Do all ICS/LABAs

provide equal
exacerbation protection
& safety benefits to
COPD patients?

 Seorang laki laki 65 tahun datang

ke KLINIK PRATAMA ENGGAL
WARAS dengan keluhan utama
sesak napas,sesak dirasakan
terutama bila melakukan
aktifitas,kadang disertai batuk
berdahak.
Pasien merokok 20 batang
perhari,kebiasaan merokok
dilakukan sejak umur 20 tahun.
Dalam setahun terakhir pernah
dirawat kerena sesak

APAKAH PPOK?
2

Author | 00 Month Year

Set area descriptor | Sub level 1

Definition
A common preventable and treatable
disease.1

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.1

Exacerbations
and
comorbidities
contribute to the overall severity in

1. Global initiative for chronic Obstructive Lung Disease updated 2013

Available from : http//www,goldcopd.org. Accessed on Jan 27,2014
2. WHO Fact Sheet No. 315 November 2012

Mechanisms Underlying Airflow Limitation in

COPD

Small Airways Disease

Parenchymal Destruction

Airway inflammation
Airway fibrosis, luminal plugs
Increased airway resistance

Loss of alveolar
attachments
Decrease of elastic recoil

AIRFLOW LIMITATION

Set area descriptor | Sub level 1

2015 Global Initiative for Chronic Obstructive Lung Disease

Diagnosis of COPD
SYMPTOMS
shortness of breath
chronic cough
sputum

EXPOSURE TO RISK
FACTORS

tobacco
occupation
indoor/outdoor pollution

SPIROMETRY: Required to establish

diagnosis

Global initiative for chronic Obstructive Lung Disease updated 2013

Available from : http//www,goldcopd.org. Accessed on Jan 27,2014

 Seorang laki laki 65 tahun datang

ke KLINIK PRATAMA ENGGAL WARAS
dengan keluhan

sesak napas,sesak dirasakan

terutama bila melakukan
aktifitas,kadang disertai
batuk merokok
berdahak.
Pasien
20 batang
perhari,kebiasaan merokok
dilakukan sejak umur 20 tahun.

Author | 00 Month Year

Set area descriptor | Sub level 1

Spirometry: Normal Trace

Showing FEV1 and FVC
FVC

Volume, liters

5
4

FEV1 = 4L

FVC = 5L

FEV1/FVC = 0.8

Time, sec
2015 Global Initiative for Chronic Obstructive Lung Disease

Spirometry: Obstructive
Disease
Normal

Volume, liters

5
4
3

FEV1 = 1.8L

FVC = 3.2L

Obstructive

FEV1/FVC = 0.56

Time, seconds
2015 Global Initiative for Chronic Obstructive Lung Disease

FEV1: 49%

ASSESSMENT COPD

Assess symptoms
Assess degree of airflow
limitation using spirometry
Assess risk of exacerbations
Assess comorbidities
10

Author | 00 Month Year

Set area descriptor | Sub level 1

Global Strategy for Diagnosis, Management and

Prevention of COPD

Symptoms of COPD
The characteristic symptoms of COPD are
chronic and progressive dyspnea, cough,
and sputum production that can be variable
from day-to-day.
Dyspnea: Progressive, persistent and
characteristically worse with exercise.
Chronic cough: May be intermittent and
may be unproductive.
Chronic sputum production: COPD patients
commonly cough up sputum.
2013 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of

COPD

Assessment of COPD

Assess symptoms
Use the COPD Assessment Test(CAT)
or
mMRC Breathlessness scale
or
Clinical COPD Questionnaire (CCQ)
2013 Global Initiative for Chronic Obstructive Lung Disease

mMRC

13

Author | 00 Month Year

Set area descriptor | Sub level 1

Global Strategy for Diagnosis, Management and Prevention of

COPD

Assessment of COPD

Assess symptoms
Assess degree of airflow limitation

using spirometry
Assess
risk of exacerbations
Use
spirometry
for grading severity
Assess comorbidities
according to spirometry, using
four
grades split at 80%, 50% and
30% of
predicted value
2013 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and

Prevention of COPD

Classification of Severity
of Airflow Limitation in
In
patients with FEV1/FVC < 0.70:
COPD*
GOLD 1: Mild

FEV1 > 80% predicted

GOLD 2: Moderate
predicted

50% < FEV1 < 80%

GOLD 3: Severe
GOLD 4: Very Severe

30% < FEV1 < 50% predicted

FEV1 < 30% predicted

*Based on Post-Bronchodilator FEV1

Global Strategy for Diagnosis, Management and Prevention of

COPD

Assessment of COPD

Assess symptoms
Assess degree of airflow limitation
using spirometry
Assess risk of exacerbations

Use Assess comorbidities

a history of exacerbations and spirometry.
Two exacerbations or more within the last
year
or an FEV1 < 50 % of predicted value are
indicators of high risk
2013 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and

Prevention of COPD

Combined Assessment of COPD

Assess symptoms
Assess degree of airflow limitation
using spirometry
Assess risk of exacerbations
Combine these assessments for the
purpose of improving management
of COPD
2013 Global Initiative for Chronic Obstructive Lung Disease

FEV1 <
30%
predicted

(C)
(C)

(D)

>2

(B)

3
30% < FEV1
< 50%
predicted

2
50% < FEV1 <
80% predicted

(A)

1
FEV1 >
80%
predicted

0
mMRC 0-1
CAT < 10

mMRC > 2
CAT > 10

Symptoms
(mMRC or CAT score))
Global initiative for chronic Obstructive Lung Disease updated 2013
Available from : http//www,goldcopd.org. Accessed on Jan 27,2014

(Exacerbation
history)

Risk

Risk
(GOLD Classification of Airflow Limitation)

Classification of COPD Patients

Manage Stable COPD: Pharmacologic

Therapy
(Medications in each box are mentioned in alphabetical order, and therefore not
necessarily in order of preference.)

Patient

Recommended
First choice

Alternative choice

Other Possible
Treatments

SAMA prn
or
SABA prn

LAMA
or
LABA
or
SABA and SAMA

Theophylline

LAMA
or
LABA

LAMA and LABA

SABA and/or SAMA

Theophylline

ICS + LABA
or
LAMA

LAMA and LABA or

LAMA and PDE4-inh. or
LABA and PDE4-inh.

ICS + LABA
and/or
LAMA

ICS + LABA and LAMA or

ICS+LABA and PDE4-inh. or
LAMA and LABA or
LAMA and PDE4-inh.

Global initiative for chronic Obstructive Lung Disease updated 2013

Available from : http//www,goldcopd.org. Accessed on Jan 27,2014

SABA and/or SAMA

Theophylline

Carbocysteine
SABA and/or SAMA
Theophylline

Why ICS/LABA
combination in
one inhaler for
COPD?

Rationale for using combination ICS/LABA

COPD is multi-component disease. Many current therapies
target just one aspect of the complex pathophysiology of
COPD.1
For optimal treatment, a therapeutic regimen that has the
potential to act on multiple underlying components of the
disease might be considered. 1
Bronchodilators are a mainstay of COPD treatment through
their ability to work by both smooth and non-smooth muscle
mechanisms. 1
ICS use is associated with reductions in the number and
severity of exacerbations experienced by patients with severe
COPD (or with FEV1 <60 predicted). Inhaled corticosteroid
therapy is associated with an increased risk of pneumonia. 1,2
The combination of a LABA with an ICS has the
1.potential
van Schayck & Reid. Prim
Care Respir
J 2006;15: 143-151many
to
address
underlying components
2. Global initiative for chronic Obstructive Lung Disease updated 2013
Available from : http//www,goldcopd.org. Accessed on Jan 27,20141
especially
in severe COPD.

What are the evidence?

Combination ICS/LABA
for COPD

Budesonide/Formoterol
in the Treatment of COPD
Two 12-month placebo-controlled studies
(Szafranski1 and Calverley2)

Szafranski W et al. Eur Respir J 2003;21:74-81.

Calverley PM et al. Eur Respir J 2003;22:912-919.

Budesonide/Formoterol in the Treatment of COPD

zafranski & Calverley Studies: Study Design

Run-in

Randomisation

Withdrawal of
preventative
medication
(Szafranski)

Treatment

Budesonide/formoterol Turbuhaler)2 x 160/4.5 g bid

Budesonide Turbuhaler 2 x 200 g bid

OR
Oral
prednisolone
30 mg od;
formoterol
2 x 4.5 g bid
(Calverley)

Formoterol Turbuhaler 2 x 4.5 g bid

Placebo

Terbutaline Turbuhaler 0.5 mg as reliever for all patients

Month:-0.5

12

Visit:

Clinic visits 18
Budesonide/Formoterol Turbuhaler 160/4.5 g delivers the same amount of budesonide and formoterol as the corresponding
Turbuhaler monoproducts
Szafranski W et al. Eur Respir J 2003;21:74-81.
Calverley PM et al. Eur Respir J 2003;22:912-919.

Budesonide/Formoterol in the Treatment of COPD

zafranski & Calverley Studies: Reduced exacerbations

Szafranski

Calverley

Mean no. of
exacerbations/
patient/year

2.0

1.8

1.8
1.6

1.4*

1.9

2.0
1.8

1.6

1.6

1.4

1.4

1.2

1.2

1.0

1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

0
Budesonide/Formoterol

Budesonide

Formoterol

1.9

Placebo

*P=0.035 vs placebo;
P=0.043 budesonide/formoterol vs formoterol

Szafranski W et al. Eur Respir J 2003;21:74-81.

Calverley PM et al. Eur Respir J 2003;22:912-919.

1.8

1.6
1.4

Budesonide/formoterol

Budesonide

*P=0.029 vs placebo;

Formoterol

Placebo

Salmeterol/fluticasone in COPD
TORCH study: Study Design
Designed as double-blind, placebo-controlled, randomized and parallelgroup study over 3-year period.
1524 received placebo
2-week
run in
period

6184 patients
were
randomized
72 patients
were excluded

1521 received salmeterol 50 mcg twice

daily
1534 received fluticasone propionate, 500 mcg
twice daily
1533 received salmeterol/fluticasone propionate,
50/500 mcg twice daily

Calverley PMA et al. NEJM 2007;356:775-89

Salmeterol/fluticasone in COPD
TORCH study: Primary endpoint was time to death from any cause.

* Only the primary comparison was adjusted because interim analyses were performed.

Calverley PMA et al. NEJM 2007;356:775-89

Unadjusted data for the primary end point are provided for comparison

Salmeterol/fluticasone in COPD
TORCH study: Secondary endpoints were frequency of exacerbations
and health status

Combination salmeterol/fluticasone significantly reducde

Calverley PMA et al. NEJM 2007;356:775-89 exacerbations and improved health status vs placebo and mono-

Salmeterol/fluticasone in COPD
TORCH study: Safety analysis

* Probability was calculated by the KaplanMeier method.

P<0.001 for the comparison between the fluticasone group and the placebo group.
P<0.001 for the comparisons between the group receiving salmeterol plus fluticasone propionate and the
placebo group and between the combination-therapy group and the salmeterol group.

Calverley PMA et al. NEJM 2007;356:775-89

Budesonide/Formoterol added to
Tiotropium
CLIMB study: Study Design
3-month, double-blind, randomised study

Treatment period

Run-in

Tiotropium 18* g od + budesonide/formoterol

Turbuhaler 320/9 g bid. n = 329
303 completed

Enrolment

Tiotropium
18* g od

302 completed

Enrolled: 990
Randomised: 660Tiotropium 18* g od + placebo Turbuhaler bid

n = 331

ICS withdrawn
visit 1

Terbutaline 0.5* mg/dose as reliever

Week:> 2

12

Visit:

LABA
withdrawn
before visit 2

Welte T, et al. Am J Respir Crit Care Med 2009; 180:741750

Budesonide/Formoterol added to
CLIMB study: Primary endpoint was the change in predose FEV1 from randomization (Week
Tiotropium
0) to the full treatment period (mean FEV1 at 1, 6, and 12 wk of treatment)
6

1.16

*
1.14

* P < 0.001

Change (%)

Pre-dose FEV1 (L)

1.12

1.10

1.08

2
1.06

Symbicort + TIO

1.04

1.02
3

PBO + TIO

Week in study

12

15

6
3

12

15

Week in study
Welte T, et al. Am J Respir Crit Care Med 2009; 180:741750

Budesonide/Formoterol added to Tiotropium

0.4
Symbicort + TIO
PBO + TIO
Exacerbations/patient

0.3
62% reduction in rate of
exacerbation*
Ratio: 0.38 (95% CI: 0.250.57)
P < 0.001

0.2

0.1

0.0
0

15

30

45

60

75

90

Days since randomisation

* Severe exacerbations defined as oral steroid use, ER visits and hospitalisations
PBO = placebo; TIO = tiotropium

Welte T, et al. Am J Respir Crit Care Med 2009; 180:741750

The Paradigm Continues:

Real World Experience to complement
RCTs

A retrospective propensity score matched cohort study

comparing combination budesonide/formoterol vs.
fluticasone/salmeterol in chronic obstructive pulmonary
disease.

PATHOS Study
Objective
Analyse Swedish healthcare utilization data
Understand evolution of COPD management
Compare the effectiveness of BUD/FORM and FLU/SAL
in propensity score matched patients with respect to:
COPD exacerbation

LSY0011MYSG20130424

COPD prescriptions other than ICS/LABA

Pneumonia events including mortality

1.

Larsson K et al. J Intern Med

2013;273:584-594

Disease
manageme
nt
evolution
over 11
years

Description of the
evolution of COPD
disease &
management

Larsson K et al. J Intern Med 2013; 273:584-94

35

Time trend analysis

Study population

Patients with COPD diagnosis during 1999 2009

Index date defined as 1st COPD diagnosis
No age restrictions
Follow up from index date to December 2009, emigration or
death
21,361 patients with a COPD diagnosis included
Mean age 68 years
Females 53%
Initial COPD diagnoses were made in primary care

Larsson K et al. J Intern Med 2013; 273:584-94

36

LSY0011MYSG20130424

Effective
ness
of fixed
ICS/LABA
Combination
s
on
Exacerbatio
ns

Comparative effectiveness of
BUD/FORM Turbuhaler and
FLU/SAL Diskus in
Propensity Matched Patients
COPD Exacerbations
Hospitalisations
Emergency visits
Prescription of oral steroids
Prescriptions of antibiotics due to COPD

1.

Larsson K et al. J Intern Med

2013;273:584-594

COPD exacerbations
Events per 100 patient/years for exacerbations in propensity matched
COPD patients treated
with BUD/FORM (n=2734) or FLU/SAL (n=2734)

80

All exacerbations

109
85
38

Antibiotics

0.74
(0.68, 0.81)

**

0.70
(0.66, 0.75)

54
15
21

Hospitalisations

2.7
3.4

0.0
LSY0011MYSG20130424

**

63

Oral steroids

Emergency visits

Rate ratio (95% CI)

0.74
(0.69, 0.79)
NNT = 3.4

20.0

**
NNT = 16

SAL/FLU
BUD/FORM

0.71
(0.65, 0.78)

**
*

40.0

0.79
(0.71, 0.89)

60.0

80.0 100.0 120.0 140.0 160.0

Adjusted yearly rates of healthcare utilisation events were compared using Poisson regression
analysis.
**P<0.0001; *P=0.0003 for difference.
CI, confidence intervals; BUD/FORM, budesonide/formoterol; FLU/SAL, fluticasone/salmeterol

1.

Larsson K et al. J Intern Med

2013;273:584-594

Study Title : Pneumonia and pneumonia-related mortality in patients

with COPD treated with fixed combinations of inhaled corticosteroid and
long-acting -2 agonist: Observational matched cohort study

Safety

LSY0011MYSG20130424

of fixed
ICS/LABA
Combinati
ons
on
Pneumoni
a

Relative Safety Difference

of
BUD/FOR Turbuhaler and
FLU/SAL Diskus in
Propensity Matched
Patients
Pneumonia-Related Events
(Physician diagnosed)
BUD/FOR: Budesonide/Formoterol
FLU/SAL: Fluticasone/Salmeterol

Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306

Cumulative Pneumonia Rate

vs Time
Post-Index

Cumulative pneumonia rate per

100 patients

LSY0011MYSG20130424

Fluticasone/Salmeterol group

110
100
90
80
70
60
50
40
30
20
10
0

Budesonide/Formoterol group

Any pneumonia

Any pneumonia

Hospitalised pneumonia

Hospitalised pneumonia
All pneumonias
RR 1.73 (1.57to 1.90)
P < .001 NNH 23

Hospitalised
pneumonias
RR 1.74 (1.56 to 1.94)
P < .001 NNH 34

4
5
Years

Adjusted yearly pneumonia event rates

compared using Poisson regression analysis.
Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306

Pneumonia and PneumoniaRelated Events

Pneumonia events in propensity matched
COPD patients, per 100 patient/years
BUD/FOR (n = 2734) or FLU/SAL (n = 2734)

LSY0011MYSG20130424

Rate
Increase risk
ratio
for FLU/SAL
(95% CI)
1.73
(1.57 to1.90)

73%
P < .001

1.74
(1.56 to1.94)

74%
P < .001

1.56
(1.39 to 1.75)

56%
P < 0.001

1.75
(1.53 to 2.00)

75%
P < 0.001

NNH
23

34

Adjusted yearly pneumonia event rates compared using Poisson regression analysis. P<0.001 for all.
CI, confidence intervals; BUD/FOR, budesonide/formoterol; FLU/SAL, fluticasone/salmeterol
Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306

Study Summary

LSY0011MYSG20130424

1. COPD patients treated with BUD/FORM

Turbuhaler were significantly less likely to
experience moderate to severe
exacerbations than patients treated with
FLU/SAL Diskus.
2. COPD patients treated with FLU/SAL Diskus
were significantly more likely to
experience pneumonia and pneumoniarelated hospitalizations than patients
treated with BUD/FORM
Turbuhaler.
1. Larsson K et al. J Intern Med 2013;273:584-594.
2. Janson C et al. BMJ 2013;346:f3306. doi:10.1136/bmj.f3306

Conclusion
COPD is preventable and treatable disease. Its progressive one
but interventions/treatment can delay the progress.
One of therapy for COPD patients is combination of ICS and LABA
in one inhaler. Its a first choice therapy for COPD patients group C
and D
Several RCTs on COPD for fixed combination ICS/LABA showed that
the combination significantly reduced exacerbations and improved
health of status
Combination ICS/LABA with LAMA gave greater benefit for COPD
patients in term of exacerbation rate
Pneumonia
incidence
happened
during
treatment
with
salmeterol/fluticasone, which had increase rate with the fixed
combination.
In
CLIMB
study
with
the
use
of
budesonide/formoterol, the incidence was <1% and comparable
between treatment arms.