Asthma Control

TAKING CONTROL OF
ASTHMA
Objectives
To understand the long-term consequences

of sub-optimal control and how and when to
step down once control has been achieved
and maintained in line with the guidelines.
How this will be achieved: The GOAL study,

currently available AHR data and biopsy data
will be presented, which support the real
benefits of long-term control. Future risk,
remodelling and step-down strategies will be
discussed.
Goal of asthma management
The goals for successful management of asthma are to:

Achieve and maintain control of symptoms
Maintain normal activity levels, including exercise
Maintain pulmonary function as close to normal as
possible
Prevent asthma exacerbations
Avoid adverse effects from asthma medications
Prevent asthma mortality
GINA 2009
Why does achievement of asthma

control matter?
Asthma is a chronic inflammatory disorder of

the airways characterized by recurrent
episodes of wheezing, breathlessness, chest
tightness and coughing1
Poorly controlled patients:

Are at an increased risk for future
exacerbations1
Are hospitalised nearly twice as often as
those who are at least well controlled1,2
1. GINA 2009. 2.Demoly et al. Eur Respir Rev 2010
Management approach based on control

Step 1
Step 2
Step 3
Step 4
Step 5
Asthma education
Environmental control
As needed rapidacting 2-agonist
Controller
options
As needed rapid-acting 2-agonist

Select one
Select one
Add one or more
Add one or more
Low-dose inhaled
ICS
Low-dose ICS plus

long-acting
2-agonist
Medium- or
high-dose ICS
plus long-acting
2-agonist
Oral
glucocorticosteroid
(lowest dose)
Leukotriene
modifier
Medium- or
high-dose ICS
Leukotriene
modifier
Anti-IgE treatment
Low-dose ICS plus

Sustained release
leukotriene
theophyline
modifier
Low-dose ICS plus
sustained-release
theophyline
In most cases, preferred controller option is an ICS/LABA combination

GINA 2009
GOAL: study design

Phase I
Phase II
8-week control assessment
4-week control assessment
Oral prednisolone +
ICS/LABA 50/500 bd
ICS/LABA 50/500 bd
or ICS 500 bd
ICS/LABA 50/250 bd
or ICS 250 bd
ICS/LABA 50/100 bd
or ICS 100 bd
-4
12
24
36
52 56
Week
Bateman et al. Am J Respir Crit Care Med 2004
Patient demographics
Stratum 1
Stratum 2
Stratum 3
ICS/LABA
ICS
ICS/LABA
ICS
ICS/LABA
ICS
548
550
585
578
576
579
FEV1
77%
79%
78%
77%
75%
76%
23%
22%
22%
22%
23%
22%
1.9
1.7
1.7
1.7
1.9
1.9
0.4
0.3
0.6
0.5
0.7
0.7
(% Pred)
Reversibility
(Median %)
Rescue use
(mean occasions/
day)
Exacerbation
rate
Achieving GINA guideline-defined

well-controlled asthma
80
78*
ICS/LABA Phase II
ICS Phase I
ICS/LABA Phase I
75**
70
62**
60
60
% Patients
ICS Phase II
47
40
20
0
Steroid nave
(Stratum 1)
Low-dose ICS
(Stratum 2)
Moderate-dose ICS
(Stratum 3)
*P=0.003; **P<0.001
% of patients who achieved

guideline-defined control in Phase I
GINA guideline-defined control is achieved with

ICS/LABA at reduced corticosteroid dose
80
ICS 500
ICS/LABA 500
ICS 250
ICS/LABA 250
ICS 100
ICS/LABA 100
500
60
500
250
40
250
100
20
100
Stratum 2, phase I
0
ICS
GOAL Study
ICS/LABA
Maintenance of control:
improved lung function over 1 year
Improvement in am PEF
80
71.1
Adjusted mean change
in am PEF (L/min)
70
57.1
60
50
49.2
45.7
ICS/LABA
40
ICS
30.0
30
21.6
20
10
0
Steroid nave
Stratum 1
Overall treatment difference: 24.3 L/min, P<0.001
Low-dose ICS
Stratum 2
Moderate-dose ICS
Stratum 3
Woodcock et al. Prim Care Respir J 2007
Maintenance of control over 1 year:

Rescue-free days (median %)
91.8
* 87.1
87.8
ICS
77.9
80
72.0
70
61.9
60
50
40
30
20
81.5
76.6
80
ICS/LABA
74.2
ICS
70
55.9
60
51.0
50
40
29.9
30
20
10
10
0
Steroid nave
Stratum 1
Low-dose ICS
Moderate-dose ICS
Steroid nave
Low-dose ICS
Stratum 2
Stratum 3
Stratum 1
Stratum 2
Moderate-dose ICS
Stratum 3
Patients achieving normal or near-normal quality of life

70
63
% Patients (AQLQ score >6)
% Rescue-free days (median)
90
90
% Symptom-free days (median)
100
Symptom-free days (median %)
ICS/LABA
NS
62
64
ICS/LABA
ICS
#
57
60
53
50
45
40
30
20
10
0
Steroid nave
Stratum 1
P=0.025
*P<0.001
# P<0.005
Low-dose ICS
Stratum 2
Moderate-dose ICS
Stratum 3
Woodcock et al. Prim Care Respir J 2007

Bateman et al. Eur Respir J 2007
When should you step down?
When control is maintained for at least 3

months, treatment can be stepped down with
the aim of establishing the lowest step and
dose of treatment that maintains control
GINA 2009
Study design
ICS/LABA 50/250g bd
n=159
ICS/LABA 50/250g bd
n=603
ICS/LABA 50/100g bd
n=157
ICS 250g bd
n=159
Week -8
Screening
Week 0
Week 4
Week 12
Randomisation
8-week run-in period
Week 24
End of treatment
6-month treatment period
Primary endpoint: mean morning PEF over the first 12 weeks of treatment.
Secondary endpoints: PEF over the last 12 weeks of the treatment period, evening PEF, daily
symptoms, short-acting bronchodilator use as rescue medication, exacerbations, FEV1 and
asthma control using the GOAL definitions of total and well controlled
Godard et al. Respir Med 2008
Adjusted mean am PEF: no

significant change from baseline
Week 24
ICS/LABA
50/250
ICS/LABA
50/100
ICS 250
10
5.5
5
l/min
1.0
0
-5
4.5 (13.2; 4.1) p=0.238
-10
-15
-14.6
20.1 (28.9; 11.3) p<0.001
Change from baseline in % of

symptom-free days
Baseline
Week 12
ICS/LABA 250
90.2
89.4
ICS/LABA 100
94.8
93.2
ICS 250
91.2
85.8
Over weeks 112, difference between ICS 250 and ICS/LABA 250
statistically significant (p=0.012); no significant difference between
ICS/LABA groups
No difference between groups over weeks 1324
Study demonstrated reducing the ICS dose and maintaining LABA

is a better for stepping down treatment
Godard et al. study conclusion
In patients whose asthma is controlled with

ICS/LABA 250/50, a step-down strategy to
ICS/LABA 100/50 is at least as effective as
maintaining a constant dose
This was not shown with ICS alone
Differences were maintained over 24 weeks
Stepping down should be considered in

patients with sufficient level of control
Stepping-down Bateman study

ICS/LABA 50/100g bd
n=208
SABA
only
ICS/LABA 50/250g bd
n=660
ICS 250g bd
n=188
Weeks
2
12
16
20
End of
treatment
Randomisation
Screening
Run-in period
24
Double-blind treatment period
Primary endpoint: mean morning PEF

Secondary endpoints: Asthma control, symptoms, and rescue albuterol usage
Bateman et al. J Allergy Clin Immunol 2006
Maintenance of asthma control

during step down
Open-label period
% of well-controlled subjects
100
80
ICS/LABA 50/250 bid

(two lines show groups that were
randomised during blinded phase)
68%
Well controlled in 68% over 4 weeks
60
40
4-wk control
assessment
20
Run-in
10
12
Weeks
Maintenance of asthma control

during step down
Open-label period
% of well-controlled subjects
100
80
Double-blind period
ICS/LABA 50/250 bid

(two lines show groups that were
randomised during blinded phase)
60
40
4 wks
Well
controlled
20
ICS 250 bid
ICS/LABA 50/250
Run-in
ICS/LABA 50/100 bid
10
12
Weeks
14
16
18
Conclusion: Stepping down to a lower dose of

ICS/LABA is more effective than switching to an
ICS alone
20
22
24
IS ASTHMA CONTROL
ACHIEVABLE?
WELL CONTROLLED asthma: continued

improvements with sustained treatment
Patients controlled each week (%)
100
All patients
80
60
ICS/LABA (n=1709)
40
ICS (n=1707)
20
0
4
12
16
20
24
28
32
36
40
44
48
52
Week
Proportion of patients achieving a well-controlled week (noncumulative)
over Weeks 4 to 52 for all strata combined on treatment
with salmeterol/fluticasone or fluticasone propionate
% of patients controlled each week
TOTAL CONTROL: Continued

improvements with sustained treatment
ICS/LABA
100
ICS
80
60
40
20
0
-4
12
16
20
24
28
32
36
40
44
48
52
Week
All patients
GSK Data on File 2011
Aiming for TOTAL CONTROL reduces

all exacerbations
ICS
Baseline
Baseline
ICS/LABA
0.7
*p<0.01
Mean exacerbation rate

per patient per year
0.6
0.5
0.4
*
0.3
0.2
0.1
*
*
0
Steroid nave (S1)
Low dose ICS (S2)
Moderate dose ICS (S3)
Requiring
oral steroids and/or antibiotics, or hospitalisations prior to the 52week study; or requiring oral steroids or hospitalisations /emergency visits
documented during the 52-week study
CAN WE ACHIEVE GOOD

CONTROL WITH VARIABLE
DOSING?
Asthma control: fixed vs variable
Managing the challenge of residual asthma

symptoms in adults using ICS/LABA has been
managed in two ways:1
Increase maintenance dose of fixed-dose
combination
Use combination as single maintenance and
reliever therapy (SMART)2
SMART suggested to offer convenience and better

improvements in outcomes with lower ICS dosing3
Does evidence support the use of this strategy?

1. Bousquet et al. Respir Med 2007. 2. Chapman et al. Thorax 2010.
3. Humbert et al. Allergy 2008.

compared to GINA target
% Symptom-free days
% symptom-free days
80
VARIABLE
FIXED
70
GINA Target
(twice a week)
60
50
40
30
20
10
AHEAD
(n=1151)
COMPASS
(n=1107)
COSMOS
(n=1067)
SMILE
(n=1113)
STEAM
(n=355)
STEP
(n=947)
STAY
(n=925)
Busse
(n=281)
Jarjour
(n=40)
Lundback
(n=95)
EXCEL
(n=694)
CONCEPT
(n=344)
GOAL
(n=1709)
1. Woodcock et al. Prim Care Respir J 2007. 2. Fitzgerald et al. Clin Ther 2005. 3. Dahl et al. Respir Med 2006.
4. Lundback Respir Med 2006. 5. Jarjour J Allergy Clin Immunol 2006. 6. Busse J Allergy Clin Immunol 2003.
7. OByrne et al. Am J Respir Crit Care Med 2005. 8. Scicchitano et al. Curr Med Res Opin 2004. 9. Rabe et al. Chest 2006. 10. Rabe
et al. Lancet 2006. 11. Vogelmeier et al. Eur Respir J 2005.12. Kuna et al. Int J Clin Pract 2007.
13. Bousquet et al. Respir Med 2007.

compared to GINA target
Average daily quick-reliever use
VARIABLE
FIXED
1
0.8
0.6
0.4
GINA target
(twice a week)
0.2
AHEAD
(n=1151)
COMPASS
(n=1107)
COSMOS
(n=1067)
SMILE
(n=1113)
STEAM
(n=355)
STEP
(n=947)
STAY
(n=925)
Busse
(n=281)
Jarjour
(n=40)
Lundback
(n=95)
EXCEL
(n=694)
CONCEPT
(n=344)
0
GOAL
(n=1709)
Average reliever use/day
1.2
AHEAD
(n=1151)
COMPASS
(n=1107)
COSMOS
(n=1067)
SMILE
(n=1113)
STEP
(n=947)
STAY
(n=925)
Busse
(n=281)
Jarjour
(n=40)
Lundback
(n=95)
EXCEL
(n=694)
CONCEPT
(n=344)
STEAM
(n=355)
VARIABLE
FIXED
90
80
70
60
50
40
30
20
10
0
GOAL
(n=1709)
%reliever-free days
% Reliever-free days
% Nights with awakenings
AHEAD
(n=1151)
COMPASS
(n=1107)
COSMOS
(n=1067)
STEP
(n=947)
STAY
(n=925)
Busse
(n=281)
Jarjour
(n=40)
Lundback
(n=95)
EXCEL
(n=694)
CONCEPT
(n=344)
SMILE
(n=1113)
VARIABLE
FIXED
STEAM
(n=355)
16
14
12
10
8
6
4
2
0
GOAL
(n=1709)
%nights with awakenings
Exacerbations rate (events/yr)
0.25
VARIABLE
FIXED
0.2
0.15
0.1
0.05
AHEAD
(n=1151)
COMPASS
(n=1107)
COSMOS
(n=1067)
SMILE
(n=1113)
STEAM
(n=355)
STEP
(n=947)
STAY
(n=925)
Busse
(n=281)
Jarjour
(n=40)
Lundback
(n=95)
EXCEL
(n=694)
CONCEPT
(n=344)
0
GOAL
(n=1709)
Exacerbation rate (events/yr)
1. Bateman et al. Am J Respir Crit Care Med 2004. 2. Fitzgerald et al. Clin Ther 2005. 3. Dahl et al. Respir Med 2006.
Asthma control: fixed vs variable:

Conclusion
At present, there is no evidence that better

asthma treatment outcomes can be
obtained by moment-to-moment symptomdriven use of ICS/LABA therapy compared
with conventional physician-monitored and
adjusted ICS/LABA therapy
Chapman et al. Thorax 2010
Maintenance and reliever versus

fixed-dose ICS/LABA
ICS/LABA 400/12 g bd + ICS 400 g bd + as-needed 2-agonist
n=63
SABA
only
ICS/LABA 200/6 g bd + as-needed ICS/LABA 200/6 g bd

n=64
Weeks
2
20
35
50
Randomisation
Run-in
52
End of
treatment
Treatment period
Primary endpoints:
Change in induced sputum eosinophil count from baseline
Change in the number of eosinophils per square millimetre of subepithelial tissue in

bronchial biopsies from baseline to week 52
Secondary endpoints: Changes in nonsquamous cell counts, neutrophil, lymphocyte,
monocyte/macrophage, and bronchial epithelial cell counts in induced sputum, and sputum
supernatant eosinophil cationic protein concentrations
Pavord et al. JACI 2009
Regular dosing vs variable dosing:

sputum inflammatory cells
% change from baseline
*p=0.0038
n=127
Regular dosing vs variable dosing:

biopsy inflammatory cells
% change from baseline
*p=0.0012; p<0.01
n=127
Pavord study conclusion
Low-dose ICS/LABA maintenance and

reliever therapy is associated with higher
eosinophil counts in sputum and bronchial
biopsy versus fixed-dose therapy
However, lung function, exacerbation

frequency, overall inflammation and airway
remodelling are not significantly affected by
treatment strategy
CLINICIANS PERSPECTIVES
Treating ongoing inflammation
Rate of response of different measures of asthma control over 18

months of ICS treatment
% Reduction
AHR, airway hyperresponsiveness; FEV1, forced expiratory volume in

1 second; ICS, inhaled corticosteroid; PEF, peak expiratory flow
AHR is a marker of inflammation
AHR
Rescue medication use
Night
symptoms Impaired FEV Impaired am PEF
1
Start of treatment
(months)
Short term
ACHIEVE CONTROL
18
Long term
Maintain CONTROL
An ongoing requirement for rescue medication is a sign that the underlying inflammation is
uncontrolled
Woolcock Clin Exp Allergy Rev 2001. GINA 2009
AHR continues to improve even after

lung function has plateaued
110
FEV1 (% baseline)
105
100
AHR
FEV1
95
Baseline
-1
Log10 PD20 (mg)
-2
6
Time (months)
12 1 month
after
treatment
Ward et al. Thorax 2002
SFC improve AHR over the 3 years

course of the study
Lundback B et al, ERS 2006
Conclusions
Continued treatment improves control, reducing

exacerbation rates
Stepping down should be considered in patients with

sufficient level of control. Stepping down to a lower dose of
ICS/LABA is more effective than switching to an ICS alone
There is no evidence that better asthma outcomes can be

obtained by moment-to-moment symptom-driven use of
ICS/LABA therapy than conventional physician-monitored
and adjusted therapy
Low-dose ICS/LABA maintenance and reliever therapy is

associated with higher eosinophil counts in sputum and
bronchial biopsy versus fixed-dose therapy
Maintenance of control necessary to continue AHR

improvements
THANK YOU FOR YOUR KIND

ATTENTION
The Disconnect
Problem:
If patients cannot recognise that they have
uncontrolled asthma, it is unlikely they will seek a
review of their treatment
Education
changes
patient
expectations
Satisfaction with control

(% of patients)
Solution:
To develop a practical system whereby patients can
recognise poor control
70
60
50
40
30
20
10
0
Haughney et al. Prim Care Respir J 2004
58%
(n=301)
satisfied
25%
drop
33%
(n=173)
satisfied
Before
After
Being shown GINA guidelines
The Disconnect
Judging
symptom
frequency
Difficulty in
breathing
Nocturnal
waking
Dry cough
Patients (n=2,232)
Primary-care physicians (n=809)
Ability to talk
affected
0
20
40
60
80
Patients experiencing symptoms 1/month (%)
Price D et al.
Asthma J 1999
Problem:
If doctors cannot identify patients with uncontrolled
asthma, it is unlikely they will prescribe the required
treatment
Solution:
To use a practical system to identify patients with poor
control Use ACT (Asthma Control Test)
Mis-diagnosis of asthma in 13-14 y

old schoolchildren in Asia Pacific
Current wheeze without "asthma ever"
Asthma ever without wheeze ever
100
90
80
70
60
50
40
30
20
10
0
AP
Ch
i
na
HK
S
Ta
In
J
M
Ph Si
T h Vi
al
do a p
K
et
n
iw
ai
ili
g
o
a
a
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pp
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ys
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n
an nam
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es re
Lai CKW et al. Thorax 2009;64:476-83

Asthma Control

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Asthma Control

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TAKING CONTROL OF

To understand the long-term consequences

How this will be achieved: The GOAL study,

Goal of asthma management

The goals for successful management of asthma are to:

Why does achievement of asthma

Asthma is a chronic inflammatory disorder of

Poorly controlled patients:

Management approach based on control

As needed rapid-acting 2-agonist

Add one or more

Add one or more

Low-dose ICS plus

Low-dose ICS plus

In most cases, preferred controller option is an ICS/LABA combination

GOAL: study design

Bateman et al. Am J Respir Crit Care Med 2004

Achieving GINA guideline-defined

% of patients who achieved

GINA guideline-defined control is achieved with

Bateman et al. Am J Respir Crit Care Med 2004

Overall treatment difference: 24.3 L/min, P<0.001

Woodcock et al. Prim Care Respir J 2007

Maintenance of control over 1 year:

Patients achieving normal or near-normal quality of life

% Patients (AQLQ score >6)

% Rescue-free days (median)

% Symptom-free days (median)

Symptom-free days (median %)

Woodcock et al. Prim Care Respir J 2007

When should you step down?

When control is maintained for at least 3

8-week run-in period

6-month treatment period

Adjusted mean am PEF: no

4.5 (13.2; 4.1) p=0.238

Godard et al. Respir Med 2008

Change from baseline in % of

No difference between groups over weeks 1324

Study demonstrated reducing the ICS dose and maintaining LABA

Godard et al. study conclusion

In patients whose asthma is controlled with

This was not shown with ICS alone

Differences were maintained over 24 weeks

Stepping down should be considered in

Godard et al. Respir Med 2008

Stepping-down Bateman study

Double-blind treatment period

Primary endpoint: mean morning PEF

Bateman et al. J Allergy Clin Immunol 2006

Maintenance of asthma control

ICS/LABA 50/250 bid

Well controlled in 68% over 4 weeks

Bateman et al. J Allergy Clin Immunol 2006

Maintenance of asthma control

ICS/LABA 50/250 bid

ICS 250 bid

ICS/LABA 50/100 bid

Conclusion: Stepping down to a lower dose of

Bateman et al. J Allergy Clin Immunol 2006

WELL CONTROLLED asthma: continued

Patients controlled each week (%)

Bateman et al. Am J Respir Crit Care Med 2004

% of patients controlled each week