The Morbidity of

COPD Symptoms
Learning Objectives
Appreciate the current epidemiology and gaps in
the management of COPD in Canada
Recognize why diagnosing and treating COPD is
important for physicians and their patients
Differentiate the clinical characteristics and
diagnostic criteria for COPD and asthma
Discuss current management strategies for
patients with COPD, contrasting the roles of
bronchodilators and anti-inflammatory agents in
current guidelines
Case Study
Mr. A.C. is a 61-year-old real-
estate agent who has recently
undergone angioplasty.

Until 6 months ago, you saw
him infrequently in your
practice, perhaps because you
usually tried to discuss
smoking cessation with him.

Following an ER visit for chest
pain he was managed by the
cardiologists and underwent
successful and uneventful
angioplasty.
Case Study (contd)
Mr. A.C. is trying to make lifestyle changes
recommended to him, including participation in
a cardiac rehab program
During his rehab, he frequently feels breathless,
earlier than others in the group
He finds the incline on the treadmill difficult
He has no history of lung disease but has cut
down his smoking to one cigarette at bedtime 4
months ago and has a 35 pack-year smoking
history
The Evolving Epidemiology of
COPD in Canada
Growing Burden of COPD
Jemal A, et al. JAMA. 2005 Sept. 14; 294(10):1255-9.
Trends in age-standardized death rates for the
6 leading causes of death in the United States,
1970-2002
COPD: The Leading Cause of Hospital
Admissions Today
*An ambulatory care sensitive condition is a condition that is normally manageable on an outpatient basis.
Data are for the Canadian population, excluding Quebec
. Canadian Institute for Health Information. Health Indicators 2008. Ottawa: CIHI; 2008.
18,000
16,000
14,000
12,000
10,000
8,000
6,000
4,000
2,000
0
COPD Angina Asthma Heart Failure Diabetes Epilepsy
Ambulatory Care Sensitive Condition
*
N
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o
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P
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Single Hospitalization
1 Repeat Hospitalization
2 or More Repeat Hospitalizations
COPD is Underdiagnosed:
Screening Spirometry in Primary Practice
*Criteria for COPD: FEV
1
/FVC < 0.70
Hill K, et al. CMAJ. 2010 Apr. 20;182(7):673-8.
Patients >40 years + 20 pack-year history of smoking
visiting a primary care physician for any reason
(n=1,003)
Screening for COPD
Patients not meeting
criteria for COPD*
(n=795; 79.3%)
Patients meeting
criteria for COPD*
(n=208; 20.7%)
Previous diagnosis of COPD
(n=67; 32.7%)
No previous diagnosis of COPD
(n=141; 67.3%)
Deterioration in Lung Function versus
Symptoms in COPD
Sutherland EM, et al. N Engl J Med 2004 Jun 24;350(26):2689-87.
100
50
20
Severe
Mild
S
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F
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1

(
%

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p
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i
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)

Axis of Progression
Lung function
normal
Asymptomatic
Lung function
reduced
Why is pursuing the diagnosis of
COPD important for Mr. A.C.?
Relationship Between FEV
1
,
Smoking Status and CV Mortality
Young RP, et al. Eur Respir J. 2007 Oct;30(4):616-22.
O
d
d
s

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f
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V

m
o
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t
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8
6
4
2
0
<65 65-79 80-100 >100
Current smoker
Ex-smoker
Never-smoker
FEV
1
% pred
Prediction of Death Within 5 years by GOLD
Categories and Presence of Comorbid Disease
*Diabetes, hypertension or CV disease
Mannino DM, et al. Eur Respir J. 2008 Oct;32(4):962-9.
100
10
1
GOLD
3/4
GOLD
2
GOLD
1
R GOLD
0
Normal
# of comorbidities*
Two
One
None
Three
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Comorbidities of COPD
Cardiovascular disease is a major comorbidity
in COPD and probably both the most frequent
and most important disease co-existing with
COPD.
Other major comorbidities:
Osteoporosis
Depression
Lung cancer (most frequent cause of death in
mild COPD)
Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011.
often underdiagnosed and associated with poor
health status and prognosis
Case Study (contd)
The rehab clinic
placed him on
salbutamol as
needed and asked for
him to follow up with
his GP.
How would you proceed with
Mr. A.Cs assessment?
Spirometry
Mr. A.C.: Spirometry Results
Parameter Pred. value Observed pre % Pred.
Observed
post
% pred. % change
FVC (L) 5.64 5.23 93 5.77 102 10.3
FEV
1
(L) 4.57 2.92 64 3.01 66 3.2
FEV
1
/FVC (%) 81 56 69 52 64 -6.4
FEF
25-75
(L/S) 11.27 5.52 49 5.70 51 3.3
FEF
50
(L/S) 5.64 2.02 36 1.73 31 -14.3
FEF
75
(L/S) 2.82 0.75 27 0.59 21 -21.2
VE (L/min) 173 -- -- -- -- --
Raw insp. (cmH
2
O/l/s) 0.68 1.71 256
Are these results more compatible
with asthma or COPD?
Spirometry Results = Asthma
Spirometry Ref Pre Meas Pre % Ref Post Meas Post % Ref Post % Chg
FVC Liters 3.81 3.45 90 3.78 99 10
FEV1 Liters 3.27 2.34 72 2.90 89 24
FEV1/FVC % 86 68 79 77 89 13
FEF25-75% L/sec 3.83 1.44 38 2.40 63 67
FEF50% L/sec 4.11 1.93 47 3.33 81 73
FEF75% L/sec 1.91 0.57 30 0.98 51 73
PEF L/sec 6.55 6.08 93 7.57 116 25
PIF L/sec 3.63 4.53 25
PULMONARY FUNCTION ANALYSIS
An acceptable effort was provided.
There is evidence of slight airflow limitation
that improved with acute bronchodilator.
This study is similar to those seen in
patients with asthma.
Distinguishing Asthma from COPD
Adapted from ODonnell DE, et al.:Can Respir J. 2007 Sep;14 Suppl B:5B-32B.
Asthma COPD
Age of onset Usually <50 years Usually >35 years
Smoking history
Not causal (but people with
asthma sometimes smoke)
Usually >10 pack-years
Sputum production
Infrequent unless poorly
controlled
Often in exacerbation-prone
chronic bronchitis, infrequent in
emphysema
Allergies
Often in early onset but less often
in late onset
1/3 of the general population
Disease course Stable (with exacerbations)
Progressive worsening (with
exacerbations)
Spirometry
More likely to normalize with
treatment
May improve but never becomes
normal
Clinical symptoms Intermittent and variable Persistent and variable
Response to
therapy
Responds well to therapy,
especially corticosteroids
Does not respond as well to
therapy
His post bronchodilator spirometry
FEV
1
66%
FVC 102%
FEV
1
/FVC 0.52

He is using his salbutamol 3-5 times a day.

Case Study (contd)
How would you proceed?
Evaluating COPD Severity
Classification of COPD By Impairment
of Lung Function*
Stage
Spirometry (post bronchodilator)
FEV
1
FEV
1
/FVC
Mild 80% predicted <0.7
Moderate 50-79% predicted <0.7
Severe 30-49% predicted <0.7
Very severe <30% predicted <0.7
*In keeping with current GOLD criteria
O'Donnell DE, et al. Can Respir J. 2008 Jan-Feb;15 Suppl A:1A-8A.
MRC Dyspnea Scale and CTS COPD
Classification
Fletcher CM, et al. Br Med J. 1959 Aug 29;1:257-66.
ODonnell DE, et al. Can Respir J. 2003 May-Jun;10 Suppl A:11A-33A.
none
severe
Mild
Moderate
Severe
Grade 1 Breathless with strenuous exercise
Grade 2
Short of breath when hurrying on the level
or walking up a slight hill
Grade 3
Walks slower than people of the same age
on the level or stops for breath while
walking at own pace on the level
Grade 4 Stops for breath after walking 100 yards
Grade 5
Too breathless to leave the house or
breathless when dressing or undressing
Lung Function and Symptoms:
Both Are Tied to Outcomes
Survival by ATS Stage
(based on FEV
1
)
Survival by
Level of Dyspnea
Nishimura K, et al. Chest. 2002 May; 121(5):1434-40.
100
80
60
40
20
0
0 10 20 30 40 50 60 70
Stage I (n=42)
Stage II (n=59)
Stage III (n=82)
p = 0.08
Months of Follow-Up
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%
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100
80
60
40
20
0
0 10 20 30 40 50 60 70
Grade II (n=67)
Grade III (n=87)
Grade IV (n=26)
p < 0.001
Months of Follow-Up
Grade V (n=3)
Scoring
range
0-40
Mr. A.C.'s
CAT score = 18
Mr. A.C.: CAT Score
I never cough I cough all the time 0 1 2 3 4 5 1
I have no phlegm (mucus) in
my chest at all
My chest is completely
full of phlegm (mucus)
0 1 2 3 4 5 0
My chest does not feel tight
at all
My chest feels very tight 0 1 2 3 4 5 3
When I walk up a hill or one
flight of stairs I am not
breathless
When I walk up a hill or
on flight of stairs I am
very breathless
0 1 2 3 4 5 3
I am not limited doing any
activities at home
I am very limited doing
activities at home
0 1 2 3 4 5 4
I am confident leaving my
home despite my lung
condition
I am not at all confident
leaving my home because
of my lung condition
0 1 2 3 4 5 3
I sleep soundly
I dont sleep soundly
because of my lung
condition
0 1 2 3 4 5 1
I have lots of energy I have no energy at all 0 1 2 3 4 5 3
How would you treat Mr. A.C.?
Benefits of Smoking
Cessation
Smoking Cessation and FEV
1
Adapted from Fletcher C, et al. Br Med J. 1977 Jun;1(6077):1645-8.
0
20
40
60
80
100
20 30 40 50 60 70 80 90
F
E
V
1

(
%
)

Age (Years)
Death
Disability
Symptoms
Quit age 45
age 55

Why do we use bronchodilators
as first-line therapy?
Ventilation (L/min)
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(
%
p
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T
L
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)

0 20 40 60 80
140
120
100
80
60
40
20
0
Normal
(n=25)
RV
IRV
IC
0 20 40 60 80
140
120
100
80
60
40
20
0
COPD
(n=105)
IC
VT
Dynamic Lung Hyperinflation
O'Donnell DE, et al. Am J Respir Crit Care Med. 2001 Sep 1;164(5):770-7.
LAACs and LABAs Available in Canada
Mode of action Individual agents
Long-acting anticholinergic (LAAC)
Also known as long-acting muscarinic antagonist (LAMA)
Tiotropium
Glycopyrronium Bromide
Long-acting beta
2
-agonist (LABA)
Formoterol
Salmeterol
Indacaterol
Long-Acting Anticholinergics
(LAACs)
Also known as long-acting
antimuscarinics (LAMAs)
Tiotropium vs. Ipratropium:
3-month FEV
1
Response
Van Noord JA, et al. Thorax. 2000 Apr;55(4):289-94.
Time after Administration (minutes)
F
E
V
1

(
L
)

Day 1 Day 8 Day 92
1.5
1.4
1.3
1.2
1.1
-60 -5 30 60 120 180 240 300 360
Tiotropium 18 mcg o.d. (n=182)
Ipratropium 40 mcg q.i.d. (n=93)
FEV
1
from 5 Minutes to 4 Hours
Post-dose on Day 1
Glycopyrronium bromide provided significant early bronchodilation following the
first dose, and was significantly more effective than OL tiotropium 18 g o.d.
Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14; Novartis, data on file.
p<0.01 for glycopyrronium bromide versus tiotropium at all timepoints 5 min to 4 h
F
E
V
1

(
L
)

Time post-dose (h)
Placebo Tiotropium Glycopyrronium bromide
1.8
1.6
1.4
1.2
1 2 3
1.7
1.5
1.3
4 0
Time to First Moderate or Severe
COPD Exacerbation
Glycopyrronium bromide 50 g o.d. significantly prolonged the time to first exacerbation versus
placebo (HR 0.66, p=0.001), comparable with OL tiotropium 18 g o.d. (HR 0.61, p=0.001 vs.
placebo)
P
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f
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(
%
)

Time to first exacerbation (weeks)
Number at Risk
Glycopyrronium bromide 495 451 426 394 370 360 341 335 318 310 296 282 239
Placebo 229 202 188 168 159 153 142 137 129 129 122 116 98
Tiotropium 245 222 209 200 190 184 176 169 166 163 157 155 129
100
90
80
70
60
50
40
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Treatment:
Glycopyrronium bromide 50 g o.d.
Placebo
OL Tiotropium 18 g o.d.
HR = hazard ratio
Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14.
Safety of anticholinergics
The key findings were that inhaled
anticholinergics are associated with
a significantly increased risk of
cardiovascular death, MI, or stroke
among patients with COPD.
Cardiovascular Events
Placebo Tiotropium Rate Ratio

(95 % CI)
n Rate

n Rate

UPLIFT
Composite endpoint 246 2.89 208 2.25 0.78 (0.65, 0.94)
Fatal composite 124 1.42 98 1.04 0.73 (0.56, 0.95)

rate ratio tio vs. placebo;

per 100 person-years of time at risk to tiotropium or placebo

*SOC cardiac (fatal), SOC vascular (fatal), MI (fatal+nonfatal), stroke (fatal+nonfatal), sudden death, sudden cardiac death
1. Singh S, et al. JAMA. 2008 Sep 24;300(12):1439-50.
2. Tashkin DP, et al. N Engl J Med. 2008 Oct 9;359(15):1543-54.
Composite Endpoint* Used by Singh et al
1
, applied to UPLIFT
2
Adverse Events (n, %)
in 3% of Any Treatment Group
Glycopyrronium
bromide
50 g o.d.
N=525
Placebo
N=268
OL Tiotropium
18 g o.d.
N=267
Any adverse event 402 (76.6) 205 (76.5) 198 (74.2)
COPD worsening 191 (36.4) 116 (43.3) 90 (33.7)
Upper respiratory tract infection 57 (10.9) 33 (12.3) 30 (11.2)
Nasopharyngitis 47 (9.0) 15 (5.6) 21 (7.9)
Sinusitis 28 (5.3) 14 (5.2) 10 (3.7)
Upper respiratory tract infection bacterial 28 (5.3) 28 (10.4) 21 (7.9)
Headache 25 (4.8) 14 (5.2) 12 (4.5)
Hypertension 21 (4.0) 12 (4.5) 14 (5.2)
Urinary tract infection 14 (2.7) 8 (3.0) 16 (6.0)
COPD worsening: includes chronic obstructive pulmonary disease (COPD) exacerbation.
Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14.
Twice-daily
Long-acting Beta
2
agonists
(LABAs)
Salmeterol vs. Ipratropium vs. Placebo in
COPD: Spirometric Impact
Mahler DA, et al. Chest. 1999 Apr; 115(4):957-65.
Time (hours)
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
1 2 3 4 5 6 7 8 9 10 11 12 13
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F
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(
L
)

Day 84
Salmeterol Ipratropium Placebo
Once-Daily LABAs
Mean Change in FEV
1
on Day 1 of
Indacaterol Treatment
Data are unadjusted means.
Adapted from:
Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012.
Novartis Pharmaceuticals Inc. Data on file (Study B2355).
0
50
100
150
200
250
0 1 2 3 4
F
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1

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m
L
)

Time post dose (hours)
Indacaterol 75 g (N=150) Placebo (N=155)
5 mins
post-dose
Sustained Bronchodilation Over 24
Hours: Indacaterol vs. Placebo
Adapted from:
Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012.
Novartis Pharmaceuticals Inc. Data on file (Study B2355).
Rapid onset
within 5 minutes
Time (hours)
F
E
V
1

(
L
)

1.30
1.35
1.40
1.45
1.50
1.55
1.60
0 4 8 12 16 20 24
1.20
1.25
Indacaterol 75 g o.d. Placebo
Improvement in FEV
1
vs. placebo at every
time point, measured by 24-hour spirometry
Recommended Next Step
for Mr. A.C.
It has been 6 months since you have seen him
He has been taking a once daily LAMA +
Salbutamol prn
Mr. A.C. has not had an exacerbation of his COPD
He states that he is still an MRC 3 dyspnea
and has been needing a breakthrough
salbutamol a few times a week
How would you proceed?
Rehabilitation Is A Powerful Tool For
Improving QOL In COPD
SGRQ = St Georges Respiratory Questionnaire
1. Donohue JF, et al. Chest. 2002 Jul;122(1):47-55.
2. Calverley P, et al. Lancet. 2003 Feb 8;361(9356):449-56.
3. Vincken W, et al. Eur Respir J. 2002 Feb;19(2):209-16.
4. Griffiths TL, et al. Lancet. 2000 Jan 29;355(9201):362-8.
C
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S
G
R
Q

s
c
o
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e

-5
-4
-3
-2
-1
0
-6
-7
-8
Salmeterol
1
Salmeterol/
fluticasone
2
Tiotropium
3
Rehabilitation
4
6 months
1 year
1 year
6 weeks
1 year


-3.5


-4.5


-3.8


-7.1


-3.4
Clinical
significance
threshold
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Combining Bronchodilators in
Mild to Moderate COPD
Formoterol (12 g b.i.d.) +
tiotropium (18 g o.d.)
Tiotropium (18 g o.d.)
Trough FEV
1
: Change from baseline Total COPD Symptom Score

Dual Bronchodilation with
Formoterol + Tiotropium
*p<0.05; p<0.001 vs. tiotropium;
sum of scores for dyspnea (0 = none to 4 = severe), wheezing, cough, and chest tightness (0 = none to 3 = very uncomfortable).
Tashkin DP, et al.:COPD .2009 Feb;6(1):17-25.
M
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*
*
*
AM PM
AM/PM
average
0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6
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f
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b
a
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i
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u
g
h

F
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1

(
m
L
)

n=118
n=127

n=106
n=121
n=121
n=121 n=129
*
n=108
*
*
Week 4 Week 8 Week 12 Last visit
250
200
150
100
50
0
LABA/LAMA Provides Better Improvements
in Lung Function at 6 Weeks Than LABA/ICS
*p<0.05 between groups at each time point
Rabe KF, et al. Chest. 2008 Aug;134(2):255-62.
Time after drug administration (hours)
Tiotropium 18 g o.d. +
formoterol 12 g b.i.d.
Salmeterol 50 g b.i.d. +
fluticasone propionate 500 g b.i.d.
F
E
V
1

(
L
)

1.8
1.7
1.6
1.5
1.4
1.3
0 1 2 3 4 5 6 7 8 9 10 11 12
Is there any reason not to use ICS
therapy at this point in his
management?
Lack of Benefit with LABA/ICS vs. LABA
Alone in Stable COPD: Meta-analysis
Rodrigo GJ, et al. Chest. 2009 Oct;136(4):1029-38.
LABAs/ICS LABAs Risk Ratio Risk Ratio
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI
1.1.1 All-cause mortality
Calverley (16) 2 358 3 372 1.1% 0.69 (0.12, 4.12)
Calverley (17) 5 254 14 255 5.3% 0.36 (0.13, 0.98)
Calverley (23) 193 1533 205 1521 78.4% 0.93 (0.78, 1.12)
Ferguson (25) 6 394 3 388 1.2% 1.97 (0.50, 7.82)
Kardos (24) 7 507 9 487 3.5% 0.75 (0.28, 1.99)
Safranski (20) 6 208 6 201 2.3% 0.97 (0.32, 2.95)
SCO100250 (29) 4 394 6 403 2.3% 0.68 (0.19, 2.40)
SCO100470 (30) 3 518 3 532 1.1% 1.03 (0.21, 5.07)
SCO40041 (28) 5 92 7 94 2.6% 0.73 (0.24, 2.22)
Tashkin (26) 7 845 1 284 0.6% 2.35 (0.29, 19.04)
Wouters (21) 2 189 4 184 1.5% 0.49 (0.09, 2.63)
Subtotal (95% CI) 5292 4721 100.0% 0.90 (0.76, 1.06)
Total events 240 261
Heterogeneity: Chi
2
= 6.52, df = 10 (P = 0.77), I
2
= 0%
Test for overall effect Z = 1.27 (P = 0.20)
Bone Density vs. Dose and Duration
of ICS Therapy
Hanania NA, et al.: J Allergy Clin Immunol 1995; 96(5 Pt 1):571-9.
0
4
-2.5
2.0
2.0
2.0
-2.5
-2.5
0
0
4
4
Dose x Duration/BMI
Dose x Duration/BMI
Dose x Duration/BMI
r=-0.53
p=0.01
r=-0.58
p=0.005
r=-0.33
p=0.08
Lumbar Spine
Femoral Neck
Wards Triangle
Z score
Z score
Z score
"More" Combination Therapies
* p<0.05
Casaburi R, et al. Chest. 2005 Mar;127(3):809-17.
*
*
32% 42%
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T
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Weeks on Treatment
Control
Tiotropium
24
20
12
16
8
0 2 4 6 8 10 12 14 16 18 20 22 24
Rehabilitation
What If. . .
Mr. A.C. has had a URTI and a
worsening of his COPD
He has ended up in the walk-in
clinic and was sent home on
antibiotics and prednisone for
one week
He comes back to you for
follow up
Should you change therapy?
Patients Who Exacerbate
Frequently Account for a Small
but Important Portion of the
Overall COPD Population
27%
16%
11%
Hurst JR, et al. N Engl J Med. 2010 Sept 16;363(12):1128-38.

GOLD: Combined Assessment of COPD
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t
o
r
y
)

mMRC 0-1
CAT < 10
> 2
1
0
4
3
2
1

mMRC > 2
CAT > 10
Symptoms
(mMRC or CAT score)
GOLD assessment
variables are similar
to 2007 Cdn.
Recommendations:

Lung function
impairment

Symptoms
(C) (D)
(A) (B)
Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011.
Summary
COPD is a lethal disease
that has a profound impact
on patient outcome as well
as on the health care
system.
Patients at risk for COPD
need to be diagnosed with
spirometry.
In the medical
management of COPD,
long-acting
bronchodilators, even in
mild or moderate disease
are clinically beneficial.
Introduction of an ICS (and
only in combination with a
LABA) should be done
appropriately and in the
right patient population.
Patient Factors in COPD
Management
Adapted from Cramer JA, et al. Can Respir J. 2007 Jan-Feb;14(1):25-9.
12-month Persistence with Inhaled
Medications: Canadian Data
% continuing for 12 months
0 20 30 40 50 10 60
Ipratropium
(Atrovent

)
8%
Ipratropium/salbutamol
(Combivent

)
12%
Formoterol
(Oxeze)
16%
Salmeterol
(Serevent)

18%
Formoterol-budesonide
(Symbicort

)
25%
Salmeterol/fluticasone
(Advair)

32%
Tiotropium
(Spiriva

)
53%
Four times daily
Twice daily
Once daily
Does the device make
a difference?
COPD Treatment Options

Tiotropium
Glycopyrronium
bromide
Salmeterol /
Fluticasone
Formoterol Salmeterol Indacaterol
Formoterol/
Budesonide
Mode
of
Action
LAAC/
LAMA
LAAC
LABA + ICS
(FDC)
LABA LABA LABA
LABA + ICS
(FDC)
Devices
Handihaler
(18 g/
inhalation)

Breezhaler
(50 g /
inhalation)
Diskus DPI
(50/250 g
and
50/500 g /
inhalation)






Aerosol MDI
(25/50,
25/125 or
25/250 g /
inhalation)




Aerolizer
(12 g /
capsule)






Turbuhaler
DPI (6 &
12 g /
inhalation)
Diskus DPI
(50 g /
inhalation)






Diskhaler
Disk DPI
(50 g /
inhalation)
Breezhaler
(75 g /
inhalation)

Turbuhaler DPI
(110/6 or
200/6 g /
inhalation)
Breezhaler

0
20
40
60
80
100
120
0 2 4 6 8 10
Inspiratory effort (kPa)
F
l
o
w

r
a
t
e

(
L
/
m
i
n
)

kPa
1/2
L
-1
min
Breezhaler

2.2 x 10
-2
Diskus

/Accuhaler

2.7 10
-2
Turbuhaler

3.4 10
-2
HandiHaler

5.1 10
-2



Increasing Resistance
Flow Rates with Various Inhalers Used
for COPD Medications
Diskus

and Accuhaler

are registered trademarks of GlaxoSmithKline; Turbuhaler

is a registered trademark of AstraZeneca;
HandiHaler

is a registered trademark of Boehringer Ingelheim; Breezhaler is a registered trademark of Novartis.

Singh D, et al. Am J Respir Crit Care Med. 2010;181:A4419 (+ additional material from poster).
Diskus

/
Accuhaler

Turbuhaler

HandiHaler

Patient Education: There is Help!
Certified Respiratory Educators (CREs) perform
a critical role in improving the lives of Canadians
living with respiratory illness.
They assists with adherence, they deal with
patient fears and review inhaler techniques.
These highly professional, knowledgeable and
skilled CREs support the disease management
approach: education
evaluation
reinforcement
Education takes time!
To be effective,
education must be
supported by a
physician and
provided by
trained educators.

Dr. Ken Chapman
President
Canadian Network for
Respiratory Care
Learn more at the Canadian Network for Respiratory Care website at http://cnrchome.net
Summary
COPD prevalence is increasing in Canada but
underdiagnosis is common
Modern COPD algorithms are driven by symptoms
plus future risk as determined by lung function and
exacerbation history
For the non-exacerbation-prone COPD with mild-
to-moderate obstruction, use long acting
bronchodilators; given once daily improves
adherence.
For exacerbation-prone patients, triple therapy is
recommended
Back-up Information
Additional supporting information
for use at the facilitators' discretion
What If?
Mr. A.C. has had two more
worsenings of his COPD over
the next 9 months?
He has ended up in walk in
clinic and was sent home on
antibiotics and prednisone for
one week.
He comes back to you for
follow up
Should you change therapy?

Mortality Increases with Frequency of
AECOPD
Soler-Catalua JJ, et al. Thorax. 2005 Nov;60(11):925-31.
Time (months)
0
P
r
o
b
a
b
i
l
i
t
y

o
f

s
u
r
v
i
v
i
n
g

0 AEs
1-2 AEs
>3 AEs
0.0
10 20 30 40 50 60
0.2
0.4
0.6
0.8
1.0
p<0.0001
p=0.069
p<0.0002
Is triple therapy effective?
OPTIMAL Study Design
Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55.
Tiotropium qd + Salmeterol MDI 2 puffs bid n=148
R
Tiotropium
+ Placebo
Run-in
Visit:
Month:
1 2 3 4 5 6
-0.5 0 1 4 8 12
Tiotropium qd + Placebo MDI 2 puffs bid n=156
Tiotropium qd + Salmeterol/Fluticasone 50/250 MDI 2 puffs bid n=145
OPTIMAL Study: Primary Outcome
Proportion of Patients with Exacerbations
Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55.
60
64.8
62.8
0 20 40 60 80
Tiotropium + fluticasone/salmeterol
(n=145)
Tiotropium + salmeterol (n=148)
Tiotropium + placebo (n=156)
% of patients
OPTIMAL Study: Secondary Outcome
Variable COPD Hospitalizations
p = 0.01
Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55.
26
38
49
0 10 20 30 40 50 60
Tiotropium + fluticasone/salmeterol
(n=145)
Tiotropium + salmeterol (n=148)
Tiotropium + placebo (n=156)
Number of patients
What is the impact of oral PDE
4

inhibitors (roflumilast)?
Proportion of Patients with a Moderate or
Severe Exacerbation
Exacerbation rates were based on a Poisson regression model.
Risk ratios (RiR) were based on a log binomial regression model.
Fabbri LM, et al. Lancet. 2009 Aug 29;374(9691):695-703.
sal or tio + placebo sal or tio + roflumilast 500 g
n = 83/467 n = 51/466 n = 58/372 n = 42/371
RiR = 0.60
(95% CI 0.43, 0.82)
p = 0.0015
RiR = 0.73
(95% CI 0.51, 1.05)
p = 0.0867
Salmeterol study Tiotropium study
20
16
12
8
4
0
n=83/467 n=51/466 n=58/372 n=42/371
P
a
t
i
e
n
t
s

w
i
t
h

a
n

e
x
a
c
e
r
b
a
t
i
o
n

(
%
)

16
11 11
18
Roflumilast: Incidence of AEs
( 2.5%)*
Adverse Event
AURA/HERMES
1 year
HELIOS
6 months
Roflumilast
(n=1547)
Placebo
(n=1545)
Tiotropium +
Roflumilast
(n=374)
Tiotropium +
Placebo
(n=369)
COPD 10% 13% 16% 19%
Weight loss 10% 3% 6% <1%
Diarrhea 8% 3% 9% <1%
Nasopharyngitis 6% 6% 6% 5%
Nausea 4% 2% 3% 1%
Bronchitis 4% 4% 2% 3%
Headache 3% 2% 2% 0%
Back pain 3% 2% 2% 1%
*Independent of investigator causality assessments
Calverley PM, et al. Lancet. 2009 Aug 29; 374(9691):685-94.
Fabbri LM, et al. Lancet. 2009 Aug 29;374(9691):695-703.
Risk of ICS
Lack of Benefit with ICS on FEV
1

Decline in COPD: Meta-analyses
1. Highland KB, et al. Ann Intern Med. 2003 Jun 17;138(12):969-73.
2. Sutherland ER, et al. Thorax. 2003 Nov;58(11):937-41.
Authors
Difference between ICS and
placebo groups (95% CI)
Highland et al. (2003)
1
5.0 mL / year (-1.2 to 11.2)
Sutherland et al. (2003)
2
7.7 mL / year (1.3 to 14.2)
Inhaled Corticosteroids and the Risk of
Cataracts - Dose Response
Data are for posterior, subcapsular cataracts
Cumming RG, et al.: N Engl J Med 1997; 337(1):8-14.
3.1
2.1
1.3
0 0.5 1 1.5 2 2.5 3 3.5
Puffs/Wk
Prevalence ratio
> 28
15-28
14 or less
p < 0.001
Increased Risk of Pneumonia with
ICS vs. Placebo in COPD: Meta-analysis
Subgroup
# of events / # of patients
Odds Ratio 95% CI
ICS No ICS
ICS vs. placebo 285 / 3881 180 / 3633 1.51 1.08 2.10
ICS + LABA vs. LABA 356 / 4754 217 / 4728 1.72 1.28 2.30
Total 641 / 8635 397 / 8361 1.60 1.33 1.92
Singh S, et al.: Arch Intern Med 2009; 169(3):219-29.
Increased Risk of New-onset Diabetes
with Increasing ICS Dose
Suissa S, et al. Am J Med. 2010 Nov;123(11):1001-6.
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0 250 500 750 1000 1250 1500 1750 2000
Daily dose in fluticasone equivalents (mcg)
R
a
t
e

R
a
t
i
o

Patient Preference
Inhaler Regimens: Patient Preferences
Venables TL, et al. Br J Clin Res. 1996;7:15-32.
61%
12%
27%
Once Daily
Twice Daily
No Preference
Breezhaler vs. Handihaler:
Comfort, Simplicity & Confidence
Breezhaler is a registered trademark of Novartis. HandiHaler is a registered trademark of Boehringer Ingelheim.
*p<0.05, ***p=0.001 between the two inhalers
Patient preference scores with respect to comfort, simplicity and confidence in use measured on a 10-point scale from
1 = not at all to 10 = extremely
Chapman K, et al. Int J Chron Obstruct Pulmon Dis. 2011;6:353-63.
***
*
*
9.2
9.0
8.8
8.6
8.4
8.2
8.0
7.8
7.6
7.4
How comfortable
is it to inhale
through the inhaler?
Overall, how simple
is it to use
the inhaler?
How confident are you
that you have taken the
medication successfully?
Breezhaler Handihaler
M
e
a
n

s
c
o
r
e

S
E

Receptor Selectivity: Glycopyrronium Bromide
versus Tiotropium
Equilibrium affinity: Glycopyrronium bromide has greater M
3
versus M
2
receptor
binding selectivity than tiotropium (5-fold vs. 2-fold)
pK
i
M
2
pK
i
M
3
Selectivity
(ratio)
Tiotropium 10.050.05
10.370.
04
2
Glycopyrronium
bromide
8.700.04
9.470.0
2
5
t

at M
2
(min)
t

at M
3
(min)
Kinetic selectivity
(ratio)
Tiotropium 10.8 46.2 4.3
Glycopyrronium
bromide
1.1 9.9 9.0
Novartis, data on file.
Kinetic selectivity:
Glycopyrronium bromide shows
faster dissociation from M
2

versus M
3
receptor than
tiotropium (9-fold vs. 4-fold)
Clinical Implications
a) faster time of onset
b) ? Increased cardiac safety
M
3
:
M
2

s
e
l
e
c
t
i
v
i
t
y

r
a
t
i
o
*

*Ratio of occupancy versus time over 24 hours
14
12
10
0
8
6
4
2
Glycopyrronium
bromide
Tiotropium
4.4
12.9
Sample:

Plan
of Action
Tools and Resources
Where can I learn more on the subject of
spirometry in primary care?

http://www.respiratoryguidelines.ca/2013-
cts-slide-kit-spirometry-in-primaary-care