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A New Approach to Asthma Management

Handoko MD

Pulmonary and Respiratory Medicine Division

Department of Internal Medicine


dr. Ramelan Navy Hospital, Surabaya

World asthma prevalence


Estimated 300 million affected individuals worldwide The global prevalence of asthma in children and adults ranges from 1-18% of the population in different countries The percentage of children reported to have had asthma increased significantly

The increases prevalence in Africa, Latin America and Asia indicate that global burden of asthma is continuing to rise
Annual worldwide deaths from asthma have been estimated at 250,000

Definition (GINA, 2012)


Chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest thightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment.

Inflammatory cells Mast cells Eosinophils Th2 cells Basophyls Neutrophils Platelets Structural cells

Mediators Histamines Leukotrienes Prostanoids PAF Kinins Adenosine Endothelins Nitric oxide Cytokines Chemokines Growth factors

Effects Bronchospasm Plasma exudation Mucus secretion AHR Structural changes

Epithelial cells Smooth muscle cells Endothelial cells Fibroblasts Nerves

Many cells and mediators are involved in asthma and have several effects in the airways (Barnes, 2004)

Pathology of asthma (Barnes, 2004)

The Pathophysiology of asthma (Barnes, 2004)

The participation of several interacting inflammatory cells results in acute and chronic inflammatory effects in the airway

Factors the development & expression of asthma (GINA, 2012) Genetic Host factors Obesity Sex Indoor: Domestic mites, furred animals (dog, cats, mice), cockroach allergen, fungi, molds, yeasts Outdoor: Pollens, fungi, molds, yeasts Infections (predominantly viral) Genes pre-disposing to atopy Genes pre-disposing to airway hyperresponsiveness

Allergens

Environmental factors

Occupational sensitizers
Tobacco smoke (passive & active smoking) Outdoor/indoor air pollution Diet

Level of control controlled partly controlled uncontrolled exacerbation

REDUCE
INCREASE

Treatment of action
maintain and find lowest controlling step consider stepping up to gain control step up until controlled

treat as exacerbation

REDUCE
STEP 1 TREATMENT STEPS STEP STEP STEP 2 3 4

INCREASE
STEP 5

Reduce Step 1 Step 2 Step 3


Asthma education

Increase Step 4 Step 5

Environment control
As needed SABA Select one Low dose inhaled ICS Controller options Leukotriene modifier As needed SABA Select one Low-dose ICS + LABA Medium / high-dose ICS Low dose ICS + leukotriene modifier Low dose ICS + Theophylline SR Add one or more Medium-dose ICS + LABA Leukotriene modifier Add one or both Oral glucocorticoid (lowest dose)

Theophylline SR

Anti-IgE treatment

What are the current asthma management goals?

Global Initiative for Asthma (GINA) guidelines


state that asthma management should:

prevent asthma exacerbations achieve and maintain control of symptoms maintain pulmonary function as close to normal
as possible maintain normal activity levels, including exercise prevent asthma mortality avoid adverse effects from asthma medications
GINA 2012

The challenges of asthma management

Over-reliance on rescue medication1 Suboptimal control1 Poor adherence to maintenance therapy1 Lack of clinical evidence to support the benefit of doubling ICS dose during worsenings2 Complexity of current treatments1 Lack of education and understanding among patients1

1FitzGerald

2Harrison

JM, et al. Can Resp J 2006;13:253259; TW, et al. Lancet 2004;363:271275.

What is Symbicort SMART?

Symbicort SMART

Patients take a regular daily maintenance dose of Symbicort, with additional inhalations if needed to provide rapid symptom relief and improved control Patients do not require a separate SABA Symbicort SMART is an asthma management approach using only one inhaler where the underlying inflammation is treated with every inhalation, even when used as-needed

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Maintenance and reliever therapy in one inhaler


Symbicort SMART provides maintenance and reliever therapy
in ONE inhaler

Daily maintenance dose, and Reliever use if needed for rescue


Budesonide
(anti-inflammatory therapy that acts within hours)

Formoterol
(rapid relief and long-acting bronchodilation)
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A separate rescue inhaler is not required

Balanag VM, et al. Pulm Pharm Ther 2006;19:139-147

Symbicort SMART is a new approach to asthma management


Conventional approach Symbicort SMART

1. Balanag VM, et al. Pulm Pharm Ther 2006;19:139-147 2. Gibson et al, Am J Respir Crit Care Med 2001;163:32-36

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Optimised daily maintenance dose

Symptom relief

Optimised daily maintenance dose

Symptom relief 1 and a timely increase in anti-inflammatory therapy 2

Why is maintenance and reliever therapy possible with Symbicort ?

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Symbicort is as effective and well tolerated as salbutamol in treating acute asthma


FEV1 (% D from baseline)
45
NS P = 0..66

Serum K+ (mmol/l)
3.90

35

3.82

25
Symbicort 1280/36 g (n = 55)

3.74
NS

3.66
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15

Salbutamol 1600 g (n= 48)

3.58 5 5 0 30 60 90 120 150 180 3.50 5 0 30 60 90 120 150 180

Time after drug administration (minutes)


Balanag VM, et al. Pulm Pharm Ther 2006;19:139147.

Symbicort is a rapid-acting reliever


Onset of action of Symbicort vs Fluticasone/Salmeterol in stable asthma
% increase in FEV1
25 20 Symbicort 160/4.5 g 1 inhalation Sal/Flu 50/250 g 1 inhalation Placebo 1 inhalation

*
15 10 5 2 5 0 5 10 15

Sal/Flu at both 3 min and 15min


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*P < 0.001 Symbicort vs

Time (minutes)
Palmqvist M, et al. Pulm Pharm Ther 2001;14:2934.

Symbicort SMART vs fixed combination or higher ICS doses

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Symbicort SMART reduces the rate of severe exacerbations requiring medical intervention
Events/patient/year
0.6
24 x Budesonide + SABA Symbicort + SABA Symbicort SMART 0.4 0.33 0.19 0.08 0.18

0.5
0.4 0.3 0.2 0.1 0 STEAM1
mild to moderate 0.35 0.35

***
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***

***
STAY2
moderate

STEP3
moderate to severe

***P < 0.001 vs both Symbicort + SABA and 24 x Budesonide + SABA

2OByrne

KF, et al. Chest 2006;129:246256; PM, et al. Am J Respir Crit Care Med 2005;171:129136; 3Scicchitano R, et al. Curr Med Res Opin 2004;20:14031418.
1Rabe

Symbicort SMART vs higher fixed doses of combination treatments

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COMPASS study design


6-month double-blind, double-dummy

Run-in
Regular ICS 500 g Enrolled: n=4399

Sal/Flu 25/125 g 2 inhalations bid + Bricasma as reliever

n=1123

Symbicort 320/9 g 1 inhalation bid + Bricasma as reliever

n=1105

n=1107

Visit: Week:

1 2

2 0

3 8

4 16

5 24

Kuna P, et al. Int J Clin Pract 2007:61(5) :725-36

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Randomised: n=3335

Symbicort 160/4.5 g 1 inhalation bid + Symbicort as reliever (SMART)

Symbicort SMART reduces the exacerbation rate compared to fixed dose combinations + SABA
Exacerbations/patients
0.20
Sal/Flu + SABA Symbicort + SABA Symbicort SMART

NS

0.15
P = 0.0048

P < 0.001

0.10
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0.05

Symbicort SMART reduces the rate of exacerbations by: 39% vs Sal/Flu + SABA 28% vs Symbicort + SABA

0 0 20 40 60 80 100 120 140 160

Days since randomisation


Kuna P, et al. Int J Clin Pract 2007:61(5) :725-36

Similar improvements in daily asthma control


Asthma control days (%)

60
43.7

NS

42.2

41.3

40

20
5.8
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5.7

5.9

Run-in

Treatment

Run-in

Treatment

Run-in

Treatment

Sal/Flu + SABA

Symbicort + SABA Symbicort SMART

Asthma control days = symptom & rescue free days

Kuna P, et al. Int J Clin Pract 2007:61(5) :725-36

COMPASS study conclusion


Symbicort SMART vs higher fixed doses of
Symbicort or Salmeterol/Fluticasone +SABA : prolongs time to first severe exacerbation reduces number of severe exacerbations All treatments provide similar improvements in daily asthma control All treatments are well tolerated

Kuna P, et al. Int J Clin Pract 2007:61(5) :725-36

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Symbicort Maintenance And Reliever Therapy


Regular maintenance budesonide Regular maintenance formoterol

Symbicort SMART
As-needed budesonide
anti-inflammatory effect within hours reduces eosinophilic inflammation prevents exacerbations

As-needed formoterol
rapid symptom relief
reduces neutrophilic inflammation prevents exacerbations

Gibson et al, Am J Respir Crit Care Med 2001, Balanag VM, et al. Pulm Pharm Ther 2006;19:139-147 Maneechotestesuwan et al, Chest 2005;128:1936-1942

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Who is Symbicort SMART suitable for?


Symbicort SMART is SUITABLE for:

Patients who are not controlled on existing ICS


therapy
or
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Patients already controlled on both inhaled


corticosteroids and long-acting beta2-agonists

Symbicort Product Information 2007

Symbicort SMART treatment plan

Take Symbicort every day

For maintenance

1.
2.

Take one dose every morning


Take one dose every evening

If needed:
Take an extra dose for relief (repeat if necessary)
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Symbicort Product Information 2007

Will Symbicort SMART lead to overuse of steroids?

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Symbicort SMART reduces corticosteroid load compared to fixed-dose combinations + SABA


Observations from the COMPASS study
Seretide 50/250 g bid (n=1123) Symbicort 320/9 g bid (n=1105) Symbicort SMART 160/4.5 g bid + prn (n=1107)

Level of use1

Mean inhaled corticosteroid dose (g/day)


Not adjusted (FP vs BUD) BDP equivalents* 500 1000 640 1000 483 755

Oral corticosteroid use/group


Total no. of events Total days with event 148 1132 139 1044 86 619
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FP, fluticasone propionate; BUD, budesonide; prn, as needed; *BDP (beclomethasone dipropionate) equivalents adapted from GINA guidelines 2006.

Kuna P, et al. Int J Clin Pract 2007:61(5) :725-36

Symbicort SMART is well tolerated

Several large clinical trials have


demonstrated that:

Symbicort SMART is well tolerated Symbicort SMART is associated with a


low incidence of candidiasis or dysphonia
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OByrne PM, et al. Am J Respir Crit Care Med 2005;171:129136; Rabe KF, et al. Lancet 2006;368:744753; Vogelmeier C, et al. Eur Respir J 2005;26:819828; Rabe KF, et al. Chest 2006;129:246256; Scicchitano R, et al. Curr Med Res Opin 2004;20:14031418; Kuna P, et al. Int J Clin Pract 2007:61(5) :725-36

Symbicort SMART in 2012 Global Initiative for Asthma (GINA)

If a combination inhaler containing formoterol and budesonide is selected, it may be used for both rescue and maintenance. Both components of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance and provide improvements in asthma control at relatively low doses of treatment. The benefit in preventing exacerbations appears to be the consequence of early intervention at a very early stage of a threatened exacerbation

GINA 2012

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Other statements about Symbicort SMART

In the context of rescue therapy with budesonide/formoterol, this could prevent the evolution of an acute exacerbation by suppressing the increase in inflammation, thus resulting in marked reduction in the number of mild and severe exacerbations.
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* Single inhaler therapy=maintenance and reliever therapy.

Barnes PJ, ERJ 2007;29:587-595

Symbicort SMART vs ICS or ICS/LABA+SABA:



Treats the underlying inflammation with every inhalation Reduces exacerbations16 Improves daily asthma control 15 Reduces overall steroid load 16 Is simple to use with only one inhaler for maintenance and relief

1OByrne

PM, et al. Am J Respir Crit Care Med 2005;171:129136; 2Rabe KF, et al. Lancet 2006;368:744753; C, et al. Eur Respir J 2005;26:819828; 4Rabe KF, et al. Chest 2006;129:246256; 5Scicchitano R, et al. Curr Med Res Opin 2004;20:14031418; 6. Kuna P, et al. Int J Clin Pract 2007:61(5) :725-36
3Vogelmeier

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Sekian aja dulu yaaa ........

Handoko & Peter J Barnes 2012