Intervention Review

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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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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms

 
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

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms
 

Description of the condition

Asthma is the most common chronic disease of childhood and is one of the leading reasons for emergency department visits (Linzer 2007) and hospitalisations (PHAC 2007). It affects an estimated 235 million individuals worldwide (WHO 2011). Asthma presents as recurrent episodes or persistent symptoms of reversible airway obstruction. It is a complex syndrome that involves bronchospasm, inflammation, secretions, and airway hyperresponsiveness (Busse 2006).

 

How the intervention might work

Daily inhaled corticosteroids (ICS) are recommended as first-line monotherapy in children with mild persistent symptoms, that is, as preferred step-2 therapy (National Asthma Council Australia 2006; BTS 2011; GINA 2011; Lougheed 2012; NAEPP 2007). ICS reduce asthma symptoms, exacerbations, airway inflammation, hyperresponsiveness, and the risk of death, and they improve quality of life (QOL) and lung function (Andersson 2001; Castro-Rodriguez 2009; Enting 2003; Pijnenburg 2005; Suissa 2000).

In case of unsatisfactory control with low doses of ICS, asthma management guidelines recommend one of the following three options as step-3 therapy:

  1. increasing the dose of ICS to a moderate dose;
  2. adding a long-acting beta₂-agonist (LABA); or

Increasing the dose of ICS is effective, but may be associated with short-term growth suppression in a dose-related, and probably a drug-dependant, fashion in children (de Benedictis 2001; Eid 2002; Sharek 1999). The efficacy of LABAs as adjunct to ICS has been thoroughly evaluated recently (Heuck 2000; Malone 2005; Pohunek 2006; Stelmach 2008). Concerns have been raised about the efficacy of LABAs in children and possibly their safety, not only when used as a monotherapy, which is no longer recommended, but also as adjunct therapy (Cates 2008; Cates 2012). Although the risk of serious adverse events of regular formoterol in children was greater than that observed in adults, the difference between age groups did not reach statistical significance (Cates 2008).

Anti-leukotriene agents (also know as leukotriene receptor antagonists or LRTA) are anti-inflammatory drugs that interfere either with leukotriene production (5-lipoxygenase inhibitors) or with receptors (leukotriene receptors antagonists) (Calhoun 2001). They have the advantage of being administered orally in a single or twice-daily dose, and importantly, they seem to lack some of the dose-dependent adverse effects associated with long-term ICS, such as growth and adrenal suppression (Muijsers 2002). Anti-leukotrienes have the potential to interfere with the pathophysiology of asthma and improve to some extent the clinical and functional manifestations of asthma (Chauhan 2012; Paggiaro 2011).

 

Why it is important to do this review

A 2004 Cochrane review (Ducharme 2004) evaluating the addition of anti-leukotrienes to ICS in children and adults with asthma identified only two paediatric trials, one of which was published as an abstract and did not contribute data to the meta-analysis. In the past decade, several additional trials were published that may shed more light on the role of anti-leukotrienes as adjunct therapy to ICS. The original review is not being updated; instead, it has been replaced by the present systematic review in children; a second review pertaining to adults will follow.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms

To compare the efficacy and safety of the combination of anti-leukotriene agents and ICS to the use of the same, an increased, or a tapering dose of ICS in children and adolescents with persistent asthma who remain symptomatic despite the use of maintenance ICS. In addition, we wished to determine the characteristics of people or treatments, if any, that influenced the magnitude of response attributable to the addition of anti-leukotrienes.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We considered for inclusion all randomised controlled trials (RCTs) with either parallel group or cross-over design.

 

Types of participants

We included children and adolescents aged one to 18 years with persistent asthma who remained symptomatic despite the use of a stable maintenance of ICS (or who were made symptomatic after ICS dose reduction).

 

Types of interventions

We focused analysis on the following three treatment protocols:

  • Anti-leukotrienes and ICS (step 3) versus the same dose of ICS (step 2).
  • Anti-leukotrienes and ICS (step 3) versus a higher dose of ICS (step 3).
  • Anti-leukotrienes and tapering dose of ICS (step 3) versus a tapering dose of ICS (tapering protocol) (step 3).

We did not permit cointerventions other than rescue beta₂-agonists and oral corticosteroids.

 

Types of outcome measures

 

Primary outcomes

  1. The number of participants with one or more exacerbations requiring oral corticosteroids (unless both groups were tapering their dose of ICS, in which case, the main outcome was the change from the baseline dose of ICS required to maintain control).

 

Secondary outcomes

  1. Exacerbations:
    • participants with one or more exacerbations leading to a hospital admission; and
    • participants with one or more exacerbations leading to an emergency department or an acute-care visit.
  2. Clinical or physiologic outcomes reflecting chronic asthma control including the following:
    1. change in pulmonary function tests (i.e. Forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR), provocative dose or concentration of the stimulus required to achieve a 20% fall in FEV1 (PC₂₀), etc);
    2. change in symptoms;
    3. change in beta₂-agonist use;
    4. days (period or change in days) without symptoms;
    5. days (period or change in days) without rescue treatment;
    6. change in night-time awakening; and
    7. change in quality of life (as measured by a validated questionnaire).
  3. Biological markers of inflammation:
    1. change in eosinophil count in blood or sputum;
    2. change in leukotrienes in biological fluids, exhaled nitric oxide, etc; and
    3. change in eosinophilic cationic protein, etc.
  4. Clinical and biochemical adverse effects:
    1. participants with overall adverse effects;
    2. participants with serious adverse health events (including death);
    3. participants with other adverse effects (elevation of liver enzymes, headache, adrenal suppression, etc); and
    4. change in growth velocity, basal cortisol, etc.
  5. Withdrawal rate:
    1. overall withdrawals;
    2. withdrawals due to poor asthma control/exacerbation; and
    3. withdrawals due to adverse effects.

 

Search methods for identification of studies

 

Electronic searches

We identified trials from the Cochrane Airways Group Specialised Register of Trials (CAGR), which is maintained by the Trials Search Co-ordinator for the Group. The Register contains trial reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, AMED (Allied and Complementary Medicine Database), and CINAHL (Cumulative Index to Nursing and Allied Health Literature); and the handsearching of respiratory journals and meeting abstracts (please see Appendix 1 for further details). We searched all records in the CAGR coded as 'asthma' using the following terms:

(leukotriene* or leucotriene* or anti-leukotriene or anti-leucotriene or montelukast or singulair or zafirlukast or accolate or pranlukast or azlaire)

AND (((steroid* or corticosteroid* or glucocorticoid*) AND inhal*) OR (fluticasone or beclomethasone or budesonide or triamcinolone or flunisolide or ciclesonide or bronalide or becotide or azmacort or aerobid or flixotide or aerobec or flovent or becloforte or pulmicort or beclovent or vanceril or alvesco))

AND (child* or paediat* or pediat* or adolescen* or infant* or toddler* or bab* or young* or *school* or newborn* or "new born*" or new-born* or neo-nat* or neonat*)

The search was conducted up to January 2013. There was no restriction on language of publication.

 

Searching other resources

We checked the clinicaltrials.gov and various pharmaceutical companies' websites for the relevant trials.

 

Data collection and analysis

Two reviewers (BFC and RBS) independently collected data for analysis.

 

Selection of studies

Two reviewers (BFC and RBS) reviewed each abstract and annotated them as follows:

  1. clearly an eligible RCT;
  2. clearly not eligible; or
  3. unclear.

We obtained full papers for all those that were clearly an eligible RCT and for those in whom the design or relevance was unclear. We contacted authors to confirm the missing information on selection criteria.

 

Data extraction and management

Two reviewers (BFC and RBS) independently extracted data and dealt with disagreement by consensus and with the input of a third reviewer (FMD), if needed.

 

Assessment of risk of bias in included studies

The methodological quality of eligible controlled trials was assessed using The Cochrane Collaboration's 'Risk of bias' tool based on six criteria: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other bias. Two reviewers (BFC and FMD) independently assessed methodological quality and deemed a study to have a high methodological quality if the reported randomisation procedures and blinding were adequate and there was a low and balanced group attrition.

 

Measures of treatment effect

We calculated treatment effects for dichotomous variables as odds ratios (OR), relative risk (RR), risk difference (RD), or a combination of the aforementioned. For continuous outcomes, such as the pulmonary function test, we calculated pooled statistics as mean differences (MD), generic inverse variance (GIV), or standardised mean differences (SMD), as indicated. We summarised differences between groups in event rates using rate ratio. We reported all estimates with 95% confidence intervals (CI). We assumed equivalence if the relative risk estimate and its 95% CI were between 0.9 and 1.1.

 

Unit of analysis issues

The unit of analysis was the participant.

 

Dealing with missing data

We did not impute missing data. We planned to contact authors to ask for missing data.

 

Assessment of heterogeneity

We tested the homogeneity of effect sizes between studies being pooled with the DerSimonian & Laird method, with P > 0.05 or an I² statistic > 40% used as the cut-off level for significance. If one or both methods suggested heterogeneity, we applied a random-effects model to the summary estimates. Unless specified otherwise, we used the fixed-effect model.

 

Assessment of reporting biases

We examined the funnel plot on the main outcome and conducted the Egger test (Egger 1997) to explore the possibility of bias.

 

Data synthesis

We reported all effect estimates with their 95% CI. We performed meta-analysis using Review Manager 5.2 (RevMan) (Higgins 2008; RevMan 2011).

 

Subgroup analysis and investigation of heterogeneity

We planned subgroup analyses to explore possible reasons for heterogeneity between study results on the primary outcome. We based a priori defined subgroups upon the following:

  1. daily dose of ICS in both groups in hydrofluoroalkane beclomethasone dipropionate or equivalent (HFA-BDPeq) (for children aged six to 11 years, ≤ 200, 201 to 400, and > 400 μg HFA-BDPeq were considered as low-, medium-, and high-dose, while for adolescents aged 12 to 18 years, ≤ 250, 251 to 500, and > 500 μg HFA-BDPeq were considered as low-, medium-, and high-dose (Lougheed 2012));
  2. age (preschool versus school-aged children versus adolescents);
  3. severity of baseline airway obstruction (mild: FEV₁ ≥ 80% of predicted, versus moderate: FEV₁ 60% to 79% of predicted, versus severe: FEV₁ < 60% of predicted) (GINA 2011);
  4. anti-leukotriene agent used (montelukast versus zafirlukast);
  5. duration of intervention (four to 12 weeks versus 24 to 52 weeks); and
  6. funding source (no funding/academic funding versus pharmaceutical industry funding).

 

Sensitivity analysis

For the primary outcome, we planned to perform two sensitivity analyses to determine the effect of publication status (abstracts or web reports only versus full peer-reviewed papers) and methodological quality, respectively. We explored a possible publication bias by removing trials not published as full text (i.e. abstracts or web reports) and bias due to poor methodological quality by removing trials not meeting all of the three following criteria: clearly reported and acceptable random sequence generation, blinding procedure, and balanced and low attrition in both groups.

 

'Summary of findings' tables

We included a summary of findings table for the two main comparisons in this review. We rated the quality of evidence using recommendations developed by the GRADE working group, presenting our ratings alongside the relative and absolute effects for the following outcomes:

  1. Exacerbations
  2. FEV₁
  3. Quality of life
  4. Rescue medication use
  5. Adverse events
  6. Withdrawals

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms
 

Description of studies

 

Results of the search

The literature search conducted until January 2013 yielded 309 citations. The reasons for exclusion of various trials are available in the 'Excluded studies' section. We reported the flow of references in a PRISMA diagram (Figure 1).

 FigureFigure 1. Study selection diagram

 

Included studies

Five trials (Lemanske 2010; Simons 2001; Stelmach 2007; Stelmach 2008; Strauch 2003) met the inclusion criteria for this review. Of these, one trial (Strauch 2003) was eligible but did not contribute data. The following results, except risk of bias in included trials, pertain to four remaining trials that were eligible and contributed data to this review.

The included trials were all published as full-text manuscripts and comprised 559 children (aged ≥ six years) and adolescents with mild to moderate asthma. Three trials compared the combination of anti-leukotrienes and ICS with the same dose ICS (Simons 2001; Stelmach 2007; Stelmach 2008), and one trial compared the combination of anti-leukotrienes and ICS with a higher dose ICS (Lemanske 2010). We did not identify studies that assessed the combination of anti-leukotrienes and ICS as a means to taper the dose of ICS.

Design: Two trials (Stelmach 2007; Stelmach 2008) used a parallel group design, while the remaining two trials used a cross-over design.

Participants: Included trials described a gender ratio ranging from 65% to 69% male. One trial (Simons 2001) recruited children aged six to 14 years while remaining trials enrolled children aged ≥ six years and adolescents. Stelmach 2007 enrolled children with moderate airway obstruction, and Lemanske 2010 enrolled children with mild to moderate airway obstruction. The remaining two trials did not report the severity of airway obstruction. Stelmach 2007 and Stelmach 2008 recruited children who had confirmed positive skin-prick tests for specific allergens. Both studies compared the combination of anti-leukotriene and ICS to the same dose ICS.

Intervention duration: The duration of intervention varied from four to 16 weeks.

Intervention drugs: All trials used montelukast (anti-leukotriene agent) at a dose of 5 mg for children aged six to 14 years and 10 mg for adolescents aged 15 years and above. Three trials used budesonide turbuhaler (Simons 2001; Stelmach 2007; Stelmach 2008), and the remaining trial (Lemanske 2010) used fluticasone metered-dose inhaler.

Cointervention: No trials reported the use of additional antiasthmatic drugs, other than rescue beta₂-agonists and systemic corticosteroids.

Outcomes: Two cross-over trials (Lemanske 2010; Simons 2001) comparing the addition of anti-leukotriene agent to ICS with the same dose or higher dose of ICS, respectively, reported the primary outcome, the number of participants experiencing one or more exacerbations requiring rescue oral corticosteroids.

A small number of trials reported other measures of asthma exacerbation (hospital admissions), lung function (FEV₁, morning PEFR) and asthma control indices (change from baseline in daily use of beta₂-agonists, change in quality of life), and biological markers of inflammation (change from baseline in blood eosinophil counts). All four trials contributing data reported withdrawals and adverse effects.

 

Excluded studies

Of 309 citations, we excluded 303 citations for the following exclusive reasons: duplicate references (N = 32); not a randomised controlled trial (N = 18); participants did not have asthma (N = 1); the control intervention was not ICS (N = 87); the test intervention was not a combination of ICS and anti-leukotriene (N = 104); participants received non-permitted co-interventions (N = 8); the tested intervention was administered for less than four weeks (N = 3); participants had an acute exacerbation (N = 2); the age of participants was more than 18 years (N = 45); participants were naive to daily ICS before enrolment in the study (N = 2); and inadequate information was available for selection criteria (N = 2). The 'Characteristics of excluded studies' tables provide reasons for exclusion.

 

Risk of bias in included studies

The 'Characteristics of included studies' tables give full details of the risk of bias for each included trial, with a graphical summary of the 'Risk of bias' judgements in Figure 2. Three of the five included trials provided enough information to assess the method of randomisation.

 FigureFigure 2. 'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study

 

Allocation

Three of the five trials provided sufficient information to confirm the adequacy of the allocation concealment.

 

Blinding

The procedures for blinding described in the trial reports were sufficient for us to judge that all the included studies were at a low risk of performance and detection bias..

 

Incomplete outcome data

All trials reported the number and reasons of withdrawals. We did not observe high or imbalanced withdrawal rate in any comparing groups.

 

Selective reporting

All trails reported all outcomes as mentioned in the methodology section of the published manuscript without any apparent bias.

 

Other potential sources of bias

We did not identify any other significant source of bias in included trials.

 

Effects of interventions

See:  Summary of findings for the main comparison Anti-leukotrienes & ICS versus same dose ICS for asthma;  Summary of findings 2 Anti-leukotrienes & ICS versus higher dose ICS for asthma

 

Anti-leukotrienes and ICS versus same dose of ICS (step 3 versus step 2)

See  Summary of findings for the main comparison.

 

Primary outcome: participants with exacerbations requiring oral corticosteroids

There was no statistically significant group difference in the only trial reporting the risk of children (aged six to 14 years) with exacerbations requiring oral corticosteroids over 12 weeks. There were eight children with an exacerbation on anti-leukotrienes, 10 on placebo, and one child who had an exacerbation on both treatments (N = 268 participants; risk ratio (RR) 0.80, 95% CI 0.34 to 1.91;  Analysis 1.1; Figure 3). Because of the lack of trials reporting the primary outcome, we did not perform subgroup analysis, funnel plot, and sensitivity analysis.

 FigureFigure 3. Forest plot of comparison: 1 Anti-leukotrienes and ICS versus same dose of ICS, outcome: 1.1 Participants with one or more exacerbations requiring oral corticosteroids

 

Secondary outcomes

 
Exacerbations

The only trial that reported this outcome ( Analysis 1.2) did not admit any participant to hospital with either treatment strategy due to asthma exacerbation.

 
Lung functions

No significant group difference was observed in the only trial reporting change from baseline FEV₁ (%) (N = 251 participants; mean difference (MD) 1.30, 95% CI -0.09 to 2.69;  Analysis 1.3). Change from baseline in AM PEFR (N = 218 participants; MD 9.70 L/min, 95% CI 1.27 to 18.13;  Analysis 1.4) and change from baseline in PM PEFR (N = 218 participants; MD 10.70 L/min, 95% CI 2.41 to 18.99;  Analysis 1.5) were reported to be significantly better with anti-leukotriene in this study, but it is not clear whether the PEFR results were based on intention-to-treat or per-protocol analysis.

 
Asthma control and biological markers of inflammation

No other included paediatric trials reported other secondary efficacy outcomes. However, the sponsor of one cross-over trial (Simons 2001) provided certain data, which we presented in  Table 1 RevMan can not calculate correct treatment effects and 95% CI from such data unless the results of paired t-tests are provided to allow for the within-participant correlation of the treatment effects, so we did not present forest plots for these outcomes.

 
Safety

Based on only one trial, there were no reported serious adverse effects ( Analysis 1.8) or death ( Analysis 1.9) in either treatment group. The only trial reporting each of the following outcomes observed no group difference in overall adverse effects (N = 270 participants; OR 0.87, 95% CI 0.62 to 1.23;  Analysis 1.10); upper respiratory tract infections (N = 270 participants; OR 0.85, 95% CI 0.46 to 1.54;  Analysis 1.111); headache (N = 270 participants; OR 1.02, 95% CI 0.55 to 1.88;  Analysis 1.111); nausea (N = 270 participants; OR 0.39, 95% CI 0.07 to 2.00;  Analysis 1.111); and elevated liver enzymes (N = 270 participants; OR 1.96, 95% CI 0.18 to 21.70;  Analysis 1.11).

 
Withdrawals

There was no statistically significant group difference in overall withdrawals (N = 368 participants; odds ratio (OR) 1.93, 95% CI 0.74 to 5.05;  Analysis 1.6) and in withdrawals due to adverse effects (N = 270 participants; OR 0.49, 95% CI 0.04 to 5.43;  Analysis 1.7). No withdrawal was observed due to poor asthma control/exacerbation with either strategy ( Analysis 1.7).

 

Anti-leukotrienes and ICS versus higher dose of ICS (step 3 versus step 3)

See  Summary of findings 2 for the results from the single cross-over study for this comparison (Lemanske 2010).

 

Primary outcome: participants with exacerbations requiring oral corticosteroids

There was no statistically significant group difference observed in children and adolescents with exacerbations requiring oral corticosteroids over 16 weeks (N = one trial: 182 participants; RR 0.82, 95% CI 0.54 to 1.25;  Analysis 2.1; Figure 4). We estimated the number of children who had one or more exacerbations requiring a course of oral corticosteroids by subtracting the number reported as having a second course of oral corticosteroids from the total number of courses on each treatment for one trial (Lemanske 2010). Because of lack of trials reporting the primary outcome, we did not perform subgroup analysis, funnel plot, and sensitivity analysis.

 FigureFigure 4. Forest plot of comparison: 2 Anti-leukotrienes and ICS versus higher dose of ICS, outcome: 2.1 Participants with one or more exacerbations requiring oral corticosteroids

 

Secondary outcomes

 
Exacerbations

There was no significant difference in exacerbations requiring hospital admission, with a single child admitted on each treatment (N = 182 participants; RR 1.00, 95% CI 0.06 to 15.87;  Analysis 2.2).

 
Lung function and asthma control

No trials reported lung function or asthma control parameters with sufficient details to be used.

 
Withdrawals

There was no statistically significant group difference in overall withdrawals (N = 182 participants; OR 1.30, 95% CI 0.47, 3.57;  Analysis 2.3). No trial reported withdrawals due to adverse effects, poor asthma control/exacerbations, or any safety parameters.

 

Anti-leukotrienes and ICS versus tapering dose of ICS

No trial reported the comparison of the combination of anti-leukotriene and ICS with tapering dose of ICS.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms
 

Summary of main results

In children who remain symptomatic with low-dose ICS, there were insufficient data to determine the effect of adding anti-leukotrienes to ICS on the number of participants with one or more exacerbations requiring oral corticosteroids. There were no data on secondary efficacy outcomes to derive any firm conclusion favouring either strategy, whether comparing the same dose or a higher-dose ICS. The limited available data revealed no significant group difference in withdrawals and safety profile, but did not meet the criteria of equivalence. No trial explored the addition of anti-leukotrienes as a strategy to taper the dose of ICS. The paucity of paediatric trials in this area and the inconsistent measurement of key outcomes preclude firm conclusions regarding the efficacy and safety of adjunctive anti-leukotriene agents in children.

Only one trial in each protocol (Lemanske 2010; Simons 2001) reported the number of participants requiring rescue oral corticosteroids. In both cases, there was no statistically significant group difference. The wide confidence intervals did not demonstrate equivalence. In the comparison testing the combination of anti-leukotrienes and ICS versus the same dose of ICS alone (step 3 versus step 2), a cross-over trial (Simons 2001) evaluated certain secondary efficacy outcomes, including lung function parameters (FEV₁ and PEFR), change in use of rescue medication, and quality of life. We could not use this data in RevMan as we did not have information on the within-participant correlation between the treatment periods. In the comparison examining the combination of anti-leukotrienes and ICS versus a higher dose of ICS (step 3 versus step 3), a cross-over trial (Lemanske 2010) reported both the main outcome and participants with exacerbation requiring hospital admission; no other secondary efficacy outcomes were reported. In other words, insufficient reporting prevented the aggregation of efficacy data in all protocols.

In both treatment protocols, the only safety outcome that we could aggregate was overall withdrawal; no significant group difference was observed with wide confidence intervals. No serious adverse events were observed in these small studies.

In view of the paucity of trials and inadequate reporting, there is inconclusive evidence to support the use of anti-leukotrienes as adjunct therapy to ICS (step-3 option) in children and adolescents (no data on preschoolers). Limited data on withdrawals prevent firm conclusions as to the safety of this strategy compared to using the same dose (step 2) or a higher dose (step 3) ICS alone.

 

Overall completeness and applicability of evidence

Of note is the strikingly low number of paediatric studies examining the best step-up therapy with anti-leukotrienes in children inadequately controlled with a low daily maintenance dose of ICS. We excluded four paediatric trials because we could not confirm that children were insufficiently controlled or because they included either well-controlled children on daily ICS or participants naive to ICS (Finn 2000; Jat 2006; Karaman 2007; Miraglia del Giudice 2007). Moreover, of the five eligible trials, one did not contribute data in the format required. Of interest, the only study (Strauch 2003) evaluating the clinical efficacy on bronchial inflammation, of adjunct treatment with leukotriene receptor antagonists in children with asthma on ICS, showed a significant reduction in airway inflammation and improved quality of life.

We identified only five eligible paediatric trials: The trials recruited 559 children, aged six years and above, and adolescents. No trial focused on preschoolers. Of the included studies, four trials reported only a limited number of outcomes of interest. The majority of secondary outcomes were measured as end of treatment values rather than change from the baseline, thus, limiting the interpretation of findings. We emphasise the need for further trials with complete reporting of efficacy outcomes, specifically exacerbations requiring rescue oral corticosteroids, hospital admission, and change from baseline in asthma control parameters.

 

Quality of the evidence

Our confidence in the effect estimates is limited by statistical imprecision due to the low number of studies and low power of our analysis.

 

Potential biases in the review process

There were insufficient data to assess the potential for bias relating to study quality and publication bias.

 

Agreements and disagreements with other studies or reviews

The Cochrane review on addition of anti-leukotriene agents to ICS for chronic asthma in children and adults published in 2004 concluded that in symptomatic people, the addition of licensed doses of anti-leukotrienes to ICS resulted in a non-significant reduction in the risk of exacerbations requiring systemic steroids (RR 0.64, 95% CI 0.38 to 1.07) with modest improvement in lung function (PEFR MD 7.7 L/min, 95% CI 3.6 to 11.8) and a decrease in the use of rescue short-acting beta₂-agonist use (MD 1 puff/week, 95% CI 0.5 to 2). With only 3 trials comparing the use of licensed doses of anti-leukotrienes with increasing the dose of ICS, no firm conclusion could be drawn about the equivalence of both treatment options (Ducharme 2004).

The prior review was heavily weighted towards adults and did not firmly conclude on the efficacy and safety of addition of anti-leukotrienes to ICS. The current review supports the same conclusion in paediatrics.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms

 

Implications for practice

There is insufficient evidence to support the use of anti-leukotriene agents as step-3 therapy in children and adolescents with mild to moderate asthma. Despite the fact that anti-leukotrienes have been licensed for over 10 years for children in many countries, there are major limitations with the evidence base: There is an appalling paucity of paediatric trials, an absence of data on preschoolers, and the reporting of clinically relevant outcomes is highly variable. These limitations prevent firm conclusions. At present, there is no firm evidence to support the efficacy and safety of anti-leukotrienes as add-on therapy to ICS as a step-3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low-dose ICS. Consequently, should a clinician wish to add anti-leukotrienes to the therapeutic regimen, it should be considered as a therapeutic trial and the clinical impact on asthma control and exacerbations should be documented in the specific person before considering prolonged therapy.

 
Implications for research

We emphasise the urgent need for further paediatric trials (including preschoolers) with sub-optimal asthma control on inhaled corticosteroids, comparing the addition of anti-leukotriene agents to existing ICS to either the same or a higher ICS. We call for complete reporting of efficacy outcomes, especially with regard to people with one or more exacerbations requiring rescue oral corticosteroids, hospital admissions, and change from baseline in asthma control indices. We also suggest considering the following issues while designing a paediatric trial:

  • children with mild to moderate persistent asthma incompletely controlled on daily inhaled corticosteroids;
  • including all paediatric age groups, including preschool-aged children;
  • favouring a parallel group design with a minimum of 24-week treatment duration;
  • measurement and reporting of participants with exacerbation requiring oral corticosteroids and hospital admission separately;
  • analysis and reporting of efficacy outcomes (including asthma control) as change from baseline or as overall period effect (instead of end of study value) (Reddel 2009);
  • measurement and reporting of severe adverse events, including anticipated adverse effects of both treatment strategies including headache, growth, behavioural changes, etc;
  • reporting of overall withdrawals with their reasons;
  • documentation of compliance; and
  • use of anti-leukotriene agents as a means to taper the dose of ICS (protocol 3).

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms

We wish to thank Emma Welsh and Elizabeth Stovold for their assistance and support during title registration and the literature search.

CRG Funding Acknowledgement: The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Airways Group.

Disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms
Download statistical data

 
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

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms
 

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register of Trials (CAGR)

 

Electronic searches: core databases


DatabaseFrequency of search

MEDLINE (Ovid)Weekly

EMBASE (Ovid)Weekly

CENTRAL (The Cochrane Library)Monthly

PSYCHINFO (Ovid)Monthly

CINAHL (EBSCO)Monthly

AMED (EBSCO)Monthly



 

 

Hand-searches: core respiratory conference abstracts


ConferenceYears searched

American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards

American Thoracic Society (ATS)2001 onwards

Asia Pacific Society of Respirology (APSR)2004 onwards

British Thoracic Society Winter Meeting (BTS)2000 onwards

Chest Meeting2003 onwards

European Respiratory Society (ERS)1992, 1994, 2000 onwards

International Primary Care Respiratory Group Congress (IPCRG)2002 onwards

Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards



 

 

MEDLINE search strategy used to identify trials for the CAGR

 

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti-asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1-15

 

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases

 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms

Dr Bhupendrasinh Chauhan wrote the protocol, reviewed the literature search until January 2013, identified and reviewed all citations for relevance, reviewed methodological quality, extracted data, analysed and interpreted the results of the meta-analysis, wrote all versions of the manuscript, and approved the final version of the manuscript.

Raja Ben Salah identified and reviewed all relevant citations with BFC and extracted data.

Prof Francine Ducharme supervised and approved the protocol, verified the extracted data, provided input in case of disagreement regarding the inclusion of trials, reviewed the methodological assessment and the interpretation of data, edited all versions of the manuscript, and approved the final version of the manuscript.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms

Dr Bhupendrasinh Chauhan received a postdoctoral research fellowship from one of Prof Francine Ducharme's CIHR funded projects.

Raja Ben Salah has no declarations of interest.

Prof Francine Ducharme has received travel support, research funds, and fees for speaking from GlaxoSmithKline, Novartis, Takeda, and Merck Frosst Inc.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Professor Francine Ducharme, Canada.
    has received travel support, research funds, and fees for speaking from GlaxoSmithKline, Novartis, and Merck Frosst Inc, producer of montelukast. She has received some travel support for meeting attendance, a research grant, and consulting fee from Merck, producer of some inhaled corticosteroids preparation to which anti-leukotriene agents have been compared.
  • Dr Bhupendrasinh Chauhan, Canada.
    received a postdoctoral scholarship from the Canadian Institute of Health Research, Canada.
  • Raja Ben Salah, Canada.
    received a scholarship from the Canadian Institute of Health Research, Canada.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms

We increased the cut-off point for significant heterogeneity from I² statistic > 25% to I² statistic > 40%. We added boundaries to classify trials as either short- or long-term.

 

Notes

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Notes
  17. Index terms

None.

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
Lemanske 2010 {published data only}
  • Lemanske RF Jr, Mauger DT, Sorkness CA, Jackson DJ, Boehmer SJ, Martinez FD, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. New England Journal of Medicine 2010;362(11):975-85.
Simons 2001 {published data only}
  • Simons FE, Villa JR, Lee BW, Teper AM, Lyttle B, Aristizabal G, et al. Montelukast added to budesonide in children with persistent asthma: a randomized, double-blind, crossover study. Journal of Pediatrics 2001;138(5):694-8.
Stelmach 2007 {published data only}
  • Stelmach I, Grzelewski T, Bobrowska-Korzeniowska M, Stelmach P, Kuna P. A randomized, double-blind trial of the effect of anti-asthma treatment on lung function in children with asthma. Pulmonary Pharmacology and Therapeutics 2007;20(6):691-700.
Stelmach 2008 {published data only}
  • Stelmach I, Grzelewski T, Majak P, Jerzynska J, Stelmach W, Kuna P. Effect of different antiasthmatic treatments on exercise-induced bronchoconstriction in children with asthma. Journal of Allergy and Clinical Immunology 2008;121(2):383-9.
Strauch 2003 {published data only}
  • Strauch E, Moske O, Thoma S, Storm Van's Gravesande K, Ihorst G, Brandis M, et al. A randomized controlled trial on the effect of montelukast on sputum eosinophil cationic protein in children with corticosteroid-dependent asthma. Pediatric Research 2003;54(2):198-203.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
Abadoglu 2005 {published data only}
  • Abadoglu O, Mungan D, Aksu O, Erekul S, Misirligil Z. The effect of montelukast on eosinophil apoptosis: induced sputum findings of patients with mild persistent asthma. Allergologia et Immunopathologia 2005;33(2):105-11.
Abdel-wahab 2009 {published data only}
  • Abdel-wahab M, Naiem AA, El-Batch M. Steroid sparing using safer drugs in the management of children and adolescents with chronic asthma. New Horizons in Allergy, Asthma & Immunology. 2009:137-44.
ALAACRC 2007 {published data only}
  • American Lung Association Asthma Clinical Research Centers (ALAACRC), Peters SP, Anthonisen N, Castro M, Holbrook JT, Irvin CG, et al. Randomized comparison of strategies for reducing treatment in mild persistent asthma. New England Journal of Medicine 2007;356(20):2027-39.
Allen-Ramey 2003 {published data only}
  • Allen-Ramey FC, Duong PT, Goodman DC, Sajjan SG, Nelsen LM, Santanello NC, et al. Treatment effectiveness of inhaled corticosteroids and leukotriene modifiers for patients with asthma: an analysis from managed care data. Allergy and Asthma Proceedings 2003;24(1):43-51.
Anonymous 2010 {published data only}
  • Anonymous. Steroids better than montelukast in acute asthma exacerbations in children. Journal of the National Medical Association 2010;102(3):259.
Bacharier 2008 {published data only}
  • Bacharier LB, Phillips BR, Zeiger RS, Szefler SJ, Martinez FD, Lemanske RF Jr, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. Journal of Allergy and Clinical Immunology 2008;122(6):1127-35.
Baek 2011 {published data only}
  • Beak H. The pathobiologic effect of montelukast and inhaled budesonide on exercise-induced bronchoconstriction in children. Journal of Allergy and Clinical Immunology 2011;127(2 Suppl 1):AB83.
Barnes 2007 {published data only}
Barnes 2007a {published data only}
  • Barnes N, Laviolette M, Allen D, Flood-Page P, Hargreave F, Corris P, et al. Effects of montelukast compared to double dose budesonide on airway inflammation and asthma control. Respiratory Medicine 2007;101(8):1652-8.
Basu 2010 {published data only}
  • Basu K, Donald HP, Lipworth BJ, Tavendale R, Macgregor DF, Ogston SA, et al. Better asthma control with montelukast than salmeterol in arg-16homozygous children with asthma. Thorax 2010;65(Suppl 4):P181.
Becker 2006 {published data only}
  • Becker AB, Kuznetsova O, Vermeulen J, Soto-Quiros ME, Young B, Reiss TF, et al. Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized double-blind study. Annals of Allergy, Asthma & Immunology 2006;96(6):800-7.
Benitez 2005 {published data only}
  • Benitez HH, Arvizu VM, Gutiérrez DJ, Fogelbach GA, Castellanos Olivares A, Vázquez Nava F, et al. Nasal budesonide plus zafirlukast vs nasal budesonide plus loratadine-pseudoephedrine for controlling the symptoms of rhinitis and asthma. Revista Alergia Mexico 2005;52(2):90-5.
Bjermer 2000 {published data only}
  • Bjermer L, Bisgaard H, Bousquet J, Fabbri LM, Greening A, Haahtela T, et al. Montelukast or salmeterol combined with an inhaled steroid in adult asthma: design and rationale of a randomized, double-blind comparative study (the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy-trial). Respiratory Medicine 2000;94(6):612-21.
Bjermer 2003 {published data only}
  • Bjermer L, Bisgaard H, Bousquet J, Fabbri LM, Greening AP, Haahtela T, et al. Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial. BMJ 2003;327:891.
Bleecker 2000 {published data only}
  • Bleecker ER, Welch MJ, Weinstein SE, Kalberg C, Johnson M, Edwards L, et al. Low-dose inhaled fluticasone propionate versus oral zafirlukast in the treatment of persistent asthma. Journal of Allergy and Clinical Immunology 2000;105(6):1123-9.
Bousquet 2005 {published data only}
  • Bousquet J, Menten J, Tozzi CA, Polos PG. Oral montelukast sodium versus inhaled fluticasone propionate in adults with mild persistent asthma. Journal of Applied Research 2005;5(3):402-14.
Bozek 2012 {published data only}
  • Bozek A, Warkocka-Szoltysek B, Filipowska-Gronska A, Jarzab J. Montelukast as an add-on therapy to inhaled corticosteroids in the treatment of severe asthma in elderly patients. Journal of Asthma 2012;49(5):530-4.
Buchvald 2002 {published data only}
  • Buchvald FF, Bisgaard H. Comparison of add-on of leukotriene receptor antagonist vs long-acting beta 2-agonist of FeNO in asthmatic children on regular inhaled budesonide. European Respiratory Journal 2002;20(Supp 38):431s.
Buchvald 2003 {published data only}
  • Buchvald F, Bisgaard H. 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):309-13.
Bukstein 2003 {published data only}
  • Bukstein DA, Luskin AT, Bernstein A. "Real-world" effectiveness of daily controller medicine in children with mild persistent asthma. Annals of Allergy, Asthma & Immunology 2003;90(5):543-9.
Busse 1999 {published data only}
  • Busse W, Nelson H, Wolfe J, Kalberg C, Yancey SW, Rickard KA. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. Journal of Allergy and Clinical Immunology 1999;103(6):1075-80.
Busse 2001 {published data only}
  • Busse W, Raphael GD, Galant S, Kalberg C, Goode-Sellers S, Srebro S, et al. Low-dose fluticasone propionate compared with montelukast for first-line treatment of persistent asthma: a randomized clinical trial. Journal of Allergy and Clinical Immunology 2001;107(3):461-8.
Caffey 2005 {published data only}
  • Caffey LF, Raissy HH, Marshik P, Kelly HW. A crossover comparison of fluticasone propionate and montelukast on inflammatory indices in children with asthma. Pediatric Asthma, Allergy & Immunology 2005;18(3):123-30.
Cakmak 2004 {published data only}
  • Cakmak G, Demir T, Gemicioglu B, Aydemir A, Serdaroglu E, Donma O. The effects of add-on zafirlukast treatment to budesonide on bronchial hyperresponsiveness and serum levels of eosinophilic cationic protein and total antioxidant capacity in asthmatic patients. Tohoku Journal of Experimental Medicine 2004;204(4):249-56.
Costa-Katz 2012 {published data only}
  • Costa-Katz CL, Livnat G, Hakim F, Vilozni D, Bentur Y, Bentur L. The effect of beclomethasone dipropionate in ultrafine particles on bronchial hyper-reactivity in young children. Acta Paediatrica 2012 Jan 27 [Epub ahead of print]; Vol. 101, issue 5:e219-24.
Currie 2003 {published data only}
Currie 2003a {published data only}
  • Currie GP, Lee DK, Haggart K, Bates CE, Lipworth BJ. Effects of montelukast on surrogate inflammatory markers in corticosteroid-treated patients with asthma. American Journal of Respiratory and Critical Care Medicine 2003;167(9):1232-9.
Davies 2004 {published data only}
  • Davies GM, Dasbach EJ, Santanello NC, Knorr BA, Bratton DL. The effect of montelukast versus usual care on health care resource utilization in children aged 2 to 5 years with asthma. Clinical Therapeutics 2004;26(11):1895-1904.
Dempsey 2002 {published data only}
  • Dempsey OJ, Fowler SJ, Wilson A, Kennedy G, Lipworth BJ. Effects of adding either a leukotriene receptor antagonist or low-dose theophylline to a low or medium dose of inhaled corticosteroid in patients with persistent asthma. Chest 2002;122(1):151-9.
Dempsey 2002a {published data only}
  • Dempsey OJ, Kennedy G, Lipworth BJ. Comparative efficacy and anti-inflammatory profile of once-daily therapy with leukotriene antagonist or low-dose inhaled corticosteroid in patients with mild persistent asthma. Journal of Allergy and Clinical Immunology 2002;109(1):68-74.
Deschildre 2012 {published data only}
  • Deschildre A, Béghin L, Salleron J, Iliescu C, Thumerelle C, Santos C, et al. Home telemonitoring (forced expiratory volume in 1 s) in children with severe asthma does not reduce exacerbations. European Respiratory Journal 2012;39(2):290-6.
Djukanović 2010 {published data only}
  • Djukanović R, Wilson SJ, Moore WC, Koenig SM, Laviolette M, Bleecker ER, et al. Montelukast added to fluticasone propionate does not alter inflammation or outcomes. Respiratory Medicine 2010;104(10):1425-35.
Duong 2012 {published data only}
  • Duong M, Amin R, Baatjes AJ, Kritzinger F, Qi Y, Meghji Z, et al. The effect of montelukast, budesonide alone, and in combination on exercise-induced bronchoconstriction. Journal of Allergy and Clinical Immunology 2012 Apr 24 [Epub ahead of print]; Vol. 130, issue 2:535-539.e3.
Eakin 2012 {published data only}
  • Eakin MN, Rand CS, Bilderback A, Bollinger ME, Butz A, Kandasamy V, et al. Asthma in Head Start children: effects of the Breathmobile program and family communication on asthma outcomes. Journal of Allergy and Clinical Immunology 2012;129(3):664-70.
Farber 2010 {published data only}
  • Farber I, Geppe N, Putyato T. Efficacy of leukotriene receptors modifiers (LRM) and inhaled glucocorticoids (ICS) in the treatment of children with bronchial asthma (BA) and allergic rhinitis (AR). Allergy 2010;65(s92):1858.
Finn 2000 {published data only}
  • Finn AF, Bonuccelli CM, Traxler BM, Beatty SE. Zafirlukast improves asthma control in children treated with and without inhaled corticosteroids. European Respiratory Journal 2000;16(Suppl 31):307.
Fogel 2010 {published data only}
  • Fogel RB, Rosario N, Aristizabal G, Loeys T, Noonan G, Gaile S, et al. Effect of montelukast or salmeterol added to inhaled fluticasone on exercise-induced bronchoconstriction in children. Annals of Allergy, Asthma & Immunology 2010;104(6):511-7.
Fritsch 2006 {published data only}
Ghiro 2001 {published data only}
  • Ghiro L, Zanconato S, Rampon O, Piovan V, Scollo M, Baraldi E. Effect of montelukast added to inhaled steroids on exhaled NO in asthmatic children. European Respiratory Journal 2001;18(33):40s.
Ghiro 2002 {published data only}
  • Ghiro L, Zanconato S, Rampon O, Piovan V, Pasquale MF, Baraldi E. Effect of montelukast added to inhaled corticosteroids on fractional exhaled nitric oxide in asthmatic children. European Respiratory Journal 2002;20(3):630-4.
Igde 2009 {published data only}
  • Igde M, Anlar FY. The efficacy of montelukast monotherapy in moderate persistent asthmatic children. Iranian Journal of Allergy, Asthma, and Immunology 2009;8(3):169-70.
Ilowite 2004 {published data only}
  • Ilowite J, Webb R, Friedman B, Kerwin E, Bird SR, Hustad CM, et al. Addition of montelukast or salmeterol to fluticasone for protection against asthma attacks: a randomized, double-blind, multicenter study. Annals of Allergy, Asthma & Immunology 2004;92(6):641-8.
Irvin 2007 {published data only}
  • Irvin CG, Kaminsky DA, Anthonisen NR, Castro M, Hanania NA, Holbrook JT, et al. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. American Journal of Respiratory and Critical Care Medicine 2007;175(3):235-42.
Jat 2006 {published data only}
  • Jat GC, Mathew JL, Singh M. Treatment with 400 mug of inhaled budesonide vs 200 mug of inhaled budesonide and oral montelukast in children with moderate persistent asthma: randomized controlled trial. Annals of Allergy, Asthma & Immunology 2006;97(3):397-401.
Jayaram 2005 {published data only}
  • Jayaram L, Duong M, Pizzichini MM, Pizzichini E, Kamada D, Efthimiadis A, et al. Failure of montelukast to reduce sputum eosinophilia in high-dose corticosteroid-dependent asthma. European Respiratory Journal 2005;25(1):41-6.
Jenkins 2005 {published data only}
Johnston 2007 {published data only}
  • Johnston NW, Mandhane PJ, Dai J, Duncan JM, Greene JM, Lambert K, et al. Attenuation of the September epidemic of asthma exacerbations in children: a randomized, controlled trial of montelukast added to usual therapy. Paediatrics 2007;120(3):e702-e712.
Jung 2006 {published data only}
  • Jung J, Lee J, Kim J. Treatment of inhaled corticosteroid and leukotriene receptor antagonist in Korean young cough variant asthma children. Journal of Allergy and Clinical Immunology 2006;117:S93.
Kamenov 2007 {published data only}
  • Kamenov S, Kamenov A, Kamenov B. Effect of fluticasone and montelukast in school children with asthma. European Respiratory Journal 2007;30(Suppl 51):459s.
Karaman 2007 {published data only}
  • Karaman O, Arli O, Uzuner N, Islekel H, Babayigit A, Olmez D, et al. The effectiveness of asthma therapy alternatives and evaluating the effectivity of asthma therapy by interleukin-13 and interferon gamma levels in children. Allergy and Asthma Proceedings 2007;28(2):204-9.
Keith 2009 {published data only}
  • Keith PK, Koch C, Djandji M, Bouchard J, Psaradellis E, Sampalis JS, et al. Montelukast as add-on therapy with inhaled corticosteroids alone or inhaled corticosteroids and long-acting beta-2-agonists in the management of patients diagnosed with asthma and concurrent allergic rhinitis (the RADAR trial). Canadian Respiratory Journal 2009;16(Suppl A):17A-31A.
Kondo 2006 {published data only}
  • Kondo N, Katsunuma T, Odajima Y, Morikawa A. A randomized open-label comparative study of montelukast versus theophylline added to inhaled corticosteroid in asthmatic children. Allergology International 2006;55(3):287-93.
Laviolette 1999 {published data only}
  • Laviolette M, Malmstrom K, Lu S, Chervinsky P, Pujet JC, Peszek I, et al. Montelukast added to inhaled beclomethasone in treatment of asthma. American Journal of Respiratory and Critical Care Medicine 1999;160(6):1862-8.
Lee 2004 {published data only}
Lipworth 2000 {published data only}
  • Lipworth BJ, Dempsey OJ, Aziz I, Wilson AM. Effects of adding a leukotriene antagonist or a long-acting beta2-agonist in asthmatic patients with the glycine-16 beta2-adrenoceptor genotype. American Journal of Medicine 2000;109:114-21.
Marogna 2010 {published data only}
  • Marogna M, Colombo F, Spadolini I, Massolo A, Berra D, Zanon P, et al. Randomized open comparison of montelukast and sublingual immunotherapy as add-on treatment in moderate persistent asthma due to birch pollen. Journal of Investigational Allergology & Clinical Immunology 2010;20(2):146-52.
Matsuse 2012 {published data only}
  • Matsuse H, Fukahori S, Tsuchida T, Kawano T, Tomari S, Matsuo N, et al. Effects of a short course of pranlukast combined with systemic corticosteroid on acute asthma exacerbation induced by upper respiratory tract infection. Journal of Asthma 2012; Vol. 49, issue 6:637-41.
Mendes 2004 {published data only}
  • Mendes ES, Campos MA, Hurtado A, Wanner A. Effect of montelukast and fluticasone propionate on airway mucosal blood flow in asthma. American Journal of Respiratory and Critical Care Medicine 2004;169(10):1131-4.
Miraglia del Giudice 2007 {published data only}
  • Miraglia del Giudice M, Piacentini GL, Capasso M, Capristo C, Maiello N, Boner AL, et al. Formoterol, montelukast, and budesonide in asthmatic children: effect on lung function and exhaled nitric oxide. Respiratory Medicine 2007;101(8):1809-13.
Nathan 2001 {published data only}
  • Nathan RA, Bleecker ER, Kalberg C, Fluticasone Propionate Study Group. A comparison of short-term treatment with inhaled fluticasone propionate and zafirlukast for patients with persistent asthma. American Journal of Medicine 2001;111(3):195-202.
Nelson 2000 {published data only}
  • Nelson HS, Busse WW, Kerwin E, Church N, Emmett A, Rickard K, et al. Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. Journal of Allergy and Clinical Immunology 2000;106(6):1088-95.
Nelson 2006 {published data only}
  • Nelson HS, Weiss ST, Bleecker EK, Yancey SW, Dorinsky PM, SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129(1):15-26.
Ng 2007 {published data only}
  • Ng DKK, Chan CH, Wu S, Chow PY, Wong LSW, Fu YM, et al. Oral montelukast versus inhaled budesonide in children with mild persistent asthma: a pilot study. The Hong Kong Journal of Paediatrics 2007;12(1):3-10.
O'Connor 2006 {published data only}
  • O'Connor RD, Gilmore AS, Manjunath R, Stanford RH, Legorreta AP, Jhingran PM. Comparing outcomes in patients with persistent asthma: a registry of two therapeutic alternatives. Current Medical Research and Opinion 2006;22(3):453-61.
O'Sullivan 2003 {published data only}
  • O'Sullivan S, Akveld M, Burke CM, Poulter LW. Effect of the addition of montelukast to inhaled fluticasone propionate on airway inflammation. American Journal of Respiratory and Critical Care Medicine 2003;167(5):745-50.
Ostrom 2003 {published data only}
  • Ostrom NK, DeCotiis BA, Lincourt WR, Edwards LD, Crim CC. A comparison of low does fluticasone propionate and montelukast in children 6-12 years of age with persistent asthma. American Thoracic Society 99thInternational Conference; 2003 May 16-21; Seattle. 2003; Vol. A117:Poster D79.
Ostrom 2005 {published data only}
  • Ostrom NK, Decotiis BA, Lincourt WR, Edwards LD, Hanson KM, Carranza Rosenzweig JR, 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.
Papadopoulos 2009 {published data only}
  • Papadopoulos NG, Philip G, Giezek H, Watkins M, Smugar SS, Polos PG. The efficacy of montelukast during the allergy season in pediatric patients with persistent asthma and seasonal aeroallergen sensitivity. Journal of Asthma 2009;46(4):413-20.
Patel 2010 {published data only}
  • Patel YA, Patel P, Bavadia H, Dave J, Tripathi CB. A randomized, open labeled, comparative study to assess the efficacy and safety of controller medications as add on to inhaled corticosteroid and long-acting β2 agonist in the treatment of moderate-to-severe persistent asthma. Journal of Postgraduate Medicine 2010;56(4):270-4.
Pedersen 2007 {published data only}
  • Pedersen S, Agertoft L, Williams-Herman D, Kuznetsova O, Reiss TF, Knorr B, et al. Placebo-controlled study of montelukast and budesonide on short-term growth in prepubertal asthmatic children. Pediatric Pulmonology 2007;42(9):838-43.
Peroni 2005 {published data only}
Philip 2011 {published data only}
  • Philip G, Villarán C, Shah SR, Vandormael K, Smugar SS, Reiss TF. The efficacy and tolerability of inhaled montelukast plus inhaled mometasone compared with mometasone alone in patients with chronic asthma. Journal of Asthma 2011;48(5):495-502.
Phipatanakul 2003 {published data only}
  • Phipatanakul W, Greene C, Downes SJ, Cronin B, Eller TJ, Schneider LC, et al. Montelukast improves asthma control in asthmatic children maintained on inhaled corticosteroids. Annals of Allergy, Asthma & Immunology 2003;91(1):49-54.
Price 2003 {published data only}
  • Price DB, Hernandez D, Magyar P, Fiterman J, Beeh KM, James IG, et al. Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax 2003;58(3):211-6.
Price 2011 {published data only}
  • Price D, Musgrave SD, Shepstone L, Hillyer EV, Sims EJ, Gilbert RF, et al. Leukotriene antagonists as first-line or add-on asthma-controller therapy. New England Journal of Medicine 2011;364(18):1695-1707.
Reiss 1997 {published data only}
  • Reiss TF, Sorkness CA, Stricker W, Botto A, Busse WW, Kundu S, et al. Effects of montelukast (MK-0476); a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled corticosteroids. Thorax 1997;52(7):45-8.
Riccioni 2005 {published data only}
  • Riccioni G, Vecchia RD, Castronuovo M, Di Ilio C, D'Orazio N. Tapering dose of inhaled budesonide in subjects with mild-to-moderate persistent asthma treated with montelukast: a 16-week single-blind randomized study. Annals of Clinical and Laboratory Science 2005;35(3):285-9.
Robinson 2001 {published data only}
  • Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial. Lancet 2001;357(9273):2007-11.
SAM40030 {published data only}
  • SAM40030. A phase IV, multicentre, randomised, double blind, single dummy, parallel group study to compare the anti-inflammatory action of Seretide 50/100 bd via MDI with Flixotide 100 μg bd via MDI plus montelukast 10mg od for 12 weeks in adults with mild to moderate asthma who are currently taking inhaled corticosteroids but have a requirement for further therapy. www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=SAM40030&studyId=1112A112-B8F4-42A0-BE6C-EF7A1620090F&compound=SAM40030&type=GSK+Study+ID&letterrange=All (accessed 3/9/13).
SAS40036 {published data only}
  • SAS40036. A multicenter, randomized, double-blind, double-dummy, parallel group, 16-week comparison of asthma control in adolescents and adults receiving either fluticasone propionate/salmeterol DISKUS combination product 100/50 mcg BID, fluticasone propionate DISKUS 100 mcg BID, salmeterol xinafoate DISKUS 50 mcg BID, or oral montelukast 10 mg QD. www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=SAS40036&studyId=28A94A00-AEBF-45B7-B75B-D13827C5F6D8&compound=SAS40036&type=GSK+Study+ID&letterrange=All (accessed 3/9/13).
SD-004CR-0216 {published data only}
  • SD-004CR-0216. Oxis Turbuhaler® (formoterol), Accolate® (zafirlukast) or placebo as add on treatment to Pulmicort Turbuhaler® (budesonide) in asthmatic patients on inhaled steroids. www.astrazenecaclinicaltrials.com/_mshost800325/content/clinical-trials/resources/pdf/8611707 (accessed 3/9/13).
Shah 2006 {published data only}
Sims 2003 {published data only}
Smith 2012 {published data only}
  • Smith JR, Noble MJ, Musgrave S, Murdoch J, Price GM, Barton GR, et al. The at-risk registers in severe asthma (ARRISA) study: a cluster-randomised controlled trial examining effectiveness and costs in primary care. Thorax 2012; Vol. 67, issue 12:1052-60.
Smugar 2009 {published data only}
  • Smugar SS, Fogel R, Aristizabal G, Rosario N, Loeys T, Gaile S, et al. Effect of montelukast or salmeterol added to inhaled fluticasone on response to albuterol in children with exercise-induced bronchoconstriction. European Respiratory Society Annual Congress 2009; Vol. 212s:P1221.
Stelmach 2002 {published data only}
Stelmach 2005 {published data only}
  • Stelmach I, Bobrowska-Korzeniowska M, Majak P, Stelmach W, Kuna P. The effect of montelukast and different doses of budesonide on IgE serum levels and clinical parameters in children with newly diagnosed asthma. Pulmonary Pharmacology & Therapeutics 2005;18(5):374-80.
Storms 2004 {published data only}
  • Storms W, Chervinsky P, Ghannam AF, Bird S, Hustad CM, Edelman JM, et al. A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge. Respiratory Medicine 2004;98(11):1051-62.
Tognella 2004 {published data only}
  • Tognella S, Micheletto C, Visconti MP, Dal Negro RW. Additive effects of montelukast on bronchial hyperresponsiveness to MCh and LTE4 urine levels in mild-persistent atopic asthmatics assuming ICS. Chest 2004;126(Suppl 4):814S.
Tohda 2002 {published data only}
Tsuchida 2005 {published data only}
  • Tsuchida T, Matsuse H, Machida I, Kondo Y, Saeki S, Tomari S, et al. Evaluation of theophylline or pranlukast, a cysteinyl leukotriene receptor 1 antagonist, as add-on therapy in uncontrolled asthmatic patients with a medium dose of inhaled corticosteroids. Allergy and Asthma Proceedings 2005;26(4):287-91.
Ulrik 2010 {published data only}
  • Ulrik CS, Diamant Z. Add-on montelukast to inhaled corticosteroids protects against excessive airway narrowing. Clinical and Experimental Allergy 2010;40(4):576-81.
Verini 2010 {published data only}
  • Verini M, Consilvio NP, Di Pillo S, Cingolani A, Spagnuolo C, Rapino D, et al. FeNO as a marker of airways inflammation: the possible implications in childhood asthma management. Journal of Allergy 2010 May 18 [Epub ahead of print].
Virchow 2000 {published data only}
  • Virchow JC Jr, Prasse A, Naya I, Summerton L, Harris A. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. American Journal of Respiratory and Critical Care Medicine 2000;162(2 Pt 1):578-85.
Virnig 2008 {published data only}
  • Virnig C, Gern JE. Attenuation of the September epidemic of asthma exacerbations in children: a randomized, controlled trial of montelukast added to usual therapy. Pediatrics 2008;122:S218-S219.
Weiss 2010 {published data only}
  • Weiss KB, Gern JE, Johnston NW, Sears MR, Jones CA, Jia G, et al. The back to school asthma study: the effect of montelukast on asthma burden when initiated prophylactically at the start of the school year. Annals of Allergy, Asthma & Immunology 2010;105(2):174-81.
Williams 2001 {published data only}
Wilson 2001 {published data only}
Wilson 2010 {published data only}
  • Wilson ECF, Price D, Musgrave SD, Sims EJ, Shepstone L, Murdoch J, et al. Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma: a pragmatic trial. PharmacoEconomics 2010;28(7):597-608.
Yaldiz 2000 {published data only}
  • Yaldiz E, Özkan G, Özdemir A, Gür A, Çamsari G. The role of montelukast in the reduction of high dose inhaled steroid in asthmatic patients. European Respiratory Journal 2000;16(Suppl 31):457s.
Yasui 2012 {published data only}
  • Yasui H, Fujisawa T, Inui N, Kato M, Hashimoto D, Enomoto N, et al. Impact of add-on pranlukast in stable asthma; the additive effect on peripheral airway inflammation. Respiratory Medicine 2012;106(4):508-14.
Yildirim 2004 {published data only}

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
Andersson 2001
  • Andersson F, Kjellman M, Forsberg G, Möller C, Arheden L. Comparison of the cost-effectiveness of budesonide and sodium cromoglycate in the management of childhood asthma in everyday clinical practice. Annals of Allergy, Asthma & Immunology 2001;86(5):537–44.
BTS 2011
  • British Thoracic Society, Scottish Intercollegiate Guidelines Network (BTS). British Guideline on the Management of Asthma (revised 2011). http://www.sign.ac.uk/guidelines/fulltext/101/ (accessed 3/9/13).
Busse 2006
  • Busse WW, O'Bryne PM, Holgate ST. Asthma pathogenesis. In: Adkinson Jr NF, Yunginger JW, Busse WW, Bochner BS, Holgate ST,  Simons FE editor(s). Middleton's Allergy, Principles & Practice. 6th Edition. Philadelphia: CV Mosby, 2006.
Calhoun 2001
  • Calhoun WJ. Anti-leukotrienes for asthma. Current Opinion in Pharmacology 2001;1:230-4.
Castro-Rodriguez 2009
  • Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis. Pediatrics 2009;123(3):e519-e525.
Cates 2008
  • Cates CJ, Cates MJ, Lasserson TJ. Regular treatment with formoterol for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD006923.pub2]
Cates 2012
  • Cates CJ, Oleszczuk M, Stovold E, Wieland LS. Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews. Cochrane Database of Systematic Reviews 2012, Issue 10. [DOI: 10.1002/14651858.CD010005.pub2]
Chauhan 2012
  • Chauhan BF, Ducharme FM. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2012, Issue 5. [DOI: 10.1002/14651858.CD002314.pub3]
de Benedictis 2001
  • de Benedictis FM, Teper A, Green RJ, Boner AL, Williams L, Medley H, International Study Group. Effect of 2 inhaled corticosteroids on growth: results of a randomized controlled trial. Archives of Pediatrics & Adolescent Medicine 2001;155(11):1248-54.
Ducharme 2004
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Egger 1997
  • Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):629-634.
Eid 2002
  • Eid E, Morton R, Olds B, Clark P, Sheikh S, Looney S. Decreased morning serum cortisol levels in children with asthma treated with inhaled fluticasone propionate. Pediatrics 2002;109(2):217-21.
Enting 2003
  • Enting D, Schokker S, Duiverman EJ, van der Molen T. The effectiveness of inhaled corticosteroid therapy in preschool children with asthma: a systematic review of literature. Primary Care Respiratory Journal 2003;12(2):52-7.
GINA 2011
  • Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention (updated 2011). www.ginasthma.org/local/uploads/files/GINA_Report2011_May4.pdf (accessed 3/9/13).
Heuck 2000
  • Heuck C, Heickendorff L, Wolthers OD. A randomized controlled trial of short term growth and collagen turnover in asthmatics with inhaled formoterol and budesonide. Archives of Disease in Childhood 2000;83(4):334-9.
Higgins 2008
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org.
Linzer 2007
  • Linzer JF. Review of asthma: pathophysiology and current treatment options. Clinical Pediatric Emergency Medicine 2007;8:87-95.
Lougheed 2012
  • Lougheed MD, Lemiere C, Ducharme FM, Licskai C, Dell SD, Rowe BH, et al. Canadian Thoracic Society Asthma Management Continuum – 2010 Consensus Summary for children six years of age and over, and adults. Canadian Respiratory Journal 2012;19(2):127-64.
Malone 2005
  • Malone R, LaForce C, Nimmagadda S, Schoaf L, House K, Ellsworth A, et al. The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma. Annals of Allergy, Asthma, & Immunology 2005;95(1):66-71.
Muijsers 2002
  • Muijsers RB, Noble S. Montelukast: a review of its therapeutic potential in asthma in children 2 to 14 years of age. Paediatric Drugs 2002;4(2):123-39.
NAEPP 2007
  • National Asthma Education and Prevention Program (NAEPP). Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf (accessed 3/9/13).
National Asthma Council Australia 2006
  • National Asthma Council Australia. Asthma Management Handbook 2006. www.nationalasthma.org.au/uploads/handbook/370-amh2006_web_5.pdf (accessed 3/9/13).
Paggiaro 2011
  • Paggiaro P, Bacci E. Montelukast in asthma: a review of its efficacy and place in therapy. Therapeutic Advances in Chronic Disease 2011;2(1):47-58.
PHAC 2007
  • Public Health Agency of Canada (PHAC). Life and Breath: Respiratory Disease in Canada. Respiratory Disease in Canada 2007.
Pijnenburg 2005
  • Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titrating steroids on exhaled nitric oxide in children with asthma a randomized controlled trial. American Journal of Respiratory and Critical Care Medicine 2005;172:831–6.
Pohunek 2006
Reddel 2009
  • Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An Official American Thoracic Society/European Respiratory Society Statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. American Journal of Respiratory and Critical Care Medicine 2009;180(1):59-99.
RevMan 2011
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Sharek 1999
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Suissa 2000
WHO 2011
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