraria from GlaxoSmithKline, AstraZeneca Pharmaceuticals LP, Novartis Pharmaceuticals Corporation, CME Incite, the Lovelace Respiratory Research Institute, the Center for Healthcare Education, UpToDate, Merion Publications; and the American Institute for Research; and is an international speaker for Takeda/Nycomed/Forest. Education Partner Financial Disclosure Statement The content collaborators at CME Incite report the following: Priya Wanchoo, MBBS, has no financial relationships disclose. Suggested Reading List Braman SS, Lee DW. Primary care management of chronic obstructive pulmonary disease: an integrated goal-directed approach. Curr Opin Pulm Med. 2010;16:83-88.

Calverley PM. COPD: What is the unmet need? Br J Pharmacol. 2008;155:487-493.

Han MK, Kim MG, Mardon R, et al. Spirometry utilization for COPD: how do we measure up? Chest. 2007;132:403-409.

Joos GF. Potential for long-acting muscarinic antagonists in chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2010;19:257-264.

1

Drug List

• Generic

– Tiotropium

– Formoterol

– Theophylline

– Albuterol

– Ipratropium

– Terbutaline

– Albuterol/ipratropium

– Roflumilast

– Aclidinium bromide (Phase III)

– Azithromycin

• Trade

– Spiriva

– Foradil

– Various

– Various

– Atrovent

– Various

– Combivent

– Daxas, Daliresp

– N/A

– Zithromax

Stephen I. Rennard, MDLarson Professor

Division of Pulmonary, Critical Care, Sleep and AllergyUniversity of Nebraska Medical Center

Omaha, Nebraska

Enhancing Patient Diagnosis and Management of COPD:

A Case-Based Review

Demographic Question

1. None

2. 1 to 10

3. 11 to 20

4. 21 to 30

5. 31 to 40

6. 41 to 50

7. 51 to 60

8. > 60

?Relative to COPD: please indicate the approximate number of patients that you see each week with this condition.

Pretest Question

1. An abnormal spirometry test

2. The patient’s history of smoking

3. A chest x-ray that shows flattening of the diaphragm and

focal bullae

4. Decreased functional capacity on the 6-minute walk test

?To make a definitive diagnosis of COPD, which of the following is the most important factor that would lead you to an accurate diagnosis?

Pretest Question

A 53-year-old white male presents for his annual visit. Although he quit 10 years ago, he is a previous cigarette smoker with a 20 pack-year history. During the past 12 months, he has had 3 episodes of bronchitis. You perform a spirometry and the results show FEV1/FVC=0.6, and the FEV1 is 67% of predicted. How would you classify his COPD?

1. Mild COPD

2. Moderate COPD

3. Severe COPD

4. Not sure

? Pretest Question

When a patient progresses from moderate to severe classification of COPD, what would be the most appropriate addition to their current treatment regimen?

1. Theophylline2. PDE4 inhibitor3. Short-acting β2-agonist

4. Long-acting β2-agonist

5. None of the above

?

2

Pretest Question

Which of the following goals can be achieved with current pharmacotherapy?

1. Improved exercise tolerance

2. Partial disease regression

3. Reduction of exacerbations

4. All of the above

5. 1 and 3 only

? Case Study 1: Meet SamPatient: Sam

• Age: 52• Race: Caucasian• Occupation: Accountant• Marital Status: Married• Lifestyle: Social smoker but used to smoke a pack a

day for 10 years

Relevant Medical History

• Reports having bronchitis a couple of times a year for the past several years. Breathlessness on physical exercise

Current Medications

• Has been treated episodically with antibiotics for his bronchitis

IS THIS TYPICAL OF WHAT YOU SEE IN YOUR OFFICE?

25 50 75

Death

Severe disability

Age (Years)

Never smoked or not susceptible to smoke

Smoked regularly and susceptible

to smoke

Smoking Cessation Slows Disease Progression: Observational Study

Stopped at 45

Stopped at 65

Fletcher C, et al. Br Med J. 1977;1:1645-1648.

100

75

50

25

0

Onset of symptoms

Inflammation in Small Airways at Different Stages of COPD Severity

0

20

40

60

80

100

GOLD stage 1

GOLD stages 2 and 3

GOLD stage 4

Adapted from Hogg JC, et al. N Engl J Med. 2004;350:2645-2653.

Air

wa

ys W

ith

Me

as

ura

ble

Ce

lls (

%)

Neutrophils Macrophages Eosinophils CD4+ Cells CD8+ Cells

Barnes PJ. N Engl J Med. 2000;343:269-280. Copyright © 2004 [2000] Massachusetts Medical Society. All rights reserved.

Disrupted alveolar attachments (emphysema)

Mucus hypersecretion (luminal obstruction)

Mucosal and peribronchial inflammation and fibrosis(obliterative bronchiolitis)

Mechanisms of Airflow Limitation in COPD

3

ARS Question

What tests would you order for Sam?

1. Chest x-ray

2. Spirometry

3. Pulse oximetry

4. None, refer to pulmonologist

? Assess: Who Has Early-Stage COPD and Who Do You Test?

• Test patients with:– Chronic cough and sputum

– Exposure to risk factors

– Even if no dyspnea

• Early stage:– Airflow limitation that is not fully reversible

– With or without the presence of symptoms

American Thoracic Society/European Respiratory Society Task Force. Standards for the Diagnosis and Management of Patients With COPD. New York, NY: American Thoracic Society. 2004.

Assess for COPD: A Common Story

• Cough– Intermittent or daily– Present throughout day; seldom only nocturnal

• Sputum– Any pattern of chronic sputum production

• Dyspnea – Progressive and persistent– “Increased effort to breathe,” “heaviness,” “air hunger,” or “gasping” – Worse on exercise – Worse during respiratory infections

• Exposure to risk factors– Tobacco smoke – Occupational dusts and chemicals – Smoke from home cooking and heating fuels

American Thoracic Society/European Respiratory Society Task Force. Standards for the Diagnosis and Management of Patients With COPD. New York, NY: American Thoracic Society. 2004.

Assess: Physical Examination

• Rarely diagnostic in COPD

• Physical signs of airflow limitation– Rarely present until significant impairment of lung function

– Low sensitivity and specificity

Assess: Spirometry to DiagnoseWhy do office spirometry?

• Diagnostic accuracy: 30% of time diagnosis changes- COPD- Not COPD

- Heart failure- Asthma- Restrictive lung disease

- Normal: Expensive meds discontinued• Respect: Patients respect physicians who

use technology (future of family medicine)• Patient convenience: You can avoid an

unnecessary referral and additional visit• Diagnostic power: You can connect

diagnostic information with rest of clinical encounter

• Financial benefit to practice

ARS Question

In terms of using spirometry in your practice, which is the biggest challenge you face?

1. Limited by availability of the equipment

2. Time constraints

3. Difficulty with interpreting the test

4. Unfamiliar with spirometric classification of COPD severity

?

4

Measurements

Abbreviation Characteristic measured

FEV1 Forced expired volume in 1 second

FVC Forced vital capacity

FEV1 /FVC Ratio Ratio of the above

PEFR Peak expiratory flow rate

Spirometry: Normal and COPD

Celli BR. Chest. 2000;117(2 suppl):15S-19S.

Spirometry: Normal and COPD

Celli BR. Chest. 2000;117(2 suppl):15S-19S.

COPD <70%

Assess: Measure Airflow

• Postbronchodilator FEV1 <80% predicted + FEV1/FVC <70% confirms the presence of airflow limitation that is not fully reversible

Category Characteristics

I: Mild COPD • FEV1/FVC <70% (for stages I-IV)• FEV1 ≥80% predicted

II: Moderate COPD ≤50% FEV1 <80% predicted

III: Severe COPD ≥30% FEV1 <50% predicted

IV: Very severe COPD <30% FEV1

Classification of Severity of Airflow Limitations COPD (GOLD 2011)

http://www.goldcopd.org/uploads/users/files/GOLD2011_Summary.pdf.

Assess: Medical History in Those With Established Disease

• Exacerbations or hospitalizations? • Comorbidities that contribute to restriction of activity • Appropriateness of current medical treatments • Impact of disease on patient’s life

– Limitation of activity– Missed work and economic impact– Effect on family routines– Depression or anxiety – Dyspnea

• Social and family support• Possibilities for reducing risk factors, especially smoking

American Thoracic Society/European Respiratory Society Task Force. Standards for the Diagnosis and Management of Patients With COPD. New York, NY: American Thoracic Society. 2004.

5

Sam’s Spirometry Results

Prebronchodilator Postbronchodilator

FEV1 2.0252% of predicted

2.2758% of predicted

FVC3.85

70% of predicted4.26

87% of predicted

FEV1/FVCratio

52% 53%

Clinical Features Differentiating COPD and Asthma

Clinical Features COPD Asthma

Smoker or ex-smoker Nearly all Possibly

Symptoms when aged younger than 35 years Rare Often

Chronic productive cough Common Uncommon

Breathlessness Persistent and progressive

Variable

Nighttime wakening with SOB and/or wheezing

Uncommon Common

Atopic symptoms and seasonal allergies Uncommon Common

Significant diurnal variability Uncommon Common

Favorable response to ICS Inconsistent Consistent

Yawn BP. Medscape J Med. 2009;11:20. Guerra S. Curr Opin Pulm Med. 2005;11:7-13.

Differential Diagnosis (Aside From Asthma)

Diagnosis Signs/Symptoms Tests

CHF Fine basilar crackles CXR, PFTs, echo

Bronchiectasis Large volumes purulent sputum, repeated infections

CT scan, PFTs

Cystic fibrosis Onset at any age CXR, sweat test, genetic testing

Bronchiolitis obliterans

Onset earlier age, nonsmokers, Hx RA, fume exposure

CT scan

Diffuse panbronchiolitis

Mostly male and nonsmokers, chronic sinusitis in almost all

CXR, HRCT

http://www.copd-ats-ers.org/summary.pdf.

COPD: Systemic Consequences/Comorbidities*

• Physical deconditioning• Exercise intolerance• Skeletal muscle dysfunction• Osteoporosis• Atherosclerotic cardiovascular disease• Metabolic syndrome• Anemia• Anxiety and depression• Lung cancer

*Mechanistic factors: Systemic inflammation and physical inactivity

Nussabaumer Y, et al. Chest. 2011;139:165-173.

Lung Volumes: Air-Trapping and Hyperinflation in COPD

TLC

TLC

ICRoom to breathe in

FRC

FRC

Room to breathe in

IC

Normal COPD

Vo

lum

e

IRV

IRV

ERV

ERV RV

RV

VT

VT

Operating Lung Volumes atRest and During Exercise

Normal COPDPredose Postdose

0

20

40

60

80

100

120

0 10 20 30 40 50Ventilation (L/min)

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Lu

ng

Vo

lum

e (

% p

red

icte

d T

LC

)

Ventilation (L/min)

0

20

40

60

80

100

120

0 10 20 30 40 50Ventilation (L/min)

EELV

IRV

VT

IC

TLC

Adapted from O’Donnell DE, et al. Am J Respir Crit Care Med. 2001;164:770-777.

IC

IC

6

Global Strategy for Diagnosis, Management, and Prevention of COPD Diagnosis and Assessment: Key Points

• A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease

• Spirometry is required to make the diagnosis; the presence of a postbronchodilator FEV1/FVC <0.70 confirms the presence of persistent airflow limitation and thus of COPD

Sam’s Diagnosis: COPD

• FEV1/FVC ratio is low• FVC and FEV1 were partially

reversible with a beta agonist, but are still substantially reduced from normal and the ratio is <0.70

• Spirometry results, in conjunction with Sam’s signs, symptoms, and history, suggest that COPD is the correct diagnosis

Goals for Treatment of Stable COPD

• Relieve symptoms

• Improve exercise tolerance

• Improve health status

• Prevent disease progression

• Prevent and treat exacerbations

• Reduce mortality

Global Strategies for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2011.

REDUCE SYMPTOMS

REDUCE RISK Fernando J. Martinez, MD, MSProfessor, Department of Internal Medicine

Director, Pulmonary Diagnostic ServicesUniversity of MichiganAnn Arbor, Michigan

Treatment Strategies and Reducing the Risk of

Exacerbation

Case Study 2: Meet George

Patient: George

• Age: 62• Race: African American

Medical History• Diagnosed with COPD 5 years ago• Previously smoked about 20 cigarettes a day but cut down to

10 after his last exacerbation. Can’t quit• HT and hypercholesterolemiaPresenting Problem

• Worsening dyspnea, cough, purulent sputum over the past 3 days

• Auscultation of the chest reveals scattered expiratory wheeze

Current Medications • Tiotropium• Albuterol PRN

Initial Treatment Considerations• Encouragement of smoking cessation

• Individual pharmacologic therapy recommendation based on severity, drug availability, and patient response

• Influenza and pneumococcal vaccination offered to every patient

• Patients who get short of breath easily should be offered rehabilitation, as it can:– Improve symptoms

– Increase quality of life

– Enhance physical and emotional participation in everyday activities

Global Strategies for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2011.

7

Therapeutic Options for COPD: Formulations and Duration of Action

Drug Class InhaledNebulizer Solution

Oral Duration of Action,

Hoursβ2-agonists

Short acting X X X 4-8

Long actingX X

X (transdermal)

12-24

Anticholinergics

Short acting X X 6-9

Long acting X 24

Combination short-acting β2-agonists plus anticholinergic in 1 inhaler

X X 6-8

Methylxanthines X Up to 24

Inhaled corticosteroids X X

Combination long-acting β2-agonists plus anticholinergic in 1 inhaler

X

Systemic corticosteroids X

Phosphodiesterase-4 inhibitors X 24

Global Strategies for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2011.

Smoking Cessation Modalities for Patients With COPD

• Nicotine replacement therapy– Transdermal system

– Gum

– Lozenge

– Inhaler

– Nasal spray

• Bupropion

• Varenicline

Continuous Abstinence Weeks 9-12 in COPD, Cardiovascular Disease, and Phase 3 Trials

1. Tashkin D, et al. Chest. In press. 2. Rigotti N, et al. Circulation. 2010;121:221-229. 3. Gonzales D, et al. JAMA. 2006;296:47-55. 4. Jorenby DE, et al. JAMA. 2006;296:56-63.

Varenicline: Most Common Adverse EventsFrom 12-Week, Fixed-Dose, Placebo-Controlled Studies

Adverse Event

Varenicline0.5 mg BID, %

(n=129)

Varenicline1.0 mg BID, %

(n=821)

Placebo, %(n=805)

Nausea 16 30 10

Insomnia* 19 18 13

Abnormal dreams 9 13 5

Constipation 5 8 3

Flatulence 9 6 3

Vomiting 1 5 2

*Includes preferred terms: Insomnia/initial, insomnia/middle, insomnia/early morning awakening.Adverse events listed occurred >5% and twice the rate seen in placebo-treated patients.

Varenicline [package insert]. New York, NY: Pfizer Inc; July 22, 2011.

Varenicline Warning• Psychiatric symptoms

– Agitation − Suicidal ideation– Depressed mood − Suicidal behavior

• Warning: Patients should be monitored, and they and their families and caregivers should be alerted to monitor for these symptoms

• Advise patients and caregivers that the patient should stop taking varenicline and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior that are not typical for the patient are observed or if the patient develops suicidal ideation or suicidal behavior (May 2008)

• July 1, 2009: FDA has required the manufacturers of the smoking cessation aid varenicline … to add new Boxed Warnings and develop patient Medication Guides highlighting the risk of serious neuropsychiatric symptoms in patients using these products

• July 2011: FDA issued new information: varenicline may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease

Bronchodilators: Mechanisms of Action

8

Bronchodilators β2-Agonists

• Short acting– Fenoterol

– Salbutamol (albuterol)

– Terbutaline

• Long acting (LABA)– Formoterol

– Salmeterol

– Indacaterol

Anticholinergic Bronchodilators

• Mode of action– Cholinergic tone is only reversible component of COPD

– Normal airways have small degree of vagal cholinergic tone

• Short acting– Ipratropium bromide

• Long acting (LAMA)– Tiotropium

– Aclidinium (currently under FDA review)

Bronchodilators: Combos and Methylxanthines

• Combination β2-agonists plus anticholinergic in 1 inhaler

– Fenoterol/Ipratropium

– Salbutamol/Ipratropium

• Methylxanthines

– Aminophylline (slow-release preparations)

– Theophylline (slow-release preparations)

– Level 8-12 mcg/mL Lu

ng

Vo

lum

e(L

)

Exercise Time (Minutes)

Effect Tiotropium on Dynamic Hyperinflation

O’Donnell DE, et al. Eur Respir J. 2004;23:832-840.

IC

Placebo Tiotropium

TLC

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

0 5 10 15

UPLIFT: Frequency of Exacerbations Compared With Control

TiotropiumMean (SE)

ControlMean (SE)

Rate Ratio 95% CI P Value

Number of exacerbations per patient-year

0.73 (0.02)

0.84 (0.02)

0.86 0.81-0.91 <0.001

14% reduction in number of exacerbations

Tashkin DP, et al. N Engl J Med. 2008;359:1543-1554.

Aclidinium Twice Daily Improves FEV1 and Health Status

Trough FEV1 SGRQ

Jones PW, et al. Eur Respir J. 2012 Mar 22. [Epub ahead of print]

9

Ferguson GT, et al. Respir Med. 2008;102:1099-1108.

Moderate exacerbation: Worsening of COPD symptoms requiring both a change in normal treatment (increased dose of prescribed medication or addition of new drugs, eg, oral steroids, antibiotics) AND medical assistance

Severe exacerbation: Worsening of COPD symptoms requiring hospital or emergency room treatment

Fluticasone Propionate/Salmeterol 250/50 Decreases Moderate to Severe COPD Exacerbations in 1-Year Comparative Study

*P<0.001

SAL 50 FSC 250/50

Exa

cerb

atio

n R

ates

(p

er Y

ear)

30.5% reduction

*1.53

1.06

00.20.40.60.8

11.21.41.61.8

SAL 50: salmeterol 50 mcg; FSC 250/50: fluticasone 250 mcg+salmeterol 50 mcg

Once-Daily Indacaterol Improves Trough FEV1 and Health Status Compared With Placebo

Adapted from Kerwin EM et al. Clin Therap. 2011;33:1974-1984.

PDE4Inhibitor

PAF; LTB4; chemokines;ROS; degranulation; CD11b

Neutrophil

TNF; IL-10; LTB4

Monocyte

Proliferation; cytokines(IL-2, -4, -5, -13, IFN)

T-lymphocyteTNF; ROS

Macrophage/dendritic cell

Permeability;E-selectin; VCAM-1

Endothelial cells

Proliferation; GM-CSF;Rantes; relaxation

Smooth muscle cells LTC4; PGD2; histamine;cytokines (IL-4, -5, -13)

MIP-1; GM-CSF

Mast cell/basophil

IL-5; LTC4; ROS; CD11b;chemotaxis; degranulation

Eosinophil

PDE4 Inhibitors TargetInflammatory and Immunocompetent Cells

Spina D. Br J Pharmacol. 2008;155:308-315. Hatzelmann A, et al. Pulm Pharmacol Ther. 2010;23:235-256.

GOLD Guidelines Updated 2011

Phosphodiesterase-4 inhibitors• In patients with stage III severe COPD or stage IV very

severe COPD (FEV1<30% of predicted) and a history of exacerbation and chronic bronchitis, the phosphodiesterase-4 inhibitor roflumilast reduces exacerbations treated with oral glucocorticoids

• These effects are also seen with roflumilast when added to long-acting bronchodilators; there are no comparison studies with inhaled glucocorticoids

Global Strategies for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2011.

Placebo

Roflumilast

P=0.0278

P=0.0035

Moderate or Severe Exacerbations

1.5

1.0

0.5

0M2-124 M2-125

Effect of Roflumilast in COPD: 1-Year Trials

Calverley PM, et al. Lancet. 2009;374:685-694.

Rat

e of

Exa

cerb

atio

ns p

er Y

ear

Pre- and Postbronchodilator FEV1 Improves With Roflumilast Therapy

=55 mL(CI: 41-69)P<0.0001

=48 mL(CI: 35-62)P<0.0001

-9

-20

0

20

40

60

80

Pre-FEV1 Post-FEV1

Placebo Roflumilast 500 µg

50

-4

40

-9

Calverley PM, et al. Lancet. 2009;374:685-694.

10

Daily Azithromycin Decreases AECOPD

Time to First AECOPD

360

0.20

0.40

0.60

0.80

1.00

0 135 180 225 270 3159045

Time (Days)

Pro

po

rtio

n F

ree

of

AE

CO

PD Azithromycin*

Placebo

Log-rank P<0.001

HR: 0.73 (95% CI: 0.63-0.84; P<0.0001)

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

*Azithromycin 250 mg daily for 1 year. Not approved for this indication

Combined Assessment of COPD

Patient CharacteristicSpirometric

ClassificationExacerbations

per YearmMRC CAT

ALow risk,

fewer symptoms

GOLD 1-2 ≤1 0-1 <10

BLow risk,

more symptoms

GOLD 1-2 ≤1 ≥2 ≥10

CHigh risk,

fewer symptoms

GOLD 3-4 ≥2 0/1 <10

DHigh risk,

more symptoms

GOLD 3-4 ≥2 ≥2 ≥10

CAT=COPD Assessment TestmMRC=Modified Medical Research Council Dyspnea Scale

Increasing Symptoms

Incr

easi

ng

Ris

k C D

A B

Incr

easi

ng

Ris

k

mMRC <2CAT <10

12

3 4

GO

LD

cla

ssif

icat

ion

o

f a

irfl

ow

lim

ita

tio

n

01

2 o

r m

ore

Exa

cerb

atio

n h

isto

ry

COPD Assessment: A New Model

mMRC >2CAT >10

Pharmacological Therapy of Stable COPD: GOLD 2011

www.goldcopd.org

Increasing Symptoms

Incr

easi

ng

Ris

k

C D

A B

GO

LD

sp

iro

met

ric

clas

sifi

cati

on

mMRC 0-1CAT <10

mMRC >2CAT >10

Incr

easi

ng

Ris

k

0

1

2

or

mo

reE

xace

rbat

ion

his

tory Patient is now in 1 of

4 categories:

A: Fewer symptoms, lower risk

B: More symptoms, lower risk

C: Fewer symptoms, higher risk

D: More symptoms, higher risk

1

2

3

4

Global Strategy for Diagnosis, Management, and Prevention of COPD

Manage Stable COPD: Pharmacologic Therapy

Patient First Choice Second Choice Alternative Choices

ASAMA prn

orSABA prn

LAMAor

LABA or

SABA and SAMA

Theophylline

BLAMA

orLABA

LAMA and LABASABA and/or SAMA

Theophylline

C

ICS + LABAor

LAMALAMA and LABA

PDE4-inh.SABA and/or SAMA

Theophylline

D

ICS + LABAor

LAMA

ICS and LAMA orICS + LABA and LAMA or

ICS+LABA and PDE4-inh. orLAMA and LABA or

LAMA and PDE4-inh.

CarbocysteineSABA and/or SAMA

Theophylline

(Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference.)

Improved COPD Survival on Long-Term Oxygen Treatment (LTOT)

Güell Rous R. Int J Chron Obstruct Pulmon Dis. 2008;3:231-237. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980;93:391-398. Medical Research Council Working Party. Lancet. 1981;1:681-686.

11

Upper Lobe Disease and Poor Exercise Function

• 1218 severe COPD patients• Rehabilitation• Assess

– CT distribution– Exercise performance

• Randomize– Surgery– Medical management

• Reevaluate: 6 months, yearly• Assess

– Survival– Exercise

Fishman A, et al. N Engl J Med. 2003;348:2059-2073.

Volume Reduction Surgery in Chronic Obstructive Pulmonary Disease: NETT Trial

Adverse Effects of ß2-Agonist Bronchodilators

Adverse effects include: • Tachycardia

• Palpitations

• Premature ventricular contractions

• Tremors

• Sleep disturbances

• Hypokalemia

Tashkin DP, et al. Respir Res. 2010;11:149.

Adverse Effects of Anticholinergic Bronchodilators

Adverse effects include: • Dry mouth

• Urinary retention

• Glaucoma (intraocular administration)

Rennard SI. Lancet. 2004;364:791-802.

Adverse Effects of Inhaled Glucocorticoids

Adverse effects include: • Dysphonia

• Thrush

• Local irritation

• Systemic effects– Skin bruising

– Bone density

– Cataracts

• Pneumonia

Saag KG, et al. UpToDate 2011. http://www.uptodate.com/contents/major-side-effects-of-inhaled-glucocorticoids.

Adverse Effects of Roflumilast in Clinical Studies

• Adverse effects associated with roflumilast therapy typically mild to moderate

• Occurred mainly within first weeks of therapy and mostly resolved on continued treatment

• Rare neuropsychiatric events

http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf.

Adverse Reactions Reported by ≥2% of Patients Taking Roflumilast

Roflumilast Placebo

N=4438 N=4192

n (%) n (%)

Diarrhea 420 (9.5) 113 (2.7)

Weight decreased 331 (7.5) 89 (2.1)

Nausea 209 (4.7) 60 (1.4)

Headache 195 (4.4) 87 (2.1)

Back pain 142 (3.2) 92 (2.2)

Influenza 124 (2.8) 112 (2.7)

Insomnia 105 (2.4) 41 (1.0)

Dizziness 92 (2.1) 45 (1.1)

Decreased appetite 91 (2.1) 15 (0.4)

Roflumilast Warning• Psychiatric symptoms

– Insomnia

– Anxiety

– Depressed mood

– Suicidal ideation

• Warning: Patients should be monitored, and they and their families and caregivers should be alerted to monitor for these symptoms

• Advise patients and caregivers that the patient should stop taking roflumilastand contact a healthcare provider immediately if emergence or worsening of following symptoms: insomnia, anxiety, depression, suicidal thoughts, or other mood changes

• Weight loss

– Patients should be monitored; if unexplained or clinically significant weight loss occurs, weight loss should be evaluated and discontinuation of roflumilast considered

Roflumilast [package insert]. St Louis, MO: Forest Laboratories; 2011.

12

Azithro (dB) Placebo (db)P Value

Mean 95% CI Mean 95% CI

Start to 3rd month -0.7 -1.0 to -0.3 -0.0 -0.4 to 0.4 0.01

Start to 12th month -1.2 -1.6 to -0.8 -0.9 -1.3 to -0.5 0.25

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

Azithromycin StudyHearing Changes

OnEnrollment

DuringStudy

Par

tici

pan

ts W

ith

Sel

ecte

dR

es

pir

ato

ry P

ath

og

en

s (

N)

60

90

120

150

30

14%

32%

14% 15%

OnEnrollment

DuringStudy

Cu

ltu

res

Wit

h M

acro

lide-

Res

ista

nt

Pat

ho

gen

s (%

)

40

60

80

100

20

81%*

41%52%

57%

Cultures from 85% and 84% of clinic visits

Cultures from 56% and 59% of patients with pathogens

Azithro

Placebo

P=0.81

P<0.001

P=0.64

P<0.0001

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

Azithromycin StudyMicrobiology

FDA Review of Azithromycin As of 5/21/2012

“A small increase in cardiovascular deaths, and in the risk of death from any cause, in persons treated with a 5-day course of azithromycin compared to persons treated with amoxicillin, ciprofloxacin, or no drug. FDA is reviewing the results from this study and will communicate any new information on azithromycin and this study or the potential risk of QT interval prolongation after the agency has completed its review.”

Clinical Course of COPD

COPD

Disability Disease Progression Death

Air trappingExpiratory flow limitation

Hyperinflation

Deconditioning Inactivity

Reduced exercise capacity

Exacerbations

Breathlessness

Quality of life

Defining Exacerbations in Patients With COPD

• GOLD guidelines1

– Change in the patient’s baseline dyspnea, cough, and/or sputum beyond normal day-to-day variation

– Acute in onset– May warrant a change in regular medication

• ATS/ERS guidelines2

– Increased symptoms requiring change in usual medications– Mild exacerbations (normally managed at home by the patient)– Moderate exacerbation (requiring consultation with PCP) – Severe exacerbation (needing hospitalization)

ATS/ERS=American Thoracic Society/European Respiratory Society; GOLD=Global Initiative for Chronic Obstructive Lung Disease1. The Global Initiative for Chronic Obstructive Lung Disease. GOLD Report – Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2011.2. American Thoracic Society/European Respiratory Society Task Force. Standards for the Diagnosis and Management of Patients with COPD. New York, NY: American Thoracic Society. 2004.

Impact of Exacerbations in COPD

Patients with frequent exacerbations

Higher mortality

Faster declinein lung function

Poorer qualityof life

Greater airwayinflammation

Adapted from Wedzicha JA, et al. Lancet. 2007;370:786-796.

13

Use of Short-Acting Bronchodilators in the Treatment of Exacerbations

• Short-acting bronchodilators are a critical component of overall care for patients with exacerbations

• Clinical trial results indicate no significant difference between the effectiveness of short-acting β-agonists and short-acting anticholinergic agents

• Combination therapy is safe, but there is no convincing evidence that it is superior to either agent alone

• There is no difference in the efficacy of short-acting bronchodilator therapy delivered by a nebulizer vs a metered-dose inhaler with a spacer

• Administration of a short-acting β-agonist during an exacerbation does not appear to have adverse cardiovascular effects

Systemic Steroids Reduce AECOPD Treatment Failure

Wood-Baker, et al. The Cochrane Library. 2006;2:1-38(A).

100.1 0.2 0.5

Relative Risk (95% Confidence Interval)

2 51

Favors PlaceboFavors Steroid

Pooled summary(RR: 0.54; 95% CI: 0.41-0.71)

Bullard 1996

Thompson 1996

Davies 1999

Niewoehner 1999

Maltais 2002

Aaron 2003

Quon BS, et al. Chest. 2008;133:756-766.

Antibiotics Reduce Risk of AECOPD Treatment Failure

Weight,%

0.67 (0.56-0.80)

0.33 (0.07-1.52)

0.70 (0.45-1.11)

0.32 (0.15-0.68)

1.03 (0.75-1.41)

0.40 (0.22-0.74)

0.57 (0.41-0.79)

100.1 0.2 0.5 2 51

Favors PlaceboFavors Antibiotic

Placebo Group,

n/N

Relative Risk, Fixed(95% CI)

Relative Risk, Fixed(95% CI)

Study Antibiotic Group,

n/N

Total events: 113 (antibiotic group), 170 (placebo group)Test for heterogeneity chi-square=15.46, df=5, P=0.009, I2=67.7%

Test for overall effect z=4.27, P=0.00002

Total (95% CI)

Alonso 1992

Anthonisen 1987

Elmes 1965

Jørgensen 1992

Pines 1968

Pines 1972

351

2/29

19/57

6/29

49/132

6/15

31/89

354

6/29

28/59

19/29

49/136

15/15

53/86

100

3.5

16.2

11.2

28.4

8.8

31.8

Ram FS, et al. Cochrane Database Syst Rev. 2006;CD004403. Permission requested.

Early Antibiotics Reduces Treatment Failure in Hospitalized AECOPD

Ram FSF. Antibiotics for exacerbations of COPD. Cochrane. 2006;3.Adapted from Rothberg MB, et al. JAMA. 2010;303:2035-2042.

P<0.001

P<0.001

Pulmonary Rehabilitation • Pulmonary rehabilitation is an efficacious and cost-effective

intervention for improving functional performance and quality of life, and decreasing health care utilization among patients with COPD

• Programs are underutilized

– Estimates suggest that fewer than 2% of patients with COPD have participated in pulmonary rehabilitation

– Many factors, including health system, physician, and patient-related, contribute to underutilization

• Components of pulmonary rehabilitation

– Exercise/physical activity training

– Psychosocial support

Coultas D, et al. Clin Pulmonary Med. 2009;16(4):183-188.

Prevent Exacerbations: Key Takeaways

• Smoking cessation, influenza, and pneumococcal vaccine and knowledge of current therapy can reduce the number of exacerbations and hospitalizations

14

Case Study 2: Meet George

Patient: George

• Age: 62• Race: African American

Medical History• Diagnosed with COPD 5 years ago• Previously smoked about 20 cigarettes a day but cut down to

10 after his last exacerbation. Can’t quit• HT and hypercholesterolemiaPresenting Problem

• Worsening dyspnea, cough, purulent sputum over the past 3 days

• Auscultation of the chest reveals scattered expiratory wheeze

Current Medications • Tiotropium• Albuterol PRN

Are you confident in treating this patient’s exacerbation?

Summary

• Spirometry is a useful tool in suspected cases of COPD

• FEV1/FVC <70%, ≥80% FEV1 predicted considered mild COPD

– FEV1 <30%, considered very severe COPD

• The benefits/goals of pharmacotherapy are to improve exercise tolerance and reduce exacerbations

• Treatment strategies adjust to the stage of the disease

– Mild disease: Avoid risk factors and add short-acting bronchodilator when needed

– Moderate disease: Same as mild but add long-acting bronchodilator when needed

– Severe disease: Add a glucocorticoid

Posttest Question

1. An abnormal spirometry test

2. The patient’s history of smoking

3. A chest x-ray that shows flattening of the diaphragm and

focal bullae

4. Decreased functional capacity on the 6-minute walk test

?To make a definitive diagnosis of COPD, which of the following is the most important factor that would lead you to an accurate diagnosis?

Posttest Question

A 53-year-old white male presents for his annual visit. Although he quit 10 years ago, he is a previous cigarette smoker with a 20 pack-year history. During the past 12 months, he has had 3 episodes of bronchitis. You perform a spirometry and the results show FEV1/FVC=0.6, and the FEV1 is 67% of predicted. How would you classify his COPD?

1. Mild COPD

2. Moderate COPD

3. Severe COPD

4. Not sure

?

Posttest Question

When a patient progresses from moderate to severe classification of COPD, what would be the most appropriate addition to their current treatment regimen?

1. Theophylline2. PDE4 inhibitor3. Short-acting β2-agonist

4. Long-acting β2-agonist

5. None of the above

? Posttest Question

Which of the following goals can be achieved with current pharmacotherapy?

1. Improved exercise tolerance

2. Partial disease regression

3. Reduction of exacerbations

4. All of the above

5. 1 and 3 only

?

15

Questions & Answers

?