This document contains information about bronchodilators used in the treatment of chronic obstructive pulmonary disease (COPD). It discusses the mechanisms of action of different bronchodilators and their effects on lung volumes, airflow limitation, hyperinflation, and exercise tolerance. It also provides treatment algorithms and guidelines for COPD pharmacotherapy. The document compares short-acting and long-acting bronchodilators and summarizes the evidence for their impact on outcomes like exacerbations, quality of life, and lung function in COPD patients.

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Bronchodilators in COPD
Ronald Dahl
Odense University Hospital Dahl
Denmark
Odense Research Center for Anaphylaxis
Center for Eosinofilsygdom

2. 2/21/2014
2
Ronald Dahl: Disclosures
• Consulting, given lectures for :
Boehringer-Ingelheim, Novartis, TEVA, MEDA,
Pfizer, ALK-Abello, Vectura, AZ, GSK, CIPLA
COPD: Drug Combinations in alphabetical order
Patient First choice Second choice Alternative Choices
A
SAMA prn
or
SABA prn
LAMA
or
LABA
or
SABA and SAMA
Theophylline
B
LAMA
or
LABA
LAMA and LABA
SABA and/or SAMA
Theophylline
C
ICS + LABA
or
LAMA
LAMA and LABA
PDE4-inh.
SABA and/or SAMA
Theophylline
D
ICS + LABA
or
LAMA
ICS and LAMA or
ICS + LABA and LAMA or
ICS+LABA and PDE4-inh.
or
LAMA and LABA or
LAMA and PDE4-inh.
Carbocysteine
SABA and/or SAMA
Theophylline
GOLD 2013

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Modified from Cooper CB, Tashkin DP. BMJ 2005;330;640-44
A clinical algorithm for the treatment of COPD
Pharmacotherapy
0
1
2
LABALAMA
3
LAMA + LABA
4
LAMA + LABA
+ roflumilast
Non-pharmacological
therapy
Smoking cessation
Avoidance of exposure
Vaccination
(influenza, pneumococcal)
Pulmonary rehabilitation
(Exercise prescription)
Supplemental oxygen
Lung volume reduction surgery
Lung transplantation
SAMA, SABA or SAMA + SABA
GOLD Spirometric
Stage
(approximate)
Clinical
stage
At risk
Intermittent
symptoms
Persistent
symptoms‡
Frequent
exacerbations
Respiratory failure
LAMA + LABA
+ ICS*
LAMA + LABA
+ azithromycin
*Clinical benefit of adding ICS to LABA+LAMA has not yet been demonstrated
or
COPD and the pathologic changes in
lung tissue and airways
Juni 2009 6

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Mechanisms of airflow obstruction in COPD:
small airways remodeling
Kim et al. Proc Am Thorac Soc 2008
Emphysema causes loss of alveolar attachments
to the airway wall, predisposing it to expiratory
collapse
Epithelial thickening (E), smooth muscle hypertrophy
(SM), and chronic airway inflammation (I)
E
SM
I
Mechanisms of airflow obstruction in COPD:
small airways remodeling
Kim et al. Proc Am Thorac Soc 2008
Emphysema causes loss of alveolar attachments
to the airway wall, predisposing it to expiratory
collapse
Epithelial thickening (E), smooth muscle hypertrophy
(SM), and chronic airway inflammation (I)
E
SM
I
The time required to empty the different parts of the lung is
determined by the product of
1. An airway component:
The airway resistance (cm H2O/L/s) and
2. A lung tissue component
The elastic recoil force (compliance) available to drive air out of
the lung (L/cm H2O).

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Airway smooth muscle contractility
and lung function in smokers
Opazo Saez et al. Am J Respir Crit Care Med 2000
0 20 8040 10060 120
0.0
0.5
1.5
2.5
3.5
1.0
2.0
3.0
Maximalisometricforce(g)
FEV1 (% predicted) FEV1/FVC (%)
0 20 8040 10060 120
0.0
0.5
1.5
2.5
3.5
1.0
2.0
3.0
Maximalisometricforce(g)
r = –0.579, p<0.004 r = –0.720, p<0.003
Effect of bronchodilator on airway
distensibility and emphysema extent
Baldi et al. J Appl Physiol 2010
1.4
1.0
0.6
0.2
−0.2
0 10 20 30 40 50
Baseline LAA (%)
DGrs/DVL(cmH2O–1•s–1)
After 400 µg albuterol
Before 400 µg albuterol
Linear regression lines before (dashed) and after (continuous) albuterol are shown
Grs = respiratory conductance; LAA = low attenuation area; VL = lung volume

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Hypotetisk model af lungedeflation
med øget luftvejskaliber
As airway patency over time increases with longer duration of bronchodilator action, emptying of peripheral
airways with trapped air is facilitated, thus reducing hyperinflation and improving breathing mechanics
(“pharmacological lung volume reduction”).
A= korttidsvirkende; B=2-gange dagligt; C=1–gang dagligt
Air trapping/hyperinflation
– –– –––
+ ++ +++
Perifer luftvej net diameter
A B C
Beeh KM & Beier J Adv Ther (2010) 27(3):1-10
COPD and the consequenses for
respiratory physiology
Juni 2009 12

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In COPD
FEV-1/FVC ≤ 70%FEV-1% predicted
80
50
30
Mild
Moderate
Severe
Very
severe
Expected normal
Mild obstruction
Moderate obstruction
Severe obstruction
Spirometry in a 50 year old male witth
different degrees of obstruction
Flow-volume trace with time
points in health and COPD
NOLAN D , and WHITE P Thorax 1999;54:468-468

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Hyperinflation
VT
IRVERV
IC
RV
Normal
Years - Decades
Disease
Progression
Rest
Static
Hyperinflation
Air Trapping
at Rest
Seconds - Minutes
Exercise
Dynamic
Hyperinflation
Additional Air
Trapping During
Exercise
What is the main reasons for
bronchodilators efficacy in COPD?

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Bronchodilation increases IC/TLC
0
1
2
3
4
5
6
7
8
Pre Post BD
Liters
IC
EELV
IC, inspiratory capacity; TLC, total lung capacity
TLC
FVC FEV1 IC EELV SVC
Changes in lung volumes after bronchodilation
ml
Celli. Chest 2003; 124:1743-1748
-1000
-800
-600
-400
-200
0
200
400
600
Tiotropium (n=37)
Placebo (n=38)

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FVC FEV1 IC EELV SVC
ml
Celli. Chest 2003; 124:1743-1748
-1000
-800
-600
-400
-200
0
200
400
600
Tiotropium (n=37)
Placebo (n=38)
Easier to breathe
Changes in lung volumes after bronchodilation
FVC FEV1 IC EELV SVC
ml
Celli. Chest 2003; 124:1743-1748
-1000
-800
-600
-400
-200
0
200
400
600
Tiotropium (n=37)
Placebo (n=38)
More air available for use
Changes in lung volumes after bronchodilation

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FVC FEV1 IC EELV SVC
ml
Celli. Chest 2003; 124:1743-1748
-1000
-800
-600
-400
-200
0
200
400
600
Tiotropium (n=37)
Placebo (n=38)
The air can be moved faster
Changes in lung volumes after bronchodilation
Constant-load 5% Wmax
TLC TLC
IC
VT
IRV
The mechanical “threshold” in COPD
O’Donnell and Laveneziana COPD 2007
0
1
2
3
4
5
6
7
0.00.51.01.52.0
IRV (L)
Dyspnea(Borg)
0.0
0.5
1.0
1.5
2.0
2.5
0 1 2 3 4 5 6 7 8 9 10
Exercise time (min)
Lungvolume(L)

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Baseline
Tiotropium
Reduction in operational lung volume
improves exercise tolerance in COPD
O’Donnell et al. Eur Respir J 2004
TLC
TLC
EELV
EILV
VT
IRV
IC
IRV
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
0 2 4 6 8 10 12
Exercise time (min)
Lungvolume(L)
1.98
1.94
2.17
2.22
1.5
1.7
1.9
2.1
2.3
2.5
Day 1 After 3 weeks
Placebo Indacaterol 300 µg
Effects of indacaterol on inspiratory capacity and
exercise tolerance in COPD
Data are least squares means and standard error
*p=0.04; **p=0.002
O’Donnell et al. Respir Med 2011
190 mL* 280 mL**
101 s*** 111 s*
Data are least squares means and standard error
*p=0.011; ***p<0.001
End-exerciseIC(L)
Time(s)
484 475
585 586
0
100
200
300
400
500
600
700
Day 1 After 3 weeks
101 s*** 111 s*

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Bronchodilator response in COPD
Cerveri et al. J Appl Physiol 2000
Before salbutamol
After salbutamol
1 2 3 4
–1
0
1
2
3
4
Volume (L)
Flow(L/s)
FEV1 and FVC responder
1 2 3 4
–1
0
1
2
3
4
Volume (L)
Flow(L/s)
FVC responder
1 2 3 4
–1
0
1
2
3
4
Volume (L)
Flow(L/s)
FEV1 and FVC responder
Bronchodilator response in COPD
• In some patients, FVC increases without an increase in FEV1
Cerveri et al. J Appl Physiol 2000
Before salbutamol After salbutamol

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FVC responders
FVC and FEV1 responders
Emphysema extent (%)
ΔFEV1(%predicted)
0
12
24
20 30 40 50 60
Bronchodilator response in COPD
• Isolated volume response is associated with prevelant emphysema
Cerveri et al. J Appl Physiol 2000
r = –0.89; p<0.001
The central role of airflow limitation leading to
symptoms in COPD
Disability Disease progression Death
Air trapping
Expiratory flow limitation
Hyperinflation
Deconditioning Inactivity
Reduced exercise
capacity
Exacerbations
COPD
Breathlessness
Quality of life
Exercise
Adapted from Cooper. Respir Med 2009

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Disability Disease progression Death
Air trapping
Expiratory flow limitation
Hyperinflation
Deconditioning Inactivity
Reduced exercise
capacity
Exacerbations
COPD
Breathlessness
Quality of life
Exercise
The central role of airflow limitation leading to
symptoms in COPD
Bronchodilators reduce airflow limitation, air
trapping and hyperinflation
Adapted from Cooper. Respir Med 2009
Disability Disease progression Death
Air trapping
Expiratory flow limitation
Hyperinflation
Deconditioning Inactivity
Reduced exercise
capacity
Exacerbations
COPD
Breathlessness
Quality of life
Exercise
The central role of airflow limitation leading to
symptoms in COPD
This leads to fewer symptoms, improved
health status, reduced exacerbation rate and
possible improved survival
Adapted from Cooper. Respir Med 2009

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As new bronchodilators are introduced there
have been more consistent improvements in outcomes for
patients with COPD
†≥12Formoterol
(‡)≥12Salmeterol
(‡)(‡)24Tiotropium
Improvement in outcome
6–8
Ipratropium
bromide
NANA4–6Albuterol
Exacerbations1–3,5,7–14
Quality
of life1–14
Exercise
endurance*1,2Breathlessness2–8
Lung
function2–8
Duration of
action
(hours)1
*Outcome demonstrated by all bronchodilators, lack of evidence of significant differences between them
†Equivocal evidence depending on formulation;5,10,11 ‡Evidence of numerical improvements over shorter acting comparator4,8
NA = evidence not available
1. GOLD 2009; 2. Celli et al. ERJ 2004; 3. Mahler et al. Chest 1999; 4. Rennard et al. AJRCCM 2001
5. Dahl et al. AJRCCM 2001; 6. Wadbo et al. ERJ 2002; 7. Vincken et al. ERJ 2002; 8. Brusasco et al. Thorax 2003
9. Rutten van-Molken et al. Eur J Health Econ 2007; 10. Szafranski et al. ERJ 2003; 11. Calverley et al. ERJ 2003
12. Calverley et al. NEJM 2007; 13. Niewoehner et al. Ann Intern Med 2005; 14. Tashkin et al. NEJM 2008
evidence of effectiveness; evidence of effectiveness over SABA or SAMA; evidence of effectiveness over LABA
Time (h)
0 126
FEV1
4 x / day = SABA or SAMA
2418
Progress in maximizing bronchodilation in COPD
4 x / day = SABA + SAMA
Trough
FEV1
Trough
FEV1
Trough
FEV1
Trough
FEV1
Beeh KM & Beier JK. Adv Ther 2010; 27:150-159

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Time (h)
0 126
FEV1
4 x / day = SABA or SAMA
2418
Progress in maximizing bronchodilation in COPD
4 x / day = SABA + SAMA
Beeh KM & Beier JK. Adv Ther 2010; 27:150-159
Trough
FEV1
Trough
FEV1
2 x / day = Long-acting e.g. LABA
Time (h)
0 126
FEV1
4 x / day = SABA or SAMA
2418
Progress in maximizing bronchodilation in COPD
4 x / day = SABA + SAMA
Beeh KM & Beier JK. Adv Ther 2010; 27:150-159
2 x / day = Long-acting e.g. LABA
Trough
FEV1
1 x / day = Ultra-long-acting (tiotropium)

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Time (h)
0 126
FEV1
2418
Progress in maximizing bronchodilation in COPD
Beeh KM & Beier JK. Adv Ther 2010; 27:150-159
2 x / day = Long-acting e.g. LABA
Trough
FEV1
1 x / day = Ultra-long-acting (tiotropium)
Onset of action
1 x / day = Ultra-long-acting (LABA/LAMA or MABA)
Short- vs long- vs ultralong – acting bronchodilators
Type Generic name Onset of action Duration of action
β-agonists Salbutamol 3–5 min <6 hours
Salmeterol 20–30 min <12 hours
Formoterol 3–10 min <12 hours
Indacaterol 3–10 min >24 hours
Anticholinergics Ipratropium 30–45 min 4–6 hours
Oxitropium 30–45 min 6–8 hours
Tiotropium 30–60 min 24 hours
Glycopyrronium 5–15 min 24 hours
Aclidinium 30–60 min >12 hours

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Dose response: indacaterol and comparators
F12 = formoterol 12 µg b.i.d.; S50 = salmeterol 50 µg b.i.d.; T18 = tiotropium 18 µg
b.i.d. = twice-daily
250
200
150
100
50
0
TroughFEV1–differencefromplacebo(mL)
18.75 75 150 300 600 F12 S50 T18
Renard et al. Respir Res 2011
MCID
95% confidence interval
95% prediction interval
Indacaterol Dose (µg) Comparators
38
Lack of Tachyphylaxis over 52 Weeks
Study B2335S/SE
0
50
100
150
200
250
TroughFEV1–
differencefromplacebo(mL)
75 µg 150 µg 300 µg
All p<0.001 vs placebo
Dotted line shows prespecified 120 mL level of clinically important difference
Trough FEV1 = mean of measurements at 23 h 10 min and 23 h 45 min post-dose
After 1 day Day 15 Week 12 Week 26 Week 52

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39
INSURE: Indacaterol onset of action
B2307 study design
Phase III, randomized, double-blind, triple-dummy, placebo controlled,
multicenter, 5-period, single-dose, complete block, crossover study
Indacaterol 150 μg Indacaterol 300 μg Placebo Salbutamol 200 μg Salmeterol/fluticasone
50/500 μg
Period II Period III Period IVPeriod I
*Screening
(–14 days)
Washout
(4–7 days)
Period V
Washout
(4–7 days)
Washout
(4–7 days)
Washout
(4–7 days)
NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI
Balint et al. Int J COPD 2010
(Study B2307)
40
INSURE: Indacaterol demonstrates fast onset of
bronchodilator effect at 5 minutes post-dose
1,2
1,3
1,4
1,5
1,6
Placebo
(n=88)
Salmeterol/
fluticasone
(n=88)
Salbutamol
(n=86)
Indacaterol
150 µg
(n=85)
Indacaterol
300 µg
(n=87)
LSmeanofFEV1(L)
***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
Numbers on bars represent the difference from placebo (mL)
**
*** ***
***
NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI
+ 50 mL
+ 90 mL + 100 mL
+ 120 mL
Balint et al. Int J COPD 2010
(Study B2307)

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41
INSURE: Significantly higher proportion of patients achieving
improvements of ≥12% and 200 mL in FEV1 at 5 minutes post-dose
with indacaterol versus placebo and salmeterol/fluticasone
0
5
10
15
20
25
30
Placebo Salmeterol/fluticasone Salbutamol
Indacaterol 150 µg Indacaterol 300 µg
Patients(%)withatleast12%and200mL
improvementinFEV1at5minutespost-dose
*
*** †††
*** †††
*** ††
*p<0.05, ***p<0.001 versus placebo; ††p≤0.01, †††p≤0.001 versus salmeterol/fluticasone for
odds ratios (likelihood of achieving this improvement)
NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI
Balint et al. Int J COPD 2010
(Study B2307)
42
Key findings
 Indacaterol has a fast onset of bronchodilation effect 5 mins
post-dose
 The bronchodilator effect at 5 min post dose was similar to
salbutamol but significantly superior to
salmeterol/fluticasone
 Indacaterol significantly increased the proportion of patients
achieving improvements of ≥12% and 200 mL in FEV1 at 5
mins post-dose compared with placebo and
salmeterol/fluticasone
 Indacaterol shows significant improvement in
bronchodilation over salbutamol and salmeterol/fluticasone
at 2 hours

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43
B2335S: Efficacy and safety of indacaterol once daily
versus placebo and open-label tiotropium over 6 months
(INHANCE)
Patients Male or female, age ≥40 years,
moderate-to-severe COPD
FEV1 <80% and ≥30% predicted; FEV1/FVC <70%
(post-bronchodilator)
Number 2,059 patients involved in Stages 1 and 2;
1,683 received selected doses/comparators in
Stage 2
Device Single-dose dry-powder inhaler (SDDPI)
Indacaterol dose 150 and 300 µg o.d.
Comparators Placebo; open-label tiotropium
Main objective Efficacy of indacaterol versus placebo (FEV1
24 hours post-dose) at Week 12
Donohue et al. AJRCCM 2010
44
Stage 1
Indacaterol 75 µg o.d. (n=115)
Indacaterol 150 µg o.d. (n=111)
Indacaterol 300 µg o.d. (n=114)
Indacaterol 600 µg o.d. (n=111)
Placebo (n=119)
Formoterol 12 μg b.i.d. (n=112)
Tiotropium* 18 μg o.d. (n=119)
Indacaterol 150 µg o.d. (n=420)
Indacaterol 300 µg o.d. (n=418)
Placebo (n=425)
Tiotropium* 18 μg o.d. (n=420)
Dose ranging
2 weeks
Efficacy and safety
26 weeks
Stage 2
Dose selection
INHANCE: 26-week efficacy and safety
B2335S study design
*Open-label
All drugs were delivered via proprietary single-dose dry powder inhalers
NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI
Donohue et al. AJRCCM 2010

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45
INHANCE: Bronchodilation achieved by all doses of
indacaterol exceeded pre-set efficacy criterion for trough
FEV1
75 µg
(n=115)
150 µg
(n=111)
300 µg
(n=114)
600 µg
(n=111)
Indacaterol once daily
Formoterol
12 μg b.i.d.
(n=112)
Tiotropium
18 μg o.d.
(n=119)
0
50
100
150
200
250
300
DifferenceintroughFEV1versusplacebo(mL)
Data are LSM and 95% confidence intervals
Barnes et al. PPT 2010
Day 15
NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI
Pre-set efficacy criterion =
highest value of:
a) tiotropium vs placebo
b) formoterol vs placebo
c) 120 mL vs placebo
46
INHANCE: Indacaterol doses of 150, 300 and 600
µg exceeded the pre-set criterion for FEV1 AUC
75 µg
(n=115)
150 µg
(n=111)
300 µg
(n=114)
600 µg
(n=111)
Indacaterol once daily
0
50
100
150
200
250
300
400
350
DifferenceinFEV1AUC1–4hversusplacebo(mL)
Lowest two effective doses selected to move
forward into Stage 2 of the study
Data are LSM and 95% confidence intervals
Barnes et al. PPT 2010
Day 14
Formoterol
12 μg b.i.d.
(n=112)
Tiotropium
18 μg o.d.
(n=119)
NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI
Pre-set efficacy criterion
(highest value among
formoterol and tiotropium)

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47
INVOLVE: 52-week efficacy and safety
52 weeks2 weeks
Indacaterol 300 μg o.d. (n=437)
Indacaterol 600 μg o.d. (n=428)
Placebo (n=432)
Formoterol 12 μg b.i.d. (n=435)
Double-blind, randomized, placebo-controlled, parallel-group study
Baseline
Screening period
N.B. Indacaterol 150 μg and 300 μg once-daily are registered doses The recommended
dose strength is 150 μg once-daily, to be increased only on medical advice
INVOLVE
Dahl et al. Thorax 2010
48
1.38
Indacaterol 300 µg provided significant improvement in
trough FEV1 over 52 weeks, superior to formoterol
*p<0.05, ***p<0.001 vs placebo; †p<0.05, †††p<0.001 vs formoterol
Data are LSM in the modified intent-to-treat population
Trough = average of 23 h 10 min and 23 h 45 min post-dose values
Placebo Formoterol 12 µg b.i.d.
Indacaterol 300 µg o.d.
***
1.43
1.45
1.31
1.32
1.28
1.48
1.31
1.38
1.55
1.50
1.45
1.40
1.35
1.30
1.25
1.20
1.15
TroughFEV1(L)
***
***
*
1.43
Day 2 Week 12 Week 52
Primary endpoint
***
†††
***
†††
†
Dahl et al. Thorax 2010
INVOLVE

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49
Pooled efficacy data
50
*** ***
*** ***
***
***
0
50
100
150
200
250
300
>12%
Prespecified level of
clinically relevant effect1
DifferenceintroughFEV1versusplacebo(mL)
***
***
***
≤12% ≤5%
INHANCE
***p<0.001 vs placebo
Data are LSM with 95% CI
MCID = minimal clinically important difference
Open-label tiotropium Indacaterol 150 µg Indacaterol 300 µg
Baseline SABA reversibility at screening
Indacaterol provides clinically significant
bronchodilation at Week 12 compared with placebo regardless
of SABA reversibility
1. Kleerup et al. ERS 2010;
2. Donohue et al. 2005
Published threshold
of MCID1

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51
1. Kleerup et al. ERS 2010;
2. Donohue et al. 2005
***
***
*** ***
***
***
0
50
100
150
200
250
300
>12%
Prespecified level of
clinically relevant effect1
*p<0.05, **p<0.01, ***p<0.001 vs placebo
Data are LSM with 95% CIs
MCID = minimal clinically important difference
DifferenceintroughFEV1versusplacebo(mL)
*
****
≤12% ≤5%
Baseline SAMA reversibility at screening
Published threshold
of MCID2
Open-label tiotropium Indacaterol 150 µg Indacaterol 300 µg
Indacaterol provides clinically significant
bronchodilation at Week 12 compared with placebo
regardless of SAMA reversibility
INHANCE
52
Indacaterol provides clinically significant
bronchodilation regardless of ICS use
Donohue et al. (ATS poster) 2010
0
20
40
60
80
100
120
140
160
180
200 ICS non-users ICS users
Data are unadjusted means and standard errors
ChangeintroughFEV1frombaseline(mL)
Tiotropium Formoterol
Prespecified
level of
clinically
relevant effect
Indacaterol 150 µg Indacaterol 300 µgPlacebo
†† ‡‡
†p<0.05, ††p=0.001 vs formoterol; ‡‡p=0.015 vs tiotropium
‡
NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI

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53
Indacaterol provides clinically significant
bronchodilation on regardless of age
0
20
40
60
80
100
120
140
160
180
200
Data are unadjusted means and standard errors
ChangeintroughFEV1frombaseline(mL)
Tiotropium Formoterol Indacaterol 150 µg Indacaterol 300 µgPlacebo
Mahler et al. (ATS poster) 2010NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI
Prespecified
level of
clinically
relevant effect
Age <65 years Age ≥65 years
54
1.25
1.30
1.35
1.40
1.45
1.50
1.55
1.60
Bronchodilation and baseline smoking status
NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI
Data are least squares means and standard errors
**p<0.01, ***p<0.001 vs placebo; †p<0.05, ††p<0.01, †††p<0.001 vs formoterol; ‡p<0.05 vs tiotropium
TroughFEV1(L)
*** ***
***
††† ***
†
***
***
†††
‡
***
†††
Ex-smokers Current smokers
***
††
Patients evaluated: 515 220 293 440 315 422 173 202 338 275
Novartis, data on file 2008
Open-label Tiotropium Formoterol Indacaterol 150 µg Indacaterol 300 µgPlacebo

28. 2/21/2014
28
55
Kleerup et al. ATS 2010
0
70
20
30
40
50
60
Plotted data are unadjusted means. *p<0.05 vs placebo for odds ratio (OR)
Difference of ≥1 = clinically important improvement in the TDI total score
TDI = Transition Dyspnea Index.
Patientswithclinicallyrelevant
increaseinTDIscorefrombaseline
(%)
45.3
57.8
54.1
60.5
65.9
Open-label
Tiotropium
Formoterol Indacaterol
150 µg o.d.
Indacaterol
300 µg o.d.
Placebo
54.3
Salmeterol
OR vs
placebo: 1.49* 2.02* 1.79* 1.91* 2.69*
20
60
Indacaterol provided significant and clinically relevant
improvements in breathlessness over 6 months
(pooled analysis)
56
Change from baseline in percentage of
days with no rescue use
NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI Siler et al. (ATS poster) 2010
0
30
5
10
15
20
25
Data are unadjusted means
* p<0.05, *** p<0.001 vs placebo; ††† p<0.001 vs tiotropium
Changefrombaselineinpercentage
ofdayswithnorescueuse
6.8
12.0
22.0 21.6
25.4
Tiotropium Formoterol Indacaterol
150 µg
Indacaterol
300 µg
Placebo
*
***
†††
***
†††
***
†††

29. 2/21/2014
29
Indacaterol and COPD exacerbation
58
Indacaterol significantly reduces the risk of COPD
exacerbations in non-ICS users over 12 weeks compared
with placebo
*
***
*
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
ICS non-users ICS users
*p<0.05, ***p<0.001 vs placebo
Data are hazard ratios and 95% confidence intervals
ICS = inhaled corticosteroid
Hazardratioforexacerbationsvsplacebo
Open-label Tiotropium Formoterol Indacaterol 150 µg o.d. Indacaterol 300 µg o.d.
Decramer et al. ERS 2010
POOLED ANALYSIS

30. 2/21/2014
30
Time to first moderate or severe
COPD exacerbation
Invigorate study Lacet Respiratory 2013
LABA – indacaterol improve symptoms more
LAMA – tiotropium, glycopyrronium etc reduce more exacerbations
GOLD 2006 revision
(+ annual updates) GOLD 2011 revision
GOLD 2006 vs 2011: first-line treatment
I: Mild II: Moderate III: Severe IV: Very severe
• FEV1/FVC <0.70
• FEV1 80% predicted
• FEV1/FVC <0.70
• 50% FEV1 <80%
predicted
• FEV1/FVC <0.70
• 30% FEV1 <50%
predicted
• FEV1/FVC <0.70
• FEV1 <30% predicted
or FEV1 <50%
predicted plus chronic
respiratory failure
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
Add regular treatment with one or more long-acting bronchodilators
(when needed); add rehabilitation
Add inhaled glucocorticosteroids if repeated
exacerbations
Add long-term oxygen
if chronic respiratory
failure
Consider surgical
treatments
Risk
GOLDclassificationofairflowlimitation
Risk
Exacerbationhistory
Symptoms
(mMRC or CAT score)
(C) (D)
(A) (B)
1
2
3
4
0
1
2
mMRC 2
CAT 10
mMRC 0–1
CAT <10

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31
Indacaterol in COPD treatment
which patients?
• In clinical practice indacaterol is of benefit in
all cases of COPD that come to the doctor.
• Especially those patients with more
breathlessness and many symptoms
Indacaterol in COPD treatment
which dose?
• 150 µg of clinical value in all cases
• 300 µg considered in the more symptomatic,
• Both dosages are without side effects and
adverse effectsh

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32
Patients (%) with notable values for laboratory
variables, vital signs and QTc interval
Indacaterol Tiotropium
Plasma potassium <3.0 mmol/L 0 0
Blood glucose >9.99 mmol/L 3.3 2.6
Pulse rate – high†
0.3 0
Systolic blood pressure – high‡ 0.9 0.6
Diastolic blood pressure – high§ 0.8 1.6
QTc interval (Fridericia’s)
Absolute value >450/470 ms (males/females) 2.9 3.1
Absolute value >500 ms 0 0.1
Increase from baseline 30–60 ms 4.6 6.0
Increase from baseline >60 ms 0.3 0
†>130 bpm, or ≥120 bpm and ≥15 bpm increase from baseline;
‡>200 mmHg, or ≥180 mmHg and ≥20 mmHg increase from baseline;
§>115 mmHg, or ≥105 mmHg and ≥15 mmHg increase from baseline
NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI
Buhl et al. Eur Respir J 2011
Indacaterol
150 µg o.d.
(N=144)
n (%)
Indacaterol
300 µg o.d.
(N=146)
n (%)
Placebo
(N=124)
n (%)
Pulse rate – higha 0 1 (0.7) 0
Systolic blood pressure – highb 1 (0.7) 2 (1.4) 2 (1.6)
Diastolic blood pressure – highc 1 (0.7) 0 2 (1.6)
QTc >450/470 ms (males/females)d 10 (6.9) 9 (6.2) 11 (8.9)
Increase 30–60 ms 28 (19.4) 30 (20.5) 30 (24.4)
Increase >60 ms 1 (0.7) 1 (0.7) 1 (0.8)
a>130 bpm, or ≥120 bpm and ≥15 bpm increase; b>200 mmHg, or ≥180 mmHg and
≥20 mmHg increase; c>115 mmHg, or ≥105 mmHg and ≥15 mmHg increase
dNo patient had value >500 ms
Cardiovascular safety profile of indacaterol:
52-week safety study
Chapman et al. Chest 2011 ()
INDORSE

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33
Safety: Indacaterol is not associated with increased risk of CCV
adverse events or serious adverse events
Indacaterol
150 µg
Indacaterol
300 µg
Indacaterol
600 µg
Indacaterol
doses
combined Formoterol Salmeterol
Open-label
Tiotropium Placebo
N 746 853 547 2146 556 333 415 1,185
Total patient years 331.04 379.31 222.25 932.87 227.49 149.79 180.23 487.41
No of CCV AEs 46 56 24 126 28 19 33 54
Patients with CCV
AEs, n (%)
39 (5.2) 43 (5.0) 18 (3.3) 100 (4.7) 22 (4.0) 16 (4.8) 24 (5.8) 41 (3.5)
Relative risk
versus placebo of
experiencing ≥
one CCV AE (95%
CI)
1.51
(0.98, 2.32)
1.46
(0.96, 2.22)
0.95
(0.55,
1.64)
1.35
(0.94, 1.92)
1.14
(0.69, 1.90)
1.39
(0.79, 2.44)
1.67
(1.02, 2.73)
p-value 0.061 0.090 1.000 0.106 0.585 0.255 0.044
No. of CCV SAEs 15 15 9 39 5 7 12 16
Patients with CCV
SAEs, n (%)
15 (2.0) 12 (1.4) 7 (1.3) 34 (1.6) 3 (0.5) 5 (1.5) 9 (2.2) 15
(1.27)
Relative risk vs
placebo of
experiencing ≥
one CCV SAE
(95% CI)
1.59
(0.78, 3.23)
1.11
(0.52, 2.36)
1.01
(0.42,
2.47)
1.25
(069, 2.29)
0.43
(0.12, 1.47)
1.19
(0.43, 3.24)
1.71
(0.76, 3.89)
p-value 0.256 0.845 1.000 0.549 0.208 0.785 0.238
Worth et al. Resp Med 2011
N.B. Registered doses of indacaterol are 150 and 300 μg once daily via Onbrez® Breezhaler®. The 600 µg dose is not registered.
Safety: Rate of CCV adverse events is similar across treatments
Indacatero
l150 µg
Indacatero
l300 µg
Indacaterol
600 µg
Formoterol
12 µg
Salmeterol
50 µg
Open-label
Tiotropium
18 µg Placebo
N 746 853 547 556 333 415 1,185
CCV AEs†, n (%)
Arrhythmia SMQ 22 (2.9) 24 (2.8) 12 (2.2) 11 (2.0) 9 (2.7) 17 (4.1) 26 (2.2)
Cardiac failure SMQ 3 (0.4) 4 (0.5) 3 (0.5) 7 (1.3) 2 (0.6) 2 (0.5) 4 (0.3)
Ischemic heart disease SMQ 10 (1.3) 12 (1.4) 5 (0.9) 4 (0.7) 6 (1.8) 7 (1.7) 6 (0.5)
Cerebrovascular disorders
SMQ
4 (0.5) 3 (0.4) 0 1 (0.2) 0 2 (0.5) 7 (0.6)
CCV SAEs†, n (%)
Arrhythmia SMQ 5 (0.7) 1 (0.1) 2 (0.4) 1 (0.2) 2 (0.6) 4 (1.0) 4 (0.3)
Cardiac failure SMQ 0 2 (0.2) 1 (0.2) 1 (0.2) 0 0 2 (0.2)
Ischemic heart disease SMQ 7 (0.9) 6 (0.7) 5 (0.9) 1 (0.2) 4 (1.2) 4 (1.0) 5 (0.4)
Cerebrovascular disorders
SMQ
3 (0.4) 3 (0.4) 0 0 0 1 (0.2) 4 (0.3)
Worth et al. Resp Med 2011
†Patients may be counted more than once across different SMQ groupings.
N.B. Registered doses of indacaterol are 150 and 300 μg once daily via Onbrez® Breezhaler®. The 600 µg dose is not registered.

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Summary: Safety
• Once-daily indacaterol was shown to have an acceptable safety profile
• The overall incidence and pattern of adverse events and serious adverse
events were similar to placebo and the active comparators tiotropium,
salmeterol and formoterol in patients with moderate-to-severe COPD
LABA is established in COPD and improves a
range of clinical outcomes
• Lung function
• Inspiratory capacity
• Exercise capacity
• Effectiveness of pulmonary rehabilitation
• Dyspnea
• Health status
• Exacerbations

35. 2/21/2014
35
COPD: Drug Combinations in alphabetical order
Patient First choice Second choice Alternative Choices
A
SAMA prn
or
SABA prn
LAMA
or
LABA
or
SABA and SAMA
Theophylline
B
LAMA
or
LABA
LAMA and LABA
SABA and/or SAMA
Theophylline
C
ICS + LABA
or
LAMA
LAMA and LABA
PDE4-inh.
SABA and/or SAMA
Theophylline
D
ICS + LABA
or
LAMA
ICS and LAMA or
ICS + LABA and LAMA or
ICS+LABA and PDE4-inh.
or
LAMA and LABA or
LAMA and PDE4-inh.
Carbocysteine
SABA and/or SAMA
Theophylline
GOLD 2013
Modified from Cooper CB, Tashkin DP. BMJ 2005;330;640-44
A clinical algorithm for the treatment of COPD
Pharmacotherapy
0
1
2
LABALAMA
3
LAMA + LABA
4
LAMA + LABA
+ roflumilast
Non-pharmacological
therapy
Smoking cessation
Avoidance of exposure
Vaccination
(influenza, pneumococcal)
Pulmonary rehabilitation
(Exercise prescription)
Supplemental oxygen
Lung volume reduction surgery
Lung transplantation
SAMA, SABA or SAMA + SABA
GOLD Spirometric
Stage
(approximate)
Clinical
stage
At risk
Intermittent
symptoms
Persistent
symptoms‡
Frequent
exacerbations
Respiratory failure
LAMA + LABA
+ ICS*
LAMA + LABA
+ azithromycin
*Clinical benefit of adding ICS to LABA+LAMA has not yet been demonstrated
or

36. 2/21/2014
36
GOLD 2013: treatment goals for stable
COPD
 Relieve symptoms
 Improve exercise endurance
 Improve health status
REDUCE
SYMPTOMS
AND
 Prevent disease progression
 Prevent and treat exacerbations
 Reduce mortality
REDUCE
RISK
COPD, chronic obstructive pulmonary disease;
GOLD, Global Initiative for Chronic Obstructive Lung Disease. GOLD 2013
GOLD 2013: treatment goals for stable
COPD
 Relieve symptoms
 Improve exercise endurance
 Improve health status
REDUCE
SYMPTOMS
AND
 Prevent disease progression
 Prevent and treat exacerbations
 Reduce mortality
REDUCE
RISK
COPD, chronic obstructive pulmonary disease;
GOLD, Global Initiative for Chronic Obstructive Lung Disease. GOLD 2013
yes
yes
yes
yes

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37
Thank you for your attention