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Addition of anti-leukotriene agents to inhaled corticosteroids in children with persistent asthma

  1. Bhupendrasinh F Chauhan1,*,
  2. Raja Ben Salah1,
  3. Francine M Ducharme2,3

Editorial Group: Cochrane Airways Group

Published Online: 2 OCT 2013

Assessed as up-to-date: 12 JAN 2013

DOI: 10.1002/14651858.CD009585.pub2


How to Cite

Chauhan BF, Ben Salah R, Ducharme FM. Addition of anti-leukotriene agents to inhaled corticosteroids in children with persistent asthma. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD009585. DOI: 10.1002/14651858.CD009585.pub2.

Author Information

  1. 1

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

  2. 2

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

  3. 3

    CHU Sainte-Justine, Research Centre, Montreal, Canada

*Bhupendrasinh F Chauhan, Clinical Research Unit on Childhood Asthma, Research Centre, CHU Sainte-Justine, 3175, Cote Sainte-Catherine, Montreal, Canada. bhupendra_chauhan@rediffmail.com. bhupendrasinh.chauhan@recherche-ste-justine.qc.ca.

Publication History

  1. Publication Status: New
  2. Published Online: 2 OCT 2013

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Characteristics of included studies [ordered by study ID]
Lemanske 2010

MethodsRandomised, 3-period cross-over trial, double-blind, clinical study


ParticipantsChildren aged 6 to 17 years of age with mild to moderate asthma diagnosed by a physician on the basis of criteria recommended by the National Asthma Education and Prevention Program

% ELIGIBLE OF SCREENED POPULATION: not reported

% RUN-IN PARTICIPANTS RANDOMISED: 37.9%

Reasons for exclusion during run-in:

  • had compliance issues
  • had asthma exacerbation
  • had consent withdrawn
  • had asthma symptoms controlled
  • did not meet reversibility or PC₂₀ criteria
  • had FEV₁ < 60% of predicted
  • were lost to follow up
  • were withdrawn by physician
  • were ineligible at first visit
  • were unable to perform pulmonary function tests (PFTs)
  • had medical condition other than asthma
  • had other reasons


RANDOMISED: 182 (cross-over trial)

LTRA + ICS: 182

ICS alone: 182

WITHDRAWALS: reported

AGE in years: mean = 11.9 years

GENDER (% men): 59.5%

SEVERITY: mild to moderate persistent asthma

MEAN AGE WHEN ASTHMA DIAGNOSED: 4 years

BASELINE % PREDICTED FEV₁ (mean): 96.8%

MEAN (± SD) beta₂-AGONIST USE (puffs per day): not reported

BASELINE DOSE OF ICS: not reported

ATOPY (%): 77% positive perennial skin test

ELIGIBILITY CRITERIA:

  • Children aged 6 to 17 years with mild to moderate asthma diagnosed by a physician on the basis of criteria recommended by the National Asthma Education and Prevention Program
  • Ability to perform reproducible spirometry, an FEV₁ of at least 60% before bronchodilation, and an increase in the FEV₁ of at least 12% (bronchodilator reversibility) or a methacholine provocation concentration causing a 20% fall (PC₂₀) in the FEV₁ of 12.5 mg per mL or less
  • Occurrence of at least 1 of the following for more than 2 days per week on average during a 2-week period: diary-reported symptoms (coughing rated as moderate or severe or wheezing rated as mild, moderate, or severe), rescue use of an inhaled bronchodilator with 2 or more puffs per day, or peak flows under 80% of the predetermined reference value


EXCLUSION CRITERIA: not reported


InterventionsPROTOCOL: LTRA + ICS versus ICS alone

OUTCOMES: reported at 16 weeks

RUN-IN: 2 to 8 weeks

INTERVENTION GROUP: 100 μg of fluticasone twice daily plus 5 or 10 mg of montelukast daily

CONTROL GROUP: 250 μg of fluticasone (Flovent Diskus, GlaxoSmithKline) twice daily

DEVICE: Flovent Diskus

COMPLIANCE: reported (84% for study tablets and 87% for study inhalers)

COTREATMENT: reported

CRITERIA FOR WITHDRAWAL FROM STUDY: reported


OutcomesANALYSIS: The primary analysis was analysed using a 1-sided exact test for binomial proportions and a rank-ordered logistic regression

OUTCOMES: % of participants responded (not change from baseline)

PULMONARY FUNCTION TEST: FEV₁

FUNCTIONAL STATUS: the need for treatment with oral prednisone for acute asthma exacerbations, the number of asthma control days

INFLAMMATORY MARKERS: not reported

ADVERSE EFFECTS: reported

WITHDRAWALS: reported with following reasons:

  • dropped out during treatment phase
  • withdrew consent
  • were lost to follow up or were no longer interested
  • were unable to continue for personal reasons or because moved out of the area
  • was dissatisfied with asthma control
  • was unable to continue owing to medical condition other than asthma
  • were withdrawn by physician
  • had other reasons


NotesFull-text publication

Source of funding: several grants reported

Confirmation of methodology and data: not obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentralised random sequence using a 3 x 3 cross-over design

Allocation concealment (selection bias)Low riskPlacebo tablets and dummy disk devices were used

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

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskBalanced low withdrawals in the study

Selective reporting (reporting bias)Low riskStudy protocol was available and all of the study's pre-specified (primary and secondary) outcomes that were of interest in the review reported in the pre-specified way

Other biasLow riskNo apparent bias was observed

Simons 2001

MethodsRandomised, cross-over, double-blind, clinical study


ParticipantsChildren aged 6 to 14 years with persistent asthma

% ELIGIBLE OF SCREENED POPULATION: not reported

% RUN-IN PARTICIPANTS RANDOMISED: not reported

RANDOMISED: 279 (cross-over trial)

LTRA + ICS: 279

ICS alone: 279

WITHDRAWALS: 15

AGE in years: mean = 10.4 years

GENDER (% men) = 67%

SEVERITY: not specified

MEAN AGE WHEN ASTHMA DIAGNOSED: not reported

BASELINE % PREDICTED FEV₁ (mean): 77.7% (10.6)

MEAN RESCUE-beta₂-AGONIST USE (mean +/- SD): 2.9 +/- 2.0 puffs per day

BASELINE DOSE OF ICS: not reported

ATOPY (%): not reported

ELIGIBILITY CRITERIA:

  • Children aged 6 to 14 years with persistent asthma who had been treated with an ICS for at least 6 weeks before the study at doses of 200 to 800 μg daily of budesonide, beclomethasone dipropionate, triamcinolone acetonide, or flunisolide, or 100 to 500 μg daily of fluticasone propionate
  • During the run-in, despite treatment with 200 μg budesonide twice daily, they were required to have FEV₁ ≥ 60% and ≤ 85% of the predicted value, a ≥ 12% improvement in FEV₁ 20 to 30 minutes after short-acting beta₂-agonist administration, and asthma symptoms requiring a minimum average of at least 2 puffs per day of a beta₂-agonist in the 14 days immediately before randomisation


EXCLUSION CRITERIA:

  • Active upper respiratory tract infection within 3 weeks
  • Active sinus disease requiring antibiotic treatment within 1 week
  • Emergency department treatment for asthma within 1 month
  • Prior intubation for asthma or hospitalisation for asthma within 3 months before the prestudy (screening) visit
  • Excluded medications included astemizole within 3 months; oral inhaled or parenteral corticosteroids within 1 month; cromolyn, nedocromil, beta₂-agonists (oral or long-acting), antihistamines cimetidine, metoclopramide, phenobarbital, phenytoin, terfenadine, loratadine, or anticholinergic agents within 2 weeks; and theophylline within 1 week before the prestudy visit
  • People receiving immunotherapy had to maintain therapy at a constant dosage during the study, and therapy had to have begun at least 6 months before the prestudy visit


InterventionsPROTOCOL: LTRA + ICS versus ICS alone

OUTCOMES: reported at 4 weeks (3 periods of 4 weeks)

RUN-IN: 4 weeks

INTERVENTION GROUP: 5 mg chewable montelukast tablet once daily at bedtime in addition to 200 μg of budesonide twice daily

CONTROL GROUP: matching placebo once daily at bedtime in addition to 200 μg of budesonide twice daily

COMPLIANCE: mentioned

COTREATMENT: Short-acting beta₂-adrenergic agonists were used as needed but were withheld for 6 hours before visits

CRITERIA FOR WITHDRAWAL FROM STUDY: presented.


OutcomesANALYSIS: intention-to-treat analysis

OUTCOMES: mean % change from baseline for all parameters

PULMONARY FUNCTION TEST: FEV₁, morning and evening PEFR.

FUNCTIONAL STATUS: change from baseline in average beta₂-adrenergic agonist use, mean percentage of asthma exacerbation days, quality of life measurement, global evaluations or asthma attacks

INFLAMMATORY MARKERS: blood eosinophil counts

ADVERSE EFFECTS: reported

WITHDRAWALS: reported with following reasons:

  • discontinued because of deviation from the protocol
  • clinical adverse events
  • miscellaneous reasons


NotesFull-text publication

Source of funding: not reported

Confirmation of methodology and data: not obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAlthough study was randomised, insufficient information was provided on means of randomisation

Allocation concealment (selection bias)Unclear riskNo details were provided on allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind study. Matching placebo was used

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskFew withdrawals. Reasons for missing outcome data unlikely to be related to true outcomes

Selective reporting (reporting bias)Low riskStudy protocol was not available, but the published reports included all expected outcomes, including those that were pre-specified

Other biasLow riskNo apparent bias was observed

Stelmach 2007

MethodsRandomised, double-blind, placebo-controlled, parallel group trial


ParticipantsChildren with a typical history of moderate asthma who were sensitive to house dust mites as shown by positive skin-prick tests and by the presence of specific IgE to Dermatophagoides pteronyssimus or Dermatophagoides farinae

% ELIGIBLE OF SCREENED POPULATION: reported

% RUN-IN PARTICIPANTS RANDOMISED: reported

RANDOMISED: 58

LTRA + ICS: 29

ICS alone: 29

WITHDRAWALS: reported

AGE in years: mean = 11.5 years

GENDER (% men): 69%

SEVERITY: moderate asthma

MEAN AGE WHEN ASTHMA DIAGNOSED: not reported

BASELINE % PREDICTED FEV₁ (mean): 94.6%

MEAN RESCUE-beta₂-AGONIST USE (mean +/- SD): not reported

BASELINE DOSE OF ICS: not reported

ATOPY (%): 100%

ELIGIBILITY CRITERIA:

  • Male and female outpatients, aged 6 to 18 with a clinical diagnosis of bronchial asthma with a duration of at least 6 months before the first visit and with current history of moderate persistent asthma
  • Patients and their parents were required to do reproducible spirometry, whole body plethysmography, and interrupter technique


EXCLUSION CRITERIA:

  • With active upper respiratory tract infection within 3 weeks before the study and acute sinus disease requiring antibiotic treatment within 1 month before the study
  • Previous intubation or asthma hospitalisation during the 3 months before the first visit
  • Clinically significant pulmonary, hematologic, hepatic, gastrointestinal, renal, endocrine, neurologic, cardiovascular, and/or psychiatric diseases, or malignancy that either put the participant at risk when participating in the study or could have influenced the results of the study or the participant's ability to participate in the study as judged by the investigator
  • Excluded medications were beta₂-blockers (eye drops included), astemizole within 3 months, or oral corticosteroids within 1 month before the first visit. People who were receiving immunotherapy were also excluded


InterventionsPROTOCOL: LTRA + ICS versus ICS alone

OUTCOMES: reported on 4 weeks

RUN-IN: 4 weeks

INTERVENTION GROUP: 200 μg per day budesonide + 5 mg montelukast, formoterol placebo

CONTROL GROUP: 200 μg per day budesonide, montelukast placebo, formoterol placebo

COMPLIANCE: not mentioned

COTREATMENT: inhaled beta₂-agonist 100 mg/dose 'as-needed' for symptomatic relief purposes

CRITERIA FOR WITHDRAWAL FROM STUDY: presented


OutcomesANALYSIS: not with intention-to-treat analysis

OUTCOMES: mean absolute values and change from baseline for all parameters

PULMONARY FUNCTION TEST: FEF25–75%, FEV₁, Rint and SRaw

FUNCTIONAL STATUS: not reported

INFLAMMATORY MARKERS: not reported

ADVERSE EFFECTS: not reported

WITHDRAWALS: all enrolled participants completed the trial


NotesFull-text publication

Source of funding: grant from Medical University of Lodz, Poland

Confirmation of methodology and data: not obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskMatching placebo and drug were blinded by the central hospital pharmacy

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind study. Double-dummy

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskFew withdrawals

Selective reporting (reporting bias)Low riskStudy protocol was not available, but the published reports included all expected outcomes, including those that were pre-specified

Other biasLow riskNo apparent bias was observed

Stelmach 2008

MethodsRandomised, double-blind, placebo-controlled, parallel group trial


ParticipantsChildren 6 to 18 years of age with atopic asthma, who were sensitive only to house dust mites as
shown by positive skin prick tests to Dermatophagoides pteronyssinus, Dermatophagoides farinae, or both

% ELIGIBLE OF SCREENED POPULATION: reported

% RUN-IN PARTICIPANTS RANDOMISED: reported

RANDOMISED: 40

LTRA + ICS: 20

ICS alone: 20

WITHDRAWALS: reported

AGE in years: mean = 12.05 years

GENDER (% men): not reported

SEVERITY: not reported

MEAN AGE WHEN ASTHMA DIAGNOSED: not reported

BASELINE % PREDICTED FEV₁ (mean): 91.2%

MEAN RESCUE-beta₂-AGONIST USE (mean +/- SD): not reported

BASELINE DOSE OF ICS: not reported

ATOPY (%): 100%

ELIGIBILITY CRITERIA:

  • Male and female outpatients age 6 to 18 with a clinical diagnosis of bronchial asthma with a duration of at least 6 months before the first visit were enrolled
  • Participants had to have a resting FEV₁ of 70% or more and a documented decrease in FEV₁ of 20% or more after a standard exercise challenge test


EXCLUSION CRITERIA:

  • With active upper respiratory tract infection within 3 weeks before the study and acute sinus disease requiring antibiotic treatment within 1 month before the study
  • Previous intubation or asthma hospitalisations during the 3 months before the prestudy visit
  • With other clinically significant pulmonary, hematologic, hepatic, gastrointestinal, renal, endocrine, neurologic, cardiovascular, and/or psychiatric diseases, or malignancy that either put the participant at risk when participating in the study or could have influenced the results of the study or the participant's ability to participate in the study as judged by the investigator
  • On medications like beta₂-blockers (eye drops included) or oral corticosteroids within 1 month before the first visit
  • People receiving immunotherapy


InterventionsPROTOCOL: LTRA + ICS versus ICS alone

OUTCOMES: reported at 4 weeks

RUN-IN: 4 weeks

INTERVENTION GROUP: 100 μg budesonide twice daily + 5 mg montelukast, formoterol placebo

CONTROL GROUP: 100 μg budesonide twice daily + montelukast placebo, formoterol placebo

COMPLIANCE: not mentioned

COTREATMENT: inhaled beta₂-agonist 'as needed' for symptomatic relief purposes

CRITERIA FOR WITHDRAWAL FROM STUDY: presented


OutcomesANALYSIS: not with intention-to-treat analysis

OUTCOMES: mean absolute values and change from baseline for all parameters

PULMONARY FUNCTION TEST: FEV₁, area under the curve for exercise induced fall in FEV₁

FUNCTIONAL STATUS: not reported

INFLAMMATORY MARKERS: not reported

ADVERSE EFFECTS: not reported

WITHDRAWALS: reported with following reasons

  • asthma exacerbation (caused by respiratory tract infection)


NotesFull-text publication

Source of funding: not reported

Confirmation of methodology and data: not obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

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

Allocation concealment (selection bias)Low riskMatching placebo and drug were blinded by the central hospital pharmacy

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind study. Double-dummy

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe balanced withdrawals were observed in both comparing groups

Selective reporting (reporting bias)Low riskStudy protocol was not available, but the published reports included all expected outcomes, including those that were pre-specified

Other biasLow riskNo apparent bias was observed

Strauch 2003

MethodsRandomised, double-blind, placebo-controlled, parallel group trial


ParticipantsChildren having mild to moderate asthma as per the American Thoracic Society

% ELIGIBLE OF SCREENED POPULATION: reported

% RUN-IN PARTICIPANTS RANDOMISED: reported

RANDOMISED: 25

WITHDRAWALS: reported but not per group

AGE in years: reported for all participants individually for every included participant

GENDER (% men): reported

SEVERITY: reported individually for every included participant

MEAN AGE WHEN ASTHMA DIAGNOSED: not reported

BASELINE % PREDICTED FEV₁ (mean): reported for all participants individually for every included participant

MEAN RESCUE-beta₂-AGONIST USE (mean +/- SD): not reported

BASELINE DOSE OF ICS: reported for all participants individually for every included participant

ATOPY (%): 100% reported in inclusion criteria

ELIGIBILITY CRITERIA:

  • Children having mild to moderate asthma as per the American Thoracic Society
  • On ICS at doses between 200 and 400 μg budesonide twice daily regularly for at least 12 weeks
  • Aged 6 to 14 years
  • All children who were allergic to common inhalant allergens
  • Free of respiratory infections or an asthma exacerbation for at least 4 weeks before enrolment
  • Bronchial inflammation demonstrated on the basis of a sputum ECP level > 100 μg/L


EXCLUSION CRITERIA:

  • People using systemic corticosteroids, cromolyn sodium, nedocromil, anticholinergics, theophyline, antihistamines, or an anti-leukotriene medication, such as montelukast


InterventionsPROTOCOL: LTRA + ICS versus ICS alone

OUTCOMES: reported on 4 weeks

RUN-IN: 7 to 10 days

INTERVENTION GROUP: 200 and 400 μg budesonide twice daily + 5 mg montelukast orally, once daily

CONTROL GROUP: 200 and 400 μg budesonide twice daily + placebo

COMPLIANCE: reported

CO-TREATMENT: inhaled beta₂-agonist 'as needed' for symptomatic relief was permitted

CRITERIA FOR WITHDRAWAL FROM STUDY: presented


OutcomesANALYSIS: not with intention-to-treat analysis

OUTCOMES: absolute values and change from baseline for all parameters

PULMONARY FUNCTION TEST: FEV₁ (%)

FUNCTIONAL STATUS: overall QOL, symptoms, activities, emotions

INFLAMMATORY MARKERS: exhaled nitric oxide, sputum eosinophil cationic protein, sputum eosinophil count, urinary excretion of eosinophil protein X

ADVERSE EFFECTS: reported

WITHDRAWALS: reported


NotesFull-text publication

Source of funding: not reported

Confirmation of methodology and data: not obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskAlthough study was randomised, insufficient information was provided on means of randomisation

Allocation concealment (selection bias)Unclear riskNo details were provided on allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind study. Double-dummy

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskFew dropouts

Selective reporting (reporting bias)Low riskStudy protocol was not available, but the published reports included all expected outcomes, including those that were pre-specified

Other biasLow riskNo apparent bias was observed

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abadoglu 2005Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Abdel-wahab 2009Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

ALAACRC 2007Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Allen-Ramey 2003Not a randomised controlled trial; it was a cohort study

Anonymous 2010Control group was not inhaled corticosteroid

Bacharier 2008Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Baek 2011Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Barnes 2007Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Barnes 2007aStudy participants were adults

Basu 2010Control group was not inhaled corticosteroid

Becker 2006Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Benitez 2005Control group was not inhaled corticosteroid

Bjermer 2000Control group was not inhaled corticosteroid

Bjermer 2003Control group was not inhaled corticosteroid

Bleecker 2000Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Bousquet 2005Control group was not inhaled corticosteroid

Bozek 2012Received non-permitted drug (LABA) in both comparing groups

Buchvald 2002Duplication: Buchvald et al. Comparisons of the complementary effect on exhaled nitric oxide of salmeterol vs montelukast in asthmatic children taking regular inhaled budesonide. Annals of Allergy, Asthma & Immunology. 2003; 91(3):309-313

Buchvald 2003Intervention was administered for < 4 weeks

Bukstein 2003Not a randomised controlled trial

Busse 1999Study participants were adults

Busse 2001Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Caffey 2005Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Cakmak 2004Study participants were adults

Costa-Katz 2012Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Currie 2003Study participants were adults

Currie 2003aIntervention was not a combination of anti-leukotriene and inhaled corticosteroid

Davies 2004Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Dempsey 2002Study participants were adults

Dempsey 2002aIntervention was not a combination of anti-leukotriene and inhaled corticosteroid

Deschildre 2012Control group was not inhaled corticosteroid

Djukanović 2010Study participants were adults

Duong 2012Intervention was administered for < 4 weeks

Eakin 2012Control group was not inhaled corticosteroid

Farber 2010Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Finn 2000Lack of information to decide whether participants were inadequately controlled with daily ICS before enrolment (step 2)

Fogel 2010Control group was not inhaled corticosteroid

Fritsch 2006Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Ghiro 2001Duplication: Ghiro et al. Effect of montelukast added to inhaled corticosteroids on fractional exhaled nitric oxide in asthmatic children. European Respiratory Journal. 2002; 20(3):630-4

Ghiro 2002Intervention was administered for < 4 weeks

Igde 2009Control group was not inhaled corticosteroid

Ilowite 2004Study participants were adults

Irvin 2007Study participants were adults

Jat 2006Lack of information to decide whether participants were inadequately controlled with daily ICS before enrolment (step 2)

Jayaram 2005Study participants were adults

Jenkins 2005Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Johnston 2007Use of non-permitted drug in subgroup of participants

Jung 2006Control group was not inhaled corticosteroid

Kamenov 2007Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Karaman 2007Participants were naive to daily ICS

Keith 2009Control group was not inhaled corticosteroid

Kondo 2006Control group was not inhaled corticosteroid

Laviolette 1999Study participants were adults

Lee 2004Study participants were adults

Lipworth 2000Study participants were adults

Marogna 2010Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Matsuse 2012Control group was not inhaled corticosteroid

Mendes 2004Study participants were adults

Miraglia del Giudice 2007Participants were naive to daily ICS

Nathan 2001Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Nelson 2000Control group was not inhaled corticosteroid

Nelson 2006Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Ng 2007Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

O'Connor 2006Control group was not inhaled corticosteroid

O'Sullivan 2003Study participants were adults

Ostrom 2003Duplication: Ostrom et al. Comparative efficacy and safety of low-dose fluticasone propionate and montelukast in children with persistent asthma. Journal of Pediatrics. 2005; 147(2):213-20

Ostrom 2005Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Papadopoulos 2009Received non-permitted drugs (nedocromil, antihistamines). Only 40% of included children were on inhaled corticosteroids

Patel 2010Study participants were adults

Pedersen 2007Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Peroni 2005Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Philip 2011Study participants were adults

Phipatanakul 2003Received non-permitted drugs (topical nasal corticosteroids, antihistamines)

Price 2003Study participants were adults

Price 2011Study participants were adults

Reiss 1997Control group was not inhaled corticosteroid

Riccioni 2005Study participants were adults

Robinson 2001Study participants were adults

SAM40030Study participants were adults

SAS40036Study participants were adults

SD-004CR-0216Study participants were adults

Shah 2006Study participants were adults

Sims 2003Study participants were adults

Smith 2012Control group was not inhaled corticosteroid

Smugar 2009Control group was not inhaled corticosteroid

Stelmach 2002Control group was not inhaled corticosteroid

Stelmach 2005Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Storms 2004Study participants were adults

Tognella 2004Study participants were adults

Tohda 2002Study participants were adults

Tsuchida 2005Study participants were adults

Ulrik 2010Study participants were adults

Verini 2010Control group was not inhaled corticosteroid

Virchow 2000Study participants were adults

Virnig 2008Duplication: Johnston et al. Attenuation of the September epidemic of asthma exacerbations in children: a randomised, controlled trial of montelukast added to usual therapy. EMBASE 2007433958. Pediatrics. 2007; 120(3):e702-e712

Weiss 2010No consistent treatment with inhaled corticosteroid in both comparing groups

Williams 2001Intervention was not a combination of anti-leukotriene and inhaled corticosteroid

Wilson 2001Study participants were adults

Wilson 2010Study participants were adults

Yaldiz 2000Study participants were adults

Yasui 2012Received non-permitted drug (LABA) in both comparing groups

Yildirim 2004Study participants were adults

 
Comparison 1. Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids

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

 1 Participants with 1 or more exacerbations requiring oral corticosteroids1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Participants with exacerbations requiring hospital admission1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

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

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

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

 6 Overall withdrawals3643Odds Ratio (M-H, Fixed, 95% CI)1.93 [0.74, 5.05]

 7 Withdrawal because of specific reasons1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    7.1 Withdrawal due to adverse events
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    7.2 Withdrawal due to poor asthma control/exacerbations
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Serious adverse effects1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 Death1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 10 Overall adverse effects1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 11 Specific adverse effects1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

    11.1 Upper respiratory tract infections
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    11.2 Headache
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    11.3 Nausea
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    11.4 Elevated liver enzymes
1Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. Anti-leukotrienes and inhaled corticosteroids versus higher dose of inhaled corticosteroids

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

 1 Participants with 1 or more exacerbations requiring oral corticosteroids1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Participants with exacerbations requiring hospital admission1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 Overall withdrawals1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Summary of findings for the main comparison. Anti-leukotrienes & ICS versus same dose ICS for asthma

Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids

Patient or population: Children with asthma
Settings: Outpatients
Intervention: Anti-leukotrienes and inhaled corticosteroids

Comparison: Same dose of inhaled corticosteroids

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlAnti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids

Participants with one or more exacerbations requiring oral corticosteroids

Follow-up: mean 4 weeks
See commentSee commentRisk Ratio

0.80 [0.34, 1.91]
279
(1 study)
⊕⊕⊝⊝
low¹
Single study reported the primary outcome

No significant group difference with wide confidence interval

Participants with exacerbations requiring hospital admission

Follow-up: mean 4 weeks
See commentSee commentNot estimable279
(1 study)
⊕⊝⊝⊝
very low²
Single study reported the outcome (but no admissions were reported)

Change from baseline FEV(%)

Follow-up: mean 4 weeks
3.3% increase from baseline FEV₁ on placebo4.6% [ 2.4%, 6.0%]1.30% [-0.09%, 2.69%]279
(1 study)
⊕⊕⊝⊝
low¹
Single study reported the outcome

No significant group difference with wide confidence interval

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: Confidence interval

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 Single study, wide confidence interval
² There were no admissions to hospital in this study
 
Summary of findings 2. Anti-leukotrienes & ICS versus higher dose ICS for asthma

Anti-leukotrienes and inhaled corticosteroids versus higher dose of inhaled corticosteroids

Patient or population: Children with asthma
Settings: Outpatients
Intervention: Anti-leukotrienes and inhaled corticosteroids

Comparison: Higher dose of inhaled corticosteroids

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlAnti-leukotrienes and inhaled corticosteroids versus higher dose of inhaled corticosteroids

Participants with one or more exacerbations requiring oral corticosteroids

Follow-up: 16 weeks
See commentSee commentRisk Ratio

0.82 [0.54, 1.25]
182
(1 study)
⊕⊕⊝⊝
low¹
Single study reported the primary outcome

No significant group of difference with wide confidence interval

Participants with exacerbations requiring hospital admission

Follow-up: 16 weeks
See commentSee commentRisk Ratio

1.00

[0.06, 15.87]
182
(1 study)
⊕⊕⊝⊝
low¹
Single study reported the outcome

No significant group of difference with wide confidence interval

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: Confidence interval; OR: Odds 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 Single study, wide confidence interval
 
Table 1. Secondary outcomes reported in cross-over trial (Simons 2001)

OutcomeLTRA + ICSICS


Mean differenceSDTotalMean differenceSDTotal

Change from baseline FEV₁ (L)0.070.252510.040.25251

Change from baseline AM PEFR (L/min)37.572.821828.176.4218

Change from baseline mean daily use of beta₂-agonists (puffs/day)-1.362.08225-1.032.44225

Change in quality of life0.540.951480.450.94148

Change from baseline eosinophil counts (× 109/L)-0.070.322320.040.36232