Overview of COPD

Overview of COPD
Lynn M. Keenan, MD, FACP, FCCP
Pulmonary/Critical Care Medicine
Northwest Hospital and Medical Center
WAPA
January 2013
Disclosures





Speakers Bureau Boehringer Ingelheim
I hate tobacco abuse
I am a old SNL and Seinfeld Fan
If you were here last year, I updated my jokes
I miss “The Closer”,
Closer”, doesn’t everyone?
everyone?
Clinical Course of COPD
COPD
COPD
Exacerbations
Expiratory Flow Limitation
Ai Trapping
Air
T
i
Hyperinflation
B thl
Breathlessness
Deconditioning
g
Inactivity
y
Reduced Exercise
Capacity
p
y
Poor Health-Related Quality of Life
Disability
Disease progression
Adapted from Decramer M. Eur Respir Rev. 2006;15:51-57.
Death
COPD
Definition and Epidemiology




GOLD: Global Initiative for Chronic Obstructive
Lung Disease
Goals: awareness,
awareness decrease mortality and
morbidity
Improve prevention and management
Systemic consequences: persistent systemic
inflammatory state leads to:

Decreased fatfat-free mass,
mass impaired systemic muscle
function, anemia, osteoporosis, depression,
pulmonary hypertension, cor pulmonale
COPD
Definition and Epidemiology








Largest disease burden
>age 40: 99-10 % adults, greater in men
Aff t 10% generall population
Affects
l ti and
d 50%
heavy smokers
> 80%
%p
pts. Under diagnosed
g
survey
y 8,215
,
p
pts.
16 million people with 110,000 deaths 2010
3rd leading cause of death 2011
3% mortality for hospital admission
50% mortality for ICU admission within 2 years
Predictors of COPD Mortality
•
•
•
•
•
•
•
•
•
•
High BODE index
Multiple severe exacerbations
CVD
Decreased FEV1
Dyspnea
H
Hyperinflation
i fl ti (IC/TLC ≤ 25%)
Pulmonary hypertension
I
Impaired
i dE
Exercise
i P
Performance
f
Depression
Low BMI
Clinical COPD –
p of the Iceberg
g
Tip
10 Million
2 Million,
Severe
Disease*
Disease
SUBCLINICAL COPD
Adapted from Mannino DM, et al. MMWR Morb Mortal Wkly Rep. 2002;51(SS06):1-16.
Airflow Limitation Starts Before
Symptoms are Evident
COPD
D fi i i and
Definition
d Epidemiology
E id i l





Women >
>er
er mortality
poorer prognosis with BMI off 25 and lower BODE
O
index
Faster decline in FEV1 has a modest increased
risk of death and time to COPD related
hospitalization
Severe COPD: increased mortality with more
advanced age, lower BMI, oxygen
supplementation, greater hyperinflation, also
patients at increased risk lung cancer,
atherosclerosis, and osteoporosis
P
Presence
off chronic
h i cough/sputum
h/
t
identifies
id tifi a
subgroup with higher risk of developing COPD,
independent of smoking habits
Question 1:
Q
Who is your average COPD patient?
The Marlboro man
 55 y
year old working
g woman
 85 yo man with ASCAD, and prostate
cancer
 80 yo retired Army thoracic surgeon

Who does COPD Affect?
Aunt Ann and my Dad.
Really?
My Aunt Carrie
Seriously?
It even looks like a fungus
COPD
Definition and Epidemiology



Risk Factors: cigarette smoking,
smoking, Marijuana,
alpha--1-antitrypsin deficiency, heavy
alpha
occupational dusts, biomass fuels and
chemical fumes, environmental tobacco
smoke, lung growth (viral, fetal exposure)
Caused by interaction of noxious inhaled
agents and host factors increasing
neutrophils and macrophages
Toxic gases generate cytokines and
chemokines control migration of inflammatory
immune
u e ce
cells,
s, leading
ead g to
o co
compromised
p o sed repair
epa
of lung structure and function, increased
apoptosis of endothelial and epithelial cells
COPD Mortality
Annual US
A
S Deaths
70000
60000
50000
40000
Male
30000
Female
20000
10000
0
1975
1980
1985
1990
1995
2000
Year
* Years after 2000 include adults aged ≥ 25y only
Mannino DM, et al. MMWR Morb Mortal Wkly Rep. 2002;51(SS-6):1-16.
Brown DW, et al. MMWR Weekly. 2008;57(45):1229-1232
2005
2010
COPD Immunology




Small airways:
y inflammatoryy cell infiltrate,,
remodeling thickens the airway and increases
resistance to flow
P
Prominent
i
iinflammatory
fl
iinfiltrates
fil
iin the
h
alveolar walls, destruction of alveoli, and
enlargement of air spaces
Inflammation mediated by TT-cells persists
after smoking cessation
Cigarette use increased oxidative stress
24
Lung Inflammation and Vascular Disease
Effects of Lung Inflammation on Blood Vessels
Tamagawa E et al. Chest. 2006;130:1631-1633.
Manifestations of COPD
• Emphysema: pathologic diagnosis
• Hyperinflation
• Mucus hypersecretion (chronic bronchitis)
• Frequent exacerbations
• Severe hypoxemia
• Low BMI
y
• Skeletal muscle dysfunction
Celli BR. Proc Am Thorac Soc. 2006;3:461-465.
Papaioannou AI, et al. Respir Med. 2009;103:650-660.
Increased Risk for Cardiovascular Disease in COPD
•
•
•
•
80
Retrospective
R
i study
d off Canadian
C di databases
d b
Subjects age ≥ 40 years
Diagnosed with COPD during 1997–2000
Received ≥ 2 Rx for dilators w/i 6 months
70.4
Perccent of Suubjects
70
60
54
COPD (N = 11,493)
Controls (N = 22,986)
50
40
31.3
30
22.8
21.1
20
11.7
10
11.2
6.4
9
5.6
96
9.6
11.2
7.9
3.2
0
Arrhythmia
y
Angina
g
Acute MI
CHF
Stroke
MI = myocardial infarction, CHF = congestive heart failure, CVD = cardiovascular disease; All
between-group differences P < 0.05 – adjusted for CV risk
Curkendall SM, et al. Ann Epidemiol. 2006;16:63-70.
Other CVD
CVD
Hospitalization
The Risk of Osteoporosis in Caucasians
With Obstructive Airways Disease
Percent o
of Subjectts with
Ostteoporosiss
35
30
33
Men
Women
P = 0.005 for trends
25
20.9
20
15
11
10.3
10
5
7.6
19
1.9
6.8
3.9
0
None
Mild
Moderate
Severity of Airflow Obstruction
Sin DD, et al. Am J Med. 2003;114:10-14.
Severe
Severe Obstructive Airway Disease Is
Associated With Greater Risk of Fracture
Osteoporotic fracture
Hip fracture
ICS - No
ICS - Yes
ICS - No
ICS - Yes
Vertebral fracture
ICS - No
ICS - Yes
0.2
*Adjusted
Adjusted in patients with severe COPD for general risk factors,
factors
smoking status, duration of enrollment, and exposure to
bronchodilators
de Vries F, et al. Eur Respir J. 2005;25:879-884.
0.5
1
2.0
Odds Ratio*
5.0
Skeletal Muscle Dysfunction
y
in COPD








L
Low
muscle
l mass
Poor capillarity
Low muscle oxidative
enzyme activity
Low fraction of type I fibers
Muscle inflammation
Corticosteroid myopathy
Low levels of anabolic
hormones
Vasoregulatory abnormalities
Maltais F, et al. Am J Respir Crit Care Med. 1996;153:288-293.
Lactate Increase
D i Exercise
During
E
i
VO2 (L/min)
Mechanisms of Muscle Wasting and
Cachexia
C h i iin COPD
Insulin
resistance
IGF-1
Muscle protein
breakdown
Muscle wasting
and cachexia
Negative
energy
balance
Hypoxemia
Steroid
treatment
Testosterone
Inflammation
Balasubramanian VP, Varkey B. Curr Opin Pulm Med. 2006;12:106-112.
Prroportion
n Survivin
ng
Low BMI Predicts
Increased Mortality
BMI (kg/m2)
■ > 29
● 24-29
✴ 20-24
▼ < 20
Months of Follow-up
p
•
•
•
Cox proportional hazards model
Low BMI was an independent predictor of increased mortality (P < 0.001)
quintiles,, the mortality
y risk was clearly
y
After stratification into BMI q
increased below 25 kg/m2
Schols AM, et al. Am J Respir Crit Care Med. 1998;157(6 Pt 1):1791-1797.
Prevalence
ev e ce of
o Depression
ep ess o in COPD
CO
 Overlap
between symptoms of depression and
COPD (fatigue, sleep, appetite)1
 Prevalence: 20%–60%1,2
 Impact
I
t3
– Decreased functional performance
– Lower QOL scores
 Inadequate recognition and treatment1
1. Kunik ME, et al. Chest. 2005;127:1205-1211.
2. Norwood R. Curr Opin Pulm Med. 2006;12:113-117.
3. Felker B, et al. Gen Hosp Psych. 2001;23:56-61.
Survivval Rate
Prognostic Impact of Pulmonary Hypertension
– – – mean PAP ≥ 25 mmHg
–––– mean PAP < 25 mmHg
PAP: pulmonary artery pressure
Kaplan-M
Meier Estim
mates
Survival time, months
mean PAP > 18 mmHg
mean PAP  18 mmHg
Years w/o Hospitalization for Exacerbation
Oswald-Mammosser M, et al. Chest. 1995;107:1193-1198.
The Majority of Patients with COPD
Are Among Working Age Population
Employees With COPD Incurred >4 Times
Higher Total Mean Healthcare Costs
Patients with COPD often have
M lti l Comorbid
Multiple
C
bid Conditions
C diti
Comorbid Conditions in Patients with COPD
Are More Likely to be Treated Than COPD
Mortality Associated With COPD
COPD Management







Prevent disease and progression
Relieve symptoms
Improve exercise tolerance
Improve health status
Prevent and treat complications
Treat exacerbations
R d
Reduce
mortality
li
The COPD Population Screener (COPD-PS)
1. During the past 4 weeks, how much of the time did you feel short of breath?
None of the
time
A little of
the time
0
Some of the
time
0
Most of the
time
All of the
time
2
1
2
2. Do you ever cough up any “stuff”, such as mucus or phlegm?
Only with
occasional
colds or chest
infections
No, never
eve
Yes, a few
days a
month
1
0
0
Yes, most
d
days
a
week
Yes,, everyy
day
2
1
3. Please select the answer that best describes you in the past 12 months,
I do less than I used to because of my breathing problems.
Strongly
disagree
Disagree
0
Unsure
Agree
Strongly
agree
0
1
2
0
4. Have you smoked at least 100 cigarettes in your ENTIRE LIFE?
No
Don’t know
Yes
2
0
0
5. How old are you?
Age 35 to 49
Martinez FJ, et al. COPD. 2008;5:85-95.
0
Age 50 to 59
1
Age 60 to 69
2
Age 70 +
2
Screening for COPD with Spirometry?
Current status
Symptom screening
Spirometry screening
1. Symptoms
2 Spirometry
2.
S i
t
Lin K, et al. Ann Intern Med. 2008;148(7):535-543.
Underrecognized
g
Overdiagnosis (other
causes of symptoms)
Overdiagnosis
(asymptomatic
healthy)
Appropriate diagnosis
Global Strategy for Diagnosis, Management and Prevention of COPD
Di
Diagnosis
i and
dA
Assessment:
t Key
K Points
P i t

A cclinical
ca d
diagnosis
ag os s o
of CO
COPD sshould
ou d be considered
co s de ed
in any patient who has dyspnea, chronic cough or
sputum production, and/or a history of exposure to
risk factors for the disease
disease.

Spirometry is required to make the diagnosis; the
presence off a postpostt-bronchodilator
b
h dil t FEV1/FVC < 0.70
0 70
confirms the presence of persistent airflow
limitation and thus of COPD.
Need a Quality Test
Spirometry:
p
y Obstructive Disease
Normall
Volu
lume, lite
ters
5
4
3
FEV1 = 1.8L
2
FVC = 3.2L
1
FEV1/FVC = 0.56
1
2
3
4
5
Ti
Time,
seconds
d
6
Obstructive
A- Restrictive
B- Normal
C- Obstructive
Flow volume loops:
N
Normal
l vs. COPD
:
Normal Flow volume loop vs.
COPD
MILD COPD
Severe COPD
Global Strategy for Diagnosis, Management and Prevention of COPD
Classification of Severity
y of Airflow
Limitation in COPD*
In patients with FEV1/FVC < 0.70:
GOLD 1: Mild
FEV1 > 80% predicted
GOLD 2: Moderate
50% < FEV1 < 80% predicted
GOLD 3: Severe
30% < FEV1 < 50% predicted
GOLD 4: Very Severe FEV1 < 30% predicted
*Based on Post-Bronchodilator FEV1
Global Strategy for Diagnosis, Management and Prevention of COPD
Assessment of COPD
 Assess symptoms
 Assess degree of airflow limitation
using
g spirometry
p
y
 Assess risk of exacerbations
Assess comorbidities
Use history of exacerbations and spirometry.
T exacerbations
Two
b i
or more within
i hi the
h llast year
or an FEV1 < 50 % of predicted value are
indicators of high risk
Global Strategy for Diagnosis, Management and Prevention of COPD
Assess Risk of Exacerbations
T assess risk
To
i k off exacerbations
b ti
use
history of exacerbations and
spirometry:
Two or more exacerbations within
the last year or an FEV1 < 50 % of
predicted
di t d value
l are indicators
i di t
off
g risk.
high
Global Strategy for Diagnosis, Management and Prevention of COPD
C bi d Assessment
Combined
A
t off COPD
 Assess symptoms
 Assess degree of airflow limitation using spirometry
 Assess risk of exacerbations
C bi th
Combine
these assessments
t ffor th
the purpose off
improving management of COPD
Global Strategy for Diagnosis, Management and Prevention of COPD
(C)
(D)
>2
(A)
(B)
1
3
2
1
0
mMRC 0-1
mMRC > 2
CAT < 10
CAT > 10
Symptoms
(mMRC or CAT score)
(Exaccerbation histtory)
4
Risk
(GOLD
D Classificattion of Airfllow Limitatiion)
Risk
Combined Assessment of COPD
Global Strategy for Diagnosis, Management and Prevention of COPD
Combined
Co
b ed Assessment
ssess e t of
o COPD
CO
Assess symptoms first
(C)
((A))
(D)
((B))
mMRC mMRC > 2
0-1
CAT > 10
Symptoms
CAT < 10
(mMRC or CAT score)
If mMRC 0-1 or CAT < 10:
Less Symptoms (A or C)
If mMRC > 2 or CAT > 10:
More Symptoms (B or D)
Global Strategy for Diagnosis, Management and Prevention of COPD
Combined Assessment of COPD
3
2
1
(C)
(D)
>2
((A))
((B))
mMRC 0-1 mMRC > 2
CAT < 10 CAT > 10
Symptoms
(mMRC or CAT score)
1
0
((Exacerbatioon history)
4
Rissk
(GOLD Claassification oof Airflow L
Limitation)
Rissk
Assess risk of exacerbations next
If GOLD 1 or 2 and only
0 or 1 exacerbations per year:
Low Risk (A or B)
If GOLD 3 or 4 or two or
more exacerbations per year:
High Risk (C or D)
Global Strategy for Diagnosis, Management and Prevention of COPD
Combined Assessment of COPD
3
2
1
(C)
(D)
>2
((A))
((B))
mMRC 0-1 mMRC > 2
CAT < 10 CAT > 10
Symptoms
(mMRC or CAT score)
1
0
(Exacerbatioon history)
4
Rissk
(GOLD Claassification oof Airflow L
Limitation)
Rissk
Use combined assessment
Patient is now in one of
four categories:
A: Les symptoms, low risk
B: More symtoms, low risk
C: Less symptoms,
y p
, high
g risk
D: More Symtoms, high risk
Global Strategy for Diagnosis, Management and
Prevention of COPD
Combined Assessment
of COPD
When assessing risk, choose the highest risk
according to GOLD grade or exacerbation history
Patien
t
Characteristic
Spirometric
Classification
Exacerbations mMRC
per year
CAT
A
Low Risk
Less Symptoms
GOLD 1-2
≤1
0-1
< 10
B
Low Risk
M
More
S
Symptoms
t
GOLD 1
1-2
2
≤1
>2
≥ 10
C
High Risk
Less Symptoms
GOLD 3-4
>2
0-1
< 10
D
High Risk
More Symptoms
GOLD 3-4
>2
>2
≥ 10
COPD Risk:
exacerbations hospitalization
exacerbations,
hospitalization, death
CAT Scores: impact and management

< 10: low impact: smoking cessation
cessation, annual
influenza vaccination, reduce exacerbation
risk, therapy
py by
y clinical assessment

10-20: medium impact: add review
10maintenance therapy, refer pulmonary rehab,
minimize exacerbation, review aggravating
factors: smoking
CAT Scores: impact and management

21-30:high impact: pt has significant room for
21improvement, consider referral to specialist,
additional pharmacologic treatments

>30: very high impact: same as high impact
Exacerbations Can Increase Healthcare
Burden Associated With COPD
•
Exacerbations of COPD can have negative impacts
on patient lung function, healthhealth-related quality of
life, and socioeconomic costs
• Lung function declined more rapidly in patients
with frequent exacerbations
• Direct
Di t medical
di l costs
t ffor exacerbations
b ti
associated
i t d
with COPD remain at approximately $18 billion
per yyear
p
1) The Global Initiative for Chronic Obstructive Lung Disease. GOLD Report—Global Strategy for the Diagnosis, Management, and Prevention of Chronic
Obstructive Pulmonary Disease. Updated 2009.; 2) Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and
lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847-852. ; 3)Anzueto A, Sethi S, Martinez FJ. Exacerbations of chronic
obstructive pulmonary disease. Proc Am Thorac Soc. 2007;4(7):554-564.
Communication Is Essential to Monitoring Exacerbations
Management of Exacerbations
Associated With COPD
The Global Initiative for Chronic Obstructive Lung Disease. GOLD Report—Global Strategy for the Diagnosis, Management, and
Prevention of Chronic Obstructive Pulmonary Disease. Updated 2009.
Impact of COPD
Th BODE IIndex
The
d
Variable
Points on BODE Index
0
1
2
3
FEV1 (% predicted)
 65
50-64
36-49
 35
Distance walked in 6 min. (M)
 350
250-349
250
349
150-249
150
249
 149
MMRC dyspnea scale
0-1
2
3
4
BMI
> 21
 21
BODE = body mass index, obstruction, dyspnea, and exercise capacity;
MMRC = Modified Medical Research Council
Celli BR, et al. N Engl J Med. 2004;350:1005-1012.
Survival in COPD
FEV1 Stage
BODE
Proobability oof Survival
1.0
0.8
0.6
0.4
P < 0.001
0.2
P < 0.001
0.0
0
4
8 12 16 20 24 28 32 36 40 44 48 52
0 4
8 12 16 20 24 28 32 36 40 44 48 52
Months
Stage I (> 50%) predicted
Stage II (36-50%) predicted
Stage III ( 35%) predicted
Celli BR, et al. N Engl J Med. 2004;350:1005-1012.
Quartile 1 (BODE 0-2)
Quartile 2 (BODE 3-4)
Quartile 3 ((BODE 5-6))
Q
Quartile 4 (BODE 7-10)
COPD DIFFERENTIAL




Asthma
Congestive heart failure
Bronchiectasis
Verklempt
More Than 50% of Patients With COPD
Were Misdiagnosed With Asthma
Tinkelman DG, Price DB, Nordyke RJ, Halbert RJ. Misdiagnosis of COPD and asthma in primary care patients 40 years of age and
over. J Asthma. 2006;43(1):75-80.
Differential Diagnosis:
g
COPD and Asthma
COPD Management





Ongoing monitoring and assessment
Progressive disease
Follow up spirometry
Monitor pharmacotherapy: therapeutics,
adherence,
dh
ttechnique,
h i
effectiveness
ff ti
off
controlling symptoms
Monitor exacerbation: frequency and severity
Question 2: If a p
patient stops
p
smoking the lung function improves



True
False
Maybe a little
Smoking Cessation Can Slow COPD
Onset and Progression
Question 3: What 4 interventions
Q
improve survival in severe COPD?
Exercise, oxygen, beta agonists,
nutrition
2. Exercise, oxygen, anticholinergics
anticholinergics,,
nutrition
3. Exercise, oxygen, quitting smoking,
inhalers
4. Exercise, oxygen, quitting smoking,
nutrition
1.
Comprehensive Approach for
COPD Management
Fi t Line
First
Li Smoking
S ki Cessation
C
ti Treatments
T t
t
• Counseling
• Nicotine replacement
– Gum
– Inhaler
– Nasal spray
p y
– Transdermal patch
– Sublingual
g
tablet
– Lozenge
• Bupropion
• Varenicline
Acidic Beverages (coffee)
GOLD Guidelines 2008. http://www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=2003.
Accessed September 2010.
Carbon Monoxide-Confirmed 4-Week
Continuous Quit Rates Weeks 9–12
100
Reesponse Raate (%)
OR = 3.85*
60
40
OR = 3.85*
OR = 1.93*
OR = 1.90*
44.0
43.9
29.8
29.5
20
17.7
0
N = 352
N = 329
N = 344
17.6
N = 344
Study I
*P
< 00.001
001
Varenicline
OR = odds ratio
Gonzales D, et al. JAMA. 2006;296:47-55.
Jorenby DE, et al. JAMA. 2006;296:56-63.
N = 342
Study II
Bupropion
Placebo
N = 341
Smoking Cessation with Varenicline
Tx Period
1o Endpoint
Tashkin DP, et al. Chest. 2010 Sep 23. [Epub ahead of print]
Varenicline: Most Common Adverse Events
From 12-week Fixed-Dose, Placebo-Controlled Studies
Ad
Adverse
E
Event
t
Varenicline
V
i li
0.5 mg BID
n = 129
Varenicline
V
i li
1 mg BID
n = 821
Placebo
Pl
b
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*
Varenicline package insert. Available at: www.pfizer.com/files/products/uspi_chantix.pdf.
Accessed September 2010.
Varenicline Warning
• Psychiatric symptoms
– Changes in behavior
– Agitation
– Depressed mood
– Suicidal ideation
– Suicidal behavior
• “Advise patients and caregivers that the patient should
stop taking CHANTIX (varenicline) and contact a health
care provider immediately if agitation
agitation, depressed mood
mood,
or changes in behavior that are not typical for the
patient are observed, or if the patient develops suicidal
ideation or suicidal behavior.”
Varenicline package insert. http://www.pfizer.com/files/products/uspi_chantix.pdf. Accessed
September 2010.
Nicotine Nasal Spray
p y with Nicotine Patch
for Smoking Cessation
Percentage (number) of participants abstinent from smoking at follow up
• 237 smokers followed for 6 years
• Combination of a 5 month nicotine patch + nicotine nasal spray is
g cessation than the p
patch alone
more effective for smoking
Blondal T, et al. BMJ. 1999;318:285-288.
Tips to Help Patients Quit Smoking
• At every encounter, ask patient if he/she is still smoking, and
chart response
• At every encounter, give strong advice to quit smoking
• Measure expired CO (> 10 ppm)
• Perform/order spirometry,
spirometry use spirometry results and ‘lung
lung age’
as leverage to advise smoking cessation
• Ask patient if they are ready to quit and their history of attempts
• Negotiate/impose
N
ti t /i
a target
t
t ‘Quit
‘Q it Day’,
D ’ have
h
staff
t ff follow
f ll
up that
th t
day
– Schedule follow-up appointments
• Refer
R f patient
ti t to
t a behavioral
b h i l supportt program or ttelephone
l h
quit
it
line
• Prescribe pharmacological support as appropriate
– NRT, bupropion SR, varenicline
Adapted from Tashkin DP, and Murray RP. Respir Med. 2009;103:963-974.
 Short
acting bronchodilators:
bronchodilators:
 B2
adrenergic agonist: albuterol, levalbuterol
 Anticholinergic
A ti h li
i agent:
t iipratropium
t i
 Combination: albuterol/ipratropium
Long acting bronchodilators
 B2 adrenergic agonists: salmeterol, formoterol
formoterol,,
aformoterol , Indacaterol
Anticholinergic: tiotropium bromide, Aclidinium
Inhaled corticosteroids:
corticosteroids: fluticasone, budesonide,
beclomethasone,, mometasone
beclomethasone
C
Combinations:
Combinations
: fluticasonef
fluticasone
-salmeterol, budesonide
budesonide-formoterol,, mometasoneformoterol
mometasone-fomoterol
Methylxanthines:
y
: theophylline
p y
Methylxanthines
PDE4 Inhibitor: Roflumilast
Antibiotics:: Azithromycin
Antibiotics
Rescue vs Maintenance
Medication in Moderate COPD
COPD Management: Pharmacologic
Theophylline







Theophylline: Thoracic Park
Smooth muscle relaxation
F ll iin ttrapped
Fall
d gas volume
l
Pulmonary vascular dilator
Level 66-10
Studies: 110 patients 100mg bid over 1 year,
favorable, decreased exacerbations,
decreased
d
d clinic
li i visits,
i it iincreased
d FEV1
42 Theophylline and 43 placebo
COPD
Management:Pharmacologic
Theophylline






May act as nonselective phosphodiesterase inhibitors
Significance is disputed
Clearance of the drug decreases with age
All studies were performed with slow release
preparations
There is evidence to show greater improvement in
FEV1 when added to salmeterol than salmeterol
alone
Toxicity: arrythmias
arrythmias,, nausea, vomiting, seizure,
GERD, plus multiple drug interactions
PDE4 Inhibitor Roflumilast
S d D
Study
Design
i





Anti-inflammatory action
Previously shown to improve lung function but not
exacerbations
Assess exacerbations in carefully selected patients
Patients: confirmed COPD
 Severe airflow limitation (FEV1/FVC ≤ 70%)
 Bronchitic symptoms
 History of exacerbations
 Current or former smokers ((≥ 20 pack-year
p
y
history)
 > 40 years old
2 parallel identical studies
Calverley PM, et al. Lancet. 2009;374(9691):685-694.
PDE4 Inhibitor Roflumilast






4 week run-in with placebo
Randomization (Study M2-124 n = 1525; M2-125 n = 1571)
 Roflumilast 500 mcg qd
 Placebo
52 weeks of treatment
Permitted co-medications
 LABA
 SABA
 Continuing short- or long-acting anticholinergics
Forbidden co-medications
 Inhaled CS
 New long-acting anticholinergics
1o endpoints
 Change
g in p
pre-bronchodilator FEV1
 Rate of COPD exacerbations
 NO NOT GIVE IN COMBINATION with Theophylline
Calverley PM, et al. Lancet. 2009;374(9691):685-694.
PDE4 Inhibitor Roflumilast
Results
M2-124
∆ pre-dilator
FEV1 (mL)
M2-125
Rof
Pbo
∆
P
Rof
Pbo
∆
P
Rof
Pbo
∆
P
46
8
39
0.0003
33
-25
58
< 0.0001
40
-9
48
< 0.0001
RR
Mean exac rate
(per pt*yr)
Pooled
1.08
1.27
0.85
RR
0.028
1.21
1.49
0.82
RR
0.004
1.14
1.37
1.37
• Study confirms efficacy in selected patients with COPD
• No roflumilast effect on mortality or CRP levels
• Diarrhea, nausea, weight loss more common with roflumilast
Calverley PM, et al. Lancet. 2009;374(9691):685-694.
0.0003
COPD Management: Pharmacologic
Beta Agonists






Sympathomimetics: Albuterol, Salbutamol,
Sympathomimetics:
Levalbuterol,, Salmeterol,
Levalbuterol
Salmeterol, Formoterol,
Formoterol,
Indacaterol
B2: bronchial smooth muscle: small and
medium airways,
airways stimulate beta2 adrenergic
receptors
Improve mucocilliary clearance
Increased response in combination therapy
Cardiovascular effects, hypokalemia,
tachyphylaxis,, lactic acidosis and respiratory
tachyphylaxis
failure
Dose: technique, spacer
COPD Management:
g
Pharmacologic
g
Beta Agonists


SABA: takes effect in 1515-20 minutes and lasts
4h
hours
LABA:





Salmeterol: takes effect in 4 hours and lasts 12
Salmeterol:
hours
Fomoterol:: takes effect in 1 hour and lasts
Fomoterol
12h
12hours
Indacaterol:: takes effect in 1 hout and lasts 24
Indacaterol
hours
All significantly improve lung volumes, dyspnea,
health related quality of life, and exacerbation rate
Aformoterol nebulized lasts 12 hours
COPD Management: Pharmacologic





Anticholinergics
Muscarinic receptors
Airway smooth muscle: M3
Chronic bronchitis and emphysema 2x -4x
increased cholinergic tone
Atropine
p
1920’s,, Ipratropium
1920’
p
p
bromide
1980’’s, Tiotropium 2004
1980
2004-- proximal bronchiole
and bronchi, Aclidinium 2012
Expiratory Airflow Limitation Leads to Air Trapping
Trapping
Airflow Limitation Leads to
Air Trapping and Hyperinflation
Hyperinflation
COPD Management: Pharmacologic




Ipratropium Dosing: 4 puffs Q6 hours
Combivent 1990
1990’’s: Albuterol + Ipratropium
 FEV1 increased 3131-33% over baseline
 Fewer exacerbations
Tiotropium Bromide
Bromide-- once daily long acting
bronchodilator
Long acting antimuscarinic agent, M3
receptors, effect one hour and lasts 24 hours
COPD Management: Pharmacologic



Minimal side effects: dry mouth, exacerbation
glaucoma and constipation
Very safe
Poorly absorbed
Donahue et al:
Indacaterol vs. Tiotropium





Evaluated Indacaterol vs. placebo and
placebo and Tiotropium over 26 weeks
1 683 patients
1,683
patients, Moderate to severe COPD
COPD,
Indacaterol 150 mcg or 300 mcg
SGRQ FEV1,
SGRQ,
FEV1 and exacerbations
post dose trough FEV1 increased 180 ml with
Indacaterol and 140 ml with Tiotropium
SGRQ improved but not statistically
significant, no improvement in decreased
exacerbations
UPLIFT Trial



Time to first exacerbation: Tiotropium 16.5
months vs placebo 12.5 months
14% reduction in # exacerbations Tiotropium
Mortality not statically significant 14.4% vs
16.3%
Clinical Course of COPD
COPD
COPD
Exacerbations
Expiratory Flow Limitation
Ai Trapping
Air
T
i
Hyperinflation
B thl
Breathlessness
Deconditioning
g
Inactivity
y
Reduced Exercise
Capacity
p
y
Poor Health-Related Quality of Life
Disability
Disease progression
Adapted from Decramer M. Eur Respir Rev. 2006;15:51-57.
Death
Question 5: what happens to your
end expiratory lung volume with
exercise?
i ?
A- increases
A
B- decreases
Lung Volume Terminology
Inspiratory reserve
Inspiratory
volume
capacity
Total
lung
capacity
p
y
Tidal volume
Expiratory reserve
volume
Vital
capacity
Functional residual capacity
Residual volume
St ti and
Static
dD
Dynamic
i L
Lung V
Volumes
l
iin COPD
R t
Rest
Exercise
E
Exercise
i
Rest
IC
TV
FRC
RV
Normal
COPD
Lung Volume Response to Exercise
Operating Lung Volumes & Exercise Endurance
Maltais et al
8.0
Tiotropium
Placebo
TLC
7.5
TLC
Lun
ng volume ((L)
IRV
7.0
IRV
6.5
VT
VT
6.0
EELV
5.5
EELV
IC
(1.78 L)
IC
(1 92 L)
(1.92
50
5.0
4.5
0
5
10
E
Exercise
i titime ((minutes)
i t )
15
Management: Aclidinium bromide



Long
g term management
g
of COPD,, chronic
bronchitis, emphysema
LAMA, twice a day, muscarinic receptor
M3 receptors
M
Management:
t Aclidinium
A lidi i
B
Bromide
id




P t ti l side
Potential
id effects:
ff t narrow angle
l
glaucoma, urinary retention, cough,
hypersensitivity to milk protein
Peak FEV1 improvements: 200mcg 235 ml
and 400mcg 264ml
Trough FEV1 improvements: 200 mg 44 ml
and 400mcg 109 ml
S t i d over 52 weeks
Sustained
k
COPD Management: Pharmacologic






Steroids: acute exacerbation of COPD
favorable results and substantial benefits
Improvement in wheezing, air flow
Improvement in abnormal mucus
Trial for 2-3 weeks
Demonstrate 20-30% improvement FEV1
Response
p
to oral steroids p
poor p
predictor
respond to inhaled steroids
COPD Management: Pharmacologic



Four large studies regular treatment with
inhaled glucocorticosteroids appropriate for
symptomatic COPD patients FEV1<
FEV1 50%
predicted
Treatment reduce frequency of exacerbations
and improve health status
Benefit 25-50% of patients: improvement 6
minute walk
TRIPLE THERAPY
Welte et al.:Efficacy and Tolerability of
Budesonide/Formoterol Added to Tiotropium
in Patients with Chronic Obstructive
Pulmonary Disease
 To assess the efficacy and tolerability of
budesonide/formoterol added to tiotropium in
patients eligible for inhaled
corticosteroid/long-acting
ti
t id/l
ti β2-agonist
β2
i t
combination therapy.
Triple Therapy

Over the treatment period,
budesonide/formoterol plus tiotropium
significantly increased predose FEV1 by 6%
(65 ml) and postdose by 11% (123 and 131
ml at 5 and 60 min p
postdose,, respectively)
p
y)
versus tiotropium alone (both P < 0.001). The
number of severe exacerbations decreased
by 62%.
62% Both treatments were well tolerated
tolerated.
FEV1 With Triple Combination Therapy
Tio +/+/ Fluc/Sal
Fl c/Sal1
Tio +/+/ Bud/Form2
● BUD/FORM + TIO
■ PBO + TIO
1. Aaron SD, et al. Ann Intern Med. 2007;146(8):545-555.
2. Welte T, et al. Am J Respir Crit Care Med. 2009;180(8):741-750.
Exacerbations With Triple Combination Therapy
Tiotropium
(n = 156)
Tiotropium
p
+
Salmeterol
(n = 148)
Tiotropium +
Salmeterol +
Fluticasone
(n = 145)
62.8 %
64.8%
60.0%
Total Exacerbations
222
226
188
Exacerbations with
Hospitalization
49
38
26
% Pts with ≥ 1
exacerbations
Incidence rate ratio
compared with tiotropium +
placebo ((95% CI))
p
Aaron SD, et al. Ann Int Med. 2007;146(8):545-555.
0.83
((0.54 to 1.27))
0.53
(0.33 to 0.86)
COPD Management: Pharmacologic






Side effects : well recognized with steroids
I h l d steroids:
Inhaled
t id orall thrush,
th h h
hoarseness,
bruising
Increased pneumonia with
fluticasone/salmeterol (TORCH trial)
Triamcinolone increased risk of bone fracture
Budesonide least absorbed, no effect on
bone mineral density
Fluticosone/salmeterol;
mometasone/formoterol;
budesonide/formoterol
COPD Management: Pharmacologic





Vaccines: influenza reduce the serious
illness and death in COPD by 50%
Pneumococcal vaccine: 65 and older,
younger
y
g p
patients with COPD FEV1< 40%,
reduction pneumonia
Alpha-1-antitrypsin augmentation therapy
Smoking cessation: Varenicline, nicotine
acetycholine receptor agonist
Mucolytics: controvertial,
controvertial some evidence in
pts not on inhaled steroids N-acetylcyseine or
carbocysteine
y
mayy reduce exacerbations
Management




Azithromycin: macrolide antibiotics have
immunomodulatory and anti-bacterial
properties
1142 COPD patients: randomized placebo to
Azithromycin 250 mg daily
Azithromycin increased time to first
exacerbation from 174 days to 266 days
37% decrease exacerbation rate
Management: Azithromycin




Effects best in patients with more moderate
GOLD II disease and former smokers
Increased hearing
g decrement 25% vs 20%
1 yr, no guidance for long term efficacy or
potential adverse effects of resistance
Patients with tachycardia and prolonged QT
excluded
Implications of Recent Trial Results





COPD mortality is increasing
Exacerbations are an important risk factor for
mortality
Treatment with current drugs and combinations can
reduce exacerbations
Currently available drugs alone and in combination
have been shown to have beneficial impacts on
lung function and patient-centered outcomes in
COPD and are useful in managing COPD.
No pharmacologic agent has thus far
f been shown
to modify the persistence or progression of the
underlying
y g inflammatory/profibrotic/elastolytic
yp
y
pathology in COPD
COPD Management: Oxygen







1895: commercially produced liquid air
1920: hypoxia and right heart failure
1956: improves exercise capacity
1967: low flow O2
1968: improvement function in patients
receiving ambulatory O2
1970: long term home O2 increase survival
1980: O2 conserving device
COPD Management: Oxygen



Mortality reduced in patients with RA PaO2 <
56 mmHg or O2 saturation < 88%
RA PaO2
P O2 < 60 mmHg
H with
ith erythrocytosis,
th
t i
mental dysfunction, CHF, or cor pulmonale
Need therapy for 18
18-24
24 hours
COPD Management: Oxygen


Improves quality of life, decreased
hospitalization, improved psychomotor
performance
Decreases pulmonary artery pressure
Improved COPD Survival on LTOT
Güell Rous R. Int J Chron Obstruct Pulmon Dis. 2008;3(2):231-237.
Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980;93:391-398.
Medical Research Council Working Party. Lancet 1981;1:681-686.
COPD Management:
g
Pulmonary Rehab



Reduces symptoms, improve quality of life,
increased physical and emotional
participation in life activities
Covers non pulmonary issues
Respiratory muscles abnormal: inactivity,
t i inflammation,
i fl
ti
malnutrition,
l t iti
systemic
increased work of breathing, impaired oxygen
delivery,
y, co morbid states,, electrolyte
y
imbalance, and drugs
COPD Management:
g
Pulmonary Rehab




Involve several health professionals
Comprehensive exercise training
Nutrition counseling
Education
Efficacyy of Pulmonary
y Rehabilitation
P = 0.000
Control
Rehabilitation
P = 0.017
20
18
16
14
12
10
8
6
4
2
0
P = 0.000
250
200
P = 0.002
150
100
50
0
Baseline
Baseline
6 wks
Dyspnea
yp
6 wks
1 yr
1 yr
Walking
Wa
g Distance
sta ce
• Patients participated in 3 half day sessions per week for 6 weeks in a
multidisciplinary rehabilitation program including smoking cessation,
occupational physical
occupational,
physical, breathing
breathing, and diet sessions
• Physical therapy included 30 min sessions in-office as well as home
sessions
–Treadmills, cycling, circuit training
Griffiths TL, et al. Lancet. 2000;355:362-368.
COPD Management:
g
Pulmonary Rehab



80 patients at LLUMC reduction from 19 to 6
days of hospitalization
L
Less
ti
time iin h
hospital,
it l ffewer ER and
d office
ffi
visits, return to work, increased ADL’s, more
self care, decreased extended care and
home care
Improved dyspnea and cough
COPD Management: Nutrition
Nutritional Supplements Have Not
Increased Weight of Patients
Study
N
N
Standardized Mean Difference (Random)
95% CI
Weight %
DeLetter 1991
18
17
9.2
Knowles 1988
13
12
7.2
Otte 1989
13
15
8.1
Rogers 1992
15
12
7.8
Schols 1995
39
25
12.9
Schols 1995a
33
38
13.9
Steiner 2003
25
35
12.6
Weekes 2004
30
25
11.9
Total
214 205
Test for overall effect Z = 1.25 P = 0.21
100.0
-4.0 -2.0 0
Control better
2.0 4.0
Supplement better
Nutritional supplementation versus placebo or usual diet
Adapted from Ferreira IM, et al. Cochrane Database Syst Rev. 2009;(2):CD000998.
COPD Management: Surgery



LVRS: resection of functionless areas of
emphysematous lung to improve mechanics
FEV1 20% and
FEV1<
d either
ith h
homogenous
emphysema or DLCO < 20% high risk for
death or unlikely to benefit
Increases exercise capacity not confer
survival advantage
COPD Management: Surgery






Yield advantage for patients both
predominantly upper lobe emphysema and
low baseline exercise capacity
Range of FEV1 improvement 250-350 ml
Improved 6 minute walk
$140,000 per quality-adjusted life year
Resection of large bullae > 1/3 hemithorax
Lung transplant
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Non-pharmacologic
Patient
Essential
A
Smoking cessation (can
include pharmacologic
treatment)
B, C, D
Smoking
S
ki cessation
i (can
(
include pharmacologic
treatment)
Pulmonary rehabilitation
Recommended
Depending on local
guidelines
Physical activity
Flu vaccination
Pneumococcal
vaccination
Physical activity
Flu vaccination
Pneumococcal
vaccination
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
A
SAMA prn
or
SABA prn
LAMA
or
LABA
or
SABA and SAMA
Theophylline
B
LAMA
or
LABA
LAMA and LABA
SABA and/or SAMA
Theophylline
LAMA and LABA
PDE4-inh.
SABA and/or SAMA
Theophylline
ICS and LAMA or
ICS + LABA and LAMA or
ICS+LABA and PDE4-inh. or
LAMA and LABA or
LAMA and PDE4-inh.
Carbocysteine
SABA and/or SAMA
Theophylline
C
D
ICS + LABA
or
LAMA
ICS + LABA
or
LAMA
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
FIRST CHOICE
ICS + LABA
or
LAMA
GOLD 3
GOLD 2
GOLD 1
D
ICS + LABA
or
LAMA
A
>2
B
SAMA prn
or
SABA prn
mMRC 0-1
CAT < 10
LABA
or
LAMA
mMRC > 2
CAT > 10
1
0
Exxacerbatiions per year
GOLD 4
C
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
SECOND CHOICE
GOLD 3
GOLD 2
GOLD 1
D
LAMA and LABA
ICS and LAMA or
>2
ICS + LABA and LAMA or
ICS + LABA and PDE4-inh or
LAMA and LABA or
LAMA andd PDE4-inh.
PDE4 Bi h
A
LAMA or
LABA o
or
SABA and SAMA
LAMA and LABA
1
0
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
Exxacerbatiions per year
GOLD 4
C
Global Strategy for Diagnosis, Management and Prevention of COPD
Manage Stable COPD: Pharmacologic Therapy
ALTERNATIVE CHOICES
PDE4-inh.
SABA and/or
SAMA
Theophylline
GOLD 4
GOLD 3
GOLD 2
A
Carbocysteine
SABA and/or SAMA
Theophylline
>2
B
Theophylline
GOLD 1
SABA and/or SAMA
Theophylline
1
0
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
Exxacerbatiions per year
D
C
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



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Jo
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al. Qua
Quality
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Meeting Abstract