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Enhancing Patient Diagnosis and Management of COPD: A Case-Based Review
June 23, 2012 New York, New York
Educational Partner: CME Incite, LLC
Session 1
Session 1: Enhancing Patient Diagnosis and Management of COPD: A Case-Based Review
Learning Objectives 1. Prevent 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 Division of Pulmonary, Critical Care, Sleep and Allergy University of Nebraska Medical Center Omaha, Nebraska Stephen Rennard, MD, is Larson Professor of Medicine in the pulmonary and critical care medicine section of the department of pathology and microbiology and the department of genetics, cell biology, and anatomy at the University of Nebraska Medical Center in Omaha. 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, Texas. He completed internal medicine training at Barnes Hospital, Washington University, in St. Louis, Missouri, 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. He is a member of the National Heart Lung Education Program Executive Committee and is the chair of the steering committee for SPIROMICS. He 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 a program of basic research in 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 Fernando J. Martinez, MD, MS, 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, Ann Arbor, Michigan. After graduating from the University of Florida School of Medicine, he completed his residency in internal medicine at Beth Israel Hospital and his fellowship in pulmonary medicine at the Boston University Pulmonary Center.
Dr Martinez’s main research interests include chronic obstructive pulmonary disease (COPD), interstitial lung disease, lung transplantation, and lung volume reduction. Currently, he is a member of numerous societies, including the American Thoracic Society, the European Respiratory Society, American College of Chest Physicians, and the Fleischner Society. Previously, he was a member of the American Thoracic Society committees that generated guidelines for the management of COPD, respiratory infections, and cardiopulmonary exercise testing and is the former chair of the Clinical Problems Assembly of the American Thoracic Society. He is currently a member of the GOLD Executive and Science Committees. Dr Martinez sits on a number of editorial boards, including those for the Journal of COPD and American Journal of Respiratory and Critical Care Medicine.
Session 1
Faculty Financial Disclosure Statements The presenting faculty report the following: Dr Rennard serves as a speaker for AARC; Almirall; American College of Osteopathic Physicians; Asan Medical Center; American Thoracic Society; California Society of Allergy; CME Incite; COPD Foundation; Creative Educational Concepts; Dey; Duke University; Forest; France Foundation; HSC Medical Education; Information TV; American Lung Association; Novartis (Horsham); Nycomed; Otsuka; PeerVoice; Pfizer; Shaw Science; University of Washington; University of Alabama Birmingham; and VA Sioux Falls. He is a consultant for ABIM; Able Associates; Adelphi Research; Align2Action; Almirall/Prescott; APT Pharma/Britnall; AstraZeneca; American Thoracic Society; Beilenson; Boehringer Ingelheim; Boehringer Ingelheim (ACCP); BoomCom!; Britnall and Nicolini; Capital Research; Chiesi; Clarus Acuity; Common Health; Complete Medical Group; ConsultComplete; COPDForum; DataMonitor; Decision Resources; Dunn Group; Easton Associates; Equinox; Forest; Frankel Group; Fulcrum; Gerson Lehrman; Globe Life Sciences; GlaxoSmithKline; Guidepoint; Health Advances; Hoffmann-La Roche; InforMed; Insyght; KOL Connection; Leerink Swann; M. Pankove; McKinsey; MDRx Financial; MedImmune; Merck; Novartis; Nycomed; Oriel; Osterman; Pearl; Penn Technology; Pennside; Pfizer; PharmaVentures; Pharmaxis; Prescott; PricewaterhouseCoopers; Propagate; Pulmonary Reviews; Pulmatrix; J. Reckner Associates; Recruiting Resource; Roche; Sankyo; Schering; Schlesinger Medical; SciMed; Smith Research; Sudler & Hennessey; Summer Street Research; Talecris; Think Equity; UBC; Uptake Medical; and Vantage Point Management. Dr Martinez receives consulting fees from GlaxoSmithKline, MedImmune/AstraZeneca, Merck, Forest, Takeda/Nycomed/Forest, Bayer, Ikaria, Actelion, Pfizer, Pearl, Carden Jennings, JK Associates, Prescott, Sudler & Hennessey, and the University of Virginia. He receives honoraria from GlaxoSmithKline, AstraZeneca, Novartis, CME Incite, Center for Healthcare Education, UpToDate, Merion, and American Institute for Research. He serves as 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 to 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(2):83-88. Calverley, PM. COPD: what is the unmet need? Br J Pharmacol. 2008;155(4):487-493. Han MK, Kim MG, Mardon R, et al. Spirometry utilization for COPD: how do we measure up? Chest. 2007;132(2):403-409. Joos GF. Potential for long-acting muscarinic antagonists in chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2010;19(2):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
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
? 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
?
2
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 ARS Question
What tests would you order for Sam?
1. Chest x-ray
2. Spirometry
3. Pulse oximetry
4. None, refer to pulmonologist
?
3
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
? 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
4
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.
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%
5
ARS Question
What is Sam’s diagnosis?
1. Asthma
2. COPD
3. Reactive airway disease
4. Bronchitis
? 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
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
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
– Indacaterol
– 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
TORCH: COPD-Related Deaths
Calverley PM, et al. N Engl J Med. 2007;356:775-789.
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
10
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.
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(Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference.)
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
11
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.
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
Roflumilast2 mcg
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)
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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.
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.
13
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.
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.
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Prevent Exacerbations: Key Takeaways
• Smoking cessation, influenza, and pneumococcal vaccine and knowledge of current therapy can reduce the number of exacerbations and hospitalizations
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
?
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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
?Questions & Answers
?