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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Prof Elif Dağlı
GINA / NIHcompositemeasure
Clark et al. Eur Respir J 2002
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
STEP 1: MILD INTERMITTENT ASTHMA of the following:
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.
Up or down
SAFETY OF INHALED STEROIDS of the following:
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
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.
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.
Pediatr Pulmonol. 2003 Apr;35(4):241-52. Years Old with Risk Factors for Asthma
Kaditis A et al.
Double blind placebo controlled randomized study Years Old with Risk Factors for Asthma
861 children 3mo-8 yrs
with better asthma score
less reliever use
Increased symptom free period
Day and night
Efficacy of Inhaled Steroids Years Old with Risk Factors for Asthma
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
Pediatr Pulmonol. 2004 Sep;38(3):250-5. Moeller A et al
31 children 6-19 mo
History of recurrent wheeze
Treatment with FDP and placebo for four months
LFT and exhaled NO measured
Fe(NO) FDP 35.0 ppb 16.5 ppb
plasebo 35.2 ppb 30.2 ppb (P = 0.05).
160 patients infants
Daily symptom score infants
under FDP or placebo
Before or after treatment
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.
Frequency of dosing of inhaled steroids never been firmly established.
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
Agertoft L & Pedersen S: N Engl J Med 2000; 343:1064-9
Jónasson G, Carlsen K-H, Mowinckel P.
Arch Dis Child 2000; 83: 330-333.
Treatment time (months)
Chromones and adult height
- 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.
Long-acting inhaled and adult heightb2 agonists
should not be used without inhaled corticosteroids.
CRITERIA FOR INTRODUCTION OF ADD-ON THERAPY and adult height
Carry out a trial of other treatments before increasing the inhaled steroiddose above 400 mcg/day in children.
Safety of LA-ß2 agonists and adult height
SNS study published
Salmeterol approved for sale in US
SMART protocol modified
Foradil aerolizer approved for sale in US
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
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
Safety of long-acting ß-agonists: an urgent children (5-12 years) is an inhaled long-acting
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
Safety of long-acting ß-agonists: ß2 déjà vu children (5-12 years) is an inhaled long-acting
P O'Byrne, E Adelroth, Chest 2006
There are no controlled trials indicating which of these is the best option.
Addition of the best option.short-acting anticholinergics is generally of no value.
Addition of chromones is ofmarginal benefit.
In patients on inhaled steroids whose asthma is stable, the best option.
no intervention has been consistentlyshown to decrease inhaled steroid requirement in a clinically significant manner compared toplacebo.
Increase steroid first?? the best option.
Before proceeding to step 5, consider referring patients with inadequately controlled asthma,
especially children, to specialist care.
Stepping down therapy with inadequately controlled asthma,:
once asthma is controlled is recommended, but often not implementedleaving some patients over-treated.
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.
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.
Of the 1974 children, children aged under 11 yrs:
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.
SEPTEMBER 22-25, 2007 children aged under 11 yrs:
The World Asthma Meeting (WAM) Committee