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

  • Review
  • Intervention

Authors


Abstract

Background

In the treatment of children with mild persistent asthma, low-dose inhaled corticosteroids (ICS) are recommended as the preferred monotherapy (referred to as step 2 of therapy). In children with inadequate asthma control on low doses of ICS (step 2), asthma management guidelines recommend adding an anti-leukotriene agent to existing ICS as one of three therapeutic options to intensify therapy (step 3).

Objectives

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.

Search methods

We identified trials from the Cochrane Airways Group Specialised Register of Trials (CAGR), which were derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, AMED, and CINAHL; and the handsearching of respiratory journals and meeting abstracts, as well as the www.clinicaltrials.gov website. The search was conducted until January 2013.

Selection criteria

We considered for inclusion randomised controlled trials (RCTs) conducted in children and adolescents, aged one to 18 years, with asthma, who remained symptomatic despite the use of a stable maintenance dose of ICS and in whom anti-leukotrienes were added to the ICS if they were compared to the same, an increased, or a tapering dose of ICS for at least four weeks.

Data collection and analysis

We used standard methods expected by The Cochrane Collaboration.

Main results

Five paediatric (parallel group or cross-over) trials met the inclusion criteria. We considered two (40%) trials to be at a low risk of bias. Four published trials, representing 559 children (aged ≥ six years) and adolescents with mild to moderate asthma, contributed data to the review. No trial enrolled preschoolers. All trials used montelukast as the anti-leukotriene agent administered for between four and 16 weeks. Three trials evaluated the combination of anti-leukotrienes and ICS compared to the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (N = 268 participants; risk ratio (RR) 0.80, 95% confidence interval (CI) 0.34 to 1.91). There was also no statistically significant difference in percentage change in FEV₁ (forced expiratory volume in 1 second) with mean difference (MD) 1.3 (95% CI -0.09 to 2.69) in this trial, but a significant group difference was observed in the morning (AM) and evening (PM) peak expiratory flow rates (PEFR): N = 218 participants; MD 9.70 L/min (95% CI 1.27 to 18.13) and MD 10.70 (95% CI 2.41 to 18.99), respectively. One trial compared the combination of anti-leukotrienes and ICS to a higher-dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over 16 weeks (N = 182 participants; RR 0.82, 95% CI 0.54 to 1.25), nor was there any significant difference in exacerbations requiring hospitalisation. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding anti-leukotrienes as a means to taper the dose of ICS.

Authors' conclusions

The addition of anti-leukotrienes to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared to the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although anti-leukotrienes have been licensed for use in children for over 10 years, the paucity of paediatric trials, the absence of data on preschoolers, and the variability in the reporting of relevant clinical outcomes considerably limit 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.

Résumé scientifique

L'ajout d'agents antileucotriènes aux corticoïdes inhalés chez les enfants souffrant d'asthme persistent

Contexte

Une faible dose de corticoïdes inhalés (CSI) est recommandée en tant que monothérapie préférée pour des enfants atteints d'asthme persistent léger (ce que l'on appelle Etape 2 du traitement). Chez les enfants avec un contrôle insuffisant de l'asthme à faibles doses de CSI (Etape 2), les protocoles de prise en charge de l'asthme recommandent d'ajouter un agent antileucotriène aux CSI existants comme l'une des trois options thérapeutiques pour intensifier la thérapie (Etape 3).

Objectifs

Comparer l'efficacité et l'innocuité de la combinaison d'agents antileucotriènes et de CSI à l'utilisation de la même dose, à une augmentation ou une réduction progressive de la dose de CSI chez des enfants et des adolescents souffrant d'asthme persistant demeurant symptomatiques malgré l'utilisation de CSI d'entretien. En plus, nous avons voulu déterminer les caractéristiques des personnes ou des traitements, le cas échéant, qui influençait l'intenstité de la réponse attribuable à l'ajout d'antileucotriènes.

Stratégie de recherche documentaire

Nous avons identifié des essais dans le registre des essais du groupe Cochrane sur les voies respiratoires (CAGR), qui ont été estimés à partir de recherches systématiques dans des bases de données bibliographiques incluant le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE, EMBASE, PsycINFO, AMED et CINAHL; et la recherche manuelle dans des journaux de pneumologie et des résumés de conférences, ainsi que sur www.clinicaltrials.gov. La recherche a été réalisée jusqu' en janvier 2013.

Critères de sélection

Nous avons pris en compte pour inclusion les essais contrôlés randomisés (ECR) réalisés chez des enfants et adolescents âgés d'un à 18 ans, atteints d'asthme, qui sont restés symptomatiques malgré l'utilisation d'une dose de CSI d'entretien stable et pour lesquels des anti-leucotriènes ont été ajoutés, si c'était comparée à la même dose, à une augmentation ou à une réduction progressive de la dose de CSI pour au moins quatre semaines.

Recueil et analyse des données

Nous avons utilisé les méthodes standards de la collaboration Cochrane.

Résultats principaux

Cinq essais en groupes parallèles ou croisés (pédiatriques) remplissaient les critères d'inclusion. Nous avons considéré deux (40%) des essais avec un faible risque de biais. Quatre essais publiés, représentant 559 enfants (âgés de plus de six ans) et des adolescents atteints d'asthme léger à modéré, ont fourni des données pour la revue. Aucun essai ne recrutait d’enfants d'âge préscolaire. Tous les essais utilisaient le Montélukast comme agent antileucotriène administré entre 4 et 16 semaines. Trois essais évaluaient la combinaison d'antileucotriènes et de CSI comparé à la même dose de CSI seuls (Etape 3 versus Etape 2). Aucune différence statistiquement significative entre les groupes était observée dans le seul essai rapportant des participants atteints de crises nécessitant des corticoïdes oraux pendant quatre semaines (N =268 participants; risque relatif (RR) à 95% 0,80, intervalle de confiance (IC) à 95%, de 0,34 à 1,91). Il n'y avait également aucune différence statistiquement significative en termes de pourcentage de variation de VEMS₁ (volume expiratoire maximal en 1 seconde) avec la différence moyenne (DM) de 1,3 (IC à 95%, de -0,09 à 2,69) dans cet essai, mais une différence significative entre les groupes était observée le matin (AM) et le soir (PM) dans les taux de débit expiratoire de pointe (DEP): N =218 participants; DM 9,70 l/mn (IC à 95%, de 1,27 à 18,13) et DM 10,70 (IC à 95%, entre 2,41 et 18,99), respectivement. Un essai comparait la combinaison d'antileucotriènes et les CSI à forte dose de CSI (Etape 3 versus Etape 3). Aucune différence significative entre les groupes était observée dans cet essai pour les participants présentant des exacerbations nécessitant des corticoïdes oraux de secours pendant 16 semaines (N =182 participants; RR 0,82, IC à 95%, de 0,54 à 1,25), il n'y avait pas non plus de différence significative dans les exacerbations nécessitant une hospitalisation. Il n'y avait aucune différence statistiquement significative entre les groupes dans les arrêts prématurés ou en relation à autre cause dans les protocoles. Aucun essai n’explorait l'impact de l'ajout d'antileucotriènes comme un moyen de diminution de la dose de CSI.

Conclusions des auteurs

L'ajout d'antileucotriènes aux CSI n'est pas associé à une réduction statistiquement significative dans le besoin de corticoïdes oraux de secours ou d'hospitalisation comparé à la même dose ou une augmentation de la dose de CSI chez les enfants et adolescents atteints d'asthme léger à modéré. Bien que les antileucotriènes ont été autorisés pour le traitement chez les enfants depuis plus de 10 ans, la rareté des essais pédiatriques, l'absence de données sur les enfants en âge préscolaire, et la variabilité de la notification des résultats cliniques pertinentes limitent considérablement de tirer des conclusions solides. À l'heure actuelle, il n'existe aucune preuve solide permettant de soutenir l'efficacité et l'innocuité des antileucotriènes en tant que traitement en complément des CSI en stade 3 en option de l'arsenel thérapeutique pour les enfants souffrant de symptômes de l'asthme non-contrôlés avec une faible dose de CSI.

Plain language summary

Is adding an anti-leukotriene to an inhaled corticosteroid better than using an inhaled corticosteroid alone in children with persistent asthma?

Background: Asthma management guidelines recommend low-dose inhaled corticosteroids (ICS) as preferred therapy for children with mild persistent asthma. In children who have inadequate control of their asthma on low doses of ICS, anti-leukotrienes can be added to ICS. Anti-leukotrienes are a class of anti-inflammatory drugs for asthma. Almost a decade ago, a Cochrane review (Ducharme 2004) evaluating the addition of anti-leukotrienes to ICS in children and adults with asthma identified only two studies of children, one of which was only published as an abstract with insufficient information to contribute data. Considering the publication of several additional studies in the past decade, we wished to update the review with the latest literature.

Review question: To compare the effectiveness and safety of the addition of an anti-leukotriene agent to ICS to the use of the same dose of ICS alone, an increased dose of ICS, or a reduced dose of ICS in children aged one to 18 years with persistent asthma who are not well controlled with ICS alone.

Study characteristics: The evidence was updated until January 2013. We found five studies of children with asthma; of them, four studies, representing 559 children (aged six to 18 years) with mild to moderate asthma, contributed data to the review. No study enrolled pre-school children (i.e. aged under six years). Three studies compared the combination of anti-leukotrienes and ICS with the same dose of ICS alone; one study compared the combination of anti-leukotrienes and ICS to a higher dose of ICS; and no study tested whether the addition of anti-leukotriene to ICS could allow the tapering of the dose of ICS while maintaining asthma control. All studies used montelukast as the anti-leukotriene agent, which was administered for four to 16 weeks. Included studies enrolled both girls and boys and between 65% and 69% were boys. All trials enrolled children with mild to moderate airway obstruction.

Results: Whether comparing the addition of anti-leukotrienes to ICS to the same dose or an increased dose of ICS, there was no difference in the number of participants experiencing one or more moderate exacerbations (that is, requiring oral corticosteroids) or severe exacerbations (i.e. requiring a hospital admission). A single study comparing the same ICS dose reported lung function tests and showed no or small group differences depending on the test used.

Conclusion: There is no firm evidence to support that adding montelukast to ICS is safe and effective to reduce the occurrence of moderate or severe asthma attacks in children taking low-dose ICS and whose symptoms remain uncontrolled. After being on the market for more than 10 years, the limited number of available studies testing antileukotrienes in children, the absence of data on preschoolers, and the inconsistency of available trials in reporting of efficacy and safety clinical outcomes is disappointing and limit the conclusions.

Quality of the results: This review is based on a small number of identified trials conducted in children with asthma; none were conducted in preschoolers. As a single study of moderate duration reported all measures of efficacy and most measures of safety, our confidence in the quality of evidence is low. Other important measures of asthma control were either not measured or reported in different formats, so they could not be pooled. In other words, there are too few paediatric trials to conclude firmly whether either treatment is superior to the other.

Résumé simplifié

L'ajout d'antileucotriènes à un corticostéroïde inhalé est plus efficace que l'utilisation de corticoïdes inhalés seuls chez les enfants souffrant d'asthme persistent?

Contexte: Les protocoles de prise en charge de l'asthme recommandent une faible dose de corticoïdes inhalés (CSI) comme traitement de choix pour les enfants atteints d'asthme persistent léger. Chez les enfants qui ne contrôlent pas suffisamment leur asthme avec de faibles doses de CSI, les anti-leucotriènes peuvent être ajoutés aux CSI. Les anti-leucotriènes sont une classe de médicaments anti-inflammatoires pour l'asthme. Presque une décennie auparavant, une revue Cochrane (Ducharme 2004) évaluant l'ajout d'antileucotriènes aux CSI chez les enfants et les adultes asthmatiques n'a identifié que deux études portant sur des enfants, l'une de ces études était uniquement publiée sous forme de résumé avec des informations insuffisantes. Étant donné la publication de plusieurs études supplémentaires dans la dernière décennie, nous souhaitions une mise à jour la revue avec la dernière littérature.

Question de cette revue: Comparer l'efficacité et l'innocuité de l'ajout d'un agent antileucotriène aux CSI à l'utilisation de la même dose de CSI seuls, un dosage supérieur de CSI ou une dose réduite de CSI chez les enfants âgés de un à 18 ans souffrant d'asthme persistant qui ne sont pas bien contrôlés sous CSI seuls.

Caractéristiques de l'étude: Les évidences ont été mises à jour jusqu' en janvier 2013. Nous avons trouvé cinq études portant sur des enfants asthmatiques; quatre études représentant 559 les enfants (âgés de 6 à 18 ans) atteints d'asthme léger à modéré, ont fourni des données pour la revue. Aucune étude ne portait sur des enfants en âge préscolaire et (c'est à dire âgés de moins de six ans). Trois études comparaient l'association d'antileucotriènes et de CSI avec la même dose de CSI seuls; une étude comparait la combinaison d'antileucotriènes et les CSI à une dose supérieure de CSI; et aucune étude n'avait testé si l'ajout d'antileucotriènes aux CSI pouvait permettre la réduction progressive de la dose de CSI tout en maintenant le contrôle de l'asthme. Toutes les études avaient utilisé du Montélukast comme agent antileucotriène, qui était administré pendant quatre à 16 semaines. Les études inclus avaient recruté des filles et garçons mais entre 65 et 69% étaient des garçons. Tous les essais recrutaient des enfants atteints d'une obstruction des voies respiratoires légère à modérée.

Résultats: Si la comparaison de l'ajout d'antileucotriènes aux CSI à la même dose ou un dosage supérieur de CSI, il n'y avait aucune différence dans le nombre de participants avec une ou plusieurs crises modérées (c' est-à-dire, nécessitant des corticoïdes oraux) ou des exacerbations sévères (comme par exemple nécessitant une hôpitalisation). Une seule étude comparant le même dosage de CSI rapportait des tests de fonction pulmonaire et montrait une petite ou aucune différence entre les groupes selon les tests utilisés.

: Conclusion Il n'existe aucune preuve solide permettant de soutenir que l'ajout du Montélukast aux CSI est sûre et efficace pour réduire l'occurrence de crises d'asthme modérées ou sévères chez les enfants sous CSI à faible dose et dont les symptômes demeurent non contrôlés. Étant sur le marché depuis plus de 10 ans, le nombre limité d'études disponibles testant des anti-leucotriènes chez les enfants, l'absence de données avant la scolarité et le manque de cohérence des essais disponibles dans les rapports d'efficacité et d'innocuité des résultats cliniques sont décevants et limitent les conclusions.

Qualité des résultats: Cette revue est basée sur un petit nombre d'essais identifiés menés chez des enfants asthmatiques; aucun n'a été mené avant la scolarité. Comme seule une étude d'une durée modérée rapportait toutes les mesures d'efficacité et la plupart des mesures de sécurité, notre confiance dans les preuves sont de faible qualité. D'autres mesures importantes de contrôle de l'asthme étaient évaluées ou rapportés dans différents formats, donc elles n'ont pas pu être ajoutées. Dans d'autres termes, il existe trop peu d'essais pédiatriques pour permettre d'affirmer si un traitement est supérieur aux autres.

Notes de traduction

Traduit par: French Cochrane Centre 31st December, 2013
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

Summary of findings(Explanation)

Summary of findings for the main comparison. Anti-leukotrienes & ICS versus same dose ICS for asthma
  1. ¹ Single study, wide confidence interval

    ² There were no admissions to hospital in this study

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
Control Anti-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 comment

Risk 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

Summary of findings 2 Anti-leukotrienes & ICS versus higher dose ICS for asthma

Summary of findings 2. Anti-leukotrienes & ICS versus higher dose ICS for asthma
  1. ¹ Single study, wide confidence interval

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
Control Anti-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 comment

Risk 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 comment

Risk 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

Background

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

  3. adding an anti-leukotriene agent (National Asthma Council Australia 2006; BTS 2011; GINA 2011; Lougheed 2012; NAEPP 2007).

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

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

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

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).

Figure 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.

Figure 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.

Figure 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.

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
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.

Figure 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

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

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

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

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 corticosteroids1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Participants with exacerbations requiring hospital admission1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Change from baseline FEV₁ (%)1 Mean Difference (Fixed, 95% CI)Totals not selected
4 Change from baseline AM PEFR (L/min)1 Mean Difference (Fixed, 95% CI)Totals not selected
5 Change from baseline PM PEFR (L/min)1 Mean 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 reasons1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
7.1 Withdrawal due to adverse events1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
7.2 Withdrawal due to poor asthma control/exacerbations1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Serious adverse effects1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
9 Death1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
10 Overall adverse effects1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
11 Specific adverse effects1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
11.1 Upper respiratory tract infections1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11.2 Headache1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11.3 Nausea1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11.4 Elevated liver enzymes1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 1 Participants with 1 or more exacerbations requiring oral corticosteroids.

Analysis 1.2.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 2 Participants with exacerbations requiring hospital admission.

Analysis 1.3.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 3 Change from baseline FEV₁ (%).

Analysis 1.4.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 4 Change from baseline AM PEFR (L/min).

Analysis 1.5.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 5 Change from baseline PM PEFR (L/min).

Analysis 1.6.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 6 Overall withdrawals.

Analysis 1.7.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 7 Withdrawal because of specific reasons.

Analysis 1.8.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 8 Serious adverse effects.

Analysis 1.9.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 9 Death.

Analysis 1.10.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 10 Overall adverse effects.

Analysis 1.11.

Comparison 1 Anti-leukotrienes and inhaled corticosteroids versus same dose of inhaled corticosteroids, Outcome 11 Specific adverse effects.

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 corticosteroids1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Participants with exacerbations requiring hospital admission1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Overall withdrawals1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Anti-leukotrienes and inhaled corticosteroids versus higher dose of inhaled corticosteroids, Outcome 1 Participants with 1 or more exacerbations requiring oral corticosteroids.

Analysis 2.2.

Comparison 2 Anti-leukotrienes and inhaled corticosteroids versus higher dose of inhaled corticosteroids, Outcome 2 Participants with exacerbations requiring hospital admission.

Analysis 2.3.

Comparison 2 Anti-leukotrienes and inhaled corticosteroids versus higher dose of inhaled corticosteroids, Outcome 3 Overall withdrawals.

Appendices

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

Electronic searches: core databases

Database Frequency 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

Conference Years 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

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

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

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

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

None.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Lemanske 2010

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

Children 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

Interventions

PROTOCOL: 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

Outcomes

ANALYSIS: 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

Notes

Full-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
Participants

Children 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

Interventions

PROTOCOL: 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.

Outcomes

ANALYSIS: 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

Notes

Full-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
Participants

Children 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

Interventions

PROTOCOL: 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

Outcomes

ANALYSIS: 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

Notes

Full-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
Participants

Children 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

Interventions

PROTOCOL: 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

Outcomes

ANALYSIS: 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)

Notes

Full-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
Participants

Children 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

Interventions

PROTOCOL: 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

Outcomes

ANALYSIS: 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

Notes

Full-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

Ancillary