Updated Managemnet of COPD Prof.M.Awad3

Report
Updated Management of COPD
Prof. Mohamed Awad Tag El Din
Agenda:
•
•
•
•
•
•
Definition
Burden
Assessment
Management
Role of bronchodilators
Clinical outcomes
Definition of COPD
 COPD, a common preventable and treatable disease, is
characterized by persistent airflow limitation that is usually
progressive and associated with an enhanced chronic
inflammatory response in the airways and the lung to noxious
particles or gases.
 Exacerbations and comorbidities contribute to the overall
severity in individual patients.
GOLD 2014
The burden of disability from COPD is
projected to increase
 Newer projections estimated COPD will be the fourth leading
cause of death in 2030.
 And the seventh leading cause of DALYs lost worldwide in 2030.
GOLD 2014
Smoking is the most encountered risk
factor for COPD
 Smoking is considered by far the most important risk factor
associated with functional decline in COPD.
 Smokers:
 Have more respiratory symptoms.
 Have a greater annual rate of lung function decline, as assessed
by change in FEV1.
 At greater risk of premature mortality due to COPD than
nonsmokers.
Proc Am Thorac Soc Vol 3. pp 635–640, 2006
Smoking cessation can slow the rate of
lung function decline
Never smoked or not
susceptible to smoke
FEV1 (% of value at age 25)
100
80
Smoked regularly
and susceptible
to its effects
60
Stopped at 45
40 Disability
20
Stopped at 65
Death
0
25
50
75
Age (years)
Adapted from Fletcher C, et al. Br Med J. 1977; 1: 1645–1648.
GOLD 2014
Initiative For
COPD
Spirometry is required for the diagnosis of
COPD

Key Indicators to Consider COPD Diagnosis:
• SYMPTOMS
1
• Dyspnea-progressive (worsens over time and with exercise)
• Chronic cough
• Sputum
• HISTORY OF EXPOSURE TO RISK FACTORS
2
3
• Tobacco smoke
• Smoke from home cooking/heating fuels
• Occupational dusts and chemical
• FAMILY HISTORY OF COPD
SPIROMETRY REQUIRED TO DIAGNOSE COPD
Presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation and thus of COPD.
Adapted from GOLD 2014
The Goals of COPD assessment
To Determine:
• The severity of the disease
• The impact on the patient’s health status
• The risk of future events.( such as exacerbations, hospital
admissions or death)
GOLD 2014
Assessment of COPD based on symptoms
and future risk
1.
2.
3.
4.
Assess symptoms
Assess degree of airflow limitation using spirometry
Assess risk of exacerbations
Assess comorbidities
GOLD 2014
1.
2.
3.
4.
Assess symptoms
Assess degree of airflow limitation using spirometry
Assess risk of exacerbations
Assess comorbidities
GOLD 2014
Assess symptoms
COPD Assessment Test (CAT)
Clinical COPD Questionnaire (CCQ)
Modified Medical Research Council Breathlessness scale
(mMRC)
Adapted from GOLD 2014
Clinical COPD Questionnaire (CCQ):
 10 item self-administered questionnaire developed to
measure clinical control in patients with COPD.
 Short and easy to administer.
 Cut point for high symptoms patient appears to be in the
range ≥1.
Global Initiative for Chronic Obstructive Lung Disease 2014
Clinical COPD Questionnaire (CCQ) cont.’:
The questions in the Clinical COPD Questionnaire (CCQ)
are divided into three areas, or domains:
 Symptoms
 Functional state
 Mental state
The total score is calculated by adding the scores of the
ten items and dividing that number by ten (= number
of items)
http://ccq.nl/?page_id=15 last accessed 18 Feb. 2014
GOLD 2014:
Use of the COPD Assessment Test (CAT) and Modified Medical Research
Council (mMRC) shortness of breath scale1
mMRC2,3
 Patient selects one statement that most closely applies to them from
five about perceived shortness of breath
◦ 0–1: From being breathless only with strenuous exercise, to being short of breath
when hurrying on the level or walking up a slight hill
◦ 2+: From being slower/having to stop than most people of the same age due to
breathlessness, to being too breathless to leave the house or breathless when
dressing
CAT4
 Patient-completed questionnaire, with eight items (cough, phlegm,
chest tightness, shortness of breath, activity limitation, confidence,
sleep and energy) to be scored on a scale of 05 depending on their
impact
 The sum of the patient’s score = impact score from 0 to 40
◦ <10: Low impact from COPD (Most days are good; condition stops people from
doing one/two things they want to do; cough several days a week)
◦ ≥10: Medium to very high impact from COPD
1. GOLD 2014; 2. Bestall et al. 1999; 3. Mahler et al. 2009; 4. Jones et al. 2009
Assessment of COPD based on symptoms
and future risk
1.
2.
3.
4.
Assess symptoms
Assess degree of airflow limitation using spirometry
Assess risk of exacerbations
Assess comorbidities
GOLD 2014
Assessment of COPD
Assess degree of airflow limitation
(Spirometry)
Spirometric classification of airflow limitation (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)
Adapted from GOLD 2014
Assessment of COPD based on symptoms
and future risk
1.
2.
3.
4.
Assess symptoms
Assess degree of airflow limitation using spirometry
Assess risk of exacerbations
Assess comorbidities
GOLD 2014
An exacerbation of COPD is:
 An acute event characterized by a worsening of the patient’s
respiratory symptoms that is beyond normal day-to-day
variations and leads to a change in medication.
© 2014 Global Initiative for Chronic Obstructive Lung Disease
Assessment of COPD
Assess risk of exacerbations
History of exacerbations (Two or more exacerbations in the
preceding year).
Spirometry (GOLD 3 or GOLD 4 categories).
Adapted from GOLD 2014
High Symptoms indicators
COPD Assessment Test CAT ≥10
Modified Medical Research Council Breathlessness scale
mMRC ≥2
Adapted from GOLD 2014
Adapted from GOLD 2014
High risk Indicators :
GOLD 3 or GOLD 4 categories
Two or more exacerbations in the preceding year.
1 exacerbation leading to hospital admission
Adapted from GOLD 2014
Adapted from GOLD 2014
Assessment of COPD based on symptoms
and future risk
1.
2.
3.
4.
Assess symptoms
Assess degree of airflow limitation using spirometry
Assess risk of exacerbations
Assess comorbidities
GOLD 2014
Assessment of COPD based on symptoms and
future risk
Assess comorbidities
Comorbidities should be actively looked for and
treated appropriately
Most frequent comorbidities are cardiovascular
disease, depression and osteoporosis
Adapted from GOLD 2014
Combined assessment of COPD

Assess symptoms first

Assess risk of exacerbations next

When assessing risk, choose the highest risk according to
GOLD grade or exacerbation history

Patient is now in one of four categories
Adapted from GOLD 2014
GOLD 2014
Combined assessment of COPD

Assess symptoms first

Assess risk of exacerbations next

When assessing risk, choose the highest risk according to
GOLD grade or exacerbation history

Patient is now in one of four categories
Adapted from GOLD 2014
COPD Management
GOLD 2014
Combined assessment of COPD
(GOLD Classification of Airflow Limitation)
GOLD 3
Less symptoms
High risk
More symptoms
high risk
GOLD 2
GOLD 1
≥2
or
≥1 leading
to hospital
admission
1 (not leading
to hospital
admission)
Less symptoms
Low risk
CAT < 10
mMRC 0–1
More symptoms
low risk
Symptoms
Breathlessness
RISK
(EXACERBATION HISTORY)
Risk
GOLD 4
0
CAT≥10
mMRC ≥ 2
Adapted from GOLD 2014
COPD Management:
 Disease Management should now be focusing on 2 key areas
1.
2.
Reducing Symptoms
Reducing Risk.
Adapted from GOLD 2014
Non Pharmacologic Treatment
Smoking Cessation
Physical Activity
Vaccination
Rehabilitation
GOLD 2014
Non-pharmacological management of COPD
Pulmonary rehabilitation offered to a broader group of patients
GOLD
2014
Patients
Essential
Recommended
Depending upon local
guidelines
A
Smoking cessation (may include Physical activity
pharmacological support)
Flu/Pneumococcal
vaccination
B–D
Smoking cessation (may include Physical activity
pharmacological support)
Pulmonary rehabilitation
Flu/Pneumococcal
vaccination
Adapted from GOLD 2014
Pharmacologic Treatment
Pharmacologic treatment is used to:
Reduce Symptoms
Reduce frequency and severity of exacerbations
Improve health status
Improve exercise tolerance
GOLD 2014
Patient Type (A)
Treatment Options
First Recommended
choice:
• SABA Prn Or SAMA Prn
Alternative choice:
•LABA
or
•LAMA
or
•SABA and SAMA
0-1
not leading
to hospital
admission
GOLD 2
GOLD 1
Less symptoms
Low risk
MMRC 01
CAT <10
Other Possible Choices*:
• Theophylline
*Other Possible Choices can be used alone or in combination with other options in the First and Second columns
Adapted from GOLD 2014
Patient Type (B)
Treatment Options
First Recommended choice:
• LABA or LAMA
Alternative choice:
GOLD 1
• LABA and LAMA
Other Possible Choices*:
• SABA and/or SAMA
• Theophylline
0-1
not leading
to hospital
admission
GOLD 2
More symptoms
low risk
MMRC ≥2
CAT ≥10
*Other Possible Choices can be used alone or in combination with other options in the First and Second columns
Adapted from GOLD 2014
Patient Type (C)
Treatment Options
First Recommended choice:
• ICS + LABA
or
• LAMA
Alternative choice:
• LABA and LAMA
GOLD 4
GOLD 3
Or
• LABA and PDE4-inh
• LAMA and PDE4-inh
Less symptoms
High risk
≥1 Or ≥2
leading
to hospital
admission
MMRC 01
CAT <10
Other Possible Choices*:
• SABA and/or SAMA
• Theophylline
*Other Possible Choices can be used alone or in combination with other options in the First and Second columns
Adapted from GOLD 2014
Patient Type (D)
Treatment Options
First Recommended choice:
• ICS + LABA
And/ or
• LAMA
GOLD 4
Alternative choice:
• ICS + LABA and LAMA or
• ICS+LABA and PDE4-inh. or
• LABA and LAMA or
• LAMA and PDE4-inh
Other Possible Choices*:
GOLD 3
More symptoms
high risk
≥1 Or ≥2
leading
to hospital
admission
MMRC ≥2
CAT ≥10
• Carbocysteine
• SABA and/or SAMA
• Theophylline
*Other Possible Choices can be used alone or in combination with other options in the First and Second columns
Adapted from GOLD 2014
Role of Bronchodilators in COPD
GOLD 2014
BD
Deflation
V  Air flow
 Improvement in flow – FEV1
 Improvement in volumes – FVC and IC
BD = bronchodilator; V = ventilation; FEV1= forced expiratory volume in 1 second;
FVC= forced vital capacity; IC = inspiratory capacity
Bronchodilators work by:
Reduces the
Improvement in
exercise tolerance
elastic load on
the
inspiratory
muscles.
Allowing improved lung
emptying with each breath
Relieve dyspnea by
deflating the lungs
Eur Respir Rev 2006; 15: 99, 37–41
Role of LABA in COPD
•In fact, several prospective randomized trials
and a high quality meta-analysis have showen
that LABAs:
Improve lung function.
Improve health status related quality of life.
Reduce exacerbations in symptomatic patients with moderateto-severe COPD.
(Manet al 2003; Sin et al 2003)
International Journal of COPD 2008:3(4) 521–529
Role of LABA in COPD
• Airway smooth muscle relaxation through β2-adrenoceptor
stimulation, leading to an increase in cyclic adenosine monophosphate, improves airway patency and provides also a
significant relief from exercise and Dyspnea.
(Manet al 2003; Sin et al 2003)
Rossi et al ,international Journal of COPD 2008:3(4):521-529
What is needed to improve bronchodilator
therapy in COPD?
There is a need for novel once-daily LABAs1
with fast onset of action and superior efficacy
over existing bronchodilators
1. Cazzola, Matera. Br J Pharmacol 2008
Once-daily treatment with fast onset
can help improve compliance
There is a need to develop effective treatments for
COPD with simplified treatment regimens
(infrequent dosing, simple delivery), rapid onset of
action and durable effect, which would increase
the probability of patient adherence.
Bourbeau & Bartlett 2008
Indacaterol once daily
β2-agonist
Indacaterol demonstrates fast onset of
bronchodilator effect at 5 minutes post-dose.1 and
sustained bronchodilation over 24 hours.2
1-Balint, et al. Int J COPD 2010;5:311–8.
2- Vogelmeier et al. Respiratory Research 2010, 11:135
Indacaterol demonstrates fast onset
of bronchodilator effect at 5 minutes
post-dose
LS mean of FEV1 ( L)
1.6
***
***
1.5
***
**
1.4
1.3
1.2
Placebo
(n=88)
N= 89 patients
Salmeterol/ Salbutamol
fluticasone
(n=86)
(n=88)
Indacaterol Indacaterol
150 µg
300 µg
(n=85)
(n=87)
***p<0.001,
**p<0.01 versus placebo
Data are least squares mean (LSM) with standard errors of the mean at 5 minutes post-dose
INSURE: INdacaterol: Starting qUickly and Remaining Effective in COPD
Balint, et al. Int J COPD 2010;5:311–8.
Indacaterol provided sustained
bronchodilation over 24 hours
1.65
†
†
1.60
Indacaterol 150 µg
†
†
†
Indacaterol 300 µg
†
†
Tiotropium
Placebo
1.55
FEV1 (L)
†
1.50
1.45
1.40
1.35
1.30
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Data are LSM±SE.
Time post-dose
(hours)
n= 153 patients
p<0.001 for indacaterol (150 and 300 µg) vs placebo at each timepoint, p<0.001 for indacaterol
150 µg vs tiotropium at 5 and 15 minutes, †p<0.05 for indacaterol 300 µg vs tiotropium, p<0.05 for
tiotropium vs placebo at each timepoint
INTIME: INdacaterol & TIotropium: Measuring Efficacy
Vogelmeier et al. Respiratory Research 2010, 11:135
 Pooled analysis of 11 placebo-controlled studies
 Aim: determine Optimal Indacaterol dosage
 Primary endpoint: trough FEV1 with a duration of at
least 14 days.
 n=7,476 COPD patients
 Patients received Indacaterol 18.75-600 µg o.d.
Renard D, et al. 2011 Respir Res; 12:54
Indacaterol 300 μg provide optimal bronchodilation,
particularly in patients with severe disease.
Ranking of efficacy by dose
Renard D, et al. 2011 Respir Res; 12:54
Indacaterol 300 µg provides significant improvement in
trough FEV1 over 52 weeks, superior to Formoterol
Formoterol 12 μg b.i.d. (n=373)
Placebo (n=364)
Indacaterol 300 μg o.d. (n=383)
100 ml
20 ml
†††
†
1.5
Trough FEV1 (L)
1.45
***
1.48
***
***
1.43
†††
***
1.45
1.43
***
1.38
1.4
1.35
110 ml
*
1.31
1.32
1.31
1.28
1.3
1.25
1.2
1.15
After 1 day
Week 12
Week 52
*p<0.05, ***p<0.001 vs placebo; †p<0.05, †††p<0.001 vs Formoterol
Dahl et al. Thorax 2010;65:473–9.
Once Daily Indacaterol Pooled Analysis Clinical efficacy in
COPD-Patients with severe dyspnoea (mMRC>2)
*p<0.05, ***p<0.001 vs placebo; †††p<0.001 for difference vs tiotropium; ‡p=0.008 for difference vs
indacaterol 150 μg
Mahler et al. ERS Annual Congress 2012
Indacaterol reduces breathlessness as indicated by
improvements in TDI score at all assessments
points
Placebo
Tiotropium 18 µg o.d.
3.0
***
†††
***
†††
2.5
TDI total score
Indacaterol 150 µg o.d.
***
Indacaterol 300 µg o.d.
***
†
***
***
***
***
***
***
***
2.0
1.5
1.0
0.5
0.0
n=
342 372 367 367
324 353 348 360
326 360 355 363
309 349 343 353
Week 4
Week 8
Week 12
Week 26
Data are LSM and 95% confidence intervals
***p<0.001 versus placebo, †p<0.05, †††p<0.001 versus tiotropium
TDI = transition dyspnea index
Donohue JF et al. Am J Respir Crit Care Med 2010;182:155–62.
Indacaterol 300 μg dose was superior compared
to the twice-daily β2-agonists
Jones PW et al, Respir Med 2011; 105 (6): 892-9.
Indacaterol 300 μg dose was superior compared
to the twice-daily β2-agonists
Differences between active and placebo treatments in TDI total score after 6 months (pooled data). 1
Patient numbers were 602 (Indacaterol 150 μg QD), 651 (Indacaterol 300 μg QD ), 317 (formoterol 12 μg
BID), 320 (tiotropium 18 μg QD ), 279 (salmeterol 50 μg BID) and 823 (placebo). 1
Data are least square means and 95% CI.1
Dotted line indicates the MCID (minimum clinically important difference) vs. placebo.
Jones PW et al, Respir Med 2011; 105 (6): 892-9.
Indacaterol 300 µg increases % of days without rescue
medication use over 52 weeks, compared with placebo
and Formoterol
Formoterol 12 μg b.i.d. (n=373)
Placebo (n=364)
Indacaterol 300 μg o.d. (n=383)
Days with no rescue use (%)
70
60
50
††
68%
improvement
***
52.1%
40
30
***
58.3%
34.8%
20
10
0
Over 52 weeks
***p<0.001 vs placebo; ††p=0.007 vs formoterol
Dahl et al. Thorax 2010;65:473–9.
Effect of Indacaterol on exercise
endurance and lung hyperinflation
in COPD
INABLE 1: Indacaterol: endurance, exercisebased, and lung evaluation 1.
Respiratory Medicine (2011) 105, 1030-1036
Exercise endurance study INABLE-1
study design
• Double-blind, placebo-controlled, two-period crossover study
Screening
Indacaterol 300 μg o.d.
Indacaterol 300 μg o.d.
Placebo
Placebo
3 weeks
3 weeks
3 weeks
Treatment 1
Washout
Treatment 2
• 90 patients randomized
• The primary efficacy variable was exercise endurance time after 3 weeks
of treatment, measured through constant-load cycle ergometry testing
performed at 75% of the peak work rate in a screening incremental
exercise test.
Respiratory Medicine (2011) 105, 1030-1036
Results
Indacaterol improves exercise endurance
time (in mins)
Placebo
Indacaterol 300 µg
Exercise endurance time (mins)
12
Δ 1.68 ***
11
Δ 1.85 *
9.75
9.77
10
9
8.07
7.92
8
7
6
5
Day 1
Data are LSM and standard errors
*p=0.011, ***p<0.001
Week 3
Respiratory Medicine (2011) 105, 1030-1036
Indacaterol improves inspiratory capacity
Placebo
Indacaterol 300 µg
End-exercise inspiratory capacity (L)
2.5
Δ 190 mL *
2.3
2.1
Δ 280 mL **
2.22
2.17
1.98
1.94
1.9
1.7
1.5
Day 1
Week 3
Data are LSM and standard errors
*p=0.04, **p=0.002
Respiratory Medicine (2011) 105, 1030-1036
Indacaterol improves bronchodilation
Placebo
1.9
Δ 0.23 ***
Indacaterol 300 µg
Δ 0.25 ***
Δ 0.20 ***
1.84
1.79
Resting FEV1 (L)
1.8
1.73
1.7
1.59
1.6
1.56
1.53
1.5
1.4
Day 1 –
75 min post-dose
Resting FEV1 was a secondary endpoint
Data are LSM and standard errors
***p<0.001
Week 3 –
60 min pre-dose
Week 3 –
75 min post-dose
Respiratory Medicine (2011) 105, 1030-1036
Indacaterol has a good overall safety & tolerability
profile
 In terms of safety, Indacaterol 300 μg demonstrated
good overall safety and tolerability profile.
 The overall rate of adverse events (AEs) was
comparable between Indacaterol and placebo, with
nearly all AEs reported being mild or moderate in
severity.
Laforce C et al, Pulm Pharmacol Ther 2011; 24 (1): 162-8.
Indacaterol has a good overall safety &
tolerability profile
 In a 52-week study that compared Indacaterol 300
and 600 μg once daily with Formoterol and placebo,
Indacaterol was also well tolerated, with a safety
profile that indicated minimal impact on QTc interval
and systemic β2-mediated events.
Laforce C et al, Pulm Pharmacol Ther 2011; 24 (1): 162-8.
Breezhaler®: Easy-to-use device for effective drug delivery
Breezhaler® has lower airflow
resistance than other inhalers
120
Flow rate (L/min)
100
80
60
40
Breezhaler
Diskus
Turbuhaler
Handihaler
20
0
0
2
4
6
Inspiratory effort (kPa)
2.2  10-2 kPa1/2 L-1 min
2.7  10-2 kPa1/2 L-1 min
3.4  10-2 kPa1/2 L-1 min
5.1  10-2 kPa1/2 L-1 min
8
10
Singh D et al. ATS 2010 (poster)
Conclusion
 COPD is caused by inhaled noxious agents, with lung damage
leading to airflow limitation.
 The GOLD guideline recommends long-acting bronchodilators as
first-line maintenance treatment in COPD.
 Bronchodilators address airflow limitation by targeting
bronchoconstriction and reducing air trapping.
Conclusion
 LABAs
 Improve lung function.
 Improve health status related quality of life.
 Reduce exacerbations in symptomatic patients with moderateto-severe COPD.
 Provide a significant relief from exercise and Dyspnea.
 There is a need for novel once-daily LABA with fast onset of
action and superior efficacy over existing bronchodilators.
Conclusion
 Indacaterol demonstrates fast onset of bronchodilator effect at
5 minutes post-dose and sustained bronchodilation over 24
hours.
 Indacaterol 300 μg provides:
- optimal bronchodilation, particularly in patients with severe
disease.
- significant improvement in trough FEV1 over 52 weeks
Conclusion
Indacaterol:
 reduces breathlessness as indicated by improvements in TDI score
at all assessments points.
 300 μg dose was superior compared to the twice-daily β2-agonists.
 300 µg increases % of days without rescue medication use over 52
weeks.
 Improves exercise endurance time, inspiratory capacity,
bronchodilation
 Has a good overall safety & tolerability profile
Thank you

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