A A NNew ew AApproach to pproach to AAsthma sthma MManagementanagement

Handoko MDHandoko MD

Pulmonary and Respiratory Medicine Division Pulmonary and Respiratory Medicine Division

Department of Internal MedicineDepartment of Internal Medicine

dr. Ramelan Navy Hospital, Surabayadr. Ramelan Navy Hospital, Surabaya

World asthma prevalence

Estimated 300 million affected individuals worldwideEstimated 300 million affected individuals worldwide

The global prevalence of asthma in children and The global prevalence of asthma in children and adults ranges from 1-18% of the population adults ranges from 1-18% of the population

in different countries in different countries

The percentage of children reported The percentage of children reported to have had asthma increased significantly to have had asthma increased significantly

The increases prevalence in The increases prevalence in Africa, Latin America and Asia Africa, Latin America and Asia indicate that global burden of asthma indicate that global burden of asthma

is continuing to rise is continuing to rise

Annual worldwide deaths from asthma Annual worldwide deaths from asthma have been estimated at 250,000 have been estimated at 250,000

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.

Definition Definition (GINA, 20(GINA, 201212))

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

Inflammatory cells

Mast cellsEosinophilsTh2 cellsBasophylsNeutrophilsPlatelets

Structural cells

Epithelial cellsSmooth muscle cellsEndothelial cellsFibroblastsNerves

Mediators

HistaminesLeukotrienesProstanoidsPAFKininsAdenosineEndothelinsNitric oxideCytokinesChemokinesGrowth factors

Effects

BronchospasmPlasma exudationMucus secretionAHRStructural changes

Pathology of asthma (Barnes, 2004)

The Pathophysiology of asthmaThe Pathophysiology of asthma (Barnes, 2004)(Barnes, 2004)

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

Factors the development & expression of asthma Factors the development & expression of asthma (GINA, 20(GINA, 201212))

Host factorsHost factors

GeneticGenetic Genes pre-disposing to atopyGenes pre-disposing to atopy

Genes pre-disposing to airway Genes pre-disposing to airway hyperresponsivenesshyperresponsiveness

ObesityObesity

SexSex

Environmental Environmental factorsfactors

AllergensAllergens

Indoor: Indoor: Domestic mites, furred animals (dog, Domestic mites, furred animals (dog, cats, mice), cockroach allergen, fungi, cats, mice), cockroach allergen, fungi, molds, yeastsmolds, yeasts

Outdoor: Outdoor: Pollens, fungi, molds, yeastsPollens, fungi, molds, yeasts

Infections (predominantly viral)Infections (predominantly viral)

Occupational sensitizersOccupational sensitizers

Tobacco smoke (passive & active smoking)Tobacco smoke (passive & active smoking)

Outdoor/indoor air pollutionOutdoor/indoor air pollution

DietDiet

controlled

partly controlled

uncontrolled

exacerbation

Level of controlLevel of control

maintain and find lowest controlling step

consider stepping up to gain control

step up until controlled

treat as exacerbation

Treatment of actionTreatment of action

TREATMENT STEPSREDUCEREDUCE INCREASE

STEP1

STEP2

STEP3

STEP4

STEP5

RED

UC

EIN

CR

EA

SE

Asthma education

Environment control

As needed SABA

As needed SABA

Controller options

Select one Select one Add one or more

Add one or both

Low dose inhaled ICS

Low-dose ICS + LABA

Medium-dose ICS +

LABA

Oral glucocorticoi

d (lowest dose)

Leukotriene modifier

Medium / high-dose ICS

Leukotriene modifier

Anti-IgE treatment

Low dose ICS + leukotriene

modifierTheophylline

SRLow dose ICS + Theophylline SR

Step 1 Step 2 Step 3 Step 4 Step 5

Reduce Increase

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 JM, et al. Can Resp J 2006;13:253–259; 2Harrison TW, et al. Lancet 2004;363:271–275.

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

A separate rescue inhaleris not required

Budesonide(anti-inflammatory therapy that acts within hours)

Formoterol(rapid relief and long-acting bronchodilation)

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

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Optimised dailymaintenance dose

Symptom relief

Conventional approach

Symbicort® SMART™

Optimised dailymaintenance dose

Symptom relief 1 and a timely increase

in anti-inflammatorytherapy

Symbicort® SMART™ is a new approach to asthma management

1. Balanag VM, et al. Pulm Pharm Ther 2006;19:139-1471. Balanag VM, et al. Pulm Pharm Ther 2006;19:139-1472. Gibson et al, Am J Respir Crit Care Med 2001;163:32-362. Gibson et al, Am J Respir Crit Care Med 2001;163:32-36

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Why is maintenance and reliever therapy possible with Symbicort® ?

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Time after drug administration (minutes)

3.50

3.90

3.82

3.74

3.66

3.58

–5 0 30 60 90 120 180150

Serum K+ (mmol/l)FEV1 (% from baseline)

Symbicort® 1280/36 µg (n = 55)

Salbutamol 1600 µg (n= 48)

–5 0 30 60 90 120

5

15

25

35

45

150 180

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

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

NS

P = 0..66

NS

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Symbicort® is a rapid-acting reliever

Symbicort® 160/4.5 µg 1 inhalation

Sal/Flu 50/250 µg 1 inhalation

*P < 0.001 Symbicort® vs Sal/Flu at both 3 min and 15min

*

25

10

5

2

–50 5 10 15

% increase in FEV1

Time (minutes)

15

20

*

Placebo 1 inhalation

Palmqvist M, et al. Pulm Pharm Ther 2001;14:29–34.

Onset of action of Symbicort® vs Fluticasone/Salmeterol in stable asthma

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Symbicort® SMART™ vs fixed combination or higher ICS doses

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2–4 x Budesonide + SABA

Symbicort® + SABA

Symbicort® SMART™

Symbicort® SMART™ reduces the rate of severe exacerbations requiring medical

intervention

Events/patient/year

***P < 0.001 vs both Symbicort + SABA and 2–4 x Budesonide + SABA

STEAM1 mild to moderate

STEP3 moderate to severe

STAY2

moderate

0

0.1

0.2

0.3

0.4

0.5

0.6

***

***

***

1Rabe KF, et al. Chest 2006;129:246–256; 2O’Byrne PM, et al. Am J Respir Crit Care Med 2005;171:129–136;

3Scicchitano R, et al. Curr Med Res Opin 2004;20:1403–1418.

0.35

0.08

0.350.4

0.19

0.330.18

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Symbicort® SMART™ vs higher fixed doses of combination

treatments

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6-month double-blind, double-dummy

COMPASS study design

Sal/Flu 25/125 µg 2 inhalations bid + Bricasma® as reliever n=1123

Symbicort® 320/9 µg 1 inhalation bid + Bricasma® as reliever n=1105

Symbicort® 160/4.5 µg 1 inhalation bid + Symbicort® as reliever (SMART™) n=1107

Visit: 1 2 3 4 5

Week: –2 0 8 16 24

Regular ICS ≥ 500 µg R

Enrolled: n=4399

Randomised: n=3335

Run-in

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

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Symbicort® SMART™ reduces the exacerbation rate compared to fixed dose combinations + SABA

P < 0.001

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

0.20

0.15

0.10

0.05

0400 60 80 100 120 140 16020

Days since randomisation

P = 0.0048

NS

Sal/Flu + SABA Symbicort® + SABA Symbicort® SMART™

Exacerbations/patients

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

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0

20

40

60

Sal/Flu + SABA Symbicort® + SABA Symbicort® SMART™

Similar improvements in daily asthma control

Asthma control days (%)

Run-in Treatment Run-in Treatment Run-in Treatment

NS

Asthma control days = symptom & rescue free days

5.7

43.7

5.9

42.2

5.8

41.3

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

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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® SMART™

Regular maintenancebudesonide

Regular maintenanceformoterol

As-needed formoterol• rapid symptom relief²• reduces neutrophilic inflammation³ • prevents exacerbations

As-needed budesonide• anti-inflammatory effect within

hours¹• reduces eosinophilic inflammation¹ • prevents exacerbations

Symbicort® Maintenance And Reliever Therapy

¹Gibson et al, Am J Respir Crit Care Med 2001, Gibson et al, Am J Respir Crit Care Med 2001, ²Balanag VM, et al. Pulm Pharm Ther 2006;19:139-147 ³Maneechotestesuwan 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

Patients already controlled on both inhaled corticosteroids and long-acting beta2-agonists

Symbicort Product Information 2007

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Symbicort ®SMART™ treatment plan

Take Symbicort®

every dayFor maintenance

1. Take one doseevery morning

2. Take one doseevery evening

If needed:

Take an extra dosefor relief (repeatif necessary)

Symbicort Symbicort ®® Product Information 2007 Product Information 2007

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Will Symbicort® SMART™ lead to overuse of steroids?

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

Level of use1

Seretide50/250 µg bid

(n=1123)

Symbicort320/9 µg bid

(n=1105)

Symbicort SMART160/4.5 µg bid + prn

(n=1107)

Mean inhaled corticosteroid dose (µg/day)

Not adjusted (FP vs BUD) 500 640 483

BDP equivalents* 1000 1000 755

Oral corticosteroid use/group

Total no. of events 148 139 86

Total days with event 1132 1044 619

FP, fluticasone propionate; BUD, budesonide; prn, as needed;

*BDP (beclomethasone dipropionate) equivalents adapted from GINA guidelines 2006.

Observations from the COMPASS study

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

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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

O’Byrne PM, et al. Am J Respir Crit Care Med 2005;171:129–136; Rabe KF, et al. Lancet 2006;368:744–753; Vogelmeier C, et al. Eur Respir J 2005;26:819–828; Rabe KF, et al. Chest 2006;129:246–256; Scicchitano R, et al. Curr Med Res Opin 2004;20:1403–1418; Kuna P, et al. Int J Clin Pract 2007:61(5) :725-36

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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.”

Barnes PJ, ERJ 2007;29:587-595Barnes PJ, ERJ 2007;29:587-595* Single inhaler therapy=maintenance and reliever therapy. Single inhaler therapy=maintenance and reliever therapy.

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Treats the underlying inflammation with every inhalation

Reduces exacerbations1–6

Improves daily asthma control 1–5

Reduces overall steroid load 1–6

Is simple to use with only one inhaler for maintenance and relief

1O’Byrne PM, et al. Am J Respir Crit Care Med 2005;171:129–136; 2Rabe KF, et al. Lancet 2006;368:744–753; 3Vogelmeier C, et al. Eur Respir J 2005;26:819–828; 4Rabe KF, et al. Chest 2006;129:246–256; 5Scicchitano R, et al. Curr Med Res Opin 2004;20:1403–1418; 6. Kuna P, et al. Int J Clin Pract 2007:61(5) :725-36

Symbicort® SMART™

vs ICS or ICS/LABA+SABA:

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Handoko & Peter J Barnes 2012

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