Improving Patient Outcomes
in COPD
James F. Donohue, MD
Professor of Medicine
Division Chief, Pulmonary & Critical Care Me...
70
0
60
50
30
Sports &
Recreation
Normal
Physical
Exertion
Social
activities
Sleeping Household
Chores
Sex
Life
40
Family
...
• Patients may misunderstand or minimize symptoms such asPatients may misunderstand or minimize symptoms such as
fatigue, ...
Diagnosing COPD: Risk Factors and SymptomsDiagnosing COPD: Risk Factors and Symptoms
Risk FactorsRisk Factors
• History of...
GOLD. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease
Report. Updat...
COPD and Comorbid Disease
From Holguin and Mannino; Chest 2005
Hospitalizations In-hospital Deaths
Ischemic
Heart
Disease
...
Depression and COPD
• DSM criteria:
– subjective report of depressed mood
– loss of interest or pleasure in activities
– p...
Conclusions
• COPD is an important and, frequently,
underdiagnosed disease
• The costs of COPD, at both the personal
and s...
0
50
100
150
200
250
20% 40% 60% 80% 100%
Lumen Content / Lumen Area (%)
Frequency
GOLD 4
Airways fully expanded
Airways a...
Barnes PJ. N Engl J Med. 2000;343:269-280. Copyright © 2004 [2000] Massachusetts
Medical Society. All rights reserved.
Dis...
COPD Risk and Smoking Cessation
Never smoked orNever smoked or
not susceptiblenot susceptible
to smoketo smoke
Stopped
smo...
What is Disease Modification?
1. Change in decline in FEV1
2. Any change in a metric that is maintained over
time.
Lung Health Study: Results
Mean Postbronchodilator FEV1
for Sustained Quitters and
Continuous Smokers Receiving
Smoking In...
Techniques for COPD Assessment
• Physiological parameters
• Dyspnea
• Patient Reported Outcomes
• Multidimensional Indexes...
00 22 44 66 88 1010 1212
33
22
11
00
LungVolume(L)
Exercise Time (minutes)
O’Donnell. AJRCCM 1999;160:545
TLC
IRVIRV
VVTT
...
Dyspnea
Instrument Type Scores
• MRC scale Category scale 5 grades
• UCSD SOB 24 items related to 0 to 120
activities of d...
Multidimensional Indices in the Assessment
of COPD Progression
• COPD is associated with clinical manifestations not
close...
Adapted with permission from Pitta F et al. Am J Respir Crit Care Med. 2005;171:972-977.
Pulmonary Function Test and Exerc...
Celli et al, NEJM 2004:350:1005-12
The Body - Mass Index, Airflow Obstruction, Dyspnea
and Exercise Capacity (BODE) index ...
BODE Score and
Probability of Survival
FEV1 and Probability
of Survival: FEV1 >
50%, FEV1 < 50 % >
36 %, FEV1 < 35%
COPD Stages
Stage Lung function Manifestations
I: Mild
FEV1/FVC < .70
FEV1 ≥ 80% predicted
With or without chronic cough
a...
Dyspnea
Exercise
Tolerance
Consequences of Airflow Limitation in COPD
Exacerbations
Airflow Limitation, Lung
Hyperinflatio...
ERS/ATS Algorithm for Pharmacologic
Treatment in COPD
Confirm Dx
of COPD
SA-BD p.r.n.
LA-BD/SA-BD q.i.d. with rescue
Alter...
Objectives of COPD Management
• Prevent disease progression
• Relieve symptoms
• Improve exercise tolerance
• Improve heal...
Bronchodilators in Stable COPD
• Bronchodilator medications are central to the
symptomatic management of COPD (Evidence A)...
Current Bronchodilator Options for COPD
Bronchodilators
Short-acting Long-acting
β-agonists:
Albuterol
Levalbuterol
Terbut...
Pre-ganglionic
nerve
Parasympathetic
ganglion
Post-ganglionic
nerve
ACh
Airway smooth
muscle
Nicotinic receptors (+)
M1 re...
ß2-AR
A
ACh
M3
M3
M3
M3
M3M1
M1
ß2-AR agonist
ß2-AR
Anticholinergic agent
Cazzola et al, Arch Bronconeumol 2004;41(Supl 2)...
Rationale for Use of Bronchodilators in COPD
• 1) Physiologic Effects
– a) ASM relaxation
– Bronchodilation: FEV1
– Decrea...
Short-term FEV1 Response to Bronchodilator Therapy is
Variable and May Underestimate Long-term Response
Study population: ...
73% of patients show reversibility*
27%
11%
(n = 280)
27%
35%
*Reversibility defined as
≥12% and > 200 mL increase
in FEV1...
Post-bronchodilator Lung Volume Changes are More Sensitive Indicators of Response in
Patients With “Irreversible” Emphysem...
Chemical Structures of LABAs
Formoterol: medium side chain
CH3
OH
N
H
O
CHCH2NHCHCH2
H
O
OH CH3
CHOH
OH
Salmeterol: long s...
Formoterol and Salmeterol: Comparison of Pharmacologic Properties
Formoterol
• Long duration (>12 hours)
• Rapid onset of ...
0.4
0.3
0.2
0.1
0
-0.1
*
**
* *
* *
*
All Patients
Day 84
*P < 0.001 salmeterol vs baseline and placebo.
FEV1 Change From ...
Effect of Tiotropium and Salmeterol on FEV1 in COPD
*P<.05 for day 169.
Donohue et al. Chest. 2002;122:47-55.
Tiotropium (...
Formoterol vs Tiotropium: Formoterol Has Faster Onset
of Bronchodilation
1.3
1.4
1.5
1.6
1.7
1.8
0 60 120 180 240 300 360 ...
Improvement in QoL with LABAs vs Placebo
-8.0-8.0 -6.0-6.0 -4.0-4.0 -2.0-2.0 00 2.02.0 4.04.0
Adapted from Sin et al. JAMA...
Improvement of Health Status with Tiotropium
• Tiotropium vs ipratropium
– 535 patients randomized (FEV1 42% predicted)
– ...
Exacerbations in COPD Patients Decreased by
Tiotropium
Adapted from Barr et al. Cochrane Database of Systematic Reviews. 2...
Bronchodilators in COPD:
Combination vs. Monotherapy
CombinationCombination FEVFEV11 SymptomsSymptoms ExacerbationsExacerb...
Ipratropium + Albuterol (n = 173) Albuterol (n = 165)
Ipratropium (n = 176)
Improvement in FEV1 with Short-acting Bronchod...
COPD: Salmeterol + Theophylline
0
1
2
Theophylline Salmeterol S+T
TDI(changefrombaseline)
ZuWallack CHEST 2001,119:1661
Tiotropium Plus Formoterol
0.9
1.0
1.1
1.2
1.3
1.4
1.5
-2 0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
FEV1(L)
Tiotropiu...
-50
0
50
100
150
200
250
300
350
0 2 4 6 8 12 16 20 24
FEV1(mL)LABA + ICS in COPD
Endpoint‡
(6%)
*
(14%)
†
(19%)
(27%)
Ti...
ICS and Mortality: Pooled Survival
Sin et al., Thorax 2005; 60:992-7.
Do ICS Slow the Decline in FEV1? - Summary AnalysisDo ICS Slow the Decline in FEV1? - Summary Analysis
Multiple ICS/placeb...
Wilt T, Niewoehner DE, Kim C, et al.Wilt T, Niewoehner DE, Kim C, et al.
AHRQ Report 05-E017-2, 2005AHRQ Report 05-E017-2,...
Aaron S, ATS Poster, 2006Aaron S, ATS Poster, 2006
00
22
00
44
00
66
00
88
00
TiotropiumTiotropium TiotropiumTiotropium
++...
00
0.010.01
0.020.02
0.030.03
0.040.04
0.050.05
0.060.06
0.070.07
0.080.08
PlaceboPlacebo SALSAL FPFP SAL+FPSAL+FP
Annuali...
Definition
• Defined as change in patient’s symptoms beyond
daily variations sufficient to cause a change in
therapy
• Cau...
Donaldson & Wedzicha Thorax 2006;61:164
Exacerbation Rate by FEV1
0
1
2
3
<1.25 1.25-
1.54
>1.54 2.40 2.5
Baseline FEV1
Ex...
0
10
20
30
40
50
60
70
80
90
100
Total Symptoms Activities Impacts
SGRQscore
* p < 0.05
0–2 exacerbations/year
3–8 exacerb...
COPD Exacerbations: Healthcare Resource Use
• 0.9% of all 11.7 million hospital admissions*
• 2.4% of all 4.2 million acut...
Management Algorithm for COPD Exacerbations
Initiate or Optimize Bronchodilator Therapy
Consider Antibiotics
Initiate or O...
Recommended Therapy at EachRecommended Therapy at Each
Stage of COPDStage of COPD11
COPDCOPD
StageStage
FEVFEV11
Influenza...
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  • The potential impact of COPD on patients’ lifestyle and quality of life was illustrated even more graphically when they were asked which aspects of their daily lives were limited by their condition. For each area defined in the questionnaire, at least 30% of patients said they were limited to at least some degree, including 34% of patients who were limited in terms of sleeping, 37% with regard to performing household chores, 55% normal physical exertion and nearly two-thirds in terms of sports and recreation. Family activities and sex life were also affected in around one-quarter of patients.
    Rennard S, et al. Impact of COPD in North America and Europe in 2000; subjects’ perspective of Confronting COPD International Survey. Eur Respir J 2002; 20: 799-805.
  • Patients with COPD often do not understand the progressive nature of their disease and thus they may not see their disease or symptoms as serious
    They may misunderstand or minimize important symptoms such as dyspnea and cough and may fail to describe these symptoms to the physician. They may misattribute such symptoms as exercise intolerance to nothing more than being “old and out of shape”
    Patients may also discount the need to receive medication for a respiratory condition that is not perceived to be serious
    Lack of awareness of the disease progression and its impact on overall health can have significant consequences for seeking treatment, for diagnosis, and on subsequent compliance with therapy
    For this reason, communicating to patients the seriousness of the disease and its symptoms is a critical component of therapy
    Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2006. Available at: http://www.goldcopd.org. Accessed November 15, 2006.
  • COPD should be suspected in all patients with a history of smoking, who are over the age of 40, and present with any of the key symptoms outlined on this slide
    Other risk factors may contribute to the disease, including environmental exposures such as occupational dust and chemicals, genetic factors, and indoor or outdoor air pollution
    Typically patients with risk factors will present with shortness of breath and chronic cough with or without sputum. This increased effort to breathe leads to fatigue and ultimately impacts usual activities, such as stair climbing, getting the daily mail, and doing housework
    Guidelines established by GOLD, ATS/ERS, and other authorities state that a diagnosis of COPD should be considered in any patient who has cough, sputum production, or dyspnea, and/or a history of exposure to risk factors for COPD1-3
  • Current guidelines cite ambitious but largely achievable goals to ameliorate the impact of COPD
    Aggressive treatment is warranted due to the progressive nature of COPD and the fact that many cases are not diagnosed until the disease is well beyond the early stage
    Lack of awareness of the disease progression and its impact on overall health can have significant consequences for patients seeking treatment, for diagnosis, and on subsequent compliance with therapy
    For this reason, communicating to patients the seriousness of the disease and its symptoms is a critical component of therapy
    A comprehensive treatment approach to COPD management is warranted, including smoking cessation, pharmacotherapy, and nonpharmacologic interventions
  • In the peripheral airways of patients with COPD, there is airflow limitation due to a variable mixture of loss of alveolar attachments, obstruction of the airway due to inflammation, airway-wall fibrosis, and airway smooth muscle constriction, as well as luminal obstruction with mucus1,2
    1. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med. 2000;343:269-280. 2. Barnes PJ. Small airways in COPD. N Engl J Med. 2004;350:2635-2637.
  • Mr. Carter: smoking cessation
  • This comparison of 50 patients with COPD to 25 healthy adults illustrates that the patients with COPD had significantly decreased pulmonary function and quadricep muscle function
    The patients with COPD also had a diminished ability to exercise as measured by a 6-minute walking distance test and a cycle ergometry maximal workload test that included measurement of peak oxygen uptake
    The 6-minute walking distance is one common way to quantify exercise endurance
    The diminished ability of patients with COPD to exercise can also lead to the development of other comorbidities
    In this study the COPD group had increased obesity, back pain most days, osteoporosis, diabetes, stable heart disease, hypertension, arthritis, vascular disorders, and depression
  • Stages of COPD: classified by severity
  • The slide represents a summary of all the aforementioned concepts.
    As destruction of the parenchyma and airflow limitation progresses, hyperinflation and gas trapping increase.
    These mechanical derangements lead to breathlessness upon exertion and eventually while at rest, as well as diminished ability to participate in physical activities.
    Patients decrease their activity as a result of the unpleasant sensation of dyspnea and as a result become deconditioned, which leads to further impairment in exercise tolerance because of the high oxygen requirements of deconditioned muscles.
    As the effects on the lungs progress, dyspnea will become present with minimal effort or even at rest.
    Ultimately, quality of life will deteriorate to the point at which patients may become oxygen-dependent and finally completely immobilized.
    Exacerbations are periodic worsenings of COPD and are more common as the disease progresses.
  • Bronchodilators in Stable COPD
    The use of bronchodilators for the treatment of COPD is central to symptom management, and an inhaled bronchodilator is preferred to systemic therapy. Bronchodilator therapy should be prescribed on an as-needed or regular basis to prevent or reduce the symptoms of COPD. Many patients find long-acting bronchodilators to be more convenient than regular treatment with short-acting agents.
    Combinations of bronchodilators with different mechanisms and durations of action may improve the degree of bronchodilation and reduce the risk of side effects over increasing the dose of a single agent.
    National Heart, Lung, and Blood Institute. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2003. Available at: www.goldcopd.com. Accessed March 24, 2004.
  • Need to add more as to what these mean
    Formoterol combines the benefits of a long duration of effect with a rapid onset of action. By contrast, salmeterol has a delayed onset of action but a similarly long duration of effect.
    Because formoterol is a full receptor agonist, it has greater potency than salmeterol — a partial receptor agonist.
    Unlike salmeterol, the effects of formoterol are dose–dependent; therefore, increasing the dose will result in greater effects.
    These properties make formoterol a more versatile treatment than salmeterol for patients with asthma.
  • Over the course of 169 days, FEV1 was measured after administration of tiotropium and salmeterol. Differences between these 2 treatments were observed during a 12-hour period. Both bronchodilators yielded a similar increase in FEV1 after initial administration. As the study progressed, differences between tiotropium and salmeterol increased, and tiotropium was found to be superior (P&amp;lt;.05 for tiotropium vs salmeterol on day 169).
  • Sin et al collected data from several trials and reviews conducted from 1980 to 2002. A compilation of these data was used to evaluate various interventions used for patients diagnosed with COPD. A meta-analysis was done on the data from 7 clinical trials that studied the effects of LABAs on the quality of life of patients with COPD (the 5 shown here used the SGRQ to measure QoL). LABAs began to be used in an effort to improve lung function in a longer-lasting and more predictable way than had been possible with the use of short-acting 2-agonists. The SGRQ is a standardized, self-completed questionnaire for measuring impaired health and perceived well-being (QoL) in airway disease. It has been designed to allow comparative measurements of health among patient populations and to quantify changes in health following therapy. Note that a negative score on the SGRQ is an indicator that health has shown improvement with the use of LABAs compared with placebo. Utilizing this questionnaire in studies performed by Wadbo et al (N=183), Chapman et al (N=408), Jones et al (N=326), Rossi et al (N=854), and Dahl et al (N=780), demonstrated improved quality of life for patients diagnosed with moderate-to-severe COPD who used LABAs versus placebo.
    Main point: Using SGRQ scores, several studies demonstrate improved quality of life for patients diagnosed with moderate to severe COPD with the use of LABAs versus placebo.
  • HRQoL was based on total scores obtained from the SGRQ. The ipratropium and tiotropium groups had similar SGRQ scores at baseline, which decreased during the course of 1 year’s treatment. The score approached baseline in the ipratropium group, but continued improvements were shown in the tiotropium group.
  • Sin et al collected data from several trials and reviews conducted during the years from 1980 to 2002. Compilation of this data was used to evaluate various interventions used for individuals diagnosed with COPD. A meta-analysis was done on the data from 7 clinical trials which studied the effects of long-acting β2-Antagonists (LABAs) on the relative risk of exacerbations for individuals with COPD. LABAs began to be used in an effort to improve lung function in a longer lasting and more predictable manner than what was currently being produced by using short-acting β2-Antagonists. Data from Wadbo et al (N=183), van Noord et al (N=144), Chapman et al (N=408), Rossi (N=854), Dahl et al (N=780), Aalbers et al (N=687), Rennard et al (N=405), and Mahler et al (N=411) combined to show a 21% reduction in exacerbation rates associated with use of LABAs as compare to placebo for individuals with moderate to severe COPD, relative risk of exacerbation ranging from 0.13 to 1.88 (95% confidence interval, 10%-31%).
    Sin et al performed a meta-analysis of data from 8 trials of patients with moderate to severe COPD that assessed how long-acting β2- Agonists (LABA) affect exacerbations. The overall reduction in COPD exacerbation rates calculated with the data from Wadbo et al, vanNoord et al, Chapman et al, Rossi et al, Dahl et al, Aalbers et al, Rennard et al, and Mahler et al was 21% (95% CI, 10%-31%).
  • Changes in FEV1 induced by once- (qd) or twice-daily (bid) formoterol 12 µg (FORM) when added to maintenance therapy with TIO 18 µg (2-week therapy)
  • Management of COPD exacerbations is dependent upon the resolution versus nonresolution of signs and symptoms.
    GOLD is a collaborative project of NHLBI and WHO. Guidelines for the management of exacerbations of COPD have been recommended for use in clinical environments in which individuals can be reassessed in a timely manner in order to improve prevention and management of COPD. After initiation or increase in bronchodilator therapy and antibiotic consideration, the patient should be reassessed within hours. If resolution or improvement of signs and symptoms is noted at that time, management should be continued and stepped down if possible. Long-term management is then reviewed. If at reassessment no resolution or improvement is noted, oral corticosteroids should be added to the treatment regimen, with a second assessment done within hours. If at that time worsening of signs and symptoms is noted, the patient should be referred to the hospital.
  • This chart shows recommended treatment guidelines as developed by GOLD1
    The stages of COPD are based on a patient’s spirometry
    Both ATS/ERS and GOLD guidelines recommend long-acting bronchodilators as preferred treatment when needed for management of moderate COPD1,2
    Albuterol PRN alone in moderate COPD may not provide adequate control1-3
    Despite development of evidence-based management guidelines for COPD, many patients are not receiving recommended treatment4
    Inhaled corticosteroids should be reserved for patients with severe disease and repeated exacerbations
    Pulmonary rehabilitation reduces symptoms, improves quality of life, and increases physical and emotional participation in daily activities. Patients with COPD at all stages of disease benefit from exercise training programs, which improve exercise tolerance and symptoms of dyspnea and fatigue
    It is important to remember that COPD is a preventable, treatable, and partially reversible disease. Regarding pharmacologic treatment, both the ATS and GOLD guidelines recommend long-acting bronchodilators as preferred treatment for the management of moderate COPD1,2
  • COPD

    1. 1. Improving Patient Outcomes in COPD James F. Donohue, MD Professor of Medicine Division Chief, Pulmonary & Critical Care Medicine University of North Carolina at Chapel Hill
    2. 2. 70 0 60 50 30 Sports & Recreation Normal Physical Exertion Social activities Sleeping Household Chores Sex Life 40 Family Activities 20 10 Some A lot 19% 41% 26% 29% 18% 17% 19% 15% 19% 18% 11% 15% 16% 13% % P17. How much do you feel your respiratory condition limits what you can do in each of the following areas? n=3265 Rennard ERJ 2002 COPD Limits Normal Daily Activities
    3. 3. • Patients may misunderstand or minimize symptoms such asPatients may misunderstand or minimize symptoms such as fatigue, dyspnea, cough. They may neglect to mention thesefatigue, dyspnea, cough. They may neglect to mention these symptoms to the physiciansymptoms to the physician • Misperception and denial are significant barriers to diagnosisMisperception and denial are significant barriers to diagnosis and managementand management • Symptoms may be misattributed to “asthma” or “getting older”Symptoms may be misattributed to “asthma” or “getting older”  ““I’ve been coughing when I wake up each morning, but it’s justI’ve been coughing when I wake up each morning, but it’s just smoker’s cough. This is normal and not harmful to my health.”smoker’s cough. This is normal and not harmful to my health.”  ““Carrying these groceries is harder than it used to be. I must beCarrying these groceries is harder than it used to be. I must be old and out of shape,”old and out of shape,” GOLD. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Report. Updated 2006. Available at: http://www.goldcopd.org. COPD: Patient MisperceptionsCOPD: Patient Misperceptions
    4. 4. Diagnosing COPD: Risk Factors and SymptomsDiagnosing COPD: Risk Factors and Symptoms Risk FactorsRisk Factors • History of smoking or exposure to other risk factorsHistory of smoking or exposure to other risk factors1-31-3 – 80% to 90% of all COPD occurrences are attributable to smoking80% to 90% of all COPD occurrences are attributable to smoking44 • Male or femaleMale or female >>40 years of age40 years of age1-51-5 OtherOther • Exposure to occupational dusts andExposure to occupational dusts and chemicals,chemicals, indoor andindoor and outdooroutdoor airair pollution,, and infectionspollution,, and infections11 • Socioeconomic statusSocioeconomic status11 SymptomsSymptoms • Dyspnea /exercise intolerance /fatigueDyspnea /exercise intolerance /fatigue11 • Chronic cough with or without sputumChronic cough with or without sputum1-31-3 • Reduction in activities of daily livingReduction in activities of daily living 1. GOLD. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Report. Updated 2006. Available at: http://www.goldcopd.org. 2. O’Donnell DE et al. Can Respir J. 2003;10:183-185. 3. Celli BR et al. Eur Respir J. 2004;23:932-946. 4. CDC. The health consequences of smoking: A report of the Surgeon General. 2004;4:463-509. Available at: http://www.cdc.gov/tobacco/sgr/sgr_2004/chapters.htm 5. Initiative for Chronic Obstructive Lung Disease. Available at: http://www.goldcopd.org/Guidelineitem.asp?l1=2&l2=1&intId=989. Accessed January 29, 2007.
    5. 5. GOLD. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease Report. Updated 2006. Available at: http://www.goldcopd.org. • Relieve symptoms • Prevent disease progression • Improve exercise tolerance • Improve health status • Prevent and treat complications • Prevent and treat exacerbations • Reduce mortality Smoking cessation Pharmacotherapy Nonpharmacologic interventions Management ApproachTreatment Goals Comprehensive TreatmentComprehensive Treatment Approach to COPDApproach to COPD
    6. 6. COPD and Comorbid Disease From Holguin and Mannino; Chest 2005 Hospitalizations In-hospital Deaths Ischemic Heart Disease Congestive Heart Failure Pneumonia COPD No COPD 0 5 10 15 1979 - 1983 1984 - 1987 1988 - 1991 1992 - 1995 1996 - 2001 0 5 10 15 0 5 10 15 20 0 10 20 30 40 1979 - 1983 1984 - 1987 1988 - 1991 1992 - 1995 1996 - 2001 0 10 20 30 40 50 0 5 10 15 20 25 0 5 10 15 0 10 20 30 40 50 0 5 10 15 20 25
    7. 7. Depression and COPD • DSM criteria: – subjective report of depressed mood – loss of interest or pleasure in activities – plus 4 specific complaints • Overlap between symptoms of depression and COPD (fatigue, sleep, appetite) • Best estimate of prevalence: 25-50% – 42% NETT Trial • Impact: Decreased functional performance, lowers QOL scores, reduces adherence, delay timely care • Inadequate recognition and treatment
    8. 8. Conclusions • COPD is an important and, frequently, underdiagnosed disease • The costs of COPD, at both the personal and societal levels, are enormous • COPD affects more than just the lungs
    9. 9. 0 50 100 150 200 250 20% 40% 60% 80% 100% Lumen Content / Lumen Area (%) Frequency GOLD 4 Airways fully expanded Airways at minimal volume N=42 cases, 531 airways GOLD 4
    10. 10. 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 COPDMechanisms of Airflow Limitation in COPD
    11. 11. COPD Risk and Smoking Cessation Never smoked orNever smoked or not susceptiblenot susceptible to smoketo smoke Stopped smoking at 45 (mild COPD) Stopped smoking at 65 (severe COPD) Smoked regularly and susceptible to effects of smoke Disability Death Age (years) 25 50 75 0 25 50 75 100 FEV1(%ofValueatAge25) Adapted from Fletcher et al. Brit Med J. 1977;1:1645-1648.
    12. 12. What is Disease Modification? 1. Change in decline in FEV1 2. Any change in a metric that is maintained over time.
    13. 13. Lung Health Study: Results Mean Postbronchodilator FEV1 for Sustained Quitters and Continuous Smokers Receiving Smoking Intervention and Placebo Anthonisen NR et al. JAMA. 1994;272:1497-1505. Mean Postbronchodilator FEV1 for All Participants Sustained Quitters Continuing Smokers Follow-Up (Years)Follow-Up (Years) MeanFEV1(L) PostbronchodilatorFEV1(L) 2.80 2.75 2.70 2.65 2.60 2.55 2.50 2.45 2.9 2.8 2.7 2.6 2.5 2.4 Screen 2 1 2 3 4 5 Screen 2 1 2 3 4 5 SIP SI + Ipratropium UC
    14. 14. Techniques for COPD Assessment • Physiological parameters • Dyspnea • Patient Reported Outcomes • Multidimensional Indexes • Exacerbations • Impact of Disease Modifying Therapies
    15. 15. 00 22 44 66 88 1010 1212 33 22 11 00 LungVolume(L) Exercise Time (minutes) O’Donnell. AJRCCM 1999;160:545 TLC IRVIRV VVTT IC Ipratropium Bromide Deflation - IC
    16. 16. Dyspnea Instrument Type Scores • MRC scale Category scale 5 grades • UCSD SOB 24 items related to 0 to 120 activities of daily living • TDI Multidimensional -9 to +9
    17. 17. Multidimensional Indices in the Assessment of COPD Progression • COPD is associated with clinical manifestations not closely related to FEV1: dyspnea, exercise intolerance, malnutrition, pulmonary hypertension, peripheral muscle weakness. • Many of the above influence mortality more strongly than airflow obstruction • Can multidimensional indexes that includes non- pulmonary factors predict mortality and assess the effect of interventions better than FEV1 alone?
    18. 18. Adapted with permission from Pitta F et al. Am J Respir Crit Care Med. 2005;171:972-977. Pulmonary Function Test and Exercise Capacity:Pulmonary Function Test and Exercise Capacity: Patients With COPD vs Healthy AdultsPatients With COPD vs Healthy Adults COPDCOPD (n=50)(n=50) HealthyHealthy (n=25)(n=25) Pulmonary FunctionPulmonary Function FEV1 (% pred.)FEV1 (% pred.) FVC (% pred.)FVC (% pred.) 43 ± 1843 ± 18 87 ± 2287 ± 22 111 ± 20111 ± 20 118 ± 19118 ± 19 pp <.0001<.0001 pp <.0001<.0001 Muscle FunctionMuscle Function Quadriceps Force (% pred.)Quadriceps Force (% pred.) 56 ± 1956 ± 19 106 ± 31106 ± 31 pp <.0001<.0001 Exercise CapacityExercise Capacity 6-minute Walk Distance (% pred.)6-minute Walk Distance (% pred.) Maximal Workload (% pred.)Maximal Workload (% pred.) Peak Oxygen Uptake (% pred.)Peak Oxygen Uptake (% pred.) 62 ± 2262 ± 22 49 ± 2349 ± 23 55 ± 2555 ± 25 98 ± 1098 ± 10 120 ± 29120 ± 29 113 ± 36113 ± 36 pp <.0001<.0001 pp <.0001<.0001 pp <.0001<.0001
    19. 19. Celli et al, NEJM 2004:350:1005-12 The Body - Mass Index, Airflow Obstruction, Dyspnea and Exercise Capacity (BODE) index in COPD
    20. 20. BODE Score and Probability of Survival FEV1 and Probability of Survival: FEV1 > 50%, FEV1 < 50 % > 36 %, FEV1 < 35%
    21. 21. COPD Stages Stage Lung function Manifestations I: Mild FEV1/FVC < .70 FEV1 ≥ 80% predicted With or without chronic cough and sputum production II: Moderate FEV1/FVC < .70 50% < FEV1 < 80% predicted Chronic cough and sputum production Dyspnea on exertion III: Severe FEV1/FVC < .70 30% < FEV1 < 50% predicted Chronic cough and sputum production Increased dyspnea Repeated exacerbations IV: Very severe FEV1/FVC < .70 FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure Signs and symptoms of chronic respiratory failure (PaO2 < 60 mm Hg with or without PaCO2 > 50 mm Hg, with or without signs of cor pulmonale) Celli BR et al. Eur Respir J. 2004;23:932–946. Global Initiative for Chronic Obstructive Lung Disease. Available at: http://www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=989. Accessed February 1, 2007.
    22. 22. Dyspnea Exercise Tolerance Consequences of Airflow Limitation in COPD Exacerbations Airflow Limitation, Lung Hyperinflation, Gas Trapping Decline in Lung Function Deterioration in Health Status Premature Mortality Inactivity Deconditioning
    23. 23. ERS/ATS Algorithm for Pharmacologic Treatment in COPD Confirm Dx of COPD SA-BD p.r.n. LA-BD/SA-BD q.i.d. with rescue Alternative class/combination (LA-BD/ICS) Add/substitute oral theophylline Limited Benefit? Limited Benefit? AE? Yes Yes Adapted from Celli et al. Eur Respir J. 2004;23:932-946. ICS, inhaled corticosteroid; LA-BD, long-acting bronchodilator; SA-BD, short-acting bronchodilator. Intermittent Sx (cough, wheeze, dyspnea) Persistent Sx (dyspnea, pm awakenings)
    24. 24. Objectives of COPD Management • Prevent disease progression • Relieve symptoms • Improve exercise tolerance • Improve health status • Prevent and treat exacerbations • Prevent and treat complications • Reduce mortality • Minimize side effects from treatment
    25. 25. Bronchodilators in Stable COPD • Bronchodilator medications are central to the symptomatic management of COPD (Evidence A). They are given on an as-needed basis or on a regular basis to prevent or reduce symptoms. • The principal bronchodilator treatments are beta2- agonists, anticholinergics, theophylline, and a combination of these drugs (Evidence A). • Long-acting inhaled bronchodilators are more convenient (Evidence A) . • Combinations of bronchodilators may improve efficacy and reduce risk of side effects vs. increasing dose of a single agent GOLD Guidelines, 2003
    26. 26. Current Bronchodilator Options for COPD Bronchodilators Short-acting Long-acting β-agonists: Albuterol Levalbuterol Terbutaline Pirbuterol Anticholinergic: Ipratropium Oxitropium β-agonists: Salmeterol Formoterol Anticholinergic: Tiotropium Methylxanthine: Theophylline Fixed Combination Albuterol + ipratropium Budesonide + formoterol Fluticasone + salmeterol
    27. 27. Pre-ganglionic nerve Parasympathetic ganglion Post-ganglionic nerve ACh Airway smooth muscle Nicotinic receptors (+) M1 receptors (+) M2 receptors (–) M3 receptors (+) Muscarinic Receptor-Drug Complex Half-Life: Tiotropium vs Ipratropium M1 : 14.6 ± 2.2 h vs 0.11 ± 0.005 h M2 : 3.6 ± 0.5 h vs 0.035 ± 0.005 h M3 : 34.7 ± 2.9 h vs 0.26 ± 0.02 h Barnes PJ. Physiol Rev. 1992;72:699-729; Disse B et al. Life Sci. 1999;64:457-464. Anticholinergics in COPD
    28. 28. ß2-AR A ACh M3 M3 M3 M3 M3M1 M1 ß2-AR agonist ß2-AR Anticholinergic agent Cazzola et al, Arch Bronconeumol 2004;41(Supl 2):24-31 Schematic presentation of the potential alternative role of ß2- adrenoceptor (AR) in the pre-synaptic control of acetylcholine (ACh) release from airway parasympathetic nerve endings. A, circulating adrenaline; ß2-AR, ß2-adrenoceptor; M1 and M3, muscarinic M1 or M3 receptors; , neuronal activity; , stimulatory effect; , inhibitory effect
    29. 29. Rationale for Use of Bronchodilators in COPD • 1) Physiologic Effects – a) ASM relaxation – Bronchodilation: FEV1 – Decreased air trapping and dynamic hyperinflation – b) Non-bronchodilator Effects (LABAs, Theophylline) • 2) Clinical Effects ↓ Breathlessness (↓ Raw, ↓ hyperinflation) ↑ Exercise tolerance (↓ dynamic hyperinflation) ↑ Sleep quality (↓ nocturnal bronchospasm) ↑ Health-related quality of life ↓ Frequency of acute exacerbations Mahler DA. J Allergy Clin Immunol 2002:110:S298 – S303 Tashkin DP, Cooper CB. Chest 2004; 125:249 – 259 Sin DD, et al. JAMA 2003; 290:2301 - 2312
    30. 30. Short-term FEV1 Response to Bronchodilator Therapy is Variable and May Underestimate Long-term Response Study population: 660 patients meeting both ERS and ATS criteria for irreversible COPD, 40-75 years of age, current or ex-tobacco smokers. Calverley PM, et al. Thorax. 2003;58:659-664. N = 660 385 287 213 48 121 75 51 Visit 0: 58% Visit 1: 62% Visit 2: 59% 275 98 74 50 46 154 103 = Positive responders = Negative responders 52% of patients changed bronchodilator responder status over a 2-month period Total % not reversible at each visit
    31. 31. 73% of patients show reversibility* 27% 11% (n = 280) 27% 35% *Reversibility defined as ≥12% and > 200 mL increase in FEV1 N = 815 Both Neither Albuterol only Ipratropium only (n = 217) (n = 222) (n = 91) Donohue JF, et al. Chest 2004; 125;125S – 137S Lack of Short-Term Response to One Class of Drug Does Not Imply Nonresponsiveness to Another Class
    32. 32. Post-bronchodilator Lung Volume Changes are More Sensitive Indicators of Response in Patients With “Irreversible” Emphysema Changefrombas *P<0.05. * * * * * * * * * 0.09 0.08 0.10 -0.37 -0.27 -0.51 -0.31 -0.21 -0.45 -1 -0.5 0 0.5 1 All Patients Moderate Severe FEV1 RV FRC O’Donnell DE, et al. Eur Respir J. 2001;18:914-920.
    33. 33. Chemical Structures of LABAs Formoterol: medium side chain CH3 OH N H O CHCH2NHCHCH2 H O OH CH3 CHOH OH Salmeterol: long side chain CHCH2NH 2 OH OCH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2
    34. 34. Formoterol and Salmeterol: Comparison of Pharmacologic Properties Formoterol • Long duration (>12 hours) • Rapid onset of action • Greater potency, binding affinity, and intrinsic activity • Full receptor agonist • Intermediate lipophilicity • Selective for ß2 receptor Salmeterol • Long duration (>12 hours) • Delayed onset of action • Partial receptor agonist • High lipophilicity • More selective for ß2 receptor
    35. 35. 0.4 0.3 0.2 0.1 0 -0.1 * ** * * * * * All Patients Day 84 *P < 0.001 salmeterol vs baseline and placebo. FEV1 Change From Baseline (L) Salmeterol 1.36 L Ipratropium 1.18 L Placebo 1.31 L 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hours) Mahler DA et al. Chest. 1999;115:957-965. Salmeterol: Effects on Lung Function in COPD
    36. 36. Effect of Tiotropium and Salmeterol on FEV1 in COPD *P<.05 for day 169. Donohue et al. Chest. 2002;122:47-55. Tiotropium (day 1) Salmeterol (day 1) Tiotropium (day 169)* Salmeterol (day 169)* -1 0 1 2 3 4 5 6 7 8 9 10 11 12 1.35 1.30 1.25 1.20 1.15 1.10 1.05 1.00 0.95 FEV1(L) Time After Administration (h)
    37. 37. Formoterol vs Tiotropium: Formoterol Has Faster Onset of Bronchodilation 1.3 1.4 1.5 1.6 1.7 1.8 0 60 120 180 240 300 360 420 480 540 600 660 720 Time (min) FEV1(mL) Form 12 µg bid Tio 18 µg od AUC FEV1 0-2 hours; Formoterol +114 mL vs tiotropium (p=0.014) Richter et al, Respiration 2006;73:414-419
    38. 38. Improvement in QoL with LABAs vs Placebo -8.0-8.0 -6.0-6.0 -4.0-4.0 -2.0-2.0 00 2.02.0 4.04.0 Adapted from Sin et al. JAMA. 2003;290:2301-2312. -10.0-10.0 6.06.0 8.08.0 10.010.0 SGRQ Reference Wadbo et al, 2002 Chapman et al, 2002 Jones et al, 1997 Rossi et al, 2002 Dahl et al, 2001 Overall Change in SGRQ
    39. 39. Improvement of Health Status with Tiotropium • Tiotropium vs ipratropium – 535 patients randomized (FEV1 42% predicted) – 443 completed SGRQ – 18 µg tiotropium qd vs 40 µg ipratropium qid – Multicenter, 1-year trial Vincken et al. Eur Respir J. 2002;19:209-216. SGRQTotalScore Test Day 46 44 42 40 38 0 100 200 300 400 Tiotropium (n=302) Ipratropium (n=141) * *4 unit ∆ SGRQ=clinical significance.
    40. 40. Exacerbations in COPD Patients Decreased by Tiotropium Adapted from Barr et al. Cochrane Database of Systematic Reviews. 2005, Issue 2 Reference Beeh et al. 2004 Brusasco et al. 2003 Calverley et al. 2003 Casaburi et al. 2002 Celli et al. 2003 Littner et al. 2000 Niewoeher et al. 2004 O’Donnell et al. 2004 Vincken et al 2002 Overall 0.5 1.0 5.0 10.0 Odds Ratio
    41. 41. Bronchodilators in COPD: Combination vs. Monotherapy CombinationCombination FEVFEV11 SymptomsSymptoms ExacerbationsExacerbations MortalityMortality SideSide effectseffects SABA + SAAC SABA + Theophylline LABA + SAAC LABA + Theophylline LAAC + SABA LAAC + LABA ↑ ↑ ↑ ↑ ↑ ↑ ↓ ↓ ↓ ↓ ↓ ↓ ↓ +/- ? ? ? ? - +/- ? ? ? ? - ↑ - +/- - - Donohue JF. Proc Am Thorac Soc 2005; 2:272 - 281
    42. 42. Ipratropium + Albuterol (n = 173) Albuterol (n = 165) Ipratropium (n = 176) Improvement in FEV1 with Short-acting Bronchodilators – Combination vs. Single Agent Percentage Changes in Mean FEV1 from Test Day Baselines Combivent Inhalation Aerosol Study Group. Chest. 1994;105:1411-1419. 40 35 30 25 20 15 10 5 0 -5 40 35 30 25 20 15 10 5 0 -5 PercentageChange PercentageChange 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Test Day 1 Test Day 85
    43. 43. COPD: Salmeterol + Theophylline 0 1 2 Theophylline Salmeterol S+T TDI(changefrombaseline) ZuWallack CHEST 2001,119:1661
    44. 44. Tiotropium Plus Formoterol 0.9 1.0 1.1 1.2 1.3 1.4 1.5 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours) FEV1(L) Tiotropium qd + formoterol qd Tiotropium qd + placebo bid Tiotropium qd + formoterol bid 9 AM 9 PM 3 AM 9 AM3 PM 24-h baseline Mean FEV1 Before (24-hour baseline) and After 2 wks of Treatment (Day 14) Van Noord et al, Chest 2006;129:509-17
    45. 45. -50 0 50 100 150 200 250 300 350 0 2 4 6 8 12 16 20 24 FEV1(mL)LABA + ICS in COPD Endpoint‡ (6%) * (14%) † (19%) (27%) Time (weeks) * P<0.001 FP/Sal vs placebo and FP/Sal vs FP. † P<0.001 salmeterol vs placebo. ‡ Last evaluable FEV1. Hanania et al. Chest. 2003;124:834-843. Placebo SAL FP 250 FP/Sal 250/50
    46. 46. ICS and Mortality: Pooled Survival Sin et al., Thorax 2005; 60:992-7.
    47. 47. Do ICS Slow the Decline in FEV1? - Summary AnalysisDo ICS Slow the Decline in FEV1? - Summary Analysis Multiple ICS/placebo controlled trials of 2-3 yearsMultiple ICS/placebo controlled trials of 2-3 years durationduration Primary outcome (Primary outcome (∆∆ slope of FEVslope of FEV11 with time)with time) negative in allnegative in all Two meta-analyses suggest possibility that ICSTwo meta-analyses suggest possibility that ICS might have small effect in slowing rate of decline inmight have small effect in slowing rate of decline in FEVFEV11 5.0 ml/yr (95% CI, -1.2 to 11.2 )5.0 ml/yr (95% CI, -1.2 to 11.2 ) Highland, et al. Ann Intern Med 2003;138:969Highland, et al. Ann Intern Med 2003;138:969 7.7 ml/yr (95% CI, 1.3 to 14.2)7.7 ml/yr (95% CI, 1.3 to 14.2) Sutherland, et al. Thorax 2003;58:937Sutherland, et al. Thorax 2003;58:937
    48. 48. Wilt T, Niewoehner DE, Kim C, et al.Wilt T, Niewoehner DE, Kim C, et al. AHRQ Report 05-E017-2, 2005AHRQ Report 05-E017-2, 2005 Relative risk (95% CI) ofRelative risk (95% CI) of >> 1 exacerbation1 exacerbation 0.20.2 110.50.5 22 55 BurgeBurge Calverley 1Calverley 1 MahlerMahler van der Valkvan der Valk PaggiaroPaggiaro SubtotalSubtotal BourbeauBourbeau Calverley 2Calverley 2 SzafranskiSzafranski VestboVestbo SubtotalSubtotal FluticasoneFluticasone BudesonideBudesonide WeirWeir SubtotalSubtotal TotalTotal BeclomethasoneBeclomethasone 0.83 (0.74 - 0.94)0.83 (0.74 - 0.94) Favors ICSFavors ICS Favors PlaceboFavors Placebo Prevention of Exacerbations – Inhaled Corticosteroids
    49. 49. Aaron S, ATS Poster, 2006Aaron S, ATS Poster, 2006 00 22 00 44 00 66 00 88 00 TiotropiumTiotropium TiotropiumTiotropium ++ SalmeterolSalmeterol TiotropiumTiotropium ++ SalmeterolSalmeterol ++ FluticasoneFluticasone % patients with% patients with >> 1 exacerbation1 exacerbation 156 148 145 Prevention of Exacerbations – Canadian Optimal Therapy Trial
    50. 50. 00 0.010.01 0.020.02 0.030.03 0.040.04 0.050.05 0.060.06 0.070.07 0.080.08 PlaceboPlacebo SALSAL FPFP SAL+FPSAL+FP Annualized rateAnnualized rate perper treatment yeartreatment year Celli B, et al. ERSCelli B, et al. ERS Poster, 2006Poster, 2006 Effect of Fluticasone on Pneumonia Rate in TORCH
    51. 51. Definition • Defined as change in patient’s symptoms beyond daily variations sufficient to cause a change in therapy • Causes can be infectious and non-infectious • Usual therapy includes bronchodilators, steroids, oxygen and sometimes antibiotics ATS/ERS Statement ERJ 2004; 23:932-946
    52. 52. Donaldson & Wedzicha Thorax 2006;61:164 Exacerbation Rate by FEV1 0 1 2 3 <1.25 1.25- 1.54 >1.54 2.40 2.5 Baseline FEV1 ExacerbationsperYear
    53. 53. 0 10 20 30 40 50 60 70 80 90 100 Total Symptoms Activities Impacts SGRQscore * p < 0.05 0–2 exacerbations/year 3–8 exacerbations/year * * * * WORSE BETTER Seemugal et al AJRCCM 1998 Effect of Exacerbations of Patient’s Quality of Life
    54. 54. COPD Exacerbations: Healthcare Resource Use • 0.9% of all 11.7 million hospital admissions* • 2.4% of all 4.2 million acute medical admission* • Admissions due to COPD 13.1 % (1998 to 2003)* • Length of stay: 10 days (mean)* • 1001 pts in 201 practices**: Median: 2 exacerbations per year * Donaldson GC, Wedzicha J. Thorax 2006 (England) ** Miratvilles M, Thorax 2006 (Spain)
    55. 55. Management Algorithm for COPD Exacerbations Initiate or Optimize Bronchodilator Therapy Consider Antibiotics Initiate or Optimize Bronchodilator Therapy Consider Antibiotics Reassess Within HoursReassess Within Hours Resolution or Improvement of Signs and Symptoms Resolution or Improvement of Signs and Symptoms Continue Management Step Down When Possible Continue Management Step Down When Possible Review Long-term ManagementReview Long-term Management No Resolution or ImprovementNo Resolution or Improvement Add Oral CorticosteroidsAdd Oral Corticosteroids Reassess Within HoursReassess Within Hours Worsening of Signs/SymptomsWorsening of Signs/Symptoms Refer to HospitalRefer to Hospital Workshop Report, Global Strategy for Diagnosis, Management, and Prevention of COPD – 2005 Update. Available at: http://www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=989. Accessed June 6, 2006 (A).
    56. 56. Recommended Therapy at EachRecommended Therapy at Each Stage of COPDStage of COPD11 COPDCOPD StageStage FEVFEV11 InfluenzaInfluenza VaccinationVaccination Short-actingShort-acting BronchodilatorsBronchodilators Long-actingLong-acting BronchodilatorsBronchodilators InhaledInhaled GlucocorticosteroidsGlucocorticosteroids II MildMild FEVFEV11≥80% of≥80% of predictedpredicted √√ √√ IIII ModerateModerate 50%≤FEV50%≤FEV11<80% of<80% of predictedpredicted √√ √√ √√ IIIIII SevereSevere 30%≤FEV30%≤FEV11<50% of<50% of predictedpredicted √√ √√ √√ √√ IVIV Very SevereVery Severe FEVFEV11<30% of<30% of predictedpredicted or FEVor FEV11<50%of<50%of predictedpredicted plus chronicplus chronic respiratory failurerespiratory failure √√ √√ √√ √√ 1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (Updated 2006). Available at: http://www.goldcopd.org. Accessed April 25, 2007.

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