Intervention Review

You have free access to this content

Intermittent versus daily inhaled corticosteroids for persistent asthma in children and adults

  1. Bhupendrasinh F Chauhan1,
  2. Caroline Chartrand2,
  3. Francine M Ducharme3,4,*

Editorial Group: Cochrane Airways Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 18 OCT 2012

DOI: 10.1002/14651858.CD009611.pub3


How to Cite

Chauhan BF, Chartrand C, Ducharme FM. Intermittent versus daily inhaled corticosteroids for persistent asthma in children and adults. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD009611. DOI: 10.1002/14651858.CD009611.pub3.

Author Information

  1. 1

    Research Centre, CHU Sainte-Justine, Clinical Research Unit on Childhood Asthma, Montreal, Canada

  2. 2

    CHU Sainte-Justine Hospital, Department of Pediatrics, Montreal, Canada

  3. 3

    University of Montreal, Department of Paediatrics, Montreal, Québec, Canada

  4. 4

    CHU Sainte-Justine, Research Centre, Montreal, Canada

*Francine M Ducharme, francine.m.ducharme@umontreal.ca.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions), comment added to review
  2. Published Online: 28 FEB 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Boushey 2005

MethodsDesign: randomised clinical study

Confirmation of methodology: not obtained


ParticipantsSymptomatic participants

Randomised: N = 149

  • intermittent: 76
  • daily: 73


Withdrawals: reported

Age: years ± SD:

  • intermittent: 32.0 ± 10.5
  • daily: 33.2 ± 9.5


Gender: N (male %):

  • intermittent: 33 (43%)
  • daily: 25 (34%)


Asthma severity: mild persistent asthma

Asthma duration (mean years ± SD):

  • intermittent: 19.5 ± 11.8
  • daily: 17.1 ± 11.0


Mean (± SD) β2-agonist use (puffs/day): not reported

Dose of ICS at study entry and at run-in: placebo controller for 4 weeks + 'as needed' albuterol

Atopy (% of patients): not reported

Eligibility criteria:

  • physician-diagnosed asthma
  • age: 18 to 65 years
  • ≥ 70 predicted FEV1
  • increase in FEV1 of at least 12% and at least 200 mL after inhalation of albuterol
  • fall of at least 20% after inhalation of methacholine of < 16 mg/mL


Exclusion criteria:

  • cigarette smoking
  • respiratory tract infection
  • corticosteroid use in the previous 6 weeks
  • hospitalisation or ≥ 2 visits to the emergency department for asthma in the previous year


  • on ICS, leukotriene receptor antagonists, theophylline and long-acting β2-agonists within the preceding 12 months of the study


InterventionsProtocol

Duration

  • run-in 4 weeks
  • intervention 52 weeks


Test group: intermittent budesonide

Control group: daily budesonide

Device: Turbuhaler and placebo-dispensing dry-powder inhaler

Dose of ICS

Between exacerbations:

  • intermittent: placebo twice daily
  • daily: budesonide 200 μg twice daily


During exacerbations:

  • intermittent: budesonide 800 μg twice daily x 2 weeks
  • daily: budesonide 800 μg twice daily x 2 weeks


Criteria for withdrawal from study: reported


OutcomesAnalysis: not ITT

Outcomes: reported at 52 weeks; outcomes were reported as change from baseline

Pulmonary function tests:

  • PEFR
  • FEV1 (%)
  • PC20


Functional status:

  • asthma quality of life score
  • asthma symptom utility index
  • number of symptom-free days


Inflammatory mediators:

  • Exhaled nitric oxide
  • Sputum eosinophils count


Adverse events: not reported

Withdrawals: mentioned

Definition of exacerbation to initiate rescue treatment:

Yellow Zone to initiate ICS:

  • awakening from asthma ≥ 3 times in a 2-week period or on 2 consecutive nights, or using albuterol for relief of symptoms ≥ 4 times/day for ≥ 2 consecutive days, or


  • albuterol has been relieving symptoms for less than 4 hours after each treatment over a 12-hour period, or


  • using albuterol for relief of symptoms daily for 7 days, and this use exceeds 2 times the weekly use of albuterol in the baseline period, or


  • exercise induces unusual breathlessness


Red Zone to initiate oral corticosteroid:

  • for the previous 24 hours, daily life activities cause shortness of breath or breathlessness is present at rest, or


  • albuterol has been relieving symptoms for less than 2 hours after each treatment over an 8-hour period


NotesFull paper (2005)

Funding: by National Institutes of Health.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTreatment assignment was stratified according to centre, and the use of an adaptive randomisation scheme ensured balance with respect to PC20, age, and racial or ethnic group

Allocation concealment (selection bias)Low riskIdentical delivery systems (pills or Turbuhaler)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind trial

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind trial

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups with similar reasons for missing data across groups

Selective reporting (reporting bias)Low riskNot observed

Other biasLow riskNo apparent bias was observed

Martinez 2011a

MethodsDesign: randomised, placebo-controlled clinical study

Confirmation of methodology: not obtained


ParticipantsSymptomatic participants

Randomised: N = 142

  • intermittent: 71
  • daily: 71


Withdrawals: reported

Age: years ± SD:

  • intermittent: 10.4 ± 2.8
  • daily: 11.4 ± 3.1


Gender: N (male %):

  • intermittent: 37 (52%)
  • daily: 39 (55%)


Asthma severity: mild persistent asthma

Asthma duration (mean years ± SD):

  • intermittent: 4.1 ± 2.9
  • daily: 4.5 ± 3.8


Mean (± SD) β2-agonist use (puffs/day): not reported

Dose of ICS at study entry and at run-in: placebo controller for 4 weeks + 'as needed' albuterol

Atopic eczema: N (% of patients):

  • intermittent: 37 (52%)
  • daily: 36 (51%)


Eligibility criteria:

  • naive to controller treatment
  • had a history of 1 to 2 exacerbations in the previous year
  • treated for the previous 8 weeks with a monotherapy other than ICS, or if their illness was controlled for the previous 8 weeks on low-dose corticosteroids as monotherapy (≤ 160 μg daily with a beclomethasone equivalent)


Exclusion criteria:

  • had a pre-bronchodilator FEV1 of < 60% predicted at the first visit
  • admitted to hospital for asthma in the previous year
  • had any asthma exacerbation in the previous 3 months or > 2 in the previous year
  • had a history of life-threatening asthma exacerbations that required intubation or mechanical ventilation, or that resulted in a hypoxic seizure


InterventionsProtocol

Duration

  • run-in 4 weeks
  • intervention 44 weeks


Daily group: beclomethasone

Intermittent group: beclomethasone

Placebo group: twice daily placebo with placebo plus albuterol as rescue

Device: hydrofluoroalkane formulation

Dose of ICS

Between exacerbations:

  • intermittent: placebo
  • daily combined: 100 μg HFA-beclomethasone/day


During exacerbations:

  • intermittent: placebo + 'as needed' 100 μg HFA-beclomethasone and salbutamol in separate devices
  • daily combined: HFA-beclomethasone 100 μg/day + 'as needed' HFA-beclomethasone 100 μg and salbutamol in separate devices


Study medication administration: each participant received 3 study inhalers. 1 inhaler contained 40 μg of HFA-beclomethasone or placebo to be used twice daily throughout the trial. 2 inhalers were to be used for rescue alone. 1 contained albuterol and the 1 contained either 40 μg of HFA-beclomethasone or placebo. Without interrupting or changing the dose of the daily inhaler, participants were instructed to use the 2 rescue inhalers, one after the other, every time the participant would have used in 'real life' an albuterol inhaler for relief of symptoms or to treat decreases in peak flow. They were instructed to always use the same number of puffs from each rescue inhaler

Criteria for withdrawal from study: reported


OutcomesAnalysis: ITT

Outcomes: reported at 44 weeks; outcomes were reported as absolute values at different time points

Primary outcomes:

  • *patients with exacerbation requiring oral corticosteroids


  • *patients with serious health events


Exacerbations:

  • *patients with exacerbation requiring hospital admission


  • *patients with exacerbation requiring acute care visits
  • *time to first exacerbation


Pulmonary function tests:

  • *PEFR
  • *diurnal PEFR
  • *FEV1 (%)


Functional status:

  • *PACQLQS scores
  • *proportions of asthma control days
  • *change in proportion of asthma control days
  • *change in use of albuterol


Inflammatory mediators:

  • *exhaled nitric oxide


Adverse events: reported, *change in height

Withdrawals: mentioned

Definition of exacerbation to initiate rescue treatment:

  • use of more than 12 puffs of albuterol in 24 h (excluding preventive use before exercise)
  • a PEFR of < 70% of reference value before each albuterol use
  • symptoms that led to inability to sleep or do daily activities for ≥ 2 consecutive days
  • a PEFR of < 50% of reference value despite relief treatment, or an emergency department visit because of worsening of asthma symptoms
  • excessive ICS use


* Data obtained directly from authors or sponsor


NotesFull paper (2011)

Funding: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated block randomisation sequence, stratified by clinical centre and age group

Allocation concealment (selection bias)Low riskCentralised allocation for package, code, and ship the drug packets to each clinical centre

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind trial

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStatisticians were also blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups with similar reasons for missing data across groups

Selective reporting (reporting bias)Low riskNot observed

Other biasLow riskNo apparent bias was observed

Martinez 2011b

MethodsDesign: randomised, placebo controlled clinical study

Confirmation of methodology: not obtained


ParticipantsSymptomatic participants

Randomised: N = 143

  • intermittent: 71
  • daily: 72


Withdrawals: reported

Age: years ± SD:

  • intermittent: 10.4 ± 2.8
  • daily: 10.8 ± 3.5


Gender: N (male %):

  • intermittent: 37 (52%)
  • daily: 42 (58%)


Asthma severity: mild persistent asthma

Asthma duration (mean years± SD):

  • intermittent: 4.1 ± 2.9
  • daily: 3.7 ± 2.7


Mean (± SD) β2-agonist use (puffs/day): not reported.

Dose of ICS at study entry and at run-in: placebo controller for 4 weeks + 'as needed' albuterol

Atopic eczema: N (% of patients):

  • intermittent: 37 (52%)
  • daily: 34 (47%)


Eligibility criteria:

  • naive to controller treatment
  • had a history of 1 to 2 exacerbations in the previous year
  • treated for the previous 8 weeks with a monotherapy other than ICS, or if their illness was controlled for the previous 8 weeks on low-dose corticosteroids as monotherapy (≤ 160 μg daily with a beclomethasone equivalent)


Exclusion criteria:

  • had a pre-bronchodilator FEV1 < 60% predicted at the first visit
  • admitted to hospital for asthma in the previous year
  • had any asthma exacerbation in the previous 3 months or more than 2 in the previous year
  • had a history of life-threatening asthma exacerbations that required intubation or mechanical ventilation, or that resulted in a hypoxic seizure


InterventionsProtocol

Duration

  • run-in 4 weeks
  • intervention 44 weeks


Daily group: beclomethasone

Intermittent group: beclomethasone

Placebo group: twice daily placebo with placebo plus albuterol as rescue

Device: hydrofluoroalkane formulation

Dose of ICS

Between exacerbations:

  • intermittent group: placebo
  • daily group: 100 μg HFA-beclomethasone/day


During exacerbations:

  • intermittent group: placebo + 'as needed' 100 μg HFA-beclomethasone and salbutamol in separate devices
  • daily group: 100 μg HFA-beclomethasone/day + 'as needed' placebo and salbutamol in separate devices


Study medication administration: each participant received 3 study inhalers. 1 inhaler contained 40 μg of HFA-beclomethasone or placebo to be used twice daily throughout the trial. 2 inhalers were to be used for rescue alone. 1 contained albuterol and 1 contained either 40 μg of HFA-beclomethasone or placebo. Without interrupting or changing the dose of the daily inhaler, participants were instructed to use the 2 rescue inhalers, one after the other, every time the participant would have used in 'real life' an albuterol inhaler for relief of symptoms or to treat decreases in peak flow. They were instructed to always use the same number of puffs from each rescue inhaler

Criteria for withdrawal from study: reported


OutcomesAnalysis: ITT

Outcomes: reported at 44 weeks; outcomes were reported as absolute values at different time points

Primary outcomes:

  • *patients with exacerbation requiring oral corticosteroids


  • *patients with serious health events


Exacerbations:

  • *patients with exacerbation requiring hospital admission


  • *patients with exacerbation requiring acute care visits
  • *time to first exacerbation


Pulmonary function tests:

  • *PEFR
  • *diurnal PEFR
  • *FEV1 (%)


Functional status:

  • *PACQLQS scores
  • *proportions of asthma control days
  • *change in proportion of asthma control days
  • *change in use of albuterol


Inflammatory mediators:

  • *exhaled nitric oxide


Adverse events: reported, *change in height

Withdrawals: mentioned

Definition of exacerbation to initiate rescue treatment:

  • use of more than 12 puffs of albuterol in 24 h (excluding preventive use before exercise)
  • a PEFR of < 70% of reference value before each albuterol use
  • symptoms that led to inability to sleep or do daily activities for 2 or more consecutive days
  • a PEFR of < 50% of reference value despite relief treatment, or an emergency department visit because of worsening of asthma symptoms
  • excessive ICS use


* Data obtained directly from authors or sponsor


NotesFull paper (2011)

Funding: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated block randomisation sequence, stratified by clinical centre and age group

Allocation concealment (selection bias)Low riskCentralised allocation for package, code, and ship the drug packets to each clinical centre

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind trial

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStatisticians were also blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups with similar reasons for missing data across groups

Selective reporting (reporting bias)Low riskNot observed. Study protocol is available

Other biasLow riskNo apparent bias was observed

Papi 2007

MethodsDesign: randomised clinical study

Confirmation of methodology: not obtained


ParticipantsSymptomatic participants

Randomised: N = 234

  • intermittent: 124
  • daily: 110


Withdrawals: reported

Age: years ± SD:

  • intermittent: 36.8 ± 13.1
  • daily: 37.9 ± 13.5


Gender: N (male %):

  • intermittent: 50 (41.0%)
  • daily: 45 (42.5%)


Asthma severity: mild asthma

Asthma duration (mean years ± SD): not reported

Mean ±SD β2-agonist use (puffs/day):

  • intermittent: 0.4 ± 0.7
  • daily: 0.4 ± 0.7


Dose of ICS at study entry and at run-in: beclomethasone 500 μg/day x 4 weeks + 'as needed' albuterol

Atopy: N (% of patients):

  • intermittent: 77 (63.1%)
  • daily: 66 (62.3%)


Eligibility criteria:

  • history of mild persistent asthma for at least 6 months
  • aged 18 to 65 years
  • pre-bronchodilator FEV1 of 75% or more of the predicted value
  • increase in FEV1 of 12% or more of the predicted value after inhalation of albuterol 200 μg
  • positive methacholine challenge (< 8 mg/mL, or a methacholine dose of < 1 mg, provokes a 20% decrease in the FEV1)


Exclusion criteria:

  • current smoking or ex-smoking habits (> 10 packs/year)
  • COPD defined by European Respiratory Society
  • history of near-fatal asthma
  • admission to emergency department/intensive care unit because of asthma
  • ≥ 3 courses of oral corticosteroids
  • hospitalisation for asthma during the previous year
  • regular treatment for > 6 months with more than 500 μg/day of beclomethasone or equivalent


InterventionsProtocol

Duration

  • run-in 4 weeks
  • intervention 24 weeks


Device: CFC inhaler

Dose of ICS

Between exacerbations:

  • intermittent: placebo twice daily
  • daily: beclomethasone 250 μg twice daily


During exacerbations:

  • intermittent: placebo twice daily + 'as needed' beclomethasone 250 μg and albuterol 100 μg in a single inhaler
  • daily: beclomethasone 250 μg twice daily + 'as needed' albuterol 100 μg


Criteria for withdrawal from study: reported


OutcomesAnalysis: ITT

Outcomes: reported at 24 weeks; outcomes were reported as absolute values and change from baseline at end point

Primary outcomes:

  • *patients with exacerbation requiring oral corticosteroids


  • patients with serious adverse health events


Exacerbations:

  • *patients with exacerbation requiring hospital admission


  • *patients with exacerbation requiring acute care visits


Pulmonary function tests:

  • morning and evening PEFR
  • PEFR variability
  • FEV1 (L)
  • FEV1 of predicted value


Functional status:

  • daytime asthma symptoms
  • night-time asthma symptom
  • nocturnal awakenings
  • 'symptom-free days' (%)
  • rescue medication (puffs/day)


Inflammatory mediators: not reported

Adverse events: reported

Withdrawals: reported

Definition of exacerbation to initiate rescue treatment:

  • awakening at night owing to asthma or
  • decrease in the morning PEFR to more than 20% below the baseline value
  • use of more than 3 additional puffs per day of rescue medication (either albuterol or beclomethasone and albuterol) as compared to the baseline period (the last week of the run-in period) for 2 or more consecutive days, or both


* Data obtained directly from authors or sponsor


NotesFull paper (2007)

Funding: Chiesi Pharmaceuticals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation sequence

Allocation concealment (selection bias)Low riskCentralised allocation for package of drug to each enrolled patient according to randomisation list

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, double-dummy

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind study

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups with similar reasons for missing data across groups

Selective reporting (reporting bias)Low riskNot observed. Study protocol was available

Other biasLow riskNo apparent bias was observed

Papi 2009

MethodsDesign: randomised clinical study

Confirmation of methodology: not obtained


ParticipantsPreschool children with frequent wheezing and symptomatic during the 2-week run-in period

Randomised: N = 220

  • intermittent: 110
  • daily: 110


Withdrawals: reported

Age: years ± SD:

  • intermittent: 2.26 ± 0.79
  • daily: 2.35 ± 0.81


Gender: N (male %):

  • intermittent: 68 (61.8%)
  • daily: 64 (58.2%)


Asthma severity: not reported

Asthma duration (mean years ± SD):

  • intermittent: 1.53 ± 0.84
  • daily: 1.59 ± 0.87


Daytime mean ± SD β2-agonist use (puffs/day):

  • intermittent: 0.26 ± 0.29
  • daily: 0.35 ± 0.41


Dose of ICS at study entry and at run-in: placebo controller for 2 weeks + 'as needed' albuterol 2500 μg/nebule

Atopy: N (% of patients): not reported

Eligibility criteria:

  • preschool children aged 1 to 4 years with frequent wheezing defined as a documented history of at least 3 episodes of wheezing requiring medical attention in the previous 6 months (indicator of asthma predictive index)
  • had wheeze and/or cough, and/or shortness of breath, and/or required relief medication on at least 7 days of the 2-week run-in period
  • did not use asthma predictive index


Exclusion criteria:

  • history of severe exacerbations requiring systemic glucocorticoid
  • chest infection
  • hospitalisation for asthma
  • treatment with inhaled glucocorticoids or methylxanthine during the previous 4 weeks or with oral glucocorticoid in the previous 8 weeks


InterventionsProtocol

Duration

  • run-in 4 weeks
  • intervention 12 weeks


Device: nebuliser

Dose of ICS

Between exacerbations:

  • intermittent: placebo 1 vial twice daily
  • daily: beclomethasone 400 μg/vial, 1 vial twice daily


During exacerbations:

  • intermittent: placebo 1 vial twice daily + 'as needed' fixed combination of beclomethasone 800 μg + salbutamol 1600 μg/vial, 1 vial
  • daily: beclomethasone 400 μg/vial, 1 vial twice daily + 'as needed' salbutamol 2500 μg/vial, 1 vial


Criteria for withdrawal from study: reported


OutcomesAnalysis: ITT

Outcomes: reported at 12 weeks; outcomes were reported as absolute values and change from baseline at end point

Primary outcomes:

  • *patients with exacerbation requiring oral corticosteroids


  • patients with serious adverse health events


Exacerbations:

  • *patients with exacerbation requiring hospital admission


  • *patients with exacerbation requiring acute care visits


Pulmonary function tests: not reported

Functional status:

  • 'symptom-free days'
  • daytime symptom score
  • night-time symptom score
  • daytime wheezing score
  • night-time wheezing score
  • daytime coughing score
  • night-time coughing score
  • number of nocturnal awakening
  • daytime rescue medication
  • night-timer rescue medication
  • salivary cortisol level


Inflammatory mediators: not reported

Adverse events: reported

Withdrawal: reported

Definition of exacerbation to initiate rescue treatment:

  • episodes of progressive increase in shortness of breath, cough or wheezing (or some combination of these symptoms) that required a change in medication
  • exacerbations confirmed by the study investigator


* Data obtained directly from authors or sponsor


NotesFull paper (2009)

Funding: Chiesi Pharmaceuticals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation table was prepared by CROS NT validated system

Allocation concealment (selection bias)Low riskSequentially assigned sealed treatment codes that were kept in locked, secure storage facility

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, double-dummy

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind trial

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups with similar reasons for missing data across groups

Selective reporting (reporting bias)Low riskNot observed

Other biasLow riskNo apparent bias was observed

Turpeinen 2008

MethodsDesign: randomised clinical study

Confirmation of methodology: not obtained


ParticipantsSymptomatic participants

Randomised: N = 116

  • intermittent: 58
  • daily: 58


Withdrawals: reported

Age: years (range):

  • intermittent: 6.7 (5.0 to 10.0)
  • daily: 7.0 (5.0 to 10.0)


Gender: (male %):

  • intermittent: 66%
  • daily: 59%


Asthma severity: mild persistent asthma

Asthma duration: mean months (range):

  • intermittent: 11.3 (2.0 to 76.4)
  • daily: 12.8 (1.1 to 70.5)


Daytime mean ± SD β2-agonist use (puffs/day): mean (range)

  • intermittent: 0.55 (0 to 3.7)
  • daily: 0.47 (0 to 4.0)


Dose of ICS at study entry and at run-in: budesonide 800 μg/day x 1 month then budesonide 400 μg/day x 5 months

Atopy: not reported

Eligibility criteria:

  • children aged 5 to 10 years
  • symptoms with wheezing, prolonged cough or shortness of breath, suggesting asthma for at least 1 month before entry into the study
  • significant bronchial reversibility
  • at least a 20% diurnal variation in repeatable PEFR
  • at least a 15% increase in PEFR at least 3 times within 2 weeks of home recording
  • at least a 15% increase in FEV1 15 min after inhalation of a β2-agonist
  • at least a 15% decline in FEV1 in an outdoor exercise test in the clinic


Exclusion criteria:

  • treatment during the preceding 2 months with ICS, cromones, leukotriene modifiers or long acting β2-agonists were excluded
  • the total cumulative doses of previously used ICS above 36 mg, 12 mg of nasal corticosteroids or oral doses equivalent to prednisolone 200 mg


InterventionsProtocol

Duration

  • run-in 2 weeks
  • intervention 52 weeks


Test group: placebo

Control group: budesonide 100 μg twice daily

Device: Turbuhaler

Dose of ICS

Between exacerbations:

  • intermittent: placebo twice daily
  • daily: budesonide 100 μg twice daily


During exacerbations:

  • intermittent: budesonide 400 μg twice daily x 2 weeks
  • daily: budesonide 400 μg twice daily x 2 weeks


Criteria for withdrawal from study: reported


OutcomesAnalysis: ITT

Outcomes: reported at 12 weeks; outcomes were reported as absolute values and change from baseline at end point

Primary outcomes:

  • *patients with exacerbation requiring oral corticosteroids


  • *patients with serious adverse health events


Exacerbations:

  • patients with exacerbation requiring hospital admission


  • *patients with exacerbation requiring acute care visits


Pulmonary function tests: not reported

Functional status:

  • change in asthma-free days
  • *mean change in height


Inflammatory mediators: not reported

Adverse events: not reported

Withdrawal: reported

Definition of exacerbation to initiate rescue treatment:

  • an increase in symptoms that were not controlled with 6 doses of rescue terbutaline per 24 hours that caused the parent to contact the clinic
  • at the clinic, upon diagnosed by a paediatrician, an exacerbation was considered


* Data obtained directly from authors or sponsor


NotesFull paper (2008)

Funding: Helsinki University Central Hospital and AstraZeneca


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBalanced block randomisation was generated by a computer program

Allocation concealment (selection bias)Unclear riskNo sufficient information was available on allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind trial

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind trial

Incomplete outcome data (attrition bias)
All outcomes
Low riskImbalance between test and control group (12 versus 6 patients); however, the reasons for withdrawals were mentioned. Analysis was done by ITT analysis

Selective reporting (reporting bias)Low riskNot observed

Other biasLow riskNo apparent bias was observed

Zeiger 2011

MethodsDesign: randomised clinical study

Confirmation of methodology: not obtained


ParticipantsPreschool children with repeated wheezing, a positive asthma predictive index and no or minimal interim symptoms

Randomised: N = 278

  • intermittent: 139
  • daily: 139


Withdrawals: reported

Age of 12 to 32 months: N (%)

  • intermittent: 64 (46.0%)
  • daily: 63 (45.3)


Gender: N (male %):

  • intermittent: 102 (73.4%)
  • daily: 90 (64.7%)


Asthma severity: not reported

Asthma duration: mean months (range): not reported

Daytime mean ± SD β2-agonist use (puffs/day): mean (range): not reported

Dose of ICS at study entry and at run-in: placebo controller for 2 weeks + 'as needed' albuterol

Eligibility criteria:

  • children aged 12 to 53 months
  • patients with mAPI status
  • had at least 4 episodes of wheezing (or 3 episodes of wheezing and controller use for ≥ 3 months), positive values on the mAPI, and at least 1 exacerbation requiring the use of systemic glucocorticoids, urgent or emergency care, or hospitalisations, and during a 2-week run-in period
  • had fewer than 3 days/week of albuterol use and fewer than 2 nights with awakening


Exclusion criteria:

  • had received more than 6 courses of oral glucocorticoids
  • hospitalised more than 2 times for wheezing during the previous year


InterventionsProtocol

Duration

  • run-in 2 weeks
  • intervention 52 weeks


Test group: placebo

Control group: budesonide 500 μg daily

Device: Pulmicort Respules (Astra-Zeneca)

Dose of ICS

Between exacerbations:

  • intermittent: placebo
  • daily: budesonide 0.5 mg/day


During exacerbations:

  • intermittent: budesonide 1 mg twice daily x 1 week
  • daily: budesonide 0.5 mg daily x 1 week


Criteria for withdrawal from study: reported


OutcomesAnalysis: ITT

Outcomes: reported at 52 weeks; outcomes were reported as absolute values and change from baseline at end point

Primary outcomes:

  • *patients with exacerbation requiring oral corticosteroids
  • patients with serious adverse health events


Exacerbations:

  • patients with exacerbation requiring hospital admission
  • *patients with exacerbation requiring acute care visits
  • *time to first exacerbation


Pulmonary function tests: not reported

Functional status:

  • number of days absent from work, school or day care
  • episode-free days
  • days with albuterol use
  • change in height and weight
  • time to first exacerbation
  • frequency of exacerbation
  • quality of life


Inflammatory mediators: not reported

Adverse events: reported

Withdrawals: reported

Definition of exacerbation to initiate rescue treatment:

  • the onset of symptoms or signs of a respiratory tract illness that was identified as child's usual starting point before the development of wheezing
  • the individualised symptoms or signs were reassessed at all study visits


* Data obtained directly from authors or sponsor


NotesFull paper (2011)

Funding: National Heart, Lung, and Blood Institute


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation sequence

Allocation concealment (selection bias)Low riskCentral allocation

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind trial

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble blind trial

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskMissing outcome data imbalanced in numbers across intervention groups; however, ITT analysis may reduce the impact partially

Selective reporting (reporting bias)Low riskNot observed. Study protocol was available

Other biasLow riskNo apparent bias was observed

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Adelroth 1990Not an RCT; test group was not intermittent ICS

Altman 1998Test group was not intermittent ICS; control group was not daily ICS

Amirav 2007Test group was not intermittent ICS; control group was not daily ICS

Anonymous 1999Not an RCT; test group was not intermittent ICS

Antmann 1990Not an RCT; test group was not intermittent ICS; control group was not daily ICS; participants did not have asthma

Apter 1996Test group was not intermittent ICS; control group was not daily ICS

Arandelovic 2007Test group was not intermittent ICS

Aubier 2010Test group was not intermittent ICS; Received non-permitted drug (formoterol) with daily ICS in control group

Bacharier 2008Control group was not daily ICS

Baiardini 2011Test group was not intermittent ICS

Bartoli 2004Not an RCT; test group was not intermittent ICS

Beeh 2007Test group was not intermittent ICS; control group was not daily ICS; treatment was received for < 4 weeks

Belcaro 2011Intermittent ICS was not one of tested strategies.

Berggren 2000Test group was not intermittent ICS

Berggren 2001Test group was not intermittent ICS

Berggren 2001aTest group was not intermittent ICS; control group was not daily ICS

Boulet 1997Test group was not intermittent ICS; control group was not daily ICS

Bousquet 2005Test group was not intermittent ICS

Bousquet 2007Test group was not intermittent ICS; control group was not daily ICS

Brenner 1988Test group was not intermittent ICS; control group was not daily ICS

Bruce 2005Received non-permitted drug (formoterol) with ICS in control group

Buist 2006Test group was not intermittent ICS; control group was not daily ICS

Busse 1998Test group was not intermittent ICS; control group was not daily ICS; received non-permitted drug

Calhoun 2012Daily ICS was not one of the tested strategies (approximately 40% patients did not receive daily ICS).

Chapman 1994Test group was not intermittent ICS; control group was not daily ICS; treatment was received for < 4 weeks

Chen 2004Not an RCT; test group was not intermittent ICS; control group was not daily ICS

Chuchalin 2002Test group was not intermittent ICS

Cloud 1994Participants did not have asthma; test group was not intermittent ICS; control group was not daily ICS

Convery 2000Test group was not intermittent ICS

Corren 2001Test group was not intermittent ICS

Costa-Katz 2012Intermittent ICS was not one of tested strategies

Covar 2010Test group was not intermittent ICS; control group was not daily ICS

Cowie 2007Test group was not intermittent ICS

Creticos 1995Test group was not intermittent ICS; control group was not daily ICS

D'Alonzo 1994Test group was not intermittent ICS; control group was not daily ICS

D'Urzo 2001Test group was not intermittent ICS

Dal Negro 1999Test group was not intermittent ICS

Dal Negro 2006Test group was not intermittent ICS; received non-permitted drug (formeterol) with daily ICS in control group

De 1997Participants did not have asthma; test group was not intermittent ICS; control group was not daily ICS

Decimo 2009Test group was not intermittent ICS; patients with acute asthma; treatment was given < 4 weeks

Dennis 1997Test group was not intermittent ICS

Donohue 2008Subjects with acute asthma; test group was not intermittent ICS; control group was not daily ICS; treatment was received for < 4 weeks

Dorow 1986Participants did not have asthma; test group was not intermittent ICS; control group was not daily ICS

Dorow 1988Test group was not intermittent ICS; control group was not daily ICS

Drazen 1996Test group was not intermittent ICS; control group was not daily ICS

Ecker 2001Test group was not intermittent ICS

Ecker 2009Not a randomized controlled trial (survey); test group was not intermittent ICS

Ellman 1997Test group was not intermittent ICS; control group was not daily ICS

Estelle 1997Test group was not intermittent ICS

Falliers 1985Participants did not have asthma; test group was not intermittent ICS; control group was not daily ICS

Fish 1997Test group was not intermittent ICS; control group was not daily ICS

Furukawa 1999Test group was not intermittent ICS; control group was not daily ICS

Fyans 1986Test group was not intermittent ICS

Galant 1996Test group was not intermittent ICS

Garcia 2001Test group was not intermittent ICS; control group was not daily ICS

Giannini 2003Test group was not intermittent ICS; control group was not daily ICS

Godfrey 1995Not an RCT

Goossens 2009Test group was not intermittent ICS

Green 1987Test group was not intermittent ICS; control group was not daily ICS; treatment was received for < 4 weeks

Guilbert 2004Test group was not intermittent ICS

Hamid 1998Test group was not intermittent ICS; control group was not daily ICS

Hanrahan 2007Test group was not intermittent ICS; control group was not daily ICS

Hederos 2009Test group was not intermittent ICS; control group was not daily ICS

Horiguchi 2005Test group was not intermittent ICS

Hung 2007Test group was not intermittent ICS; control group was not daily ICS

Ige 2002Test group was not intermittent ICS

Ind 2002aNot a randomized controlled trial (survey); test group was not intermittent ICS; control group was not daily ICS

Indinnimeo 2009Test group was not intermittent ICS; received non-permitted drug (formoterol) with daily ICS

Israel 2000Test group was not intermittent ICS; control group was not daily ICS

Israel 2001Test group was not intermittent ICS; control group was not daily ICS

Israel 2004Test group was not intermittent ICS; control group was not daily ICS

Janson 2003Test group was not intermittent ICS

Jarvis 1999Not a randomized controlled trial; test group was not intermittent ICS; control group was not daily ICS

Johansson 2006Test group was not intermittent ICS; received non-permitted drug (formeterol) with daily ICS in control group

Jonkman 1988Test group was not intermittent ICS; control group was not daily ICS

Karaman 2004Test group was not intermittent ICS

Kemp 1998Test group was not intermittent ICS; control group was not daily ICS

Kemp 1998aTest group was not intermittent ICS; control group was not daily ICS

Kesten 1991Test group was not intermittent ICS

Koenig 2008Test group was not intermittent ICS

Koutsoubari 2012Daily ICS was not one of the tested strategies.

Kriz 1977Not a randomized controlled trial; test group was not intermittent ICS

Kuna 2007Test group was not intermittent ICS; received non-permitted drug (salmeterold and formeterol) with daily ICS in control group

La 1997Test group was not intermittent ICS

LaForce 2005Test group was not intermittent ICS; control group was not daily ICS

Lal 1993Test group was not intermittent ICS

Lenney 1979Test group was not intermittent ICS; control group was not daily ICS

Lipworth 1989Test group was not intermittent ICS; control group was not daily ICS; treatment was received for < 4 weeks

Lockey 1999Test group was not intermittent ICS

Louis 2009Test group was not intermittent ICS; received non-permitted drug (Formoterol) with daily ICS

Lundborg 2006Test group was not intermittent ICS; received non-permitted drug (Formeoterol) with daily ICS in control group

Magnussen 2008Test group was not intermittent ICS

Malmstrom 1999Test group was not intermittent ICS

Marogna 2011Test group was not intermittent ICS; control group was not daily ICS

Mendes 2004Test group was not intermittent ICS

Metelitsa 1991Participants did not have asthma; test group was not intermittent ICS; control group was not daily ICS

Muijsers 2002Not a randomized controlled trial (review article); test group was not intermittent ICS; control group was not daily ICS

Murphy 2006Test group was not intermittent ICS; control group was not daily ICS

Murray 2004Test group was not intermittent ICS

Nathan 1995Test group was not intermittent ICS; control group was not daily ICS

NCT00163293Test group was not intermittent ICS

NCT00200850Ongoing as results are not available yet; test group was not intermittent ICS

NCT00287365Ongoing as results are not available yet; test group was not intermittent ICS

NCT00295737Ongoing as results are not available yet; test group was not intermittent ICS

NCT00337675Test group was not intermittent ICS; control group was not daily ICS

NCT00517816Received non-permitted drugs

NCT00529477Ongoing as results are not available yet; test group was not intermittent ICS

NCT00565591Test group was not intermittent ICS; control group was not daily ICS; results are not available yet

NCT00599027Test group was not intermittent ICS; control group was not daily ICS

NCT00805324Ongoing as results are not available yet; test group was not intermittent ICS

NCT00875082Ongoing as results are not available yet; test group was not intermittent ICS

NCT00928668Test group was not intermittent ICS; ongoing as results are not available yet

NCT00989833Test group was not intermittent ICS; received non-permitted drug (formoterol) with ICS

NCT01002690Ongoing as results are not available yet; test group was not intermittent ICS

NCT01025648This trial was withdrawn prior to recruitment.

NCT01095627Ongoing as results are not available yet; test group was not intermittent ICS

NCT01113489Ongoing as results are not available yet; test group was not intermittent ICS

NCT01127035Participants did not have asthma; ongoing as results are not available yet; test group was not intermittent ICS

NCT01137565Ongoing as results are not available yet; test group was not intermittent ICS

NCT01144429Ongoing as results are not available yet; test group was not intermittent ICS

NCT01252758Ongoing as results are not available yet; test group was not intermittent ICS

NCT01312805Ongoing as results are not available yet; test group was not intermittent ICS; control group was not daily ICS

NCT01383564Ongoing as results are not available yet; test group was not intermittent ICS

NCT01395485Treatment duration was < 4 weeks

NCT01436890Ongoing as results are not available yet; test group was not intermittent ICS

Nelson 2003Received non-permitted drug (salmeterol); test group was not intermittent ICS

Newhouse 2000Test group was not intermittent ICS

Nielsen 1999Test group was not intermittent ICS

Nightingale 2000Subjects were not asthmatics;

test group was not intermittent ICS;

treatment was received for < 4 weeks

Noonan 1998Test group was not intermittent ICS; control group was not daily ICS

O'Byrne 1996Test group was not intermittent ICS

O'Driscoll 1988Not an RCT; test group was not intermittent ICS; control group was not daily ICS

Paggiaro 2006Treatment was received for <4 weeks;

test group was not intermittent ICS; control group was not daily ICS

Pao 2002Test group was not intermittent ICS

Papi 2009aDuplication of already published paper

Patakas 1988Test group was not intermittent IC; control group was not daily ICS

Pauwels 1997Test group was not intermittent ICS; received non-permitted drug (formoterol) with ICS

Pavord 2009Received non-permitted drug (formoterol) with daily ICS

Pearlman 1992Test group was not intermittent ICS

Pearlman 1995Test group was not intermittent ICS

Perrin-Fayolle 1997Test group was not intermittent ICS; control group was not daily ICS

Philip 2004Test group was not intermittent ICS; control group was not daily ICS

Philip 2005Test group was not intermittent ICS; control group was not daily ICS

Phillips 1981Treatment was received for < 4 weeks; test group was not intermittent ICS; control group was not daily ICS

Pinnas 1987Test group was not intermittent ICS

Pinnas 2005Test group was not intermittent ICS

Poiani 2011Patients had an acute asthma exacerbation or were treated in emergency department, or both.

Polverino 1994Participants did not have asthma; test group was not intermittent ICS; control group was not daily ICS

Ponticiello 1997Test group was not intermittent ICS

Price 2007Received non-permitted drug (salmeterol) with ICS; test group was not intermittent ICS

Quirce 2011Received non-permitted drug (formoterol) with daily ICS

Rabe 2006Test group was not intermittent ICS; received non-permitted drug (formeterol) with daily ICS in control group

Rachelefsky 1975Not an RCT; test group was not intermittent ICS; control group was not daily ICS

Rachelefsky 1982Test group was not intermittent ICS; control group was not daily ICS

Radzik 2006Not an RCT ; test group was not intermittent ICS

Rak 2001Test group was not intermittent ICS; control group was not daily ICS

Ramsdell 1998Test group was not intermittent ICS

Ream 2001Patients were having acute asthma; test group was not intermittent ICS; control group was not daily ICS

Reiss 1998Test group was not intermittent ICS; control group was not daily ICS

Renzi 2010Test group was not intermittent ICS

Renzi 2010aTest group was not intermittent ICS

Richter 2007Test group was not intermittent ICS; received non-permitted drug (formoterol) with ICS

Riemersma 2012Intermittent ICS was not one of tested strategies.

Ringbaek 1996Received non-permitted drug; test group was not intermittent ICS

Rivington 1995Test group was not intermittent ICS

Rosenthal 1999Test group was not intermittent ICS; control group was not daily ICS

Rutkowski 2009Test group was not intermittent ICS; received non-permitted drug (formoterol) with daily ICS

Schmidtmann 2005Test group was not intermittent ICS; received non-permitted drug (salmeterol) with daily ICS

Schwarz 1990Test group was not intermittent ICS; control group was not daily ICS

Scicchitano 2004Test group was not intermittent ICS

SD-039-0734Received non-permitted drug (formoterol); test group was not intermittent ICS

Sears 2000Not an RCT; test group was not intermittent ICS

Sears 2008Test group was not intermittent ICS; control group was not daily ICS; received non-permitted drug (formeterol) with daily ICS

Segal 2003Treatment was received for < 4 weeks; test group was not intermittent ICS; control group was not daily ICS

Selroos 2008Test group was not intermittent ICS

Shah 2010Test group was not intermittent ICS; control group was not daily ICS

Shapiro 1991Test group was not intermittent ICS

Shapiro 1999Test group was not intermittent ICS

Shapiro 2000Test group was not intermittent ICS; control group was not daily ICS

Shingo 2002Test group was not intermittent ICS

Simons 1997Test group was not intermittent ICS

Sims 2004Not an RCT; test group was not intermittent ICS; control group was not daily ICS

Slader 2006Test group was not intermittent ICS;

control group was not daily ICS

Soes-Petersen 2011Test group was not intermittent ICS; received non-permitted drug (formoterol) with ICS

Sontag 2003Test group was not intermittent ICS; control group was not daily ICS

Staehr 1995Test group was not intermittent ICS; control group was not daily ICS; received non-permitted drug

Stallberg 2008Test group was not intermittent ICS; received non-permitted drug

Strunk 2003Test group was not intermittent ICS; control group was not daily ICS

Suissa 1997Test group was not intermittent ICS; control group was not daily ICS

Svedmyr 1999Control group was not daily ICS

Swystun 1998Treatment was received for < 4 weeks; test group was not intermittent ICS

Tagaya 2008Test group was not intermittent ICS

Takahashi 1986Test group was not intermittent ICS; control group was not daily ICS

Tamaoki 2008Test group was not intermittent ICS

Tashkin 1999Test group was not intermittent ICS; control group was not daily ICS

Tattersfield 2001Test group was not intermittent ICS; control group was not daily ICS

Taylor 1975Test group was not intermittent ICS

Taylor 1993Test group was not intermittent ICS;

control group was not daily ICS

Tomac 1996Test group was not intermittent ICS

Tormey 1997Test group was not intermittent ICS

Twiss 2002Test group was not intermittent ICS; control group was not daily ICS

Vagaggini 1999Test group was not intermittent ICS; control group was not daily ICS

Valovirta 2011Test group was not intermittent ICS; control group was not daily ICS

van Schayck 2010Test group was not intermittent ICS; received non-permitted drug (formoterol) with daily ICS

Vogelmeier 2012Daily ICS was not one of the tested strategies.

Waring 2005aTest group was not intermittent ICS; control group was not daily ICS

Warman 2001Not an RCT (survey); test group was not intermittent ICS; control group was not daily ICS

Wasserman 1995Test group was not intermittent ICS; control group was not daily ICS

Weiner 2002Test group was not intermittent ICS; control group was not daily ICS

Weinstein 1997Treatment was received for < 4 weeks; test group was not intermittent ICS

Weinstein 1998Test group was not intermittent ICS

Williams 1989Test group was not intermittent ICS; control group was not daily ICS

Williams 1999Test group was not intermittent ICS; control group was not daily ICS; patients were not asthmatics

Wilson 1990Control group was not daily ICS

Wolfe 1995Test group was not intermittent ICS

Wu 2011Not a randomized controlled trial (posthoc analysis); test group was not intermittent ICS

Xu 2005Test group was not intermittent ICS

Yang 2007Test group was not intermittent ICS

Zeiger 1999Not a randomized controlled trial; test group was not intermittent ICS

Zeiger 2006Test group was not intermittent ICS

Zellweger 1986Test group was not intermittent ICS; control group was not daily ICS

 
Comparison 1. Intermittent 'as needed' ICS versus daily ICS

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Patients with 1 or more exacerbations requiring oral corticosteroids71204Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.87, 1.32]

    1.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
2264Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.44, 2.13]

    1.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.80, 1.34]

    1.3 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.67, 2.03]

    1.4 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
3555Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.71, 2.04]

 2 Exacerbations requiring oral corticosteroids: subgroup analysis for age71204Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.87, 1.32]

    2.1 Preschool children
2498Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.85, 1.41]

    2.2 School-aged children
3329Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.84, 1.88]

    2.3 Adults
2377Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.26, 1.34]

 3 Exacerbations requiring oral corticosteroids: subgroup analysis for duration of treatment71204Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.87, 1.32]

    3.1 12 to 24 weeks
2448Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.37, 3.39]

    3.2 44 to 52 weeks
5756Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.87, 1.32]

 4 Exacerbations requiring oral corticosteroids: subgroup analysis for severity of airway obstruction71204Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.87, 1.32]

    4.1 Mild airway obstruction
61089Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.86, 1.30]

    4.2 Moderate airway obstruction
1115Risk Ratio (M-H, Fixed, 95% CI)2.95 [0.32, 27.51]

 5 Patients with serious adverse health events61055Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.33, 2.03]

    5.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1115Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.04, 3.06]

    5.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.34, 4.56]

    5.3 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.03, 15.53]

    5.4 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
3555Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.10, 6.22]

 6 Patients with at least 1 exacerbation requiring emergency department/acute care visit61055Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.90, 1.30]

    6.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1115Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.06, 15.34]

    6.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.90, 1.30]

    6.3 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.4 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
3555Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Patients with at least 1 exacerbation requiring hospital admission71204Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.29, 2.49]

    7.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
2264Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.04, 3.06]

    7.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.34, 4.56]

    7.3 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    7.4 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
3555Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Number of exacerbations requiring emergency department visits2264Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.14, 3.44]

    8.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
2264Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.14, 3.44]

 9 Time to exacerbation requiring oral corticosteroids3Hazard Ratio (Random, 95% CI)0.88 [0.55, 1.40]

    9.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1Hazard Ratio (Random, 95% CI)0.97 [0.68, 1.38]

    9.2 'As needed' ICS+β2-agonist use during exacerbations in both groups
1Hazard Ratio (Random, 95% CI)0.60 [0.36, 1.01]

    9.3 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1Hazard Ratio (Random, 95% CI)1.93 [0.55, 6.76]

 10 Change from baseline AM PEFR (%)3350Mean Difference (IV, Fixed, 95% CI)-2.56 [-4.49, -0.63]

    10.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1136Mean Difference (IV, Fixed, 95% CI)-1.20 [-6.61, 4.21]

    10.2 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Mean Difference (IV, Fixed, 95% CI)-2.42 [-5.34, 0.50]

    10.3 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1107Mean Difference (IV, Fixed, 95% CI)-3.10 [-6.02, -0.18]

 11 Change from baseline AM PEFR (L/min)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    11.1 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 12 Change from baseline FEV1 (%)2365Mean Difference (IV, Random, 95% CI)-0.49 [-5.82, 4.84]

    12.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1137Mean Difference (IV, Random, 95% CI)-3.3 [-6.49, -0.11]

    12.2 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1228Mean Difference (IV, Random, 95% CI)2.14 [-0.40, 4.68]

 13 Change from baseline FEV1 (L)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    13.1 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 14 Change from baseline mean diurnal variation in PEFR3442Mean Difference (IV, Fixed, 95% CI)0.02 [-0.71, 0.76]

    14.1 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Mean Difference (IV, Fixed, 95% CI)-0.14 [-1.42, 1.14]

    14.2 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
2335Mean Difference (IV, Fixed, 95% CI)0.10 [-0.79, 1.00]

 15 Change in PC201Mean Difference (IV, Fixed, 95% CI)Totals not selected

    15.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 16 Change from baseline in asthma control days2214Mean Difference (IV, Fixed, 95% CI)-0.07 [-0.14, -0.01]

    16.1 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Mean Difference (IV, Fixed, 95% CI)-0.06 [-0.15, 0.04]

    16.2 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1107Mean Difference (IV, Fixed, 95% CI)-0.09 [-0.18, 0.01]

 17 Proportion of asthma control days over the period3330Mean Difference (IV, Fixed, 95% CI)-0.09 [-0.14, -0.04]

    17.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1116Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    17.2 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Mean Difference (IV, Fixed, 95% CI)-0.09 [-0.16, -0.02]

    17.3 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1107Mean Difference (IV, Fixed, 95% CI)-0.09 [-0.16, -0.02]

 18 Change from baseline mean daily use of β2-agonists (puffs/day)3442Mean Difference (IV, Fixed, 95% CI)0.12 [0.00, 0.23]

    18.1 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Mean Difference (IV, Fixed, 95% CI)0.15 [-0.05, 0.35]

    18.2 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
2335Mean Difference (IV, Fixed, 95% CI)0.10 [-0.04, 0.24]

 19 Cumulative dose of rescue albuterol (μg) over the period2214Mean Difference (IV, Fixed, 95% CI)51.47 [11.36, 91.57]

    19.1 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Mean Difference (IV, Fixed, 95% CI)59.30 [4.83, 113.77]

    19.2 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1107Mean Difference (IV, Fixed, 95% CI)42.2 [-17.06, 101.46]

 20 Change from baseline in daytime symptom scores3591Std. Mean Difference (IV, Fixed, 95% CI)0.13 [-0.04, 0.29]

    20.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1143Std. Mean Difference (IV, Fixed, 95% CI)0.15 [-0.18, 0.48]

    20.2 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
2448Std. Mean Difference (IV, Fixed, 95% CI)0.12 [-0.07, 0.30]

 21 Change from baseline in asthma symptoms utility index1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    21.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 22 Change in proportion of 'symptom-free days'5984Std. Mean Difference (IV, Fixed, 95% CI)-0.15 [-0.28, -0.03]

    22.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
2258Std. Mean Difference (IV, Fixed, 95% CI)-0.32 [-0.57, -0.07]

    22.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Std. Mean Difference (IV, Fixed, 95% CI)0.0 [-0.24, 0.24]

    22.3 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
2448Std. Mean Difference (IV, Fixed, 95% CI)-0.15 [-0.34, 0.03]

 23 Change from baseline in night-time awakenings2448Mean Difference (IV, Fixed, 95% CI)-0.03 [-0.08, 0.02]

    23.1 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
2448Mean Difference (IV, Fixed, 95% CI)-0.03 [-0.08, 0.02]

 24 Change from baseline in quality of life (QoL)2389Std. Mean Difference (IV, Fixed, 95% CI)-0.16 [-0.36, 0.04]

    24.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1137Std. Mean Difference (IV, Fixed, 95% CI)-0.24 [-0.58, 0.10]

    24.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1252Std. Mean Difference (IV, Fixed, 95% CI)-0.11 [-0.36, 0.14]

 25 Days with use of β2-agonists (%)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    25.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 26 Change in exhaled nitric oxide (ppb)2214Mean Difference (IV, Fixed, 95% CI)16.80 [11.95, 21.64]

    26.1 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Mean Difference (IV, Fixed, 95% CI)18.16 [11.09, 25.23]

    26.2 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1107Mean Difference (IV, Fixed, 95% CI)15.59 [8.94, 22.24]

 27 Change in height (cm)4532Mean Difference (IV, Fixed, 95% CI)0.41 [0.13, 0.69]

    27.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
195Mean Difference (IV, Fixed, 95% CI)0.61 [0.12, 1.10]

    27.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1223Mean Difference (IV, Fixed, 95% CI)0.25 [-0.17, 0.67]

    27.3 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Mean Difference (IV, Fixed, 95% CI)0.46 [-0.37, 1.29]

    27.4 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1107Mean Difference (IV, Fixed, 95% CI)0.40 [-0.43, 1.23]

 28 Change in height (Z-score)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    28.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 29 Change in weight (Z-score)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    29.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 30 Change in weight (kg)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    30.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 31 Salivary cortisol level1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    31.1 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 32 Overall withdrawals71210Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.75, 1.46]

    32.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
2264Odds Ratio (M-H, Fixed, 95% CI)1.54 [0.71, 3.34]

    32.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Odds Ratio (M-H, Fixed, 95% CI)0.59 [0.34, 1.04]

    32.3 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Odds Ratio (M-H, Fixed, 95% CI)1.90 [0.63, 5.74]

    32.4 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
3561Odds Ratio (M-H, Fixed, 95% CI)1.32 [0.75, 2.30]

 33 Oral candidiasis2343Odds Ratio (M-H, Fixed, 95% CI)0.30 [0.03, 2.95]

    33.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1115Odds Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 8.07]

    33.2 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1228Odds Ratio (M-H, Fixed, 95% CI)0.29 [0.01, 7.12]

 34 Withdrawal owing to adverse events61063Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.21, 2.93]

    34.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1117Odds Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.35]

    34.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Odds Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.14]

    34.3 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    34.4 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
3561Odds Ratio (M-H, Fixed, 95% CI)2.85 [0.29, 27.61]

 35 Cumulative dose of ICS over the period (μg beclomethasone equivalent)2213Mean Difference (IV, Random, 95% CI)-16334.36 [-19189.04, -13479.69]

    35.1 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Mean Difference (IV, Random, 95% CI)-17787.0 [-20164.04, -15409.96]

    35.2 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
1106Mean Difference (IV, Random, 95% CI)-14874.0 [-17269.16, -12478.84]

 36 Overall adverse effects3726Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.70, 1.44]

    36.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Odds Ratio (M-H, Fixed, 95% CI)0.94 [0.46, 1.90]

    36.2 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
2448Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.68, 1.57]

 37 Withdrawal owing to poor asthma control/exacerbations61063Odds Ratio (M-H, Random, 95% CI)1.66 [0.54, 5.13]

    37.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1117Odds Ratio (M-H, Random, 95% CI)3.43 [0.88, 13.38]

    37.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Odds Ratio (M-H, Random, 95% CI)0.28 [0.08, 1.06]

    37.3 'As needed' ICS+β2-agonist use during exacerbations in both groups
1107Odds Ratio (M-H, Random, 95% CI)2.70 [0.68, 10.76]

    37.4 'As needed' ICS+β2-agonist use during exacerbations in intermittent group only
3561Odds Ratio (M-H, Random, 95% CI)2.44 [0.39, 15.41]

 38 Pneumonia1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    38.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 39 Nausea2393Odds Ratio (M-H, Fixed, 95% CI)1.16 [0.54, 2.51]

    39.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1115Odds Ratio (M-H, Fixed, 95% CI)0.98 [0.23, 4.13]

    39.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Odds Ratio (M-H, Fixed, 95% CI)1.24 [0.50, 3.10]

 40 Headache1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    40.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 41 Upper respiratory tract infections2393Odds Ratio (M-H, Fixed, 95% CI)1.47 [0.89, 2.43]

    41.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1115Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    41.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Odds Ratio (M-H, Fixed, 95% CI)1.47 [0.89, 2.43]

 42 Death2393Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    42.1 Pre-emptive 4-fold step-up ICS dose during exacerbations in both groups
1115Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    42.2 Pre-emptive 4-fold step-up ICS dose during exacerbations in intermittent group only
1278Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Summary of findings for the main comparison. Intermittent 'as needed' ICS versus daily ICS for persistent asthma in children and adults

Intermittent 'as needed' ICS versus daily ICS for persistent asthma in children and adults

Patient or population: Children and adults with persistent asthma.
Settings: Outpatients
Intervention: Intermittent 'as needed' ICS versus daily ICS

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Daily ICSIntermittent ICS

Patients with 1 or more exacerbations requiring oral corticosteroids

(duration 12 to 52 weeks)
19 per 10020 (17 to 25) per 100RR 1.07
(0.87 to 1.32)
1204
(7 studies)
⊕⊕⊝⊝
low1,2

Patients with serious adverse health events

(duration 12 to 52 weeks)
2 per 1002 (1 to 4) per 100RR 0.82 (0.33 to 2.03)1055

(6 studies)
⊕⊕⊝⊝
low1,2

Patients with at least 1 exacerbation requiring emergency department/acute care visit

(duration 12 to 52 weeks)
15 per 10018 (14 to 20) per 100RR 1.08
(0.9 to 1.3)
1055
(6 studies)
⊕⊕⊝⊝
low1,2

Change from baseline AM PEFR (%)

(duration 44 to 52 weeks)
The mean change from baseline am PEFR (%) in the intermittent groups was 2.56% lower than daily ICS group
(4.49 to 0.63 lower)
MD -2.56

(-4.49 to -0.63)
350
(3 studies)
⊕⊕⊕⊝
moderate2

Proportion of asthma control days over the period

(duration 44 to 52 weeks)
The mean proportion of asthma control days over the period in the intermittent groups was 9% lower than daily ICS group (4% to 14%)MD -0.09

(-0.14 to -0.04)
330
(3 studies)
⊕⊕⊕⊝
moderate2

Change from baseline mean daily use of β2-agonists (puffs/day)

(duration 24 to 44 weeks)
The mean change from baseline mean daily use of β2-agonists (puffs/day) in the intermittent groups was 0.12 puffs/day higher than daily ICS group
(0 to 0.23 higher)
MD 0.12

(0.00 to 0.23)
442
(3 studies)
⊕⊕⊕⊝

moderate2

Change in height (cm)

(duration 44 to 52 weeks)
The mean change in height (cm) in the intermittent groups was 0.41 cm higher than daily ICS group (0.13 to 0.69 higher)MD 0.41 (0.13 to 0.69)532
(4 studies)
⊕⊕⊕⊝
moderate2

Overall withdrawals

(duration 12 to 52 weeks)
14 per 10014 (11 to 19) per 100OR 1.05
(0.75 to 1.46)
1210
(7 studies)
⊕⊕⊝⊝
low1,2

*The basis for the assumed risk was the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect (and its 95% CI).
CI: confidence interval; ICS: inhaled corticosteroid; MD: mean difference; OR: odds ratio; PEFR: peak expiratory flow rate; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1. Confidence intervals were too wide to exclude important differences between treatments for this outcome.
2. Diversity of ways in which intermittent ICS regimens were implemented and the variety of participants in the trials limits the confidence in our estimate of the treatment effects