Morbidity of copd symptoms
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The Morbidity of COPD Symptoms
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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
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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.
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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
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The Evolving Epidemiology of COPD in Canada
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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
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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*
Nu
mb
er
of
Pat
ien
ts
Single Hospitalization
1 Repeat Hospitalization
2 or More Repeat Hospitalizations
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COPD is Underdiagnosed: Screening Spirometry in Primary Practice
*Criteria for COPD: FEV1/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%)
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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
Sym
pto
ms
FEV
1 (
% o
f p
red
icte
d)
Axis of Progression
Lung function normal
Asymptomatic
Lung function reduced
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Why is pursuing the diagnosis of COPD important for Mr. A.C.?
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Relationship Between FEV1, Smoking Status and CV Mortality
Young RP, et al. Eur Respir J. 2007 Oct;30(4):616-22.
Od
ds
Rat
io f
or
CV
mo
rtal
ity
8
6
4
2
0 <65 65-79 80-100 >100
Current smoker
Ex-smoker
Never-smoker
FEV1 % pred
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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
Haz
ard
rat
io
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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
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Case Study (cont’d)
The rehab clinic placed him on salbutamol as needed and asked for him to follow up with his GP.
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How would you proceed with Mr. A.C’s assessment?
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Spirometry
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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
FEV1 (L) 4.57 2.92 64 3.01 66 3.2
FEV1/FVC (%) 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
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Are these results more compatible with asthma or COPD?
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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.
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Distinguishing Asthma from COPD
Adapted from O’Donnell 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
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His post bronchodilator spirometry FEV1 66%
FVC 102%
FEV1/FVC 0.52
He is using his salbutamol 3-5 times a day.
Case Study (cont’d)
How would you proceed?
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Evaluating COPD Severity
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Classification of COPD By Impairment of Lung Function*
Stage Spirometry (post bronchodilator)
FEV1 FEV1/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.
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MRC Dyspnea Scale and CTS COPD Classification
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.
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
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Lung Function and Symptoms: Both Are Tied to Outcomes
Survival by ATS Stage (based on FEV1)
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
Cu
mu
lati
ve P
erce
nt
Surv
ival
(%
) 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)
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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 don’t 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
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How would you treat Mr. A.C.?
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Benefits of Smoking Cessation
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Smoking Cessation and FEV1
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
FEV
1 (
%)
Age (Years)
Death
Disability
Symptoms Quit age 45
age 55
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Why do we use bronchodilators as first-line therapy?
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Ventilation (L/min)
Vo
lum
e (
%p
red
TLC
)
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.
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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 beta2-agonist (LABA)
Formoterol
Salmeterol
Indacaterol
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Long-Acting Anticholinergics (LAACs)
Also known as long-acting antimuscarinics (LAMAs)
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Tiotropium vs. Ipratropium: 3-month FEV1 Response
Van Noord JA, et al. Thorax. 2000 Apr;55(4):289-94.
Time after Administration (minutes)
FEV
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)
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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.
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
FEV
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
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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)
Pat
ien
ts e
xace
rbat
ion
fre
e (
%)
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 μg o.d.
Placebo
OL Tiotropium 18 μg o.d.
HR = hazard ratio Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14.
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Safety of anticholinergics
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The key findings were that inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.
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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 al1, applied to UPLIFT2
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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.
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Twice-daily Long-acting Beta2 agonists (LABAs)
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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 Ch
ange
fro
m b
ase
line
in F
EV1
(L)
Day 84
Salmeterol Ipratropium Placebo
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Once-Daily LABAs
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Mean Change in FEV1 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
FEV
1 m
ean
ch
ange
fro
m b
ase
line
(m
L)
Time post dose (hours)
Indacaterol 75 µg (N=150) Placebo (N=155)
5 mins post-dose
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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)
FEV
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 µg o.d. Placebo
Improvement in FEV1 vs. placebo at every time point, measured by 24-hour spirometry
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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?
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Rehabilitation Is A Powerful Tool For Improving QOL In COPD
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.
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.
Ch
ange
s in
to
tal S
GR
Q s
core
-5
-4
-3
-2
-1
0
-6
-7
-8
Salmeterol1
Salmeterol/ fluticasone2 Tiotropium3 Rehabilitation4
6 months
1 year
1 year
6 weeks
1 year
-3.5
-4.5
-3.8
-7.1
-3.4
Clinical significance threshold
Imp
rove
me
nt
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Combining Bronchodilators in Mild to Moderate COPD
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Formoterol (12 µg b.i.d.) + tiotropium (18 µg o.d.)
Tiotropium (18 µg o.d.)
Trough FEV1: 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.
Me
an c
han
ge in
sym
pto
m s
core
*
* *
AM PM AM/PM average
0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6
Ch
ange
fro
m b
ase
line
in
tro
ugh
FEV
1 (
mL)
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
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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 μg o.d. + formoterol 12 μg b.i.d.
Salmeterol 50 μg b.i.d. + fluticasone propionate 500 μg b.i.d.
FEV
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
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Is there any reason not to use ICS therapy at this point in his management?
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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: Chi2 = 6.52, df = 10 (P = 0.77), I2 = 0%
Test for overall effect Z = 1.27 (P = 0.20)
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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
Ward’s Triangle
Z score Z score
Z score
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"More" Combination Therapies
* p<0.05 Casaburi R, et al. Chest. 2005 Mar;127(3):809-17.
* *
32% 42%
End
ura
nce
Tim
e (
min
s)
Weeks on Treatment
Control
Tiotropium
24
20
12
16
8 0 2 4 6 8 10 12 14 16 18 20 22 24
Rehabilitation
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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?
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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.
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GOLD: Combined Assessment of COPD
Ris
k
(GO
LD C
lass
ific
atio
n o
f A
irfl
ow
Lim
itat
ion
)
Ris
k
(Exa
cerb
atio
n h
isto
ry)
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.
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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.
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Patient Factors in COPD Management
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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
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Does the device make a difference?
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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 µg/
inhalation)
Breezhaler (50 µg /
inhalation)
Diskus DPI (50/250 µg
and 50/500 µg / inhalation)
Aerosol MDI (25/50,
25/125 or 25/250 µg / inhalation)
Aerolizer (12 µg / capsule)
Turbuhaler DPI (6 & 12 µg /
inhalation)
Diskus DPI (50 µg /
inhalation)
Diskhaler Disk DPI (50 µg /
inhalation)
Breezhaler (75 µg /
inhalation)
Turbuhaler DPI (110/6 or
200/6 μg / inhalation)
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Breezhaler®
0
20
40
60
80
100
120
0 2 4 6 8 10
Inspiratory effort (kPa)
Flo
w r
ate
(L/
min
)
kPa1/2 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®
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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
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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
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Back-up Information
Additional supporting information for use at the facilitators' discretion
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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?
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Mortality Increases with Frequency of AECOPD
Soler-Cataluña JJ, et al. Thorax. 2005 Nov;60(11):925-31.
Time (months)
0
Pro
bab
ility
of
surv
ivin
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
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Is triple therapy effective?
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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
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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
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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
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What is the impact of oral PDE4 inhibitors (roflumilast)?
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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 µg
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
atie
nts
wit
h a
n e
xace
rbat
ion
(%
)
16
11 11
18
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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.
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Risk of ICS
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Lack of Benefit with ICS on FEV1 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)
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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
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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.
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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)
Rat
e R
atio
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Patient Preference
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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
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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®
Me
an s
core
± S
E
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Receptor Selectivity: Glycopyrronium Bromide versus Tiotropium
Equilibrium affinity: Glycopyrronium bromide has greater M3 versus M2 receptor binding selectivity than tiotropium (5-fold vs. 2-fold)
pKi M2 pKi M3
Selectivity (ratio)
Tiotropium 10.050.05 10.370.
04 2
Glycopyrronium bromide
8.700.04 9.470.0
2 5
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
M3
:M2
se
lect
ivit
y ra
tio
*
*Ratio of occupancy versus time over 24 hours
14 12 10
0
8 6 4 2
Glycopyrronium bromide
Tiotropium
4.4
12.9
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Sample: Plan of Action
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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