1. The Morbidity of
COPD Symptoms

2. 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

3. Case Study
Mr. A.C. is a 61-year-old realestate 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.

4. Case Study (cont’d)
• 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

5. The Evolving Epidemiology of
COPD in Canada

6. Growing Burden of COPD
Trends in age-standardized death rates for the
6 leading causes of death in the United States,
1970-2002
Jemal A, et al. JAMA. 2005 Sept. 14; 294(10):1255-9.

7. COPD: The Leading Cause of Hospital
Admissions Today
18,000
Single Hospitalization
1 Repeat Hospitalization
2 or More Repeat Hospitalizations
Number of Patients
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*
*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.

8. COPD is Underdiagnosed:
Screening Spirometry in Primary Practice
Patients >40 years + 20 pack-year history of smoking
visiting a primary care physician for any reason
(n=1,003)
Screening for COPD
Patients meeting
criteria for COPD*
(n=208; 20.7%)
Previous diagnosis of COPD
(n=67; 32.7%)
*Criteria for COPD: FEV1/FVC < 0.70
Hill K, et al. CMAJ. 2010 Apr. 20;182(7):673-8.
Patients not meeting
criteria for COPD*
(n=795; 79.3%)
No previous diagnosis of COPD
(n=141; 67.3%)

9. Deterioration in Lung Function versus
Symptoms in COPD
100
Symptoms
FEV1 (% of predicted)
Severe
50
Asymptomatic
20
Lung function Lung function
normal
reduced
Mild
Axis of Progression
Sutherland EM, et al. N Engl J Med 2004 Jun 24;350(26):2689-87.

10. Why is pursuing the diagnosis of
COPD important for Mr. A.C.?

11. Relationship Between FEV1,
Smoking Status and CV Mortality
8
Odds Ratio for CV mortality
Current smoker
Ex-smoker
6
Never-smoker
4
2
0
<65
65-79
80-100
FEV1 % pred
Young RP, et al. Eur Respir J. 2007 Oct;30(4):616-22.
>100

12. Prediction of Death Within 5 years by GOLD
Categories and Presence of Comorbid Disease
# of comorbidities*
Hazard ratio
100
Three
Two
One
None
10
1
GOLD
3/4
GOLD
2
GOLD
1
*Diabetes, hypertension or CV disease
Mannino DM, et al. Eur Respir J. 2008 Oct;32(4):962-9.
R
GOLD
0
Normal

13. 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 often underdiagnosed and associated with poor
health status and prognosis
– Depression
– Lung cancer (most frequent cause of death in
mild COPD)
Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011.

14. Case Study (cont’d)
The rehab clinic
placed him on
salbutamol as
needed and asked for
him to follow up with
his GP.

15. How would you proceed with
Mr. A.C’s assessment?

16. Spirometry

17. Mr. A.C.: Spirometry Results
Pred. value
Observed pre
% Pred.
Observed
post
% pred.
% change
FVC (L)
5.64
5.23
93
5.77
102
10.3
FEV1 (L)
4.57
2.92
64
3.01
66
3.2
81
56
69
52
64
-6.4
FEF25-75 (L/S)
11.27
5.52
49
5.70
51
3.3
FEF50 (L/S)
5.64
2.02
36
1.73
31
-14.3
FEF75 (L/S)
2.82
0.75
27
0.59
21
-21.2
VE (L/min)
173
--
--
--
--
--
Raw insp. (cmH2O/l/s)
0.68
1.71
256
Parameter
FEV1/FVC (%)

18. Are these results more compatible
with asthma or COPD?

19. Spirometry Results = Asthma
PULMONARY FUNCTION ANALYSIS
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
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.

20. Distinguishing Asthma from COPD
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
Infrequent unless poorly
Sputum production
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
Adapted from O’Donnell DE, et al.:Can Respir J. 2007 Sep;14 Suppl B:5B-32B.

21. Case Study (cont’d)
His post bronchodilator spirometry
FEV1
FVC
FEV1/FVC
66%
102%
0.52
He is using his salbutamol 3-5 times a day.
How would you proceed?

22. Evaluating COPD Severity

23. Classification of COPD By Impairment
of Lung Function*
Spirometry (post bronchodilator)
Stage
FEV1
FEV1/FVC
≥80% predicted
<0.7
Moderate
50-79% predicted
<0.7
Severe
30-49% predicted
<0.7
<30% predicted
<0.7
Mild
Very severe
*In keeping with current GOLD criteria
O'Donnell DE, et al. Can Respir J. 2008 Jan-Feb;15 Suppl A:1A-8A.

24. MRC Dyspnea Scale and CTS COPD
Classification
none
Grade 1
Grade 2
severe
Stops for breath after walking 100 yards
Grade 5
Severe
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
Moderate
Short of breath when hurrying on the level
or walking up a slight hill
Grade 3
Mild
Breathless with strenuous exercise
Too breathless to leave the house or
breathless when dressing or undressing
Fletcher CM, et al. Br Med J. 1959 Aug 29;1:257-66.
O’Donnell DE, et al. Can Respir J. 2003 May-Jun;10 Suppl A:11A-33A.

25. Lung Function and Symptoms:
Both Are Tied to Outcomes
Cumulative Percent Survival (%)
Survival by ATS Stage
(based on FEV1)
Survival by
Level of Dyspnea
100
100
Grade II (n=67)
Stage I (n=42)
Stage II (n=59)
80
Stage III (n=82)
60
80
60
40
40
20
Grade III (n=87)
20
p = 0.08
Grade IV (n=26)
p < 0.001
Grade V (n=3)
0
0
0
10
20
30
40
50
Months of Follow-Up
Nishimura K, et al. Chest. 2002 May; 121(5):1434-40.
60
70
0
10
20
30 40
50
Months of Follow-Up
60
70

26. Mr. A.C.: CAT Score
I never cough
I cough all the time
1
I have no phlegm (mucus) in
my chest at all
0 1 2 3 4 5
My chest is completely
full of phlegm (mucus)
0
My chest does not feel tight
at all
0 1 2 3 4 5
My chest feels very tight
3
When I walk up a hill or one
flight of stairs I am not
breathless
0 1 2 3 4 5
When I walk up a hill or
on flight of stairs I am
very breathless
3
I am not limited doing any
activities at home
0 1 2 3 4 5
I am very limited doing
activities at home
4
0 1 2 3 4 5
I am not at all confident
leaving my home because
of my lung condition
3
I sleep soundly
Scoring
range
0-40
0 1 2 3 4 5
0 1 2 3 4 5
I don’t sleep soundly
because of my lung
condition
1
I have lots of energy
0 1 2 3 4 5
I have no energy at all
3
I am confident leaving my
home despite my lung
condition
Mr. A.C.'s
CAT score = 18

27. How would you treat Mr. A.C.?

28. Benefits of Smoking
Cessation

29. Smoking Cessation and FEV1
100
80
FEV1 (%)
60
40
Quit age 45
Symptoms
age 55
Disability
20
Death
0
20
30
40
50
60
Age (Years)
Adapted from Fletcher C, et al. Br Med J. 1977 Jun;1(6077):1645-8.
70
80
90

32. Why do we use bronchodilators
as first-line therapy?

33. Dynamic Lung Hyperinflation
Normal
COPD
(n=25)
(n=105)
Volume (%pred TLC)
140
140
120
120
100
VT IC
100
IRV
IC
80
80
60
60
40
40
RV
20
20
0
0
0
20
40
60
80
0
Ventilation (L/min)
O'Donnell DE, et al. Am J Respir Crit Care Med. 2001 Sep 1;164(5):770-7.
20
40
60
80

34. LAACs and LABAs Available in Canada
Mode of action
Long-acting anticholinergic (LAAC)
Also known as long-acting muscarinic antagonist (LAMA)
Individual agents
Tiotropium
Glycopyrronium Bromide
Formoterol
Long-acting beta2-agonist (LABA)
Salmeterol
Indacaterol

35. Long-Acting Anticholinergics
(LAACs)
Also known as long-acting
antimuscarinics (LAMAs)

36. Tiotropium vs. Ipratropium:
3-month FEV1 Response
Day 1
Day 8
Day 92
1.5
FEV1 (L)
1.4
1.3
1.2
Tiotropium 18 mcg o.d. (n=182)
Ipratropium 40 mcg q.i.d. (n=93)
1.1
-60
-5 30 60
120
180
240
Time after Administration (minutes)
Van Noord JA, et al. Thorax. 2000 Apr;55(4):289-94.
300
360

37. FEV1 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 µg o.d.
Placebo
1.8
Tiotropium
Glycopyrronium bromide
1.7
FEV1 (L)
1.6
1.5
1.4
1.3
1.2
0
1
2
3
Time post-dose (h)
p<0.01 for glycopyrronium bromide versus tiotropium at all timepoints 5 min to 4 h
Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14; Novartis, data on file.
4

38. Time to First Moderate or Severe
COPD Exacerbation
Glycopyrronium bromide 50 µg o.d. significantly prolonged the time to first exacerbation versus
placebo (HR 0.66, p=0.001), comparable with OL tiotropium 18 µg o.d. (HR 0.61, p=0.001 vs.
placebo)
Patients exacerbation free (%)
100
Treatment:
Glycopyrronium bromide 50 μg o.d.
Placebo
OL Tiotropium 18 μg o.d.
90
80
70
60
50
40
0
4
8
12
Number at Risk
Glycopyrronium bromide 495
Placebo
229
Tiotropium
245
451
202
222
426
188
209
16 20 24 28 32 36 40
Time to first exacerbation (weeks)
394
168
200
HR = hazard ratio
Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14.
370
159
190
360
153
184
341
142
176
335
137
169
318
129
166
310
129
163
44
48
52
296
122
157
282
116
155
239
98
129

39. Safety of anticholinergics

40. The key findings were that inhaled
anticholinergics are associated with
a significantly increased risk of
cardiovascular death, MI, or stroke
among patients with COPD.

42. Cardiovascular Events
Composite Endpoint* Used by Singh et al1, applied to UPLIFT2
Placebo
Tiotropium
Rate Ratio† (95 % CI)
n
Rate‡
n
Rate‡
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)
UPLIFT
†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.

43. Adverse Events (n, %)
in ≥3% of Any Treatment Group
Glycopyrronium
bromide
50 µg o.d.
N=525
Placebo
N=268
OL Tiotropium
18 µg 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.

44. Twice-daily
Long-acting Beta2 agonists
(LABAs)

45. Salmeterol vs. Ipratropium vs. Placebo in
COPD: Spirometric Impact
Change from baseline in FEV1(L)
0.5
Salmeterol
Ipratropium
Placebo
0.4
Day 84
0.3
0.2
0.1
0.0
1
2
3
4
-0.1
Mahler DA, et al. Chest. 1999 Apr; 115(4):957-65.
5
6
7
8
Time (hours)
9
10
11 12 13

46. Once-Daily LABAs

47. Mean Change in FEV1 on Day 1 of
Indacaterol Treatment
FEV1 mean change from baseline (mL)
Indacaterol 75 µg (N=150)
Placebo (N=155)
250
200
150
5 mins
post-dose
100
50
0
0
1
2
3
Time post dose (hours)
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).
4

48. Sustained Bronchodilation Over 24
Hours: Indacaterol vs. Placebo
1.60
Indacaterol 75 µg o.d.
Placebo
Improvement in FEV1 vs. placebo at every
time point, measured by 24-hour spirometry
1.55
1.50
FEV1 (L)
1.45
1.40
1.35
1.30
1.25
Rapid onset
within 5 minutes
1.20
0
4
8
12
Time (hours)
16
20
Adapted from:
Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012.
Novartis Pharmaceuticals Inc. Data on file (Study B2355).
24

49. 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?

51. Rehabilitation Is A Powerful Tool For
Improving QOL In COPD
0
Salmeterol1
Salmeterol/
fluticasone2 Tiotropium3
Rehabilitation4
-3.5
-4.5
-3.8
-7.1
-3.4
-2
-3
1 year
-4
6 months
-5
1 year
Clinical
significance
threshold
1 year
Improvement
Changes in total SGRQ score
-1
-6
-7
-8
SGRQ = St George’s 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.
6 weeks
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.

53. Combining Bronchodilators in
Mild to Moderate COPD

54. Dual Bronchodilation with
Formoterol + Tiotropium
Total COPD Symptom Score‡
Trough FEV1: Change from baseline
200
150
†
n=108
*
n=118
n=127
0
*
n=106
*
n=121
n=121
n=121
100
n=129
50
0
Week 4
Week 8
Week 12
Last visit
Mean change in symptom score
Change from baseline
in trough FEV1 (mL)
250
AM
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
*
-1.4
-1.6
Formoterol (12 µg b.i.d.) +
tiotropium (18 µg o.d.)
PM
AM/PM
average
*
*
Tiotropium (18 µg o.d.)
*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.

55. LABA/LAMA Provides Better Improvements
in Lung Function at 6 Weeks Than LABA/ICS
Tiotropium 18 μg o.d. +
formoterol 12 μg b.i.d.
1.8
Salmeterol 50 μg b.i.d. +
fluticasone propionate 500 μg b.i.d.
FEV1 (L)
1.7
1.6
1.5
1.4
1.3
0
1
2
3
4
5
6
7
8
9
Time after drug administration (hours)
*p<0.05 between groups at each time point
Rabe KF, et al. Chest. 2008 Aug;134(2):255-62.
10
11
12

56. Is there any reason not to use ICS
therapy at this point in his
management?

57. Lack of Benefit with LABA/ICS vs. LABA
Alone in Stable COPD: Meta-analysis
Study or Subgroup
LABAs/ICS
LABAs
Risk Ratio
Risk Ratio
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%
Calverley (17)
5 254
14 255
5.3%
Calverley (23)
193 1533 205 1521 78.4%
Ferguson (25)
6 394
3 388
1.2%
Kardos (24)
7 507
9 487
3.5%
Safranski (20)
6 208
6 201
2.3%
SCO100250 (29)
4 394
6 403
2.3%
SCO100470 (30)
3 518
3 532
1.1%
SCO40041 (28)
5
92
7
94
2.6%
Tashkin (26)
7 845
1 284
0.6%
Wouters (21)
2 189
4 184
1.5%
Subtotal (95% CI)
5292
4721 100.0%
Total events
240
261
Heterogeneity: Chi2 = 6.52, df = 10 (P = 0.77), I2 = 0%
Test for overall effect Z = 1.27 (P = 0.20)
Rodrigo GJ, et al. Chest. 2009 Oct;136(4):1029-38.
0.69 (0.12, 4.12)
0.36 (0.13, 0.98)
0.93 (0.78, 1.12)
1.97 (0.50, 7.82)
0.75 (0.28, 1.99)
0.97 (0.32, 2.95)
0.68 (0.19, 2.40)
1.03 (0.21, 5.07)
0.73 (0.24, 2.22)
2.35 (0.29, 19.04)
0.49 (0.09, 2.63)
0.90 (0.76, 1.06)

58. Bone Density vs. Dose and Duration
of ICS Therapy
Lumbar Spine
2.0
Ward’s Triangle
2.0
r=-0.53
p=0.01
r=-0.58
p=0.005
Z score
Z score
2.0
Femoral Neck
-2.5
-2.5
0
Dose x Duration/BMI
4
r=-0.33
p=0.08
Z score
-2.5
0
Dose x Duration/BMI
Hanania NA, et al.: J Allergy Clin Immunol 1995; 96(5 Pt 1):571-9.
4
0
Dose x Duration/BMI
4

59. "More" Combination Therapies
Endurance Time (mins)
24
*
Rehabilitation *
20
32%
42%
16
Control
12
8
Tiotropium
0
2
4
6
8
10
12
14
16
Weeks on Treatment
* p<0.05
Casaburi R, et al. Chest. 2005 Mar;127(3):809-17.
18
20
22
24

60. 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?

61. Patients Who Exacerbate
Frequently Account for a Small
but Important Portion of the
Overall COPD Population
27%
16%
Hurst JR, et al. N Engl J Med. 2010 Sept 16;363(12):1128-38.
11%

63. Risk
Symptoms
(C)
(D)
>2
3
2
(A)
(B)
1
1
0
mMRC 0-1
CAT < 10
mMRC > 2
CAT > 10
Symptoms
(mMRC or CAT score)
Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011.
(Exacerbation history)
Lung function
impairment
4
Risk
GOLD assessment
variables are similar
to 2007 Cdn.
Recommendations:
(GOLD Classification of Airflow Limitation)
GOLD: Combined Assessment of COPD

65. 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.

66. Patient Factors in COPD
Management

67. 12-month Persistence with Inhaled
Medications: Canadian Data
Ipratropium
(Atrovent®)
8%
Four times daily
Ipratropium/salbutamol
(Combivent®)
12%
Formoterol
(Oxeze®)
Salmeterol
(Serevent)®
16%
18%
Twice daily
Formoterol-budesonide
(Symbicort®)
25%
Salmeterol/fluticasone
(Advair)®
32%
Once daily
Tiotropium
(Spiriva®)
53%
0
10
20
30
40
% continuing for 12 months
Adapted from Cramer JA, et al. Can Respir J. 2007 Jan-Feb;14(1):25-9.
50
60

68. Does the device make
a difference?

69. COPD Treatment Options
Tiotropium
Salmeterol /
Fluticasone
Formoterol
Salmeterol
Indacaterol
Formoterol/
Budesonide
LAAC/
LAMA
LAAC
LABA + ICS
(FDC)
LABA
LABA
LABA
LABA + ICS
(FDC)
Handihaler
(18 µg/
inhalation)
Mode
of
Action
Glycopyrronium
bromide
Breezhaler
(50 µg /
inhalation)
Aerolizer
(12 µg /
capsule)
Diskus DPI
(50 µg /
inhalation)
Breezhaler
(75 µg /
inhalation)
Turbuhaler
DPI (6 &
12 µg /
inhalation)
Diskhaler
Disk DPI
(50 µg /
inhalation)
Diskus DPI
(50/250 µg
and
50/500 µg /
inhalation)
Devices
Aerosol MDI
(25/50,
25/125 or
25/250 µg /
inhalation)
Turbuhaler DPI
(110/6 or
200/6 μg /
inhalation)

70. Flow Rates with Various Inhalers Used
for COPD Medications
120
Increasing Resistance
Breezhaler®
Flow rate (L/min)
100
Diskus® /
Accuhaler®
80
Turbuhaler®
HandiHaler®
60
kPa1/2 L-1 min
40
Breezhaler®
Diskus®/Accuhaler®
Turbuhaler®
HandiHaler®
20
0
0
2
4
6
Inspiratory effort (kPa)
8
2.2 x 10-2
2.7 × 10-2
3.4 × 10-2
5.1 × 10-2
10
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).

71. 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

72. 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 mildto-moderate obstruction, use long acting
bronchodilators; given once daily improves
adherence.
• For exacerbation-prone patients, triple therapy is
recommended

73. Back-up Information
Additional supporting information
for use at the facilitators' discretion

74. 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?

76. Mortality Increases with Frequency of
AECOPD
1.0
Probability of surviving
0.8
0 AEs
p<0.0002
0.6
1-2 AEs
0.4
p=0.069
>3 AEs
0.2
0.0
0
10
30
20
Time (months)
Soler-Cataluña JJ, et al. Thorax. 2005 Nov;60(11):925-31.
40
50
60
p<0.0001

77. Is triple therapy effective?

78. OPTIMAL Study Design
Tiotropium qd + Placebo MDI 2 puffs bid n=156
Run-in
Tiotropium
+ Placebo
R
Tiotropium qd + Salmeterol MDI 2 puffs bid n=148
Tiotropium qd + Salmeterol/Fluticasone 50/250 MDI 2 puffs bid n=145
Visit:
Month:
1
-0.5
2
0
3
1
Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55.
4
4
5
8
6
12

79. OPTIMAL Study: Primary Outcome –
Proportion of Patients with Exacerbations
Tiotropium + placebo (n=156)
62.8
Tiotropium + salmeterol (n=148)
64.8
Tiotropium + fluticasone/salmeterol
(n=145)
60
0
Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55.
20
40
% of patients
60
80

80. OPTIMAL Study: Secondary Outcome
Variable – COPD Hospitalizations
Tiotropium + placebo (n=156)
49
Tiotropium + salmeterol (n=148)
38
Tiotropium + fluticasone/salmeterol
(n=145)
p = 0.01
26
0
Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55.
10
20
30
40
Number of patients
50
60

81. What is the impact of oral PDE4
inhibitors (roflumilast)?

82. Proportion of Patients with a Moderate or
Severe Exacerbation
Patients with an exacerbation (%)
sal or tio + placebo
20
18
16
16
12
sal or tio + roflumilast 500 µg
11
11
8
4
0
n=83/467 n=51/466
n = 83/467 n = 51/466
Salmeterol study
RiR = 0.60
(95% CI 0.43, 0.82)
p = 0.0015
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.
n=58/372
n = 58/372
n=42/371
n = 42/371
Tiotropium study
RiR = 0.73
(95% CI 0.51, 1.05)
p = 0.0867

83. Roflumilast: Incidence of AEs
( 2.5%)*
AURA/HERMES
1 year
Adverse Event
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.

84. Risk of ICS

85. Lack of Benefit with ICS on FEV1
Decline in COPD: Meta-analyses
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)
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.

86. Inhaled Corticosteroids and the Risk of
Cataracts - Dose Response
3.1
Puffs/Wk
> 28
15-28
14 or less
2.1
1.3
0
0.5
1
p < 0.001
Data are for posterior, subcapsular cataracts
Cumming RG, et al.: N Engl J Med 1997; 337(1):8-14.
1.5
2
Prevalence ratio
2.5
3
3.5

87. Increased Risk of Pneumonia with
ICS vs. Placebo in COPD: Meta-analysis
Subgroup
# of events / # of patients
Odds Ratio
95% CI
180 / 3633
1.51
1.08 – 2.10
356 / 4754
217 / 4728
1.72
1.28 – 2.30
641 / 8635
397 / 8361
1.60
1.33 – 1.92
ICS
No ICS
ICS vs. placebo
285 / 3881
ICS + LABA vs. LABA
Total
Singh S, et al.: Arch Intern Med 2009; 169(3):219-29.

88. Increased Risk of New-onset Diabetes
with Increasing ICS Dose
3.5
Rate Ratio
3.0
2.5
2.0
1.5
1.0
0.5
0
250
500
750
1000
1250
1500
Daily dose in fluticasone equivalents (mcg)
Suissa S, et al. Am J Med. 2010 Nov;123(11):1001-6.
1750
2000

89. Patient Preference

90. Inhaler Regimens: Patient Preferences
27%
Once Daily
Twice Daily
No Preference
12%
Venables TL, et al. Br J Clin Res. 1996;7:15-32.
61%

91. Breezhaler® vs. Handihaler®:
Comfort, Simplicity & Confidence
Mean score ± SE
Breezhaler®
9.2
9.0
8.8
8.6
8.4
8.2
8.0
7.8
7.6
7.4
Handihaler®
***
*
*
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® 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.

92. Receptor Selectivity: Glycopyrronium Bromide
versus Tiotropium
M3:M2 selectivity
ratio*
Equilibrium affinity: Glycopyrronium bromide has greater M3 versus M2 receptor
binding selectivity than tiotropium (5-fold vs. 2-fold)
14
12
10
8
6
4
2
0
12.9
Selectivity
(ratio)
pKi M2
Tiotropium
Glycopyrronium
bromide
Tiotropium
10.050.05
10.370.
04
2
Glycopyrronium
bromide
4.4
pKi M3
8.700.04
9.470.0
2
5
*Ratio of occupancy versus time over 24 hours
t½ at M2
(min)
t½ at M3
(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 M2
versus M3 receptor than
tiotropium (9-fold vs. 4-fold)
Clinical Implications
a) faster time of onset
b) ? Increased cardiac safety

93. Sample:
Plan
of Action

94. Tools and Resources
Where can I learn more on the subject of
spirometry in primary care?
http://www.respiratoryguidelines.ca/2013cts-slide-kit-spirometry-in-primaary-care