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Evidence-based Pharmacological management. Prof Elif Dağlı Marmara University Istanbul Turkey. Objectives. minimal symptoms during day and night minimal need for reliever medication no exacerbations no limitation of physical activity

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Evidence-based Pharmacological management

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Evidence based pharmacological management


Pharmacological management

Prof Elif Dağlı

Marmara University

Istanbul Turkey

Evidence based pharmacological management


  • minimal symptoms during day and night

  • minimal need for reliever medication

  • no exacerbations

  • no limitation of physical activity

  • normal lung function (in practical terms FEV1 and/or PEF >80% predicted or best)

Single endpoints can over estimate asthma control

Single endpoints canover estimate asthma control


% patients








Rescue use




GINA / NIHcompositemeasure

Clark et al. Eur Respir J 2002

What are the different treatment modalities in childhood asthma

What are the different treatment modalities in childhood asthma?

  • Reliever therapy:

    • Inhaled ß2-agonists, short-acting

    • Other bronchodilators

  • Controller therapy:

    • Inhaled steroids

    • Long-acting ß2-agonists

    • Leukotriene-antagonists

    • Slow release theophylline

    • Oral steroids

Evidence based pharmacological management


Inhaled steroids are the most effective preventer drug for adults and children for achieving overalltreatment goals.

Inhaled steroids are the recommended preventer drug for adults andchildren for achieving overall treatment goals.

Evidence A for all ages

Evidence based pharmacological management

  • Inhaled steroids should be considered for patients with any of the following:

  • exacerbations of asthma in the last two years

  • using inhaled b2 agonists three times a week or more

  • symptomatic three times a week or more, or waking one night a week.

  • 2004

Evidence B,

Recommended practice

Evidence based pharmacological management


The following medicines act as short-acting bronchodilators:

inhaled short-acting b2 agonists

inhaled ipratropium bromide

b2 agonist tablets or syrup


Short-acting inhaled b2 agonists work more quickly and/or with fewer side-effects than thealternatives.

Evidence based pharmacological management

  • Starting dose of inhaled steroids

  • In mild to moderate asthma, starting at very high doses of inhaled steroids and stepping downconfers no benefit.

  • Start patients at a dose of inhaled steroids appropriate to the severity of disease.

Up or down

Recommended practice

Evidence based pharmacological management

  • In children a reasonable starting dose will usually be 200 mcg per day. In children under 5 years, higher doses may be required if there areproblems in obtaining consistent drug delivery.

  • Titrate the dose of inhaled steroid to the lowest dose at which effective control of asthmais maintained.

Recommended practice

Inhaled steroids in young children

Inhaled steroids in young children

  • The effect of inhaled steroids in young children is debated

    • Positive effect reported in infants and young children with severe asthma

    • The effect in recurrent viral wheeze in young children is uncertain

  • Critical questions:

    • The effect of steroids on the growing lung

      • Before birth

      • In infants

      • In pre-school children

      • In the young child with airways inflammation

Evidence based pharmacological management


Administration of inhaled steroids at or above 400 mcg a day of BDP or equivalent may beassociated with systemic side-effects.

short-term growth suppression

adrenal suppression

hypoglycaemic episodes.

Monitor children’s height on a regular basis.

Consider the possibility of adrenal insufficiency in any child maintained on inhaled steroidspresenting with a decreased level of consciousness; blood glucose levels should be checkedurgently.

Consider whether intramuscular (IM) hydrocortisone is required.

Fluticasone improves pulmonary function in children under 2 years old with risk factors for asthma

Fluticasone Improves Pulmonary Function in Children under 2 Years Old with Risk Factors for Asthma

Children 6 – 20 months old with recurrent wheeze (≥3 episodes) and risk factors for asthma:

FP/placebo treatment for 6 months.

Individual changes in Z-score V˙maxFRC: (a) FP (n=14);

(b) placebo (n=12) (thick lines = mean values);

(c ) variation in Z score for both groups (boxes: median, 25th

and 75th centiles; whiskers: minimum and maximum values).

AM Teper, CD Kofman, GA Szulman, SM Vidaurreta, AF Maffey. Am J Respir Crit Care Med 2005;171:587–590.

Evidence based pharmacological management

Pediatr Pulmonol. 2003 Apr;35(4):241-52.

Kaditis A et al.

  • 24 randomized, placebo controlled, double blind trials

  • 1966-1996

  • 10 preschool children studies

  • 377 children with frequent wheeze or persistant wheezing

  • Inhaled steroids compared with placebo

  • Decreased mean symptom score

  • Decreased bronchodilator and oral steroid use

  • Increased mean PEF


Evidence based pharmacological management

Double blind placebo controlled randomized study

861 children 3mo-8 yrs

481 patients

Budesonide group

with better asthma score

less reliever use

305 patients


Increased symptom free period

Day and night

Evidence: A

Evidence based pharmacological management

Efficacy of Inhaled Steroids

In Infants and Young Children

1)Inhaled steroids for treatment of recurrent wheezing in early childhood

Bisgaard H et al Lancet 1990;336:649

2) The effect of inhaled budesonide on symptoms, lung function and cold air and metacholine responsiveness in 2-5 year asthmatic children

Nielsen KG Bisgaard H Am J Respir Crit Care Med 2000;162:1500

3)The effect of inhaled fluticasone propionate in treatment of young asthmatic children: a dose comparison study

Bisgaard H, Gillies J et al Am J Respir Crit Care Med 1999;160:126

4) Response of preschool children with asthma symptoms to fluticasone propianate

RJ Roorda, G Mezei, H Bisgaard, C Maden J Allergy Clin Immunol 2001;108:540

Evidence based pharmacological management

Inhaled fluticasone decreases NO levels in recurrent wheezy infants

Pediatr Pulmonol. 2004 Sep;38(3):250-5. Moeller A et al

31 children 6-19 mo

History of recurrent wheeze

Parental atopy

Treatment with FDP and placebo for four months

LFT and exhaled NO measured

before after

Fe(NO) FDP 35.0 ppb 16.5 ppb

plasebo 35.2 ppb 30.2 ppb (P = 0.05).

Evidence based pharmacological management

160 patients

12-47 mo


FDP or


Evidence based pharmacological management

Daily symptom score

under FDP or placebo

Morning cortisol

Before or after treatment

Dose titration studies in asthmatic pre school children

Dose titration studies in asthmatic pre-school children:

  • Parallel-group blind randomised study for 18 weeks

  • 102 children, mean age 22 (5-47) months, started with 0.25 or 1 mg neb. budesonide b.i.d.

  • If symptom control was achieved the dose was reduced

  • The median time to 7 consecutive days without any asthma symptoms was 1 month with both regimens, highlighting the importance of the duration of therapy rather than the benefits of a high starting dose.

  • In 18 of 24 children who attained the placebo stage, symptoms had reappeared at the last visit.

  • 47% achieved symptom control on 0.25 mg b.i.d.

  • Wennergren G et al: Acta Paediatr 1996; 85:183-9.:

Evidence based pharmacological management

The exact threshold for introduction of inhaled steroids has never been firmly established.

Tworecent studies have shown benefit from regular use of inhaled steroids in patients with mildasthma.

Benefit in these studies was seen even with an FEV1 of 90% predicted.

OíByrne PM, Barnes PJ, Rodriguez-Roisin R, et al. AmJ Respir Crit Care Med 2001;164(8 Pt 1):1392

Pauwels RA, Pedersen S, Busse WW, et al. Lancet2003;361(9363):1071-6.

Evidence based pharmacological management

Frequency of dosing of inhaled steroids

Current inhaled steroids are slightly more effective when taken twice rather than once daily

There is little evidence of benefit for dosage frequency more than twice daily

Give inhaled steroids initially twice daily.

Once a day inhaled steroids at the same total daily dose can be consideredif good control is established.

Evidence: A- D -D

Long term treatment with budesonide in children with asthma and adult height

Long term treatment with budesonide in children with asthma and adult height

  • 332 children enrolled for long term follow up – finally 142 children with budesonide, 18 controls (asthma without inhaled steroids), 51 siblings

  • Visit every six months

  • Mean duration of budesonide treatment: 9.2 years

Agertoft L & Pedersen S: N Engl J Med 2000; 343:1064-9

Adherence with prescribed therapy results from a long term clinical study on inhaled steroids

Adherence with prescribed therapyResults from a long term clinical study on inhaled steroids




Jónasson G, Carlsen K-H, Mowinckel P.

Arch Dis Child 2000; 83: 330-333.


% Compliance



BUD morning


Placebo morning







Treatment time (months)

Evidence based pharmacological management


- Sodium cromoglicate is of some benefit in adults

- The evidence of benefits of sodium cromoglicates in children is


- Nedocromil sodium is of some benefit

Leukotriene receptor antagonists

have some beneficial clinical effect and an effect oneosinophilic inflammation

Theophyllines have some beneficial effect side-effects are more common and monitoringof plasma levels is required.

Antihistamines and ketotifen are ineffective.

Evidence based pharmacological management

Long-acting inhaled b2 agonists

should not be used without inhaled corticosteroids.

Recommended practice

Evidence based pharmacological management


Carry out a trial of other treatments before increasing the inhaled steroiddose above 400 mcg/day in children.

A-B-Recomended practice

Evidence based pharmacological management

Safety of LA-ß2 agonists



SNS study published

Salmeterol approved for sale in US

SMART begins

SMART protocol modified

Foradil aerolizer approved for sale in US

SMART halted

Unpublished Foradil data shows increase in serious asthma-related events

FDA convenes advisory committee meeting on LABA safety

FDA public health advisory on LABA safety

F. Martinez article in NEJM

Manuscript on LABA safety data, label changes

Evidence based pharmacological management

The first choice as add-on therapy to inhaled steroids in children (5-12 years) is an inhaled long-acting b2 agonist.

If, there is no response to inhaled long-acting b2 agonist, stop theLABA and increase the dose of inhaled steroid to 400 mcg/day

If there is a response to LABA, but control remains poor, continuewith the LABA and increase the dose of inhaled steroid


Evidence based pharmacological management

Safety of long-acting ß-agonists: an urgent

Need to clear the air

FD Martinez, N Engl J Med, Dec 22, 2005

- SMART study (Nelson et al Chest 2006)

- Salmeterol vs placebo

- 27000 patients enrolled for 6 months

- Study stopped due to an increased risk of deaths in

the SMR group (4 vs 13)

- Pb: most patients who died were not under ICS and were

living in deprived areas

Evidence based pharmacological management

Safety of long-acting ß-agonists: ß2 déjà vu

P O'Byrne, E Adelroth, Chest 2006

  • LA ß2 agonists should always be given with ICS

  • Combination therapy not as first line treatment

  • Are salmeterol and formoterol similar ?

Evidence based pharmacological management

There are no controlled trials indicating which of these is the best option.

Evidence based pharmacological management

Addition of short-acting anticholinergics is generally of no value.

Addition of chromones is ofmarginal benefit.

Evidence based pharmacological management

In patients on inhaled steroids whose asthma is stable,

no intervention has been consistentlyshown to decrease inhaled steroid requirement in a clinically significant manner compared toplacebo.

Evidence based pharmacological management

Increase steroid first??

Evidence based pharmacological management

Before proceeding to step 5, consider referring patients with inadequately controlled asthma,

especially children, to specialist care.

Evidence based pharmacological management

Stepping down therapy :

once asthma is controlled is recommended, but often not implementedleaving some patients over-treated.

Evidence based pharmacological management

There are few studies that have investigated the most appropriateway to step down treatment.

A study in adults on at least 900mcg per day of inhaled steroids hasshown that for patients who are stable it is reasonable to attempt to halve the dose of inhaledsteroids every three months.

Evidence based pharmacological management

  • Patients should be maintained at the lowest possible dose of inhaled steroid.

  • Reductionin inhaled steroid dose should be slow as patients deteriorate at different rates.

  • Reductionsshould be considered every three months, decreasing the dose by approximately 25-50%each time.

Evidence based pharmacological management

Early intervention of recent onset mild persistent asthma in children aged under 11 yrs:

the Steroid Treatment As Regular Therapy in early asthma (START) trial.Chen YZ, Busse WW, Pedersen S, Tan W, Lamin CJ, O’byrne PM Pediatr Allergy Immunol. 2006

The objective of this study was to determine the long-term efficacy of regular inhaled low-dose budesonide in children aged <11 yrs with mild persistent asthma with onset within 2 yrs of enrollment.

Children aged 5-10 yrs formed part of the population of the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study, and they were randomized in a double-blind manner to treatment with once daily budesonide 200 mug or placebo via Turbuhaler(TM) in addition to usual clinical care and other asthma medication.

The double-blind treatment phase continued for 3 yrs.

Evidence based pharmacological management

Of the 1974 children,

1000 in the budesonide group and

974 in the placebo group, were analyzed for efficacy.

Children receiving budesonide also needed significantly less intervention with other inhaled corticosteroids (12.3% vs. 22.5% over 3 yrs; p < 0.01), with trends towards decreased usage of oral/systemic corticosteroids and inhaled short-acting beta(2)-agonists.

Budesonide treatment also had a significant beneficial effect on lung function relative to placebo.

In conclusion, early intervention adding once-daily budesonide to usual care in children with mild, persistent asthma of recent onset reduces the long-term risk and frequency of SAREs and improves lung function compared with usual care alone.

Evidence based pharmacological management

SEPTEMBER 22-25, 2007


The World Asthma Meeting (WAM) Committee

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