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Evidence-based Pharmacological management

Prof Elif DağlıMarmara UniversityIstanbul Turkey

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•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)

Objectives

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20

60

Rescue use0

Single endpoints canover estimate asthma control

Passed

Failed

Clark et al. Eur Respir J 2002

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80

PEF Symptoms Night-timeawakenings

GINA / NIHcompositemeasure

100

% patients

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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

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STEP 2: INTRODUCTION OF REGULAR PREVENTER THERAPY

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

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

Evidence A for all ages

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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.

2004Evidence B, Recommended practice

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STEP 1: MILD INTERMITTENT ASTHMA

The following medicines act as short-acting bronchodilators:

inhaled short-acting 2 agonists

inhaled ipratropium bromide

2 agonist tablets or syrup

theophyllines.

Short-acting inhaled 2 agonists work more quickly and/or with fewer side-effects than the alternatives.

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Starting dose of inhaled steroids

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

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

Recommended practice

Up or down

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•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 are problems in obtaining consistent drug delivery.

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

Recommended practice

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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

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SAFETY OF INHALED STEROIDS

Administration of inhaled steroids at or above 400 mcg a day of BDP or equivalent may be associated 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 steroids presenting with a decreased level of consciousness; blood glucose levels should be checked urgently.

Consider whether intramuscular (IM) hydrocortisone is required.

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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, 25thand 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.

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24 randomized, placebo controlled, double blind trials1966-1996

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:A

Pediatr Pulmonol. 2003 Apr;35(4):241-52. Kaditis A et al.

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Double blind placebo controlled randomized study861 children 3mo-8 yrs

481 patients Budesonide group with better asthma scoreless reliever use

305 patientsfluticasoneIncreased symptom free periodDay and nightEvidence: A

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Efficacy of Inhaled Steroids In Infants and Young Children

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

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31 children 6-19 mo History of recurrent wheeze Parental atopyTreatment with FDP and placebo for four monthsLFT and exhaled NO measured

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

Inhaled fluticasone decreases NO levels in recurrent wheezy infants

Fe(NO) FDP 35.0 ppb 16.5 ppb plasebo 35.2 ppb 30.2 ppb (P = 0.05).

before after

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160 patients12-47 morandomizedFDP orplacebo

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Morning cortisolBefore or after treatment

Daily symptom scoreunder FDP or placebo

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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.:

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

Two recent studies have shown benefit from regular use of inhaled steroids in patients with mild asthma.

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

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

Pauwels RA, Pedersen S, Busse WW, et al. Lancet 2003;361(9363):1071-6.

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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 considered if good control is established.

Evidence: A- D -D

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

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

• Visit every six monthsVisit every six months

• Mean duration of Mean duration of budesonide treatment: 9.2 budesonide treatment: 9.2 yearsyears

Budesonide Controls Siblings0

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Measured adult height

Target adult height

160

165

170

175

180

Hei

gh

t (c

m)

Budesonide Controls Siblings0

25

Measured adult height

Target adult height

160

165

170

175

180

Hei

gh

t (c

m)

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

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

Treatment time (months)

27211593Baseline

% C

om

plia

nce

80

70

60

50

40

30

20

BUD morning

Placebo morning

     Jónasson G, Carlsen K-H, Mowinckel P. Arch Dis Child 2000; 83: 330-333.

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Chromones

- Sodium cromoglicate is of some benefit in adults

- The evidence of benefits of sodium cromoglicates in children is

contentious.

- Nedocromil sodium is of some benefit

Leukotriene receptor antagonists

have some beneficial clinical effect and an effect on eosinophilic inflammation

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

Antihistamines and ketotifen are ineffective.

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Long-acting inhaled 2 agonists should not be used without inhaled corticosteroids.

Recommended practice

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CRITERIA FOR INTRODUCTION OF ADD-ON THERAPY

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

A-B-Recomended practice

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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

Safety of LA-ß2 agonists

1993

2006

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The first choice as add-on therapy to inhaled steroids in children (5-12 years) is an inhaled long-acting 2 agonist.

If, there is no response to inhaled long-acting 2 agonist, stop the LABA and increase the dose of inhaled steroid to 400 mcg/day

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

A-B

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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 inthe SMR group (4 vs 13)- Pb: most patients who died were not under ICS and were living in deprived areas

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Safety of long-acting ß-agonists: ß2 déjà vuP 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 ?

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

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

Addition of chromones is of marginal benefit.

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In patients on inhaled steroids whose asthma is stable,

no intervention has been consistently shown to decrease inhaled steroid requirement in a clinically significant manner compared to placebo.

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Increase steroid first??

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

especially children, to specialist care.

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Stepping down therapy :

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

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

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

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

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

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

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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.

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

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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.

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The World Asthma Meeting (WAM) Committee

SEPTEMBER 22-25, 2007

EAACI ERS