Asthma management in clinical practice

“When the Preferred Approach
is Supported by the Desired Efficacy”
Asthma Management in
Clinical practice
By Ahmed M. Abdelhafeez
Assistant Professor of Chest Diseases,
Cairo University.

Definition of asthma
Asthma is a heterogeneous disease, usually characterized by
chronic airway inflammation.
It is defined by the history of respiratory symptoms such as wheeze,
shortness of breath, chest tightness and cough that vary over time
and in intensity, together with variable expiratory airflow limitation.
NEW!
GINA 2014

Burden of asthma
Asthma is one of the most common chronic diseases
worldwide with an estimated 300 million affected
individuals
Prevalence is increasing in many countries, especially in
children
Asthma is a major cause of school and work absence
Health care expenditure on asthma is very high
 Developed economies might expect to spend 1-2 percent of total
health care expenditures on asthma.
 Developing economies likely to face increased demand due to
increasing prevalence of asthma
 Poorly controlled asthma is expensive
 However, investment in prevention medication is likely to yield cost
savings in emergency care
GINA 2014

© Global Initiative for Asthma
Prevalence of asthma in children aged 13-14 years
© Global Initiative for AsthmaGINA 2014 Appendix Box A1-1; figure provided by R Beasley

Asthma in childhood
In the US, childhood asthma
accounts for 7.3 million days
missed from school/year.
Twice the learning
disabilities in asthmatic
children.

Asthma in adults
In Australia, one study reported that asthma
accounted for 1.5 million days lost production per
year.
In the US, asthma accounted for the loss of million
worked days among persons 18 years old and older.

Asthma Pathology
Asthma is a chronic inflammatory disease associated with airway
hyperresponsiveness (AHR), short-term consequences…
Airway obstruction and
symptoms by:
Bronchoconstriction
Mucus plugs
Mucosal edema
Inflammatory cell
infiltration/activation
Remodelling:
Increased vascularity
Epithelial cell disruption
Increased airway smooth
muscle mass (hyperplasia)
Reticular basement
membrane thickening
…and long-term consequences
Bousquet J et al. Am J Respir Crit Care Med 2000;161:1720–1745;
Beckett PA et al. Thorax 2003;58:163–174

Diagnosis of asthma
The diagnosis of asthma should be based on:
 A history of characteristic symptom patterns
 Evidence of variable airflow limitation, from bronchodilator
reversibility testing or other tests
Document evidence for the diagnosis in the patient’s
notes, preferably before starting controller treatment
 It is often more difficult to confirm the diagnosis after treatment
has been started
Asthma is usually characterized by airway inflammation
and airway hyper-responsiveness, but these are not
necessary or sufficient to make the diagnosis of asthma.
GINA 2014

GINA 2014, Box 1-1 © Global Initiative for Asthma
NEW!

Goals of asthma management
The long-term goals of asthma management are
1. Symptom control: to achieve good control of symptoms and
maintain normal activity levels
2. Risk reduction: to minimize future risk of exacerbations, fixed
airflow limitation and medication side-effects
Achieving these goals requires a partnership between
patient and their health care providers
 Ask the patient about their own goals regarding their asthma
 Good communication strategies are essential
 Consider the health care system, medication availability,
cultural and personal preferences and health literacy
GINA 2014

Stepwise approach to control asthma symptoms
and reduce risk
GINA 2014, Box 3-5
NEW!

Stepwise management - pharmacotherapy
*For children 6-11 years,
theophylline is not
recommended, and preferred
Step 3 is medium dose ICS
**For patients prescribed
BDP/formoterol or BUD/
formoterol maintenance and
reliever therapy
GINA 2014, Box 3-5 (upper part)

Step 1 – as-needed inhaled short-acting
beta2-agonist (SABA)
*For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS
**For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy
GINA 2014, Box 3-5, Step 1

Step 2 – low-dose controller + as-needed
inhaled SABA

Step 3 – one or two controllers + as-needed
inhaled reliever

Step 4 – two or more controllers + as-needed
inhaled reliever

Step 5 – higher level care and/or add-on
treatment

GINA 2015 – changes to Steps 4 and 5
© Global Initiative for AsthmaGINA 2015, Box 3-5, Steps 4 and 5
# Tiotropium by soft-mist inhaler is indicated as add-on treatment for patients with a history of exacerbations;
it is not indicated in children <18 years.
Other
controller
options
RELIEVER
STEP 1 STEP 2
STEP 3
STEP 4
STEP 5
Low dose ICS
Consider low
dose ICS
Leukotriene receptor antagonists (LTRA)
Low dose theophylline*
Med/high dose ICS
Low dose ICS+LTRA
(or + theoph*)
As-needed short-acting beta2-agonist (SABA)
Low dose
ICS/LABA*
Med/high
ICS/LABA
Refer for
add-on
treatment
e.g.
anti-IgE
PREFERRED
CONTROLLER
CHOICE
Add tiotropium#
High dose ICS
+ LTRA
(or + theoph*)
Add
tiotropium#
Add low
dose OCS
As-needed SABA or
low dose ICS/formoterol**

Reviewing response and adjusting
treatment
 How often should asthma be reviewed?
 1-3 months after treatment started, then every 3-12 months
 During pregnancy, every 4-6 weeks
 After an exacerbation, within 1 week
 Stepping up asthma treatment
 Sustained step-up, for at least 2-3 months if asthma poorly controlled
 Important: first check for common causes (symptoms not due to asthma,
incorrect inhaler technique, poor adherence)
 Short-term step-up, for 1-2 weeks, e.g. with viral infection or allergen
 May be initiated by patient with written asthma action plan
 Day-to-day adjustment
 For patients prescribed low-dose ICS/formoterol maintenance and reliever
regimen*
 Stepping down asthma treatment
 Consider step-down after good control maintained for 3 months
 Find each patient’s minimum effective dose, that controls both
symptoms and exacerbations
GINA 2014
*Approved only for low dose beclometasone/formoterol and low dose budesonide/formoterol

Non-pharmacological interventions
 Avoidance of tobacco smoke exposure
 Provide advice and resources at every visit; advise against exposure of children to
environmental tobacco smoke (house, car)
 Physical activity
 Encouraged because of its general health benefits. Provide advice about exercise-induced
bronchoconstriction
 Occupational asthma
 Ask patients with adult-onset asthma about work history. Remove sensitizers as soon as
possible. Refer for expert advice, if available
 Avoid medications that may worsen asthma
 Always ask about asthma before prescribing NSAIDs or beta-blockers
 Breathing techniques (no specific technique)
 May be a useful supplement to asthma medications
 (Allergen avoidance)
 (Not recommended as a general strategy for asthma)
 See GINA Box 3-9 and online Appendix for details
GINA 2014, Box 3-9
This slide shows examples of interventions with high quality evidence

Montelukast in
Real World Studies

Study Design
Montelukast 10 mg/day +
fluticasone 200 µg/day + SP
Salmeterol 100 µg/day +
fluticasone 200 µg/day + MP
Fluticasone
200 µg/day
MP + SP
Period I Period II
Visit
Week -4 -2 0 8 16 24 32 40 48
1 2 3 4 5 6 7 8 9
n=743
n=747
MP = montelukast placebo; SP = salmeterol placebo
Bjermer L et al Respir Med 2000;94:612-621.

Study Endpoints
Primary endpoint
 Percentage of patients with at least one asthma exacerbation. An
asthma exacerbation was defined as worsening asthma requiring
an:
 unscheduled visit to the doctor’s office
 unscheduled visit to the emergency room
 unscheduled visit to hospital
 treatment with course of oral, intravenous or intramuscular corticosteroids
Secondary endpoints included
 Peripheral blood eosinophil counts, asthma-specific quality of life,
nocturnal awakenings, healthcare resource utilization and
morning PEFR
In addition, the study compared the tolerability profiles of
montelukast and salmeterol in combination with inhaled
fluticasone
Bjermer L et al Respir Med 2000;94:612-621.

Percentage of Patients with No Asthma Exacerbations
Was Similar between Treatment Groups
Montelukast
+ fluticasone (n=747)*
Salmeterol
+ fluticasone (n=743)**
p=NS
Patients
with
no asthma
exacerbations
(%)
*Montelukast 10 mg + fluticasone 200 mg, **salmeterol 100 mg + fluticasone 200 mg.
Modified-intention-to-treat approach. 20.1% and 19.1% of patients in the 2 groups, respectively, had 1 asthma exacerbation.
Bjermer L et al BMJ 2003;327:891-895.
79.9% 80.9%
0
20
40
60
80
100
Efficacy on Symptoms

Montelukast with Fluticasone Produced
Superior Reduction in Blood & Sputum Eosinophils
Sputum EosinophilsBlood Eosinophils
Efficacy on Inflammation

Key Conclusion
SINGULAIR in combination with ICS represents an
essential tool to better treat the inflammation. This
approach has also proven to provide high efficacy
on asthma symptoms.
The efficacy of the SINGULAIR/ICS approach on
symptoms results from its superior efficacy on
inflammation, the underlying cause of asthma.

block
steroid-
sensitive
mediators
blocks the
effects of
CysLTs
Inhaled steroidsMontelukast
Montelukast Combined with a Steroid Affects
the Dual Pathways of Inflammation
The slide represents an artistic rendition.
Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Bisgaard H Allergy
2001;56(suppl 66):7-11.
Steroid-sensitive
mediators
play a key role
in asthmatic
inflammation
CysLTs
play a key role
in asthmatic
inflammation
Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients
DUAL PATHWAY
Dual Pathways of Inflammation

The MONICA Trial
Efficacy of montelukast in asthma
patients inadequately controlled
on an ICS or an ICS + LABA
Slide 31

 Design
Multicenter, open-label, prospective study
 Objective
To assess the impact of montelukast added to an ICS or an ICS +
LABA
in patients with uncontrolled asthma
 Setting
Subjects recruited by office-based pulmonary specialists at 290 sites
in Germany
 Patient population
Patients aged ≥18 years with mild to moderate persistent asthma
uncontrolled by ICS or ICS + LABA therapy
 Treatment
Montelukast 10 mg once daily in addition to current asthma treatmenta
 Duration
12 months: 6 months (primary study) + 6 months (extension phase)
MONICA1,2
Study Design and Methods
aConcomitant medications included short-acting β-agonists, ICS, LABA, fixed combinations of ICS and LABA, theophylline, or, in some cases,oral corticosteroids.
1. Virchow JC et al. Respir Med. 2010;104:644–651; 2. Virchow JC et al. J Asthma. 2010;47(9):986–993.
Slide 32

 Primary
ACT scores
 Secondary
German version of the validated MiniAQLQ
 Other
Lung function (assessed by FEV1 and PEF)
MONICA1
Effectiveness End Points at Month 6
(Primary Study)
ACT=asthma control test.
1. Virchow JC et al. Respir Med. 2010;104:644–651.
Slide 33

AR=allergic rhinitis.
1. Virchow JC et al. J Asthma. 2010;47(9):986–993.
 Previous therapy (ICS, ICS + LABA)
 Presence of AR
 Sex
 Age group (<30 years, 30–50 years, >50 years)
 Duration of asthma (<5 years, ≥5 years)
MONICA1
Subgroup Analyses at Month 12
Slide 34Slide 34

 Primary end point: Mean ACT score improved significantly from baseline with ICS or ICS + LABA (14.6 ± 4.6) at both Month 6 (19.4 ± 4.4) and
Month 12 (20.3 ± 4.2) of add-on montelukast (P<0.0001 for both time points).
MONICA1,2
Improvements in ACT Scores
With Add-On Montelukast
ICS or ICS + LABA at baseline; add-on montelukast at Months 3 and 6.
Slide 35
PatientsinEach
ACTCategory,%
ACT Scores
25 (Completely controlled)
20–24 (Well controlled)
16–19 (Poorly controlled)
<16 (Uncontrolled)
0
100
75
50
25
Baseline
(n=1,681)
1.2
13.9
25.0
57.5
Month 6
(n=1,303)
11.4
47.5
21.7
17.6
Month 3
(n=1,477)
7.2
41.8
27.2
21.0

MONICA1
Improvements in Lung Function
With Add-On Montelukast
aP<0.0001 vs baseline.
Lung function measurements were performed at the investigator’s discretion; thus, not all patients had data for these parameters.
1. Virchow JC et al. Respir Med. 2010;104:644–651.
FEV1,L
PEF,L/s
0
3
2
1
0
7
3
2
1
5
4
62.46
Baseline
(n=1,445)
2.61a
Month 3
(n=1,057)
2.60a
Month 6
(n=914)
5.76
Baseline
(n=967)
6.20a
Month 3
(n=669)
6.22a
Month 6
(n=563)
ICS or ICS + LABA Montelukast + baseline therapy

 Benefits of add-on montelukast in a 12-month real-world study of patients
already receiving an ICS or an ICS + LABA who had uncontrolled asthma
symptoms:
 Asthma control (Months 3, 6, and 12): significant improvements
in ACT score (P<0.0001 vs baseline) (primary end point)
 Quality of life (Months 3, 6, and 12): significant improvements in
the MiniAQLQ score (P<0.0001 vs baseline)
 Lung function (Months 3 and 6): significant improvements in FEV1
and PEF (P<0.0001 vs baseline)
 Clinically relevant improvements in asthma control and quality of life in
All prior therapy subgroups (ICS or ICS + LABA)
All AR subgroups (present or absent)
MONICA1,2
Summary and Conclusions

Asthma with Allergic Rhinitis
A common airway disease..!!

ARIA = Allergic Rhinitis and its Impact on Asthma.
Bousquet et al. J Allergy Clin Immunol. 2001;108 (5 suppl):S147.
ARIA Guidelines: Recommendations
for Management of Allergic Rhinitis 2001
Mild
intermittent
Moderate
severe
intermittent
Mild
persistent
Moderate
severe
persistent
Immunotherapy
Allergen and irritant avoidance
Intranasal decongestant (<10 days) or oral decongestant
Second-generation nonsedating H1 antihistamine
Leukotriene receptor antagonists
Local cromone
Intra-nasal steroid
ARIA Guidelines: Recommendations for
Management of Allergic Rhinitis

Population
• Adults 15–55 years of age (N=701)
• Mild to moderate asthma
• Evidence of AR
Design
• 2-year pre–post multicenter
retrospective cohort study
in Italy, Poland, and Spain
• Effect of adding montelukast
in a 12-month post period
was compared to 12 months
of prior treatment with ICS or
ICS + LABA
PRAACTICAL=Patient-level Review of Asthma and Allergy Care Therapy Including Corticosteroids and Anti-Leukotrienes
Adapted from Borderias L et al. Presented at the 15th Annual Congress of the European RespiratorySociety, Copenhagen, Denmark, September 17–21, 2005. Poster 3692.
Outcome measures
Long-term asthma control
• Frequency of asthma attacks
Short-term asthma control
• SABA use
Asthma-related resource use
• Hospitalizations, emergency
visits, unscheduled visits, oral
corticosteroid use

Reduction from
1:3 patients to
1:10 patients
N=701
Asthma attack: worsening of asthma requiringhospitalization,emergency visit, or oral corticosteroids use.
Adapted from Borderias L et al. Presented at the 15th Annual Congress of the European RespiratorySociety, Copenhagen, Denmark,
September 17–21, 2005. Poster 3692.
p=0.001
% of
patients per
year with
asthma
attacks
0
5
10
15
20
35
Prior to
montelukast
31.8%
10.1%
25
30
Post
montelukast
77%

Crossover study; N=701
*p=0.001 vs. prior to montelukast;**p=0.031 vs. prior to montelukast
Adapted from Borderias L et al. Presented at the 15th Annual Congress of the European RespiratorySociety, Copenhagen, Denmark,
September 17–21, 2005. Poster 3692.
Emergency
room visits
Oral
corticosteroid use
Hospitalizations
*
* *
*
**
**
23.3
16.6
14.1
19.5
8
29
4.8
3.3 3.6
7.1
2
8
ICS ICS+LABA ICS ICS+LABA ICS ICS+LABA
% of patients
per year
0
10
15
20
25
30
35
Prior to montelukast
Post montelukast
5
75%
79%80%
74%
64% 72%

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