Antileucotriene PDF

Anti-leukotriene agents compared to inhaled corticosteroids
in the management of recurrent and/or chronic asthma in

adults and children (Review)
Ducharme F, di Salvio F
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2008, Issue 4
http://www.thecochranelibrary.com
Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and
children (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Analysis 1.1. Comparison 1 Anti-leukotriene (AL) vs. Inhaled glucocorticoids (in CFC-BDP equivalent), Outcome 1
Change from baseline FEV1 at 6 +/- 2 weeks. . . . . . . . . . . . . . . . . . . . . . . . 103
Change from baseline FEV1 ( L or %) pre or post bronchodilator at 12 +/- 4 weeks. . . . . . . . . . 104
Change from baseline FEV1 (L) at 24 +/- 4 weeks. . . . . . . . . . . . . . . . . . . . . . 105
Change from baseline FEV1 (L) at 40 +/- 8 weeks. . . . . . . . . . . . . . . . . . . . . . 105
Change from baseline AM PEFR (L/min) at 6 +/- 2 weeks. . . . . . . . . . . . . . . . . . . 106
Change from baseline AM PEFR (L/min) at 12 +/- 4 weeks. . . . . . . . . . . . . . . . . . . 107
Change from baseline in AM PEFR (L/min) at 24 +/- 4 weeks. . . . . . . . . . . . . . . . . . 108
Change from baseline in AM PEFR (L/min) at 40 +/- 8 weeks. . . . . . . . . . . . . . . . . . 108
Change from baseline daytime symptom scores at 6 +/- 2 weeks. . . . . . . . . . . . . . . . . 109
Analysis 1.13. Comparison 1 Anti-leukotriene (AL) vs. Inhaled glucocorticoids (in CFC-BDP equivalent), Outcome
13 Change from baseline in night-time awakenings (awakenings/night or awakenings/week->williams) at 6 +/- 2
week. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Change from baseline in night-time awakenings (awakenings/night or /week->Williams) at 12 +/- 4 weeks. . 113
Change from baseline in night-time awakenings (# or %) at 24 +/- 4 weeks. . . . . . . . . . . . . 114
Change from baseline in night-time awakenings (awakenings per week) at 40 +/- 8 weeks. . . . . . . . 114
Change from baseline mean daily use of B2-agonists (puffs/day or % ) at 6. . . . . . . . . . . . . 115
Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and i
children (Review)
Change from baseline mean daily use of B2-agonists (puffs/day) at 12 +/- 4 weeks. . . . . . . . . . . 116
Change in proportion of symptom-free days (%) at 6 +/- 2 weeks. . . . . . . . . . . . . . . . . 118
Change in proportion of symptom-free days (%) at 12 +/- 4 weeks. . . . . . . . . . . . . . . . 119
Change in proportion of symptom-free days (%) at 24 +/- 4 weeks. . . . . . . . . . . . . . . . 120
Change in rescue-free days (%) at 6 +/-2 weeks. . . . . . . . . . . . . . . . . . . . . . . 120
Change in rescue-free days (%) at 12 +/-4 weeks. . . . . . . . . . . . . . . . . . . . . . . 121
Change in rescue-free days (%) at 24 +/- 4 weeks. . . . . . . . . . . . . . . . . . . . . . 122
Days off work or school at 6 +/- 2 weeks. . . . . . . . . . . . . . . . . . . . . . . . . 122
Change from baseline quality of life (QOL) at 6 +/- 2 weeks. . . . . . . . . . . . . . . . . . 125
Change from baseline blood eosinophils at 6 +/- 2 weeks. . . . . . . . . . . . . . . . . . . . 127
Change from baseline blood eosinophils at 12 +/- 4 weeks. . . . . . . . . . . . . . . . . . . 128
Change from baseline blood eosinophils at 40 +/- 8 weeks. . . . . . . . . . . . . . . . . . . 128
LTC4 concentration (ng/mL) in nasal wash at 12 +/- 4 weeks. . . . . . . . . . . . . . . . . . 129
LTC4 concentration (ng/mL) in nasal wash at 24 +/- 4 weeks. . . . . . . . . . . . . . . . . . 129
Patients with at least 1 exacerbation requiring systemic steroids. . . . . . . . . . . . . . . . . . 130
Patients with at least 1 exacerbation requiring admission. . . . . . . . . . . . . . . . . . . . 131
Overall Withdrawals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Withdrawal due to poor asthma control/exacerbations. . . . . . . . . . . . . . . . . . . . 134
Withdrawals due to adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . 136
Overall Adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and ii
children (Review)
Elevated liver enzymes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Headache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Nausea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Oral candidiasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Patient satisfied with treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Main outcome - stratified on age. . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Main outcome - stratified on methodological quality. . . . . . . . . . . . . . . . . . . . . 147
Main outcome - stratified on ICS. . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Main outcome - stratified on duration of intervention. . . . . . . . . . . . . . . . . . . . . 149
Main outcome -stratified on asthma severity. . . . . . . . . . . . . . . . . . . . . . . . 151
Main outcome- stratified on publication status. . . . . . . . . . . . . . . . . . . . . . . 152
Main outcome- stratified on funding source. . . . . . . . . . . . . . . . . . . . . . . . 154
Analysis 1.58. Comparison 1 Anti-leukotriene (AL) vs. Inhaled glucocorticoids (in CFC-BDP equivalent), Outcome 58 %
Asthma control days during intervention period at 6 +/- 2 weeks. . . . . . . . . . . . . . . . . 155
Hoarseness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Change in sputum eosinophils. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Change in PC20. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
rescue - free days. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and iii
children (Review)
[Intervention Review]
Anti-leukotriene agents compared to inhaled corticosteroids

in the management of recurrent and/or chronic asthma in
adults and children
Francine Ducharme1 , Franco di Salvio2
1
Department of Pediatrics, McGill University Health Centre, Montreal, Canada. 2 c/o Prof Francine Ducharme , Montreal , Canada
Contact address: Francine Ducharme, Department of Pediatrics, McGill University Health Centre, Montreal Childrens Hospital, 2300
Tupper Street, Room C-538E, Montreal, Quebec, H3H 1P3, Canada. francine.ducharme@mcgill.ca.
Editorial group: Cochrane Airways Group.

Publication status and date: Edited (no change to conclusions), published in Issue 4, 2008.
Review content assessed as up-to-date: 16 October 2003.
Citation: Ducharme F, di Salvio F. 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 2004, Issue 1. Art. No.: CD002314. DOI:
10.1002/14651858.CD002314.pub2.
ABSTRACT
Background
Anti-leukotrienes agents are currently being studied as alternative first line agents to inhaled corticosteroids in mild to moderate chronic
asthma.
Objectives
To compare the safety and efficacy of anti-leukotriene agents with inhaled glucocorticoids (ICS) and to determine the dose-equivalence
of anti-leukotrienes to daily dose of ICS.
Search strategy
We searched MEDLINE (1966 to Aug 2003), EMBASE (1980 to Aug 2003), CINAHL (1982 to Aug 2003), the Cochrane Airways
Group trials register, and the Cochrane Central Register of Controlled Trials (August 2003), abstract books, and reference lists of review
articles and trials. We contacted colleagues and international headquarters of anti-leukotrienes producers.
Selection criteria
Randomised controlled trials that compared anti-leukotrienes with inhaled corticosteroids during a minimal 30-day intervention period
in asthmatic patients aged 2 years and older.
Data collection and analysis
Two reviewers independently assessed the methodological quality or trials and extracted trial data. The primary outcome was the rate
of exacerbations requiring systemic corticosteroids. Secondary outcomes included lung function, indices of chronic asthma control,
adverse effects and withdrawal rates.
Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and 1
children (Review)
Main results
27 trials (including 1 trial testing two protocols) met the inclusion criteria; 13 were of high methodological quality; 20 are published
in full-text. All trials pertained to patients with mild to moderate persistent asthma. Only 3 trials focused on children and adolescents.
Trial duration varied from 4 to 37 weeks. In most trials, daily dose of ICS was 400 mcg of beclomethasone or equivalent. Patients
treated with anti-leukotrienes were 65% more likely to suffer an exacerbation requiring systemic steroids [Relative Risk 1.65; 95%
Confidence Interval (CI) 1.36 to 2.00]. Twenty six (95% CI: 17 to 47) patients must be treated with anti-leukotrienes instead of
inhaled corticosteroids to cause one extra exacerbation. Significant differences favouring ICS were noted in secondary outcomes where
the improvement in FEV1 reached 130 mL [13 trials; 95% CI: 50, 140 mL ]. Other significant benefits of ICS were seen for symptoms,
nocturnal awakenings, rescue medication use, symptom-free days, and quality of life. Anti-leukotriene therapy was associated with
160% increased risk of withdrawals due to poor asthma control. Twenty nine (95% CI 20 to 48) patients must be treated with anti-
leukotrienes instead of inhaled corticosteroids to cause one extra withdrawal due to poor control . Risk of side effects was not different
between groups.
Authors conclusions
Inhaled steroids at a dose of 400 mcg/day of beclomethasone or equivalent are more effective than anti-leukotriene agents given in
the usual licensed doses. The exact dose-equivalence of anti-leukotriene agents in mcg of ICS remains to be determined. Inhaled
glucocorticoids should remain the first line monotherapy for persistent asthma.
PLAIN LANGUAGE SUMMARY
Anti-leukotriene agents compared to inhaled corticosteroids for people with asthma
In an asthma attack, the airways (passages to the lungs) narrow from muscle spasms and swelling (inflammation), which can cause
breathing problems, wheezing and coughing. Inhaled corticosteroid drugs are used to reduce the swelling of the airways in people with
asthma. Anti-leukotrienes are a new class of anti-inflammatory drugs that may have fewer adverse effects than inhaled corticosteroids.
The review suggests that this class of drug is safe but it is slightly less effective than a low dose of inhaled corticosteroids. More research
is needed to determine its efficacy in children.
BACKGROUND
such as ketotifen, sodium cromoglycate and sodium nedocromil
Infiltration of bronchial airways with eosinophils and neutrophils have anti-inflammatory properties, inhaled glucocorticoids re-
with production of inflammatory mediators is characteristic of main the cornerstone of asthma management because of their ef-
asthma (Murphy 1993). The most potent inflammatory mediators ficacy, tolerance, and rapid onset of action (Spahn 1996a). Pro-
may be the cysteinyl leukotrienes, which are produced by the 5- longed administration of inhaled glucocorticoids is generally con-
lipoxygenase pathway of the arachidonic acid metabolism. These sidered safe, unless the daily dose required for control of symptoms
mediators stimulate the production of airway secretions, cause remains high for a prolonged period. In these conditions, adverse
micro vascular leakage and enhance eosinophilic migration in the effects such as growth stunting in children, (Kamada 1995) sup-
airways; thus, leukotrienes are believed to play a major role in pression of the adrenal axis, (Phillip 1992; Padfield 1993; Bisgaard
mediating bronchoconstriction and inflammatory changes pivotal 1988) and bone osteopenia may be observed (Heuck 1997; Todd
in the pathophysiology of asthma (Piper 1989). 1996).
All recent consensus statements on asthma now advocate aggres- Anti-leukotrienes form a new class of anti-inflammatory drugs,
sive treatment of airway inflammation (BTS 2003; GINA 2002; which may have important glucocorticoids-sparing effects. These
Australia 2002; USA 2002; CTS 1999). Although several drugs drugs interfere either with leukotriene production (5- lipoxyge-
children (Review)
nase inhibitors) or with leukotriene receptors (leukotriene recep- Types of participants
tors antagonists). Anti-leukotrienes have the advantage of being Children aged 2 to 17 years, and adults, with chronic asthma.
administered orally in a single or twice daily dose and importantly,
seem to lack the adverse effects on growth, bone mineralisation
and on the adrenal axis, associated with long-term systemic glu- Types of interventions
cocorticoid therapy.
The intervention consisted of daily oral anti-leukotrienes at usual
It was foreseen that anti-leukotrienes may be used as first line agents licensed doses while the control intervention was any type of
in the management of mild-moderate chronic asthma. A Cochrane inhaled glucocorticoids. Interventions must have been adminis-
review (last updated in January 2002) summarised the accumu- tered for at least 30 days. No additional anti-inflammatory or
lating evidence derived from 13 randomised controlled trials and anti-asthmatic drug was allowed other than the rescue drugs,
concluded that low doses of inhaled glucocorticoids were supe- namely inhaled short-acting beta-2-agonists and short courses of
rior to leukotriene receptor antagonists. Several national guide- oral steroids.
lines currently advocate their use as second choice monotherapy
after inhaled glucocorticoids in mild asthma (BTS 2003; GINA
2002; Australia 2002; USA 2002; Boulet 2001; CTS 1999). With Types of outcome measures
the publications of new randomised controlled trials, an update
of the systematic review of the randomised controlled trials was
indicated to review the safety and efficacy of anti-leukotrienes as Primary outcomes
monotherapy as compared to inhaled glucocorticoids and to pro-
The primary outcome was the number of exacerbations requiring
vide better insight into the influence of study characteristics on
systemic corticosteroids.
results.
Secondary outcomes
OBJECTIVES
1. Other clinical outcomes reflecting the severity of asthma
The aim of this systematic review was (1) to compare the safety exacerbations such hospital admissions;
and efficacy of daily oral anti-leukotrienes with that of inhaled 2. Clinical or physiologic outcomes reflecting chronic asthma
glucocorticoids in the management of children and adults with control (such as change in symptom score, measures of
chronic asthma and (2) to determine the minimal required dose functional status and/or of quality of life, 2-agonist use, and
of maintenance inhaled glucocorticoids equivalent to the effect of pulmonary function tests);
anti-leukotriene agents. 3. Clinical and biochemical adverse effects (e.g., elevation of
We also sought to determine whether the anti-leukotriene and liver enzymes)
inhaled steroid used, intervention duration, disease severity, pa- 4. Withdrawal rates.
tients age, methodological quality, publication status and spon- Trials that only documented compliance were excluded.
sorship influenced the magnitude of effect attributable to anti- In studies designed to identify the minimum effective dose of
leukotrienes. inhaled corticosteroids needed to achieve asthma control, and
in which the control was similar to that obtained with anti-
leukotriene agents, we reported the mean (SD) effective dose of
corticosteroids. This dose may be taken to be equivalent in effect
METHODS to that of the anti-leukotriene agents.
Criteria for considering studies for this review

Search methods for identification of studies
Types of studies
Randomised controlled trials conducted in adults and/or in chil- Electronic searches
dren in which leukotriene antagonists were compared to inhaled The Cochrane Airways Group register of RCTs in asthma was
corticosteroids were included. Sensitivity analyses were performed searched using the following terms: (leukotriene* OR anti-
based on the reported quality of randomisation, concealment of leukotriene* OR leukotriene* antagonist* OR *lukast) AND [in-
allocation, blind assessment of outcomes, and description of with- haled steroids*,beclomethasone*, fluticasone*, budesonide*, tri-
drawals and dropouts. amcinolone*)
children (Review)
An advanced search of CENTRAL, the Cochrane Controlled Tri- Measures of treatment effect
als Register was completed using the above search strategy until
Difference between groups in event rates, such as number of ex-
August 2003.
acerbations in a specific period, were summarised by a ratio of
rates. In continuous outcomes, such as pulmonary function tests
or quality of life scores, the weighted or standardised mean differ-
Searching other resources ence method was used as indicated to estimate the individual and
pooled effect sizes.
Reference lists of all identified RCTs were checked to identify po-
The analysis focused on the following comparison:
tentially relevant citations. Thirdly, the international headquarters
of pharmaceutical companies producing anti-leukotrienes, were
Anti-leukotrienes versus inhaled glucocorticoids.
contacted. Enquiries regarding other published or unpublished
studies known and/or supported by these companies or their sub-
sidiaries were made so that these results could be included in our Studies designed to test equivalence in treatment efficacy require
review. We searched the abstract books of the American Tho- a different analytical approach to that used for trials in which the
racic Society and the European Respiratory Society Meetings from hypothesis under test is that one treatment has greater efficacy
1998-2003. Finally, personal contact with colleagues and trialists than its comparator. This is because small trials may favour the
working in the field of paediatric asthma were made to identify conclusion that there was no difference between treatments, since
potentially relevant trials. the confidence intervals for the two treatments will be wide and
therefore more likely to include the line of no difference between
the two treatments. Limits of treatment efficacy were set at +/- 0.10
on either side of the no-difference line for the number of patients
who experienced exacerbations requiring systemic corticosteroids
Data collection and analysis
and for FEV1. The null hypothesis tested whether the confidence
interval for the difference between the two treatments included
one of these limits.
Selection of studies
Each abstract was then reviewed and annotated as (1) RCT, (2)
clearly not an RCT or (3) unclear. The full text publications of Assessment of heterogeneity
references annotated as clearly, or potentially, relevant RCTs were Homogeneity of effect sizes between studies being pooled were
obtained and reviewed. tested by the DerSimonian & Laird method, with p<0.05 being
used as the cut-off level for significance. If heterogeneity was sug-
gested, the DerSimonian & Laird random-effects model was ap-
plied to the summary estimates. Unless specified otherwise, the
Data extraction and management
fixed effect model was used, hereafter.
Data were extracted independently by two contributors (FMD
and FDS or GH) and disagreement was dealt with by consensus.
Again, confirmation of data extraction for all included trials was
Assessment of reporting biases
sought directly from the authors and/or the funding pharmaceu-
tical companies. Funnel plots were used to test for the presence of possible publi-
cation bias (Egger 1997).
Assessment of risk of bias in included studies

Data synthesis
The methodological quality of the eligible controlled trials was
assessed with a 5-point scoring instrument, proposed by Jadad et All estimates were reported with their 95% confidence interval.
al. (Jadad 1995). This instrument evaluates the reported quality The meta-analysis was performed using MetaView, version 4.2
of randomisation, blinding, and description of withdrawals and (Cochrane Review Manager, Cochrane Collaboration, Oxford).
dropouts. This quality assessment was done independently by two Number Needed to Treat (NNT) or Number Needed to Harm
reviewers (FMD and FDS or GH). Disagreement was dealt with by (NNH) were derived from the pooled Odds Ratio using Visual
consensus. We sought confirmation of methodology for included Rx (www.nntonline.net). This method was chosen because the
trials directly from the authors and/or the funding pharmaceutical resulting NNT or NNH is independent of the way that the data
companies. is entered, which is not the case for Relative Risk, (Cates 2002).
children (Review)
Subgroup analysis and investigation of heterogeneity Busse 2001a;Israel 2002; Kanniess 2002;Kim 2000; Laviolette
Subgroup analyses were planned to explore possible reasons for 1999; Malmstrom 1999; Maspero 2001;Meltzer 2002; Nathan
heterogeneity of the primary outcome. A priori defined subgroups 2001; Riccioni 2001; Riccioni 2002b; Riccioni 2002a; Stelmach
were based on (1) anti-leukotriene, (2) inhaled steroid used, (3) 2002a; Stelmach 2002b; Williams 2001; Yamauchi 2001), three
intervention duration, (4) disease severity, and (5) patients age. were published as abstracts with additional unpublished report
Difference in the magnitude of effect attributable to these sub- provided by the authors (Hughes 1999 (BDP);Laitinen 1997;
groups was examined with the residual Chi2 test from the Peto Zieger) and the remaining 4 citations were available only in ab-
Odds Ratios (Deeks 2001). stract form (Basyigit 2001;Dempsey 2002a;Jayaram 2002;Sheth
2001a). available only in abstract form.
Design: All trials had a parallel-group design and were ran-
Sensitivity analysis domised.
For all outcomes, sensitivity analyses were performed to investigate Participants: All but three trials focused on adults, including one
the effect of methodological quality, publication bias, and fund- trial that involved adults and adolescents aged 12 years and older
ing bias, i.e. expected bias in favour of the drug marketed by the (Busse 2001b (JFP)). The three pediatric trials Maspero 2001,
sponsor(s) of the study, on study results. The fail-safe N test was Stelmach 2002a; Stelmach 2002b) pertained to children with a
used to assess the robustness of the results (Gleser 1996). mean age of 10 to 12 years. Most trials described a gender ra-
tio hovering around 40-60% males; eight trials (Dempsey 2002a;
Hughes 1999 (BDP); Laitinen 1997; Maspero 2001; Riccioni
2001; Riccioni 2002b; Riccioni 2002a;Yamauchi 2001) focused
on asthmatics with mild airway obstruction, as defined by a base-
RESULTS line FEV1 >= 80% of predicted, while the remaining trials en-
rolled patients with moderate airway obstruction (i.e. with a base-
line FEV1 between 50-80% of predicted). Three trials did not re-
Description of studies port baseline FEV1( Basyigit 2001;Jayaram 2002;Williams 2001).
Asthma triggers were seldom reported; when atopy was reported,
See: Characteristics of included studies; Characteristics of excluded
it involved 32% to 100% of participants.
studies.
Intervention duration: The trials varied in the duration of in-

Results of the search tervention from 4-8 weeks (Basyigit 2001; Baumgartner 2003;
Brabson 2002; ; Dempsey 2002a; Hughes 1999 (BDP); Israel
The search strategy last updated in August 2003 yielded additional
2002; Jayaram 2002; Kanniess 2002; Kim 2000; Laitinen 1997;
212 citations for a total of 658 citations. Of these 630 citations
Nathan 2001; Riccioni 2001; Stelmach 2002a; Stelmach 2002b;
were excluded for the following mutually exclusive reasons: (1)
Yamauchi 2001), 12-16 weeks (Bleecker 2000; Busse 2001b (JFP);
duplicate references (N = 162) including 2 previously included
Laviolette 1999; Malmstrom 1999; Riccioni 2002b; Riccioni
trials (Baumgartner 1999, Skalky 1999) now published in full text
2002a; Sheth 2001a; Zieger), and 24 to 37 weeks (Busse 2001b;
(Baumgartner 2003;Israel 2002), (2) not a randomised controlled
Meltzer 2002; Maspero 2001; Williams 2001).
trial (N = 253) or ongoing trials (N =1), (3) subjects were not
Intervention drugs were: montelukast 5 to 10 mg die, depend-
asthmatics (N = 17), (4) the tested intervention was not anti-
ing on age, for the 3 paediatric studies (Maspero 2001; Stelmach
leukotrienes (N = 17), (5) the control intervention was not inhaled
2002a; Stelmach 2002b), montelukast 10 mg die for 14 adult stud-
corticosteroids (N = 124), (6) use of higher than licensed doses
ies (Baumgartner 2003; Busse 2001b; Dempsey 2002a; Hughes
of anti-leukotrienes (N=1), namely a previously included trial (
1999 (BDP); Israel 2002; Jayaram 2002; Kanniess 2002;Laviolette
Korenblat 1998), (7) use of non permitted drugs (N = 28), (8) the
1999; Malmstrom 1999; Meltzer 2002; Riccioni 2002b; Riccioni
tested intervention was administered for less than 4 weeks (N =
2002a; Williams 2001;Zieger), pranlukast 450 mg die for one trial
19), (9) outcomes measures did not reflect asthma control (N =
(Yamauchi 2001),and zafirlukast 20 mg bid for the remaining 9
8) and (10) acute care setting (N=1). Due to the large number of
trials (Basyigit 2001;Bleecker 2000; Brabson 2002;Busse 2001b
citations considered, the references and reasons for exclusion are
(JFP); Kim 2000; Laitinen 1997; Nathan 2001; Riccioni 2001;
provided only for full-text randomised controlled trials.
Sheth 2001a). One study tested two doses of anti-leukotrienes, in-
cluding a higher than licensed doses of zafirlukast (i.e., 80 mg bid)
Included studies (Laitinen 1997). Only data pertaining to licensed doses of anti-
leukotrienes that is, montelukast 5 mg die (children <15 years),
Twenty seven, including 14 new, trials met the inclusion crite-
montelukast 10 mg die (patients aged 15 years), zafirlukast mg
ria for this review. Of these, 20 were published in full text (
bid (patients 12 years) and pranlukast 450 die (adults) were in-
Baumgartner 2003;Bleecker 2000; Brabson 2002;Busse 2001b;
children (Review)
cluded. Fourteen trials had high (4) reported quality as per the 5-
The daily dose of inhaled corticosteroids (control intervention) in point Jadad score. Methodology was confirmed in all but ten
mcg beclomethasone dipropionate (BDP)-equivalent was uniform trials (Basyigit 2001; Brabson 2002; Dempsey 2002a; Jayaram
across 21 trials; seven trials tested a daily dose of 400 mcg of BDP 2002; Kanniess 2002; Meltzer 2002; Nathan 2001; Sheth 2001a;
(Baumgartner 2003; Hughes 1999 (BDP); Israel 2002; Laviolette Yamauchi 2001; Zieger)
1999; Malmstrom 1999; Williams 2001; Yamauchi 2001;), one Randomisation. Seventeen trials reported an appropriate randomi-
trial used 400-500 mcg/day of BDP (Laitinen 1997) while the 11 sation method. Nine trials failed to describe the method of ran-
trials used fluticasone propionate 200 mcg/day (Bleecker 2000; domisation so appropriateness could not be assessed (Basyigit
Brabson 2002 ;Busse 2001b; Busse 2001b (JFP); Hughes 1999 2001; Brabson 2002; Dempsey 2002a; Jayaram 2002; Kanniess
(FP); Kanniess 2002; Kim 2000; Meltzer 2002; Nathan 2001; 2002; Nathan 2001; Sheth 2001a; Yamauchi 2001;Zieger). In one
Sheth 2001a; Zieger). Only 3 trials testing a high dose of gluco- trial (Williams 2001), however, the randomisation was clearly con-
corticoids (800 mcg/day of budesonide) (Riccioni 2001;Riccioni sidered inadequate. The first phase of this study was a randomised
2002b;Riccioni 2002a) while one trial (Jayaram 2002) failed to re- trial of anti-leukotrienes compared to placebo, followed by an ex-
port the dose used. Three trials used a low dose of beclomethasone tension phase comparing anti-leukotrienes with inhaled corticos-
or equivalent ( Dempsey 2002a; Maspero 2001; Stelmach 2002a). teroids. No second randomisation procedure was performed at
One study (Hughes 1999 (BDP)) used two control interventions, the beginning of the extension phase despite a 51% (459/895)
each a different type of inhaled corticosteroid; reported as Hughes dropout rate from the initial trial.
1999 (BDP) with 400 mcg of BDP and Hughes 1999 (FP) with Blinding of allocation. Most trials were double blind. Double
200 mcg/day of fluticasone dipropionate. The study is hereafter re- blinding was clearly reported by all but 8 trials, 3 of which clearly
ported as 2 studies; however to avoid counting the patients twice, used an open-label design (Hughes 1999 (BDP); Maspero 2001;
the sample of the control group was divided by two for each sub Yamauchi 2001); 3 trials reported double-blinding (of patients
trial and assessors) with no use of placebo raising doubt as to bias by
In all trials, the dose of inhaled corticosteroids was maintained the treating physician (Riccioni 2001; Riccioni 2002b; Riccioni
throughout the intervention period; no trial tapered the dose of 2002a) and the remaining 2 abstracts failed to report whether any
inhaled corticosteroids to the minimum effective dose. The dose of blinding occurred (Basyigit 2001; Jayaram 2002).
inhaled glucocorticoids, reported ex-valve, was recorded as User Withdrawals were usually well described. Withdrawal rates varied
defined order in mcg of chlorofluorocarbon (CFC)-propelled between 0% (Hughes 1999 (BDP)) and 29% (Busse 2001b) in
beclomethasone-equivalent, where irrespective of delivery sys- the anti-leukotriene groups and 0% (Hughes 1999 (BDP)) and
tem used, 1 mcg of beclomethasone = 1 mcg of budesonide = 0.5 28% (Busse 2001b (JFP)) in the inhaled corticosteroid groups.
mcg of fluticasone = 2 mcg of triamcinolone = 2 mcg of flunisolide.
USA 2002
Co-intervention. With the exception of Williams 2001 that re- Effects of interventions
ported the use of theophylline in some patients, no trials reported
Of the 27 included trials (28 trials when counting as 2 trials
the use of additional anti-asthmatic drugs other than rescue 2-
the study testing two inhaled steroid preparations Hughes 1999
agonists and oral corticosteroids.
(BDP); Hughes 1999 (FP), four trials all published only in ab-
Outcomes
stract form (Basyigit 2001; Dempsey 2002a; Jayaram 2002; Sheth
Whenever possible, outcomes measured at 6 2 week, 12 4
2001a) reported data in a way that could not be used in this review.
weeks, and 24 weeks or more were considered. The primary out-
The meta-analysis therefore pertains to 24 trials contributing data
come, the number of patients with exacerbations requiring sys-
to one or more of the following outcomes.
temic steroids, was documented in 18 trials. Other reported out-
comes included change in forced expiratory volume in one second
EXACERBATIONS REQUIRING SYSTEMIC STEROIDS
(FEV1), change in morning peak expiratory flow rate (PEFR),
Eighteen trials (counting twice the trial comparing leukotriene re-
symptom scores, quality of life, daily 2-agonist use, percentage
ceptor antagonists to two inhaled glucocorticoids Hughes 1999
of rescue-free days, number of patients with exacerbations requir-
(BDP); Hughes 1999 (FP) ) contributed complete data to the pri-
ing hospital admission, withdrawals and adverse effects. Four tri-
mary outcome. Patients treated with anti-leukotrienes displayed a
als, all published in abstract form (Basyigit 2001;Dempsey 2002a;
65% increased risk of experiencing an exacerbation requiring sys-
Jayaram 2002; Sheth 2001a) contributed no data in the format
temic steroids as compared to those treated with inhaled steroids
required for the meta-analysis.
[Relative Risk (RR)=1.65, (95% Confidence Interval (CI): 1.36,
2.00, Figure 1]. If 26 (95% CI 17 to 47) patients are treated with
anti-leukotrienes rather than inhaled corticosteroids, there will be
one extra exacerbation requiring systemic steroids (NNH), Figure
Risk of bias in included studies 2. There was no evidence of systematic bias identified by the test
children (Review)
for funnel plot asymmetry (intercept 0.33, 95% CI -0.10 to 0.75).
The fail-safe N (the number of unpublished studies with null re-
sults needed to negate the current finding) was 110. Selecting only
one inhaled steroids group (BDP or FP) as comparator in the 3-
group Hughes trial fail to affect the overall estimate due to the
absence of event in this study. Although, there was no heterogene-
ity between and within anti-leukotrienes, the following subgroup
analyses were performed on the main outcome to explore possible
effect modifiers.
Figure 1. Forest plot of comparison: 1 Anti-leukotriene (AL) vs. Inhaled glucocorticoids (in CFC-BDP
equivalent), outcome: 1.38 Patients with at least 1 exacerbation requiring systemic steroids.
children (Review)
Figure 2. If 100 people are treated with ALA rather than ICS there will be four extra patients with at least
one exacerbation.
Anti-leukotrienes lent, there was no significant group difference (Chi2 = 0.97 (1df ),
There was no significant difference in the risk of exacerbations re- P=0.9) between trials using fluticasone [n=6 trials: RR=2.11 (95%
quiring systemic steroids, attributable to the anti-leukotrienes used CI:1.39 to 3.49)] as compared to those using beclomethasone
(Chi2 = 5.16 (2 df ), P=0.08). Low dose inhaled glucocorticoids dipropionate [n=5 trials: RR=1.54 (95% CI:0.92 to 2.56), ran-
were more protective for exacerbations than anti-leukotrienes. In- dom effect model] . Six trials were excluded as they tested higher
deed, leukotriene receptor antagonists were associated with an or lower dose of BDP-equivalent.
increased risk of exacerbations whether pooling the trials test- Duration of intervention
ing montelukast 10 mg once daily [N= 10 trials, Relative Risk The duration of intervention appeared as a determinant of the
(RR)=1.56, (95% Confidence Interval (CI): 1.25 to 1.94] or those magnitude of effect (Chi2 = 5.97 (2 df ), P=0.05). As expected by
using zafirlukast 20 mg twice daily [N=5 trials, Relative Risk the nature of the main outcome, the magnitude of effect increased
(RR)=2.62, 95% Confidence Interval (CI): 1.57 to 4.38]. The with duration of treatment, where 4 to 8 weeks of treatment re-
3 pediatric trials testing montelukast 5 to 10 mg, could not be sulted in a 73% increased risk of exacerbations requiring systemic
pooled because two reported no event. No heterogeneity was ob- steroids [9 trials: RR=1.73, (95% CI: 1.09 to 2.74) and 12 to
served within trials using either montelukast or zafirlukast. 16 weeks of treatment was associated with a 130% increased risk
favouring inhaled glucocorticoids [6 trials: RR=2.28, (95% CI:
Inhaled corticosteroids 1.62 to 3.21)]. Trials of 24 weeks or more showed no significant
Focusing on the 11 trials using the same dose-equivalency of in- group differences [3 trials: RR=1.25, (95% CI: 0.95 to 1.65), fixed
haled steroids, i.e., 400 mcg/day of CFC-beclomethasone-equiva-
children (Review)
effect model]. Of note, two of these three trials suffer from no A significant group difference in the improvement from baseline
blinding (Maspero 2001) or improper randomisation procedure ( in FEV1 was observed at all points in time in favour of inhaled cor-
Williams 2001), raising doubts to the validity of these latter find- ticosteroids : at 6 2 weeks [13 trials: Standardised Mean Differ-
ings. ence (SMD)= -0.26, 95% CI: -0.33 to -0.20, fixed effect model],
Asthma severity at 12 4 weeks [8 trials: SMD= -0.25, 95% CI: -0.40 to -0.11,
Asthma severity on baseline also influenced the relative risk of exac- random effect model], and at 24 or more weeks [4 trials: WMD=
erbations (Chi2 = 6.57 (1 df ), P=0.01). The superiority of inhaled 130 mL, 95% CI: 80 to 180].
steroids was clearly more apparent in patients with moderate air- Greater improvement in morning PEF was also apparent in the
way obstruction, i.e., with a baseline FEV1 between 50% and 80% group treated with inhaled corticosteroids as compared to anti-
of predicted [10 trials: RR=2.15, (95% CI: 1.64 to 2.81)] than in leukotrienes with changes of 19 to 27 L/min at 6 2 weeks [10
those with mild obstruction, i.e., with baseline FEV1 80% of trials: WMD= 19 L/min, 95% CI: 15 to 23], at 12 4 weeks
predicted [7 trials: RR=0.83, (95% CI: 0.43 to 1.58)]. One trial ( [6 trials: WMD= 22 L/min, 95% CI: 13 to 32, random effect
Williams 2001) which failed to report baseline airway obstruction model], and at 24 or more weeks [3 trials: WMD= 27 L/min, 95%
was excluded from this subgroup analysis. CI: .20, 35].
Age of subjects Significant group differences in favour of inhaled corticosteroids
Among the three pediatric trials, only one 24-week open-label trial were also observed for the following outcomes at all points in time.
(Maspero 2001) reported any exacerbations requiring systemic For sake of simplicity, only data measured at 12 weeks are pre-
steroids; thus no pooling of pediatric trials was possible for the sented; a lower improvement with anti-leukotrienes were observed
main outcome. Although the protective effect of anti-leukotrienes for the change in symptom score [6 trials, SMD=0.29, 95% CI:
is clearly inferior to that of inhaled glucocorticoids in adults [N=15 0.21 to 0.37], nocturnal awakenings [6 trials, SMD=0.21, 95%
trials: RR=1.71 (95% CI:1.40 to 2.09)], there is insufficient to CI: 0.13 to 0.30], daily use of 2-agonists [6 trials, WMD= 0.28
make any conclusion as to their efficacy in children. puffs/day, 95% CI: 0.20 to 0.36], symptom-free days [3 trials,
Methodological quality WMD= -12, 95% CI: -16 to -7], rescue-free days [3 trials, WMD=
Reported methodological quality of trials influenced the mag- -14%, 95% CI: -18 to -10], and quality of life [2 trials: WMD=-
nitude of the group difference ( Chi2 = 4.98 (1 df ), P=0.03). 0.3, 95% CI: -0.4 to -0.2]. Similarly, the percentage, instead of
While there was no significant group difference among the 7 tri- change, of asthma control days [3 trials: WMD=-8 %, 95% CI:
als with low reported methodological quality, i.e., Jadads score -15 to -1] and of rescue-free days [2 trials: WMD= -9%, 95%
<4, [RR=0.83, 95% CI: 0.43 to 1.59], the superiority of inhaled CI: -14 to -03] favoured inhaled glucocorticoids. The standard
glucocorticoids over leukotriene receptor antagonists was striking mean difference was used for the symptom scores and nocturnal
among 11 methodologically strong trials, i.e., Jadads score 4, awakenings because scales differed between trials. There was no
reporting this outcome [RR=1.83, 95% CI: 1.29 to 2.60]. significant group difference in the number of days off school/work
Publication [2 trials, WMD= 0.06 days, -0.03 to 0.15] or hoarseness [2 trials:
Due to the paucity of unpublished studies reporting an any ex- RR=0.25, 95% CI: 0.03, 2.24].
acerbation requiring systemic steroids (Zieger, the possibility of Although few trials examined indices of airway inflammation,
publication bias could not be assessed. there was a significant group difference in the change in serum
Funding source eosinophils in favour of inhaled corticosteroids at 6 weeks [4 tri-
Source of funding did not significantly influence results (Chi2 = als, WMD=0.06 x 109 , 95% CI: 0.03 to 0.08, fixed effect model]
4.54 (2 df ), P=0.10). Combining the results of trials published but not at 12-16 weeks [2 trials, WMD=0.0 x 109 , 95% CI: -
by producers of anti-leukotrienes gave equivocal results [6 trials: 0.03 to 0.02]. One pediatric trial examined the change in LTC4
RR=1.38, (95% CI: 0.90, 2.12] whilst the combined results of concentration in nasal washes with no group difference observed
trials published by producers of inhaled steroids reported greater at 12 weeks [0.70 ng/mL, 95% CI: -2.51 to 1.11] or 24 weeks [-
effect of their own product[7 trials: RR=2.24, (95% CI: 1.44, 0.50 ng/mL, 95% CI: -2.55 to 1.55].
3.49) and the small trials with no industry funding reported no WITHDRAWALS
group difference, but the confidence intervals were wide [5 trials: Anti-leukotriene therapy was associated with a 30% increased
RR=0.57, (95% CI: 0.12, 2.61, random effect). risk of overall withdrawals [N=19 trials, RR=1.3, 95% CI: 1.1 to
OTHER OUTCOMES REFLECTING THE SEVERITY OF 1.6, random effect model]. The withdrawals appeared to be at-
ASTHMA EXACERBATIONS tributable to a marked increased risk of withdrawals due to poor
There was no significant group difference in the number of pa- asthma control [N=17 trials, RR=2.6, 95% CI: 2.0 to 3.4, fixed
tients experiencing an exacerbation requiring hospital admission effect model] and not due to adverse effects [N=14 trials, RR=1.2,
[5 trials: RR=1.62 (95% Confidence Interval: 0.64, 4.15]. 95% CI: 0.9 to 1.6, fixed effect model]. If 29 patients are treated
OUTCOMES REFLECTING CHRONIC ASTHMA CON- with anti-leukotrienes rather than inhaled corticosteroids there
TROL will be one extra withdrawal due to poor asthma control , NNH
children (Review)
29 (95% CI 20 to 48). over anti-leukotriene agents. Inhaled corticosteroids were more ef-
fective than anti-leukotrienes in improving spirometry (FEV1 and
ADVERSE EFFECTS PEFR), quality of life, the percentage of symptom-free and rescue-
There was no significant group difference in the number of patients free days, as well as in reducing symptoms, night awakenings and
who experienced any adverse effects, [N=15 trials, RR=0.99, rescue 2-agonist use. These group differences, evident within 4-
95% CI: 0.93 to 1.04, fixed effect model], which met our defi- 6 weeks of treatment, persisted for 12 to 37 weeks.
nition of equivalence. There was also no significant difference in
elevation of liver enzymes, [N=6 trials, RR=1.3, 95% CI: 0.7 to No trial attempted to taper inhaled corticosteroids to the lowest
2.3], headaches [N=16 trials, RR=0.9, (95% CI: 0.8 to 1.1], nau- effective dose. Thus, the study design of identified studies did
sea [N=12 trials, RR=1.0, 95% CI: 0.7 to 1.5)], oral candidiasis not allow the precise determination of the glucocorticoid-dose
[N=2 trials, RR=0.15, 95% CI: 0.02 to, 1.18], or death which was equivalency of anti-leukotrienes. Based on the above evidence,
reported in only 1 trial. No heterogeneity was observed for any of however, anti-leukotrienes at usual licensed doses are less effective
the above outcomes. than 400 mcg/day of beclomethasone-equivalent.
The risk of overall adverse effects was similar in both groups, meet-
ing our a priori definition of equivalence. There was no group
difference in the following specific adverse effects, namely liver
DISCUSSION enzyme elevation, headaches, oral candidiasis, nausea, and death.
Anti-leukotriene use was not associated with an increased risk of
In symptomatic subjects with mild to moderate persistent asthma,
withdrawals due to adverse effects. However, adverse effects typi-
4 to 37 weeks of treatment with daily oral anti-leukotrienes carries
cally associated with inhaled steroids such as growth suppression
a 65% increased risk of an asthma exacerbation requiring systemic
(in children), osteopenia and adrenal suppression were not mea-
corticosteroids than treatment with 400 mcg/day of inhaled be-
sured, thus preventing a fair comparison of the safety of long-term
clomethasone or equivalent. Although the magnitude of the effect
use of inhaled steroids vs. anti-leukotrienes.
was not significantly influenced by the selection of anti-leukotriene
and inhaled steroid preparations, publication status, or funding The increase risk of overall withdrawals was significantly higher
source, three factors clearly affected the importance of the findings: among patients treated with anti-leukotriene agents as compared
severity of baseline airway obstruction, duration of intervention, to inhaled steroids. Most of the increased risk seems attributable
and reported methodological quality. The superiority of inhaled to the 160% increased risk of withdrawals due to poor asthma
glucorticoids was marked in patients with a baseline FEV1 of 50% control with the use of anti-leukotrienes.
to 80% of predicted who experienced a 100% increased risk of
exacerbations requiring systemic steroids with leukotriene recep-
tor antagonists, while there was no significant group difference,
nor equivalence, among patients with normal baseline spirome- The results of this review pertain to asthmatic adults with a mild
try. Although, the increased risk of exacerbations associated with to moderate persistent asthma, i.e., with a mean baseline FEV1
leukotriene receptor antagonists was present within 4 to 8 weeks greater than 50% of predicted. The results should be generalized
of treatment, the effect was particularly striking after 12-16 weeks with caution to children; the three pediatric trials could not be
where a 130% increased risk was noted. While no significant group pooled on the risk of exacerbations and contributed few data on
difference were observed when pooling trials with lower reported the secondary outcomes. More trials are needed to compare the
methodological quality (due to inappropriate/unclear blinding or safety and efficacy of anti-leukotrienes versus inhaled steroids as
randomisation procedures), the superiority of inhaled glucocorti- monotherapy in the treatment of pediatric asthma
coids was marked among the trials with high quality. The indi-
Despite the abundance of literature on anti-leukotrienes, only
vidual effect of these three factors could not be distinguished as
11% of randomised controlled trials were designed to compare
the number of trials was insufficient to perform a meta-regression.
the safety and efficacy of anti-leukotrienes with that of inhaled
Due to poor reporting, it was impossible to examine the effect of
glucocorticoids; 51% of trials failed to compare anti-leukotrienes
allergic rhinitis or atopy on the comparative effectiveness of both
to the inhaled glucocorticoids, the current standard of therapy. In
treatment options. The paucity of methodologically strong pedi-
most cases, the comparator group received placebo. Most (14/23)
atric trials, preventing any firm conclusion in children is worrying,
included trials contributing data to the meta-analysis were of high
particularly in view of the high prescription rate of leukotriene
reported methodological quality (Jadad score 4). The direct
receptor antagonists instead of inhaled glucocorticoids in some
confirmation of methodology and extracted data from the authors
countries, such as the USA.
or sponsors of 17 of 23 trials contributing data and the voluntary
All but two secondary outcomes (the percentage of days off school disclosure of data for 3 unpublished trials, strengthen the value of
or work and admission) favoured the use of inhaled corticosteroids this review.
children (Review)
This review summarises the best evidence available until August compare leukotriene receptor antagonists to 200 mcg/day or to
2003. With 14 new trials, it represents a significant update from the minimal effective dose of beclomethasone-equivalent .
the previous update in January 2002. In line with the previous
Future trials should aim for the following design characteristics:
update, the present review clearly identified a large effect size in
favour of inhaled steroids. The robustness of the study results is - double blinding, adequate randomisation, and complete report-
further supported by a fail-safe N of 110 trials, indicating strong ing of withdrawals and dropouts with intention to treat analyses
support for the superiority of inhaled steroids, administered at 400
- parallel-group
mcg/day of beclomethasone or equivalent, over anti-leukotrienes.
The effect appeared stronger in patients with moderate as com- - mild asthmatics (children and adults reported separately)
pared to mild airway obstruction, with increased duration of treat-
- tapering of inhaled corticosteroids to the minimal effective dose
ment, and in trials with higher reported methodological quality.
or stable at 200 mcg/day or equivalent
However, the individual effect of these three factors on the main
outcome could not be untangled because of the insufficient num- - have a minimal intervention period of 24-52 weeks to assess the
ber of trials to perform a meta-regression. long-term side effects of both interventions (anti-leukotrienes and
inhaled corticosteroids)
- complete reporting of continuous (denominators, mean change
AUTHORS CONCLUSIONS and mean standard deviation of change) and dichotomous (de-
Implications for practice nominators and rate) data.
In symptomatic adult asthmatics with mild to moderate asthma, - specific reporting of exacerbations requiring systemic steroids
anti-leukotrienes are less effective than inhaled corticosteroids in
maintaining asthma control. The use of anti-leukotrienes is as- - systematically document reasons for withdrawals and adverse ef-
sociated with a 65% increased risk of experiencing an exacerba- fects, including those associated with inhaled corticosteroids such
tion requiring systemic steroids. The superiority of inhaled cor- as oral candidiasis, osteopenia, adrenal suppression, growth sup-
ticosteroids is observed within 4 to 8 weeks of treatment. Anti- pression, etc.
leukotrienes are also less effective than inhaled corticosteroids - comparing different anti-leukotriene agents (synthesis inhibitor
in improving lung function and quality of life, and in reducing and receptor antagonists)
symptoms, nocturnal awakenings, and use of rescue 2-agonists.
The observed disadvantage persists at 12-16 weeks of treatment.
The higher rate of withdrawals due to poor asthma control in
the anti-leukotriene group supports the above findings. Although
ACKNOWLEDGEMENTS
anti-leukotrienes have a similar safety profile than that of inhaled
steroids, one must take note that adverse effects typically associated We wish to thank Franco Di Salvio and Giselle Hicks for their par-
with inhaled steroids such as growth suppression (in children), os- ticipation in the assessment of methodology and data extraction,
teopenia and adrenal suppression have not been measured in these and diligent data entry. We are indebted to the following individ-
trials. The evidence does not support the use of anti-leukotrienes uals who replied to our request for confirmation of methodology
as substitute for inhaled steroids that should remain the first line and data extraction, and graciously provided additional data when-
therapy for asthma. ever possible: Christopher Miller and Susan Shaffer from Astra-
Zeneca, USA; Ian Naya and Roger Metcalf for Astra-Zeneca, Swe-
Implications for research den; Theodore F Reiss and GP Noonan from Merck Frosst, USA;
Frank Kanniess from the Pulmonary Research Institute, Germany;
Future studies should focus on children in whom few method-
and Graziano Riccioni, Italy, Sept-Oct 2003 .
ologically strong trials have been published. Long-term trials with
adequate documentation of adverse effects associated with inhaled We are indebted to the Cochrane Airways Review Group, namely
glucocorticoids should be preferred to provide a fair comparison Toby Lasserson and Karen Blackhall, for the literature search and
of the safety of both treatment options. In order to better assess ongoing support, and Paul Jones and Christopher Cates for their
the dose-equivalence of anti-leukotrienes, which is clearly less than constructive comments. A special thanks to Mrs Anne James from
400 mcg/day of beclomethasone or equivalent, future trials should the Consumer group for writing the original synopsis.
children (Review)
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2002;109(1):6874. F, et al.Oral montelukast versus inhaled beclomethasone in 6 to 11-
Hughes 1999 (BDP) {unpublished data only} year old children with asthma: results of an open-label extension
Hughes GL, Edelman JM, Turpin JA, Liss C, Weeks K, et study evaluating long-term safety, satisfaction, and adherence to
al.Randomized, open-label pilot study comparing the effects of therapy. Current Medical Research and Opinion In Press 2001.
montelukast sodium tablets, fluticasone aerosol inhaler, and Meltzer 2002 {published data only}
budesonide dry powder inhaler on asthma control in mild Meltzer EO, Lockey RF, Friedman BF, Kalberg C, Goode-Sellers S,
asthmatics. American Journal of Respiratory & Critical Care Medicine Srebro S, Edwards L, Rickard K for the Fluticasone Propionale
1999;159:A641. Clinical Research Study Group. Efficacy and safety of low-dose
Hughes 1999 (FP) {unpublished data only} fluticasone propionate compared with montelukast for maintenance
Hughes GL, Edelman JM, Turpin JA, Liss C, Weeks K, et treatment of persistent asthma. Mayo Clin Proc 2002;77:437445.
al.Randomized, open-label pilot study comparing the effects of Nathan 2001 {published data only}
montelukast sodium tablets, fluticasone aerosol inhaler, and Nathan RA, Bleecker ER, Kalberg C and the Fluticasone
budesonide dry powder inhaler on asthma control in mild Propionate Study Group. A comparison of short-term treatment
children (Review)
with inhaled fluticasone propionate and zafirlukast for patients with Zieger {published data only}
persistent asthma. Am J Med 2001;111:195202. Zieger RS for the MIAMI Study Research Group. Rescue-free days
Riccioni 2001 {published data only} in patients with mild persistent asthma receiving montelukast
Riccioni G, Castronuove M, De Benedictis M, Pace-Palitti V, Di sodium or an inhaled corticosteroid. Poster.
Gioacchino M, Della Vecchia R, Schiavone C, Sensi S, Guagnano References to studies excluded from this review
M.T. Zafirlukast versus budesonide on bronchial reactivity in
subjects with mild-persistent asthma. International Journal of Abbott Pharma 1996 {published data only}
Immunopathology and Pharmacology 2001;14(2):8792. Abbott Pharmaceuticals. Zyflo Filmtab (zileuton) product
description. Abbott Laboratories 1996.
Riccioni 2002a {published data only}
Riccioni G, DOrazio N, Di Ilio C, Della Vecchia R, De Lorenzo Allen 1997 {published data only}
A. Effectiveness and safety of montelukast versus budesonide at Allen A, Georgiou P, Compton C, Walls C, Hibell M, Tomson DJ,
difference doses on bronchial reactivity in subjects with mild- et al.Lack of pharmacokinetic and pharmacodynamic interactions
persistent asthma [Efficacia e tollerabilita del montelukast verso between pranlukast (Ultair) and terfenadine. American Thoracic
budesonide a diverso dosaggio sulla reattivita bronchiale in soggetti Society. 1997:Abs C49.
con asma di grado lievepersistente]. Clin Ter 2002;155(317):321. Altman 1998 {published data only}
Riccioni 2002b {published data only} Altman LC, Munk Z, Seltzer J, Noonan N, Shingo S, Zhang J, et
Riccioni G, Ballone E, DOrazio N, Sensi S, Di Nicola M, Di al.A placebo-controlled, dose-ranging study of montelukast, a
Mascio R, Santilli F, Guagnano MT, Della Vecchia R. Effectiveness cysteinyl leukotriene-receptor antagonist. Journal of Allergy &
of montelukast versus budesonide on quality of life and bronchial Clinical Immunology 1998;102:506.
reactivity in subjects with mild-persistent asthma. Int J Anonymous 1997 {published data only}
Immunopathol Pharmacol 2002;15(2):149155. Anonymous. Zileuton for asthma. Medical Letter on Drugs &
Sheth 2001a {published data only} Therapeutics 1997;39(995):189.
Sheth K, Edwards L, Srebro S, Rickard K. Effects of baseline Barnes 1996 {published data only}
pulmonary function on treatment response: low-dose fluticasone Barnes NC, Black B, Syrett N, Cohn J. Reduction of exacerbations
versus zafirlukast. Am Allergy Asthma Immunol 2001;86:2001. of asthma in multi-national clinical trials with zafirlukast
(Accolate). Allergy 1996;51(Suppl 30):84.
Sheth 2001b {published data only}
Sheth K, Edwards L, Srebro S, Rickard K. Effects of baseline Barnes 1997 {published data only}
pulmonary function on treatment response: low-dose fluticasone Barnes NC, de Jong B, Miyamoto T. Worldwide clinical experience
versus zafirlukast. Am Allergy Asthma Immunol 2001;86:2001. with the first marketed leukotriene receptor antagonist. Chest 1997;
111 Suppl(2):5260.
Skalky 1999 {unpublished data only}
Skalky CS, Edelman JM, Polis A, Bird S, Gormley GJ, Israel E. Barnes 1997b {published data only}
Montelukast sodium (MK) compared to inhaled beclomethasone Barnes NC, Pujet J-C. Pranlukast, a novel leukotriene recpetor
dipropionate (BD) in adult asthmatics: a randomized clinical trial. antagonist: results of the first european, placebo controlled,
Journal of Allergy & Clinical Immunology. 1999; Vol. 103, issue 1 multicentre clinical study in asthma. Thorax 1997;52:5237.
Part 2:Abs. 880, protocol #070. Barnes 2001 {unpublished data only}
Stelmach 2002a {published and unpublished data} Barnes N, Wei LX, Reiss TF, Leff JA, Shingo S, Yu C, et al.Analysis
Stelmach I, Jerzynska J, Kuna P. A randomized, double-blind trial of montelukast in mild persistent asthmatic patients with near-
of the effect of glucocorticoid, antileukotriene and beta-agonist normal lung function. Respiratory Medicine 2001;95(5):37986.
treatment on IL-10 serum levels in children with asthma. Clin Exp Bateman 1995 {published data only}
Allergy 2002;32(2):264269. Bateman ED, Holgate ST, Binks SM, Tarns IP. A multicentre study
Stelmach 2002b {published and unpublished data} to assess the steroid-sparing potential of accolate (zafirlukast; 20 mg
Stelmach I, Grzelewski T, Stelmach W, Majak P, Jerzynska J, Gorski bd). Allergy 1995;50 Suppl(26):320, Abs P-0709.
P, Kuna P. Effect of triamcinolone acetonide, montelukast, Baumgartner 1999 {published data only}
nedocromil sodium and formoterol on eosinophil blood counts, Baumgartner RA, Polis A, Angner R, Bird S, Reiss TF. Comparison
ECP serum levels and clinical progression of asthma in children between montelukast and inhaled beclomethasone therapy in
[Polish]. Polski Merkuriusz Lekarski 2002;12(69):208213. chroni asthma: a double blind, placebo controlled, parallel study in
Williams 2001 {published and unpublished data} asthmatic patients. Merck Research Laboratories 1999.
Williams B, Noonan G, Reiss TF, Knorr B, Guerra J, White R, et Bilancia 2000 {published data only}
al.Long-term asthma control with oral montelukast and inhaled Bilancia R, Margiotta D, Balacco D. Low doses of budesonide (B)
beclomethasone. Clinical & Experimental Allergy 2001;31:110. plus montelukast (M) versus high doses of budesonide in asthamtic
Yamauchi 2001 {published data only} patients. American Journal of Respiratory and Critical Care Medicine

Yamauchi K, Tanifuji Y, Pan LH, Yoshida T, Sakurai S, Goto SI, 2000;161(supp 3):A197.
et al.Effects of Pranlukast, a Leukotriene receptor antagonist, on Bisgaard 1999 {published data only}
airway inflammation in mild asthmatics. Journal of Asthma 2001; Bisgaard H, Loland L, Anhoj J. NO in exhaled air of asthmatic
38(1):517. children is reduced by the leukotriene receptor antagonist
children (Review)
montelukast. American Journal of Respiratory & Critical Care Camargo 2002 {published data only}
Medicine 1999;160:122731. Camargo C A, Smithline H A, Marie-Pierre M, Green S A, Reiss T
Bisgaard 2000 {published data only} F. A Randomized Controlled Trial of Intravenous Montelukast in
Bisgaard H, Nielsen KG. Bronchoprotection with a leukotriene Acute Asthma. Am J Respir Crit Care Med 2002.
receptor antagonist in asthmatic preschool children. American Capella 2001 {published data only}
Journal of Respiratory & Critical Care Medicine 2000;162(1): Capella GL, Frigerio E, Altomare G. A randomized trial of
18790. leukotriene receptor antagonist montelukast in moderate-to-severe
Bjermer 2002 {published data only} atopic dermatitis of adults. European Journal of Dermatology 2001;
Bjermer L, Greening A, Haahtela T, Bousquet J, Holgate ST, 11(3):20913.
Picado C, Bisgaard H, Fabbri L, Menten J, Lef JA, IMPACT study Chiba 1997 {published data only}
group. Addition of montelukast or salmeterol to fluticasone in Chiba M, Xu X, Nishime JA, Balani SK, Lin JH. Hepatic
patients with uncontrolled asthma: results of the IMPACT trial.. microsomal metabolism of montelukast, a potent leukotriene D4
Chest 2002:434. receptor antagonist, in humans. Drug Metabolism and Disposition
Brannan 2001 {published data only} 1997;25(9):102231.
Brannan JD, Anderson SD, Gomes K, King GG, Chan HK, Seale Chuchalin 2002 {published data only}
JP. Fenofenadine decreases sensitivity to and montelukast improves Chuchalin A G, Ovcharenko S I, Goriachkina L A, Sidorenko I V,
recovery from inhaled manitol. American Journal of Respiratory & Tsoi A N, Alekseev V G, Bart B Y, Borisova N K, Belousov Y B,
Critical Care Medicine 2001;163(6):14205. Golovko M G, Goriachkina L A, Chereiskaya N K, Daniliak I G,
Brocks 1996 {published data only} Didkovsky N A, Dobrotina I S, Emelyanov A V, Korovina O V,
Brocks DR, Upward JW, Georgiou P, Stelman G, Doyle E, Allen E, Mamtsev B N, Sokurenko S I, Valekjanina T G, Zadionchenko V
et al.The single and multiple dose pharmacokinetics of pranlukast S. The safety and efficacy of formoterol OxisRTurbuhalerR plus
in healthy volunteers. European Journal of Clinical Pharmacology budesonide PulmicortRTurbuhaler in mild to moderate asthma: A
1996;51:3038. comparison with budesonide Turbuhaler alone and current non-
Bronsky 1997 {published data only} corticosteroid therapy in Russia. International Journal of Clinical
Bronsky E, Grossman J, Nathan RA, de Jong B. Pranlukast (Ultair) Practice 2002;56(1):1520.
reduces symptoms of seasonal allergic rhinitis: results of the first US Claesson 1998 {published data only}
double-blind, placebo controlled trial in 484 patients. SmithKline Claesson HE, Dahlen SE. Asthma and leukotrienes:
Beecham Pharmaceuticals 1997. antileukotrienes as novel anti-asthmatic drugs. Journal of Internal
Bruce 2002 {published data only} Medicine 1999;245(3):20527.
Bruce C, Palmqvist M, Sjstrand M, Aronsson B, Arvidsson P, Cloud 1989 {published data only}
Lotvall J. Greater attenuation of the late asthmatic reaction by Cloud ML, Enas GC, Kemp J, Platts-Mills T, Altman LC, Townley
fluticasone propionate compared to montelukast. American Journal R, et al.A specific LTD4-LTE4-receptor antagonist improves
of Respiratory and Critical Care Medicine 2002;165(Suppl 8):A215. pulmonary function in patients with mild, chronic asthma.
Busse 1999 {published data only} American Review of Respiratory Disease 1989;140:13369.
Busse W, Nelson H, Wolfe J, Kalberg C, Yancey SW, Rickard KA. Currie 2003 (B) {published data only}
Comparison of inhaled salmeterol and oral zafirlukast in patients Currie G P, Lee D K C, Haggart K, Bates C E, Lipworth B J.
with asthma. Journal of Allergy & Clinical Immunology 1999;103: Effects of montelukast on surrogate inflammatory markers in
107580. corticosteroid-treated patients with asthma. American Journal of
Cakmak 2000 {published data only} Respiratory and Critical Care Medicine 2003;167(9):12321238.
Cakmak G, Demir T, Aydemir A, Serdaroglu E, Erginoz E, Donma Cylly 2003 {published data only}
O, Gemicioglu B. The effect of adding zafirlukast to budesonide Cylly A, Kara A, Ozdemir T, Ogus C, Gulkesen K H. Effects of oral
treatment on total antoxydant capacity. European Respiratory montelukast on airway function in acute asthma. Respir Med 2003;
Journal 2000;16(Supplement 31):457s. 97(5):533536.
Calhoun 1997 {published data only} Dahlen In Press {unpublished data only}
Calhoun WJ, Weisberg SC, Faiferman I, Stober PW. Pranlukast Dahln SE, Malmstrom K, Nizankowska E, Dahln B, Kuna P,
(Ultair) is effective in improving asthma: results of a 12-week, Kowalski M, et al.Improvement of aspirin-intolerant asthma by
multicenter, dose-range study. Journal of Allergy & Clinical montelukast, a leukotriene antagonist. A randomised, double-
Immunology 1997;99:S318, Abs 1305. blind, placebo controlled trial. American Journal of Respiratory
Calhoun 2001 {published data only} and Critical Care Medicine 2001 (In Press):In Press.
Calhoun W J, Nelson H S, Nathan R A, Pepsin P J, Kalberg C, Daikh 2003 {published data only}
Emmett A, Rickard K A, Dorinsky P. Comparison of fluticasone Daikh B E, Ryan C K, Schwartz R H. Montelukast reduces
propionate-salmeterol combination therapy and montelukast in peripheral blood eosinophilia but not tissue eosinophilia or
patients who are symptomatic on short-acting beta(2)-agonists symptoms in a patient with eosinophilic gastroenteritis and
alone. American Journal of Respiratory & Critical Care Medicine. esophageal stricture. Annals of Allergy, Asthma, & Immunology
2001; 164(5):759-63. 2001;164(5):759763. 2003;90(1):2327.
children (Review)
Dempsey 1999 {published data only} Faul 2002 {published data only}
Dempsey OJ, Wilson AM, Sims EJ, Lipworth BJ. A comparison of Faul JL, Canfield JC, Gould MK, Wilson SR, Kischner WG. A
once daily topical budesonide (BUD) and oral montelukast randomized, double-blind, placebo-controlled, crossover study
(MON) in seasonal allergic rhinitis (SAR) and asthma. European comparing the effects of inhaled fluticasone propionate (880
Respiratory Society 1999. Micrograms per day) and montelukast (10 MG per day) on glucose
Dempsey 2000 {published data only} control patients with diabetes and asthma. American Journal of
Dempsey OJ, Wilson AM, Sims EJ, Mistry C, Lipworth BJ. Respiratory and Critical Care Medicine 2002;165(Suppl 8):A217.
Additive bronchoprotective and bronchodilator effects with single Findlay 1992 {published data only}
doses of salmeterol and montelukast in asthmatic patients receiving Findlay SR, Barden JM, Easley CB, Glass M. Effect of the oral
inhaled corticosteroids. Chest 2000;117:9503. leukotriene antagonist, ICI 204,219, on antigen-induced
Dempsey 2000 (B) {published data only} bronchoconstriction in subjects with asthma. Journal of Allergy &
Dempsey OJ, Wilson AM, Sims EJ, Lipworth BJ. Additive anti- Clinical Immunology 1992;89:10405.
inflammatory effects of montelukast but not salmeterol in
asthmatics suboptimally controlled on inhaled steroids [abstract]. Finn 2000 {published data only}
American Journal of Respiratory and Critical Care Medicine 2000; Finn AF, Bonuccelli CM, Traxler BM, Beatty SE. Zafirlukast
161(3 Suppl):A198. improves asthma control in children treated with and without
inhaled corticosteroids. Eur Resp J 2000;16(Supp 31):307.
Dempsey 2002b {published data only}
Dempsey OJ, Fowler SJ, Wilson A, Kennedy G, Lipworth BJ. Fischer 1995 {published data only}
Effects of adding either a leukotriene receptor antagonist or low- Fischer AR, McFadden CA, Frantz R, Awni WM, Cohn J, Drazen
dose theophylline to a low or medium dose of inhaled corticosteroid JM, et al.Effect of chronic 5-lipoxygenase inhibition on airway
in patients with persistent asthma. Chest 2002;122(1):151159. hyperresponsiveness in asthmatic subjects. American Journal of
Demuro-Mercon 2001 {published data only} Respiratory & Critical Care Medicine 1995;152(4 part 1):120307.
Demuro-Mercon C, . Turpin J, Santanello N, Firriolo K, Edelman Fischer 1997 {published data only}
J. Montelukast improves asthma quality of life when added to Fischer AR, Rosenberg MA, Roth M, Loper M, Jungerwirth S,
fluticasone. Journal of Allergy and Clinical Immunology 2001;107 Israel E. Effect of a novel 5-lipoxygenase activating protein
(2):S248. inhibitor, BAYx 1005, on asthma induced by cold air. Thorax 1997;
Dessanges 1999 {published data only} 52:10747.
Dessanges JF, Prefaut C, Taytard A, Matran R, Naya I, Compagnon
Fish 1997 {published data only}
A, et al.The effect of zafirlukast on repetitive exercise-induced
Fish JE, Kemp JP, Lockey RF, Glass M, Hanby L, Bonuccelli CM.
bronchoconstriction: The possible role of leukotrienes in exercise-
Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week
induced refractoriness. Journal of Allergy & Clinical Immunology
multicenter study. Clinical Therapeutics 1997;19(4):67590.
1999;104(6):115561.
Diamant 1997 {published data only} Fish 2001 {published data only}
Diamant Z, et al.Effect of oral montelukast on allergen-induced Fish JE, Israel E, Murray JJ, Emmett A, Boone R, Yancey SW, et
airway responses in asthmatic subjects. American Journal of al.Salmeterol powder provides significantly better benefit than
Respiratory & Critical Care Medicine 1997. montelukast in asthmatic patients receiving concomitant inhaled
Dicpinigaitis 2002 {published data only} corticosteroid therapy. Chest 2001;120(2):42330.
Dicpinigaitis P V, Dobkin J B, Reichel J. Antitussive effect of the Franzen 1994 {published data only}
leukotriene receptor antagonist zafirlukast in subjects with cough- Franzen L, Kumlin M, Dahlen SE. Pharmacologic modulation of
variant asthma. Journal of Asthma 2002;39(4):291297. leukotriene and histamine release in the human lung. Abbott
Dockhorn 2000 {published data only} Laboratories 1994.
Dockhorn RJ, Baumgartner RA, Leff JA, Noonan M, Vandormael
Fujimura 1993 {published data only}
K, Stricker W, et al.Comparison of the effects of intravenous and
Fujimura M, Sakamoto S, Kamio Y, Matsuda T. Effect of a
oral montelukast on airway function: A double blind, placebo
leukotriene antagonist, ONO-1078, on bronchial
controlled, three period, crossover study in asthmatic patients.
hyperresponsiveness in patients with asthma. Respiratory Medicine
Thorax 2000;55(4):2605.
1993;87:1338.
Eliraz 2001 {published data only}
Eliraz A, Raminez-Rivera A, Ferranti P, et al.Similar efficacy Gaddy 1990 {published data only}
following four weeks treatment of asthmatics with formoterol 12 Gaddy J, Bush RK, Margolskee D, Williams VC, Busse W. The
mcg bid delivered by two different dry powder inhalers: differences effects of a leukotriene D4 (LTD4) antagonist (MK-571) in mild to
in inhaler handling. International Journal of Clinical Practice 2001; moderate asthma. Journal of Allergy & Clinical Immunology 1990;
55(3):16470. 85:197, Abs. 216.
Fabbri 1996 {published data only} Geha 2001 {published data only}
Fabbri LM, Piattella M, Caramori G, Ciaccia A. Oral vs inhaled Geha RS. Desloratadine: a new, nonsedating, oral antihistamine.
asthma therapy. Drugs 1996;52 Suppl(6):208. Journal of Allergy & Clinical Immunology 2001;107(4):75162.
children (Review)
Georgiou 1997 {published data only} Hassall 1998 {published data only}
Georgiou P, Compton C, Allen A, Hust R, Collie H. Pranlukast Hassell SM, Miller C, Harris A. Zafirlukast (Accolate) reduces the
(Ultair) has no effect on cardiovascular parameters in healthy male need for oral steroid bursts. American Journal of Respiratory &
subjects. American Thoracic Society. 1997:Abs C49. Critical Care Medicine 1998;157(3):A411.
Ghiro 2002 {published data only} Hay 1997 {published data only}
Ghiro L, Zanconato S, Rampon O, Piovan V, Pasquale M F, Baraldi Hay DWP. Pharmacology of leukotriene receptor antagonists: more
E. Effect of montelukast added to inhaled corticosteroids on than inhibitors of bronchoconstriction. Chest 1997;111(2):
fractional exhaled nitric oxide in asthmatic children. Eur Respir J. 35S45S.
2002;20(3):630634. Henderson 1994 {published data only}
Gold 2001 {published data only} Henderson WR. The role of leukotrienes in inflammation. Annals
Gold M, Jgi R, Mulder PGH, Akveld MLM. Salmeterol/ of Internal Medicine 1994;121(9):68497.
fluticasone propionate combination 50/100g bid is more effective Hood 1999 {published data only}
than fluticasone propionate 100g bid plus montelukast 10 mg Hood PP, Cotter TP, Costello JF, Sampson AP. Effect of intravenous
once daily in reducing exacerbations. European Respiratory Journal corticosteroid on ex vivo leukotriene generation by blood leucocytes
2001;18(Supp 33):262s. of normal and asthmatic patients. Thorax 1999;54(12):107582.
Gold 2001 1 {published data only}
Howland 1994 {published data only}
Gold M, Jgi R, Mulder PGH, Akveld MLM. Salmeterol/
Howland III W, Segal A, Glass M, Minkwitz MC. 6-week therapy
fluticasone propionate combination 50/100g bid is more effective
with the oral leukotriene-receptor antagonist, ICI 204,219, in the
than fluticasone propionate 100g bid plus montelukast 10 mg
treatment of asthma. Journal of Allergy & Clinical Immunology
once daily in reducing exacerbations. European Respiratory Journal
1994;93(1 Part 2):259, Abs. 581.
2001;18(Supp 33):262s.
Hsieh 1996 {published data only}
Green 2002 {published data only}
Hsieh, K-H. Evaluation of efficacy of traditional chinese medicines
Green RH, Brightling S, Mckenna B, Hargadon B, Parker D,
in the treatment of childhood bronchial asthma: clinical trial,
Wardlaw AJ, Pavord ID. A placebo controlled comparison of
immunological tests and animal study. Pediatric Allergy &
formoterol, montelukast or higher dose of inhaled corticosteroids in
Immunology 1996;7:13040.
subjects with symptomatic asthma despite treatment with low dose
inhaled corticosteroids. Thorax 2002;57(Supp III). Hui K 1991 {published data only}
Hui K, Barnes NC. Lung function improvement in asthma with a
Green 2002 1 {published data only}
cysteinyl-leukotriene receptor antagonist. Lancet 1991;337:
Green RH, Brightling CE, McKenna S, Hargadon B, Parker D,
10623.
Bradding P, Wardlaw A J, Pavord I D. Asthma exacerbations and
sputum eosinophil counts: A randomised controlled trial. Lancet Ikeda 1997 {published data only}
2002;360(9347):17151721. Ikeda K, Hyashi M, Obata H, Fujita H, Nakanishi T, Izumi T. Two
weeks observation of pranlukast (ONO-1078), leukotriene
Grossman 1995 {published data only}
receptor antagonist) by peak expiratory flow rate (PEFR) was
Grossman J, Bronsky E, Busse W, Montanaro A, Southern L,
enough to evaluate clinical efficacies in severe chronic adult
Tinkelman D, et al.A multicenter, double-blind, placebo-controlled
asthmatics. American Thoracic Society. 1997:Abs C49.
study to evaluate the safety, tolerability and clinical activity of oral,
twice-daily LTA, Pranlukast (SB 205312) in patients with mild to Israel 1990 {published data only}
moderate asthma. Journal of Allergy & Clinical Immunology 1995; Israel E, Dermarkarkian R, Rosenberg M, Sperling R, Taylor G,
95(1):352, Abs 846. Rubin P, et al.The effects of a 5-lipoxygenase inhibitor on asthma
Grossman 1997 {published data only} induced by cold, dry air. New England Journal of Medicine 1990;
Grossman J, Faiferman I, Dubb JW, Tompson DJ, Busse W, 323:17404.
Bronsky E, et al.Results of the first U.S. double-blind, placebo- Israel 1992 {published data only}
controlled, multicenter clinical study in asthma with pranlukast, a Israel E, Drazen J, Pearlman H, Cohn J, Rubin P. A double-blind
novel leukotriene receptor antagonist. Journal of Asthma 1997;34 multicenter study of zileuton, a potent 5-lipoxygenase (5-LO)
(4):3218. inhibitor versus placebo in the treatment of spontaneous asthma in
Haahtela 1994 {published data only} adults. Journal of Allergy & Clinical Immunology 1992;89:236, Abs.
Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, 368.
Lehtonen K, et al.Effects of discontinuing inhaled budesonide in Israel 1993 {published data only}
patients with mild asthma. New England Journal of Medicine 1994; Israel E, Rubin P, Kemp JP, Grossman J, Pierson W, Siegel SC, et
331:7005. al.The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-
Hamilton 1998 {published data only} moderate asthma. Annals of Internal Medicine 1993;119(11):
Hamilton AL, Faiferman I, Stober P, Watson RM, OByrne PM. 105966.
Pranlukast, a cysteinyl leukotriene receptor antagonist, attenuates Israel 1996 {published data only}
allergen-induced early and late phase bronchoconstriction and Israel E, Cohn J, Dube L, Drazen JM. Effect of treatment with
airway hyperresponsiveness in asthmatic subjects. SmithKline zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. JAMA
Beecham Pharmaceuticals 1998. 1996;275(12):9316.
children (Review)
Johnson 1999 {unpublished data only} induced bronchoconstriction in the human. American Review of
Johnson MC, Srebro S, Edwards L, Bowers B, Rickard K. Respiratory Disease 1991;144:61721.
Physician- and patient-rated assessments correlate well with clinical Knorr 1998 {published data only}
efficacy measurements in a study comparing fluticasone and Knorr B, Matz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss
zafirlukast. Journal of Allergy & Clinical Immunology. 1999; Vol. TF, et al.Montelukast for chronic asthma in 6- to 14-year-old
103, issue 1 Part 2:Abs. 882. children. JAMA 1998;279(15):11816.
Juniper 1995 {published data only}
Knorr 1999 {published data only}
Juniper EF, Dube L, Swanson LJ, Zileuton Study Group. The effect
Knorr B, Nguycn HH, Seidenberg BC, Reiss TF, Montelukast
of zileuton, a 5-lipoxygenase inhibitor, on asthma quality of life.
Pediatric Study Group. Montelukast, a leukotriene receptor
Asthma. 1995.
antaconist, provides additional clinical benefit in asthmatic children
Kalberg 1999 {published data only} aged 6 to 14 years using inhaled corticosteroids. European
Kalberg CJ, Yancey S, Emmett AH, Rickard K. A comparison of Respiratory Society 1999;P363.
salmeterol versus zafirlukast in patients using inhaled
corticosteroids. Journal of Allergy & Clinical Immunology 1999; Knorr 2001 {published data only}
Vol. 103, issue 1 part 2:abs 881. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P,
Santanello N, et al.Montelukast, a leukotriene receptor antagonist,
Kane 1994 {published data only} for the treatment of persistent asthma in children aged 2 to 5 years.
Kane G, Pollice M, Tolino M, Cohn J, Dworski R, Murray J, et Pediatrics 2001;108(3):E48.
al.Effect of zileuton on eosinophil influx and leukotrienes in
Kohrogi 1997 {published data only}
humans undergoing segmental antigen challenge. Abbott
Kohrogi H, Iwagoe H, Fujii K, Fukuda K, Kawano O, Hamamoto
Laboratories 1994.
J, et al.The effect of leukotriene antagonist pranlukast on moderate
Kanniess 2002 1 {published and unpublished data}
and severe persistent asthma continues more than one year.
Kanniess F, Richter K, Janicki S, Schleiss MB, Jorres RA,
American Journal of Respiratory & Critical Care Medicine 1997;155:
Magnussen H. Dose reduction of inhaled corticosteroids under
A662.
concomitant medication with montelukast in patients with asthma.
Korenblat 1998 {published data only}
Eur Respir J 2002;20:10801087.
Korenblat P, Chervinsky P, Wenzel S, Faiferman I, Bakst A.
Kemp 1995 {published data only} Pranlukast (Ultair) reduces health care utilization and improves
Kemp JP, Glass M, Minkwitz MC. Onset of action of the quality of life in adult patients with mild-to-moderate asthma.
leukotriene-receptor antagonist, zafirlukast (Accolate), in patients American Journal of Respiratory & Critical Care Medicine. 1998;
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antagonist: a new class of therapy for patients with asthma. Todays antagonist, improves asthma control in aspirin-intolerant asthmatic
Therapeutic Trends 1996;14(2):89102. patients. American Journal of Respiratory & Critical Care Medicine
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Kemp 1998 {published data only} peripheral eosinophil data from a 13-week trial. American Journal of
Kemp JP, Tinkelman D, Sublett J, Compton C, Georgiou P. Respiratory & Critical Care Medicine 1998;157(3):A410.
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Kemp JP, Minkwitz MC, Bonuccelli CM, Warren MS. Therapeutic doses of inhaled steroid optimised between 800 and 2000 mcg per
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Ketchell RI, DAmato M, Jensen MW, OConnor BJ. Contrasting L, et al.Montelukast, a leukotriene-receptor antagonist, for the
effects of allergen challenge on airway responsiveness to cysteinyl treatment of mild asthma and exercise-induced
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Kips JC, Joos GF, de Lepeleire I, Margolskee DJ, Buntinx A, Leigh R, Vethanayagam D, Yoshida M, Watson R M, Rerecich T,
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asthmatic responses, and post-allergen airway hyperresponsiveness Cost-efficacy analysis of fluticasone propionate versus zafirlukast in
[abstract]. American Journal of Respiratory and Critical Care patients with persistent asthma. Pharmacoeconomics 2001;19(8):
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911. Minkwitz 1998 {published data only}
Liebke 2001 {published data only} Minkwitz MC, et al.Zafirlukast (Accolate) response in severe
Liebke C, Sommerfeld C, Wahn U, Niggemann B. [Preventive persistent ...??. American Journal of Respiratory & Critical Care
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German. Pneumologie 2001;55(5):2317. Miyamoto T, Accolate clinical trial committee. Effects of
Lipworth 1999 {published data only} zafirlukast on symptoms and pulmonary function of asthmatic
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Immunology 1996;98:85971. Nathan RA, Bernstein JA, Bielory L, Bonuccelli CM, Calhoun WJ,
Galant SP, et al.Zafirlukast improves asthma symptoms and quality
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Negro JM, Miralles JC, Ortiz JL, Funes E, Garcia A. Leukotrienes
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Nsouli SM, McNutt WJ. The addition of montelukast to a low al.Urinary excretion of leukotriene E4 and 11-dehydrothromboxane
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the signs and symptoms of asthma over one year of treatment.
Pizzichini E, Leff JA, Reiss TF, Hendeles L, Boulet L-P, Wei LX, et
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Pullerits T, Praks L, Baker R, Ani R, Lotvall J. Comparison of nasal
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Robinson 2001 {published data only}
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Pullerits T, Praks L, Ristioja V, Lotvall J. Comparison of a nasal antagonists to therapy in chronic persistent asthma: a randomised
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Ramsay 1997 {published data only} Sahn 1997 {published data only}
Ramsay CF, van Kan CI, Nieman RB, Wang J, van Krieken JHJM, Sahn SA, Galant S, Murray J, Bronsky E, Spector S, Faiferman I, et
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Shingo 2001 {unpublished data only} mild-to-moderate asthma: a randomized, double-blind, placebo-
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composite clinical score allows safe tapering of inhaled Suzuki 1997 {published data only}
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(Personal Communication:Theodore Reiss June 2001) 2001. al.Efficacy of oral pranlukast, a leukotriene-receptor antagonist, in
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of fluticasone propionate inhalation on levels of arachidonic acid for oral zafirlukast vs inhaled beclomethasone in adolescent
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disease. Mediators of Inflammation 2001;10(1):216. P0333.
Welch 1994 {published data only}
Vethanayagam 2002 {published data only} Welch MJ, Nelson HS, Paull BR, Smith JA, Feiss G, Tobey RE.
Vethanayagam D, Leigh R, Yoshida M, Watson RM, Rerecich T, Effect of RG 12525, a new leukotriene antagonist, on pulmonary
Killian K, OByrne PM. Effects of montelukast and budesonide function of asthmatic adults. Annals of Allergy 1994;72:34852.
alone and together on allergen-induced airway inflammation in
asthma [abstract]. American Journal of Respiratory and Critical Care Wenzel 1994 {published data only}
Medicine 2002;165(8 Suppl):A216. Wenzel S, Cohn J, Trudeau J, Wilson W, Martin R, Westcott J.
Zileuton (Leutrol) decreases urine LTE4, BALF LTB4 and improves
Vidal 2001 {published data only} lung function in nocturnal asthmatics. Abbott Laboratories 1994.
Vidal C, Fernandez-Ovide E, Pineiro J, et al.Comparison of
Wenzel 1995 {published data only}
montelukast versus budesonide in the treatment of exercise-induced
Wenzel SE, Trudeau JB, Kaminsky DA, Cohn J, Martin RJ,
bronchoconstriction. Annals of Allergy, Asthma, & Immunology
Westcott JY. Effect of 5-lipoxygenase inhibition on
2001;86(6):6558.
bronchoconstriction and airway inflammation in nocturnal asthma.
Vidal 2001 1 {published data only} American Journal of Respiratory & Critical Care Medicine 1995;152
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bronchoconstriction. Annals of Allergy, Asthma, & Immunology Wenzel S, Chervinsky P, Kerwin E, Silvers W, Faiferman I, Dubb J.
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Virchow 1997 {published data only} 12-week trial in patients with asthma. American Journal of
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494500.
Indicates the major publication for the study
children (Review)
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Basyigit 2001
Methods DESIGN
-not mentioned
ALLOCATION
-random
-method of randomization: not described
-means of assignment: not described
BLINDING
-not mentioned
WITHDRAW/DROPOUT
-not mentioned
JADADs Quality = 1
Confirmation of methodology:
not obtained
Participants SYMPTOMATIC PARTICIPANTS

RANDOMISED
N=30
WITHDRAWALS
-not mentioned
AGE
-not mentioned
GENDER
-not mentioned
ASTHMA SEVERITY
-mild persistent asthma
ASTHMA DURATION
-not mentioned
% pred. FEV1 %(+- SD)
-not mentioned
MEAN (+-SD) BETA2AGONIST USE (puffs per day)
-not described
DOSE OF ICS AT STUDY ENTRY AND AT RUN-IN:
-not mentioned
ATOPY
-not mentioned
ELIGIBILITY CRITERIA
EXCLUSION
-not mentioned
Interventions PROTOCOL
DURATION
-Run-in= 15 days
-Intervention= 8 weeks
TEST GROUP
children (Review)
Basyigit 2001 (Continued)
-Zafirlukast
TEST GROUP 2
-Theophylline
CONTROL GROUP
-Budesonide
DEVICE
-not mentioned
CRITERIA FOR WITHDRAWAL FROM STUDY
-not mentioned
Outcomes ANALYSIS (ITT)

OUTCOMES
-reported at 8 weeks
-report outcomes are repoted as pre- and post-values (not change from baseline)
PULMONARY FUNCTION TESTS
-*ECP levels
FUNCTIONAL STATUS
-not mentioned
INFLAMMATORY MEDIATORS
-not described
ADVERSE EVENTS
-not mentioned
WITHDRAWALS
-not mentioned
*primary outcomes
Notes -Abs (2001)

-Funding not mentioned
-Confirmation of methodology and data extraction not obtained
Risk of bias
Item Authors judgement Description
Allocation concealment? Unclear D - Not used
children (Review)
Baumgartner 2003
Methods DESIGN
-parallel-group
-multicentre (16 centres, Canada, Brazil, Chile, Peru, Venezuela, Mexico, Costa Rica, Guatemala)
ALLOCATION
-Random
-computer-generated allocation
-opaque consecutive-numbered envelopes
BLINDING
-triple-blind
-double dummy
-identical placebo
WITHDRAWAL/DROPOUT
-described
JADADs Quality Score =5
-Confirmation of methodology obtained

RANDOMISED
N = 730
M: 313
BDP:314
Placebo: 103
WITHDRAWALS
M: 22 (7%)
BDP: 19 (6%)
Placebo: 10 (10%)
AGE (SD) in yrs: M: 35.914.9
BDP:35.5 15.0
Placebo:35.5 14.6
GENDER (% male)
M: 33%
BDP:38 %
Placebo:
ASTHMA SEVERITY:
not described
ASTHMA DURATION:
-not reported
% Pred. FEV1 % (SD)
M: 69 12
BDP:68 11
Placebo: 6812
MEAN (SD) BETA2-AGONIST USE (puffs per day)
M: 5.2 3.7
BDP: 5.1 3.3
Placebo: 5.5 3.9
ATOPY:
M: 69%
BDP: 68%
children (Review)
Baumgartner 2003 (Continued)
-Age>= 15 years
-current tx with only beta2-agonist
-asthma history x 1 year
->=50 and <=85% FEV1 Pred
-reversibility >=15% after two puffs short-acting beta2-agonist
-daily use of beta2-agonist > 2 puffs/day during run-in
-non-smokers for more than 1 year
EXCLUSION:
-ED tx in past 1 month
-hospital admission for asthma in past 3 months
-URTI in past 3 weeks
-significant sinus disease
-systemic steroids in past month
-inhaled steroids in past 2 weeks
-astemizole within 3 months or xanthine derivatives
-oral or long-acting inhaled B-agonists
-cromolyn sodium or nedocromil, inhaled anticholinergic agents, oral leukotriene receptor antagonists or
leukotriene synthesis inhibitors within 1 week before the start
Duration
-Run-in Period: 2 weeks
-Intervention Period: 6 weeks
TEST GROUP
Montelukast 10 mg die
CONTROL GROUP 1
Beclomethasone 200ug/bid
CONTROL GROUP 2
-Placebo (not used in this review)
DEVICE
-MDI (actuation inhaler)
CO-INTERVENTION:
not specified
CRITERIA FOR WITHRAWAL FROM STUDY
-not described
Outcomes ANALYSIS BY MODIFIED INTENTION-TO-TREAT

OUTCOMES reported at 6 weeks
-Change from baseline FEV1
SYMPTOM SCORES
-Change in mean asthma score (6-point)
FUNCTIONAL STATUS
-Change from baseline mean daily beta2-agonist use
-* % asthma control days (<= 2 puffs of beta2-agonist use, no nighttime awakenings, no unscheduled
asthma care, and no systemic steroid rescue required)
-patients with exacerbations requiring systemic steroids
-Physician global evaluation
children (Review)
Baumgartner 2003 (Continued)
- change from baseline in serum eosinophils

ADVERSE EVENTS
-reported
WITHDRAWALS
reported
* Primary outcome
Notes -Full-test
publication
-Funded by Merck Research Labratories
-confirmation of methodology and data extraction received from Dr Theodore Reiss
USER-DEFINED ORDER: 400 (daily dose of BDP-equivalent=400 mcg )
Risk of bias
Allocation concealment? Yes A - Adequate
Bleecker 2000
Methods DESIGN
-parallel-group
ALLOCATION
-Random
-means of assignment not described
BLINDING
-double-blind
-identical placebo
WITHDRAWAL/DROPOUT
-described

RANDOMISED
N = 451
Z: 220
FP: 231
WITHDRAWALS
Z: 23 %
FP: 13%
AGE (SD):
Z: 31 (12-66)
FP: 31 (12-68)
GENDER (% male)
Z: 49%
children (Review)
Bleecker 2000 (Continued)
FP: 52%
ASTHMA SEVERITY:
not described
% Pred. FEV1 (mean SD)
Z: 68
FP: 67
Mean (SD) beta2-agonist use (puffs per day)
not reported
ATOPY:
Z: 43 %
FP: 46%
ASTHMA DURATION (years): 10 years
-Age: >=12 years
-persistent asthma for >=6 months
-50-80% pred. FEV1
-prn use of beta2-agonist > 2 puffs
-during run-in: use of rescue beta2-agonist >- 5 days or asthma symptom score >=2 (on a 5-point scale)
on >= 3days.
EXCLUSION:
- AL < 2 weeks
-inhaled or systemic steroids < 2 months
-life-threatening asthma
->=3 bursts of systemic steroids in < 1 year
-tabacco use < 1 year or >10 pack-year
-respiratory infection < 2 weeks
Duration
-Run-in Period: 8-14 days
TEST GROUP
-Zafirlukast 20 mg bid
CONTROL GROUP
-Inhaled Fluticasone 100 mcg bid
DEVICE
-not described
CO-INTERVENTION:
none allowed
Outcomes ANALYSIS ( ITT )

-*Change from baseline FEV1
-Change from baseline in morning PEF
SYMPTOM SCORES
-Change in mean symptom score (average/week)
FUNCTIONAL STATUS
children (Review)
Bleecker 2000 (Continued)
-Change from baseline mean daily beta2-agonist use (puffs/day)

-change in nightime awakenings
- change in symptom-free days
-change in rescue-free days
-patients with exacerbations requiring hospital admission
not reported
ADVERSE EVENTS
reported
WITHDRAWALS
reported
* Primary outcome
Notes -Full-text publication

-Funded by Glaxo Wellcome
-Confirmation of methodology and data extraction received from Gerry Hogan
-USER-DEFINED ORDER:
400 (daily dose of fluticasone x conversation rate in BDP-equivalent= 200 x 2 )
Risk of bias
Brabson 2002
Methods DESIGN
-parallel-group
- Multicentre (44 sites in USA)
ALLOCATION
-random
BLINDING
-double-blind
-double-dummy
-identical placebo
WITHDRAWL/DROPOUT
-described
JADADs quatlity Score = 4
Confirmation of methodology not obtained

RANDOMISED
N = 440
Z: 216
children (Review)
Brabson 2002 (Continued)
FP: 224
WITHDRAWALS
Z: 45 (21%)
FP: 17 (8)%
AGE (SD):
Z: 35 (16)
FP: 36 (14)
GENDER (% male)
Z: 75 (35%)
FP: 90 (40%)
ASTHMA SEVERITY:
not described
ASTHMA DURATION:
not described
% Pred. FEV1
(SD)
Z: 73 7
FP: 73 7
not reported
DOSE OF ICS AT STUDT ENTRY AND AT RUN-IN:
Z=
BDP 25680ug/d
T 600213ug/d
FP=
BDP27173 ug/d
T 603169 ug/d
ATOPY:
not described
-Age: >=12 years
-asthma
-low-dose inhaled corticosteroids (excluding Fluticasone, Flunisolide)at least 8 weeks -60 and 85 % pred
FEV1 at screening and prior to randomization
EXCLUSION:
during run-in
->4 puffs of albuterol/day
->1 nighttime awakening during 7 days before randomization
At screening:
- any oral or parenteral corticosteroids within 6 weeks
- > 1 burst of oral corticosteroids within 6 months
- inhaled fluticasone or flunisolide within 4 weeks
- leukotriene modifiers within 1 week
Duration
-Run-in Period: 8 days
TEST GROUP
-Zafirlukast 20 mg twice daily
children (Review)
Brabson 2002 (Continued)
CONTROL GROUP
-Fluticasone 100 ug bid
DEVICE
-Metered-dose inhaler
CRITERIA FOR WITHDRAWAL FROM STUDY
->20 % decrease in baseline FEV1
->3 days with > 12 puffs of rescue albuterol
->4 days where PF decreased by >= 20% of baseline
->3 nights with awakenings due to asthma

-*Change from baseline FEV1 (L)
-Change from baseline in morning PEF (L/s)
-Change from baseline in evening PEF(L/s)
SYMPTOM SCORES
-Change in symptom-free days (%)
-Change in mean symptom score (6-point)
FUNCTIONAL STATUS
-Change from baseline in use of rescue beta2-agonist use (puffs/day)
-change in rescue free days (%)
- exacerbations requiring systemic steroids
-exacerbations requiring ED visits
-change in nights with uninterrupted sleep
- physician-rated global assessment of Rx effectiveness
not reported
ADVERSE EVENTS
reported
WITHDRAWALS
reported
* Primary outcome

-Funded by Glaxo SmithKline
-Confirmation of methodology and data extraction: not obtained
Risk of bias
children (Review)
Busse 2001a
Methods DESIGN
-parallel-group
-multicentre (34 sites in US)
ALLOCATION
-Random
-computer-generated allocation in blocks of 6
-means of assignment by numbered medication supplied by pharmacy
BLINDING
-double-blind
-identical placebo
-double-dummy
(MDI and pill)
WITHDRAWAL/DROPOUT
-Described
Confirmation of methodology obtained

RANDOMISED
N = 338
Z: 111
FP: 113
Placebo (not used):114
WITHDRAWALS
Z: 19%
FP: 14%
AGE (SD): 12-75 years
Z: 33.8 13.1
FP: 29.6 11.4
GENDER (% male): 50%
Z: 41 %
FP: 58%
ASTHMA SEVERITY:
% moderate:
Z: 82%
FP: 77%
% Pred. FEV1 (mean SD): 66-67%
Z: 69.1 7.5
FP: 68.1 8.3
Z: 4.7 (SE 0.27)
FP: 4.8 (SE:0.26)
ATOPY:
Z: 42%
FP: 23%
ASTHMA DURATION (years): at least 10 years for
Z:69%
FP: 65%
children (Review)
Busse 2001a (Continued)
-Age: >=12 years

-prn or regular use of short-acting Beta2-agonist for at least 6 weeks
-50-80% pred. FEV1
EXCLUSION:
-use of tobacco within 1 year or smoking history of >10 packs-year
-systemic steroids within 6 months
-inhaled steroids < 1 month
-use of leukotriene modifier < 1 week
Duration
-Run-in Period: 8-14 days to establish baseline respiratory function
TEST GROUP
-Zafirlukast 20 mg bid po
CONTROL GROUP
-Inhaled Fluticasone 100 mcg bid (2 puffs of 50 mcg bid)
DEVICE
-Metered dose inhaler (no spacer)
CO-INTERVENTION:
none allowed other than rescue beta2-agonist and systemic steroids

OUTCOMES reported at 6 and 12 weeks (also documented at 2, 4, 8 weeks)
-Change from baseline in morning and evening PEF
SYMPTOM SCORES
-weekly average symptom score (6-point scale)
FUNCTIONAL STATUS
-Change from baseline mean daily beta2-agonist use, averaged over 1 week (puffs/day)
-change in nightime awakenings (waking/nights) averaged over 1 week
- change in symptom-free days
-change in qol (Juniper)
-work or school loss days
-patients with exacerbations requiring hospital admission
-patient satisfaction
-physicians rated effectiveness
not reported
ADVERSE EVENTS
reported
WITHDRAWALS
reported
* Primary outcome
children (Review)
Busse 2001a (Continued)

-Confirmation of methodology and data extraction obtained from Shailesh Patel and Rob Pearson, Nov
2, 2001
Risk of bias
Busse 2001b
Methods DESIGN
-parallel-group
ALLOCATION
-Random
-coded medication
BLINDING
-double-blind
-identical placebo
WITHDRAWAL/DROPOUT
-described

RANDOMISED
N = 533
M: 262
FP: 271
WITHDRAWALS
M:29%
FP:28%
AGE (SD) years: M: 34.4 (15-67)
FP: 35.4 (15-83)
GENDER (% male)
M: 42 %
FP: 47%
ASTHMA SEVERITY:
not described
M: 65.4 8.2
FP: 65.6 9.2
Mean (SD) beta2-agonist use (puffs per day):
children (Review)
Busse 2001b (Continued)
not reported
ATOPY:
not reported
ASTHMA DURATION (years):
not reported
-Age: >=15 years
-persistent asthma for >=6 months
-50-80% pred. FEV1
-prn or regular use of beta2-agonist > 3 months
-during run-in: use of rescue beta2-agonist >- 6 of 7 days and asthma symptom score >=2 (on a 5-point
scale) on >=4 of 7 days.
EXCLUSION:
-inhaled steroids < 2 months
-tabacco use < 1 year or >10 pack-year
-hospital admission for asthma in <3 months
-respiratory infection < 4 weeks
Duration
TEST GROUP
-Montelukat 10 mg die
CONTROL GROUP
-Inhaled Fluticasone 100 mcg bid
DEVICE
-Metered dose inhaler
CO-INTERVENTION:
none allowed

OUTCOMES reported at 4, 8, 12, 16, 24 weeks
-*Change from baseline FEV1 (L and %)
-Change from baseline PEF (L/min)
SYMPTOM SCORES
-change in mean symptom score/week (6-point scale)
FUNCTIONAL STATUS
-Change from baseline mean daily beta2-agonist use (puffs/day)
-change in nightime awakenings
-change in % symptom-free days
-change in % rescue-free days
-change in qol (Juniper)
-days off work or school
-exacerbations requiring systemic steroids
-exacerbations requiring hospital admission
children (Review)
Busse 2001b (Continued)
not reported
ADVERSE EVENTS
reported
WITHDRAWALS
reported
* Primary outcome

-Confirmation of methodology and data extraction and additional unpublished data obtained from and
Shailesh Patel and Rob Pearson
400 (daily dose of fluticasone x conversation rate in BDP-equivalent = 200 x 2)
Risk of bias
Dempsey 2002a
Methods DESIGN
-cross-over
design
ALLOCATION
-random
BLINDING
-single-blind
-double-dummy
-identical placebo
WITHDRAWL/DROPOUT
-not described
JADADs quatlity Score = 3
Confirmation of methodology :
not obtained

RANDOMISED
N = 21
WITHDRAWALS
-not mentioned
AGE (years):
n=33.5
GENDER (% male)
-not mentioned
children (Review)
Dempsey 2002a (Continued)
ASTHMA SEVERITY:
-mild persistent atopic asthma
ASTHMA DURATION:
-not described
% Pred. FEV1
n=96.3
-not reported
DOSE OF ICS AT STUDY ENTRY AND AT RUN-IN:
-not mentioned
ATOPY:
not described
EXCLUSION:
-not mentioned
Duration
-Run-in Period: 1-2 weeks
CONTROL GROUP
-hfa-triamcinolone acetonide (taa) 450 ug od
TEST GROUP
-montelukast 10 mg od
DEVICE
-not mentioned
Criteria for withdrawal from study
-not mentioned
Outcomes ANALSIS (ITT)

-Change from baseline in morning PEF
-Change from baseline in evening PEF
SYMPTOM SCORES
-Change in mean symptoms
FUNCTIONAL STATUS
-Change from baseline in night-time use of rescue beta2-agonist use (puffs/day)
-change from baseline in blood eosinophilis
-change from baseline in exhaled NO
ADVERSE EVENTS
-not reported
WITHDRAWALS
-not reported
* Primary outcome
children (Review)
Dempsey 2002a (Continued)
Notes Abs 2001

USER-DEFINED ORDER:450 x 0.5=225
Risk of bias
Hughes 1999 (BDP)
Methods DESIGN
-parallel-group
ALLOCATION
-Computer generated random number
-allocation by opaque consecutive numbered envelopes containing assignment
BLINDING -open-label
-no allocation concealment
WITHDRAWAL/DROPOUT
-described
JADADs Quality Score = 3
-Confirmation of methodology obtained (08/01)

RANDOMISED
N = 71
M:25
FP:23
BDP:23
WITHDRAWALS
M: 0 (0%)
FP: 1 (4%)
BDP:0 (0%)
AGE (SD):
M: 29.0 11.7
FP: 30.7 10.7
BDP: 31.6 9.6
GENDER (% male)
M: 39%
FP:60%
BDP: 64%
ASTHMA SEVERITY:
mild
% Pred. FEV1 % (SD)
M: 83.0 11.7
children (Review)
Hughes 1999 (BDP) (Continued)
FP:85.3 10.7
BDP:84.9 11.0
M: 1.2 1.0
FP: 1.4 1.5
BDP: 1.2 1.5
ATOPY or ALLERGIC RHINITIS:
M:84%
FP:96%
BUD:78%
-Age>=15 years old
-recruited from managed care affiliated sites
-6-month history of asthma
-FEV1 % Pred >=70
-airway reversibiliy >= 12% twice
-beta2-agonist use 1-6 days/wk
-FEV1/FVC < 80% if FEV1 reversibility 10-12%
-Non or ex-smoker (<15 pack years)
-No pregnancy or on birth control for women
EXCLUSION CRITERIA:
-<15 years
-known intolerance to study medications
-unable to perform spirometry
-Within 2 weeks of run-in and prior to randomisation:
any exacerbation requiring unscheduled visit to MD, emergent or urgent care visit, hospital admissin or
rescue oral steroids.
-Intake of oral or inhaled ICS, nedocromil, cromolyn, salmeterol, theophylline within 1 week of study
entry
Duration
TEST GROUP
-Montelukast 10 mg
CONTROL GROUP 1
-Fluticasone 100 mcg bid
CONTROL GROUP 2
-Budesonide 200 mcg bid
DEVICE
-Aerosol inhaler for Fluticasone
-Dry powder inhaler for Budesonide
CO-INTERVENTION:
none allowed other than rescue B2-agonist and systemic steroids
Outcomes ANALYSIS ( ITT)

(if received at leat one study medication)
children (Review)
Hughes 1999 (BDP) (Continued)

-Change from baseline FEV1 (L)
-Change from baseline in PEFR (L/min)
SYMPTOM SCORES
not reported
FUNCTIONAL STATUS
-% Change from baseline median daily beta2-agonist use (puffs/day)
-*Change from baseline in percentage of rescue-free days (no unscheduled office visit, ER, or hospital-
ization)
-change from baseline in serum eosinophils
ADVERSE EVENTS
reported
WITHDRAWALS
reported
* Primary outcome
Notes -Abstract & Poster (1999)

-Funded by Merck
-letter, meth sent to Hughes December 1999
-Confirmation of methodology, data extraction and additional data provided by Merck Laboratories
(08/01)
-USER-DEFINED ORDER: 400
(daily dose of fluticasone x conversation rate in BDP-equivalent = 200 x 2 )
Risk of bias
Hughes 1999 (FP)
Methods as above
Participants as above
Interventions as above
Outcomes as above
Notes as above
Risk of bias
children (Review)
Israel 2002
Methods DESIGN
-Multicentre (64 sites in USA)
-parallel-group
ALLOCATION
-Random
-method of randomization: blinded allocation schedule
BLINDING
-double blind
-double-dummy
-identical placebo
WITHDRAWL/DROPOUT
-described
JADADs Quality = 5

RANDOMISED
N= 782
M=339
BDP=332
Placebo=111
WITHDRAWALS
M: 11(3.2%)
BDP: 14(4.2%)
Placebo: 5(4.5%)
AGE (years, range)
M=33.5 (15-71)
BDP=33.9 (15-74)
placebo=33.3 (15-64)
GENDER (% male)
M=162 (47.8%)
BDP=156 (47%)
Placebo=54 (48.7%)
ASTHMA SEVERITY: not mentioned
ASTHMA DURATION: not mentioned
% PRED. FEV1% (+-SD)
M=67.4 11.1
BDP=65.9 11.7
P=66.8 12.3
MEAN (SD) BETA2-AGONIST USE (puffs per day):
M=5.6 2.9
BDP=5.8 2.9
Placebo=5.72.6
DOSE OF ICS AT STUDY ENTRY AND DURING RUN-IN: not reported
ATOPY: not described
ELIGIBILITY CRITERIA:
->= 15 years
->= 1 year history of clinical symptoms of asthma
-use of only B-agonist for asthma treatment
children (Review)
Israel 2002 (Continued)
-FEV1 between 50%-80%

->= 15% increase in FEV1 after albuterol use
-> 2 puffs per day during run-in
-non-smokers for at least 1 year with smoking history of no more than 7 packs-year
EXCLUSION
-ICS for 2 weeks prior to 1st visit
-URTI within 3 weeks
-ER visit for asthma within 1 month
-Hospitalization for asthma in past 3 months
-systemic steroids for 1 month before 1st visit
DURATION
run-in: 2 weeks
intervention: 6 weeks
TEST GROUP
-Montelukast: 10 mg once daily
CONTROL GROUP 1
-BDP: 200 ug bid
CONTROL GROUP 2
-Placebo
DEVICE: MDI + spacer
CRITERIA FOR WITHDRAWAL FROM STUDY:
-not described
CO-INTERVENTION: short-acting anti-histamines

PULMINARY FUNCTION TESTS
-*change from baseline FEV1
SYMPTOM SCORES:
-% of days with asthma control
FUNCTIONAL STATUS
-change from baseline in use of beta2-agonist(puffs/day)
-asthma exacerabations
-rescue corticosteroid use (%)
-% asthma controlled days defined as a day with <= 2 puffs of albuterol, no nighttime awakenings, and
no asthma attacks
INFLAMMATORY MEDIATORS: not reported
ADVERSE EVENTS: reported
WITHDRAWALS:
reported
*primary outcome

-Funded by Merck
-Confirmation of methodology and data extraction not obtained
400 (daily dose in BDP equivalent)
children (Review)
Israel 2002 (Continued)
Risk of bias
Jayaram 2002
Methods DESIGN
-Multicentre (4 sites)
-parallel-group
ALLOCATION
-random
method of randomization: not described
BLINDING
-not described
WITHDRAWL/DROPOUT
-not mentioned
JADADs Quality = 1
not obtained

RANDOMISED
N=50
M=19
FP=18
Placebo=13
WITHDRAWALS
-not mentioned
AGE (years)
-not mentioned
GENDER (% female)
-not mentioned
ASTHMA SEVERITY:
-not described
ASTHMA DURATION:
-not mentioned
% PRED. FEV1% (+ SD)
-not mentioned
MEAN (+SD) BETA2AGONIST USE (puffs per day):
-not mentioned
DOSE OF ICS AT STUDY ENTRY AND DURING RUN-IN:
-not reported
ATOPY:
- not described
ELIGIBILITY CRITERIA:
children (Review)
Jayaram 2002 (Continued)
-steroid-naive asthma
-sputum eosinophilis (Eo) count of > 3.5%
EXCLUSION
-not mentioned
DURATION
run-in: not mentioned
intervention: 8 weeks
TEST GROUP
-Montelukast (dose un-specified: probably 10 mg die)
CONTROL GROUP 1
-Fluticasone (dose un-specified)
CONTROL GROUP 2
-Placebo
DEVICE: not described
CRITERIA FOR WITHDRAWAL FROM STUDY: not described
Outcomes ANALYSIS (ITT not specified)

OUTCOMES -reported at 8 weeks
-report outcomes are reported as pre- and post-values (not change from baseline)
-FEV1
-morning PEFR (L/min)
-evening PEFR (L/min)
SYMPTOM SCORES:
-change in symptoms
FUNCTIONAL STATUS
-change from baseline in use of b-agonist
INFLAMMATORY MEDULATOR:
-*change in sputum Eo (%)
ADVERSE EVENTS:
-not reported
WITHDRAWALS:
-not reported
*primary outcomes
Notes -Abstract 2002

-USER-DEFINED ORDER: unknown
Risk of bias
children (Review)
Kanniess 2002
Methods DESIGN
-cross-over study
ALLOCATION
-random
BLINDING
-double blind
-double dummy
WITHDRAWALS/DROPOUTS
-not reported
JADADs quality score =3
-Confirmation of methodology not obtained

RANDOMISED
n = 40
WITHDRAWALS
-not reported
AGE mean (years, range)
-37 (18-60)
GENDER
-24 male (60%)
-16 female
ASTHMA SEVERITY
-moderate allergic bronchial asthma
FEV1 % pred (Mean SD)
-74.2 (10.6)
-not reported
ATOPY
-100% of patients
ASTHMA DURATION:
-not reported
-FEV1 within 15% at screening value
-20% fall in FEV1(PC20) within 1.5 boubling concentrations
-atopic patients according to skin-prick test
-bronchodilator effect of >15% after 200mcg of salbutamol
EXCLUSION:
-smokers
-acute exacerbation or respiratory tract infection within 4 weeks before each visit
-inhaled corticosteroids within 3 months
-systemic corticosteroids within 6 months
-antihistamines or theophylline within 4 weeks
DURATION
run-in: 1-2 weeks
treatment: 4 weeks
children (Review)
Kanniess 2002 (Continued)
wash-out: 3-8 weeks

TEST GROUP
-Fluticasone 100 ug bid
CONTROL GROUP
-Montelukast 10 mg at night-time
DEVICE: diskus
CRITERIA FOR WITHDRAWAL FROM STUDY: not described
CO-INTERVENTION
-not permitted
Outcomes ANALYSIS (not by ITT)

OUTCOMES
reported at 4 weeks
-% change from baseline FEV1
-bronchial responsiveness to metacholine(PC20)
-Morning Peakflow rate
SYMPTOM SCORES:
-symptom score daytime and nighttime (range 0-4)
FUNCTIONAL STATUS
-change from baseline in use of beta2-agonist
-occurence of asthma attacks and asthma flare-ups
-rescue corticosteroid use
INFLAMMATORY MEDIATORS:
-sputum eosinophils (geometric means)
-exhaled NO
(sievers) (geometric means)
ADVERSE EVENTS: reported
WITHDRAWALS:
not reported
PRIMARY OUTCOMES:
-not reported

-Funded by GlaxoSmithKline, d20354 Hamburg, Germany
Confirmation of methodology and data extraction: not obtained
-USER-DEFINED ORDER: 400 (dose/day of FDx2 conversion rate in BDP-equivalent = 200x2)
Risk of bias
children (Review)
Kim 2000
Methods DESIGN
-parallel-group
ALLOCATION
-Computer-generated randomisation
BLINDING
-double-blind
-double-dummy
-identical placebo
WITHDRAWAL/DROPOUT
-described
Participants ASYMPTOMATIC PARTICIPANTS

RANDOMISED
N = 437
Z: 221
FP: 216
WITHDRAWALS:
Z: 46 (21%)
FP:19 (9%)
AGE (years, range):
Z: 32.9 (12-71)
FP: 35.5 (12-81)
GENDER (%male)
Z: 19 %
FP: 18 %
ASTHMA SEVERITY:
mild stable
FEV1 (Mean SD)
Z: 2.53 0.04
FP: 2.58 0.04
not reported
ATOPY:
Z: 58%
FP: 56%
ASTHMA DURATION:
10 years
-Age >=12 years
-60-85% Pred FEV1
->=12% improvement after inhaled beta-agonist
-use of low doses of ICS (BDP 200-400/day or triamcinolone 400-800 mcg/day for >= 8 weeks
- use of beta-agonist use prn.
- during run-in: stable asthma, i.e., <= 4 rescue puffs/day of short-acting beta2-agonist, <= 1 night
awakening
-FEV1 between 60% and 85%
EXCLUSION:
children (Review)
Kim 2000 (Continued)
->= 1 burst of systemic steroids in < 6 months
-smoking in < 12 months
-respiratory infection in < 2 weeks
Duration
-Run-in Period: 1 week
TEST GROUP
CONTROL GROUP
DEVICE
-MDI
CO-INTERVENTION:
none
Outcomes ANALYSIS BY INTENTION-TO-TREAT

-Change in morning PEFR (L/min)
SYMPTOM SCORES
-change in mean symptom score (6-point scale)
FUNCTIONAL STATUS
-Change from baseline daily mean B2-agonist use (puffs/day)
-Change in nighttime awakenings
-Change in symptom-free days
-Change from baseline quality of life scores
-Patients requiring hospital admission
not reported
ADVERSE EVENTS
reported
WITHDRAWALS
reported
* Primary outcome

-Confirmation of methodology and data extraction received from Gerry Hogan
400 (daily dose of fluticasone x conversation rate in BDP-equivalent = 200 x 2 )
Risk of bias
children (Review)
Kim 2000 (Continued)
Laitinen 1997
Methods DESIGN
-parallel-group
ALLOCATION
-computer-generated randomisation
-assignment by numbered coded drugs provided by pharmacy
BLINDING
-double-blind
-identical placebo
WITHDRAWAL/DROPOUT
-described

RANDOMISED:
-N = 481
Z80:159
Z20:162
BDP:160
WITHDRAWALS:
Z80:10 (6.3%)
Z20:14 (8.6%)
BDP:13 (8.1)%
AGE:
Z80:38.7 12.6
Z20:37.8 14.0
BDP:38.3 13.6
GENDER (% male):
Z80: 50.9%
Z20:53.1%
BDP:48.1%
Z80: 79 12.8
Z20:78.9 12.9
BDP:80.8 12.7
not described
ATOPY/ALLERGIC RHINITIS:
Z80:88 (55%)
Z20:86 (53%)
BDP:86 (54%)
children (Review)
Laitinen 1997 (Continued)
ASTHMA DURATION (Years, SD)

Z80:13.4 11
Z20:11.3 10
BDP:13.3 12
--Age: 12-70 years
-FEV1 >=60% of Pred
-improvement >15% FEV1 after B2-agonist use
-prn short-acting beta2-agonist with or without inhaled steroids<=500 BUD or BDP or <=250 FP
-daytime asthma score >-10 in past 7 days
EXCLUSION:
-abnormal LFT
-use of other asthma Rx other than prn beta2-agonist during run-in
-respiratory infection during run-in
Duration
-Run-in Period: not described
TEST GROUP 1
-Zafirlukast (Accolate) 20 mg bid p.o.
TEST GROUP 2
-Zafirlukast (Accolate) 80 mg bid p.o.
CONTROL GROUP
-Inhaled beclomethasone dipropionate 200-250 ug bid
DEVICE
-not described
CO-INTERVENTION:
not specified
Outcomes ANALYSIS (ITT not specified)

-Change from baseline AM PEFR (L/min)
SYMPTOM SCORES
-Change from baseline daytime symptom scores (max = 21)
FUNCTIONAL STATUS
-Change from baseline mean daily B2-agonist use (puffs/day)
-Change from baseline nocturnal awakenings
(/night)
INFLAMMATORY MARKERS
change in eosinophil counts
ADVERSE EVENTS
reported
WITHDRAWALS
reported
* Primary outcome
children (Review)
Laitinen 1997 (Continued)
Notes -Abstract (1997)

-funded by Zeneca
-confirmation of methodology and data extraction
450 (daily dose of beclomethasone = 450)
Risk of bias
Laviolette 1999
Methods DESIGN
-parallel-group
ALLOCATION
-Random
-opaque consecutive-numbered envelopes containing assignment
BLINDING
-double-blind
-double-dummy
-identical placebo
WITHDRAWAL/DROPOUT
-described

RANDOMISED
-N = 642
M:201
BDP:200
Placebo:48
M+BDP:193
WITHDRAWALS:
M: 42 (21%)
BDP:22 (11%)
AGE:
M:38 (15-75)
BDP:39 (15-78)
GENDER (% male):
M:49%
BDP: 52%
M: 72 12
children (Review)
Laviolette 1999 (Continued)
BDP: 72 12
M: 3.5 2.3
BDP: 3.5 2.5
ATOPY/ALLERGIC RHINITIS:
M: 74%
BDP: 74%
-Age: >15 years old
-healthy, non-smoking
-history of >=one year of intermittent or persistent asthma symptoms
-ICS treatment >=6wks prior to prestudy visit (ICS dose comparable to beclomethasone 400-500 mcg)
-50-85% FEV1 Pred
Duration
TEST GROUP 1
-Montelukast 10 mg die + Placebo (after blind beclomethasone removal)
TEST GROUP 2
-Montelukast 10 mg die + inhaled beclomethasone 200 mcg bid (not used in this review)
CONTROL GROUP 1
-Placebo + inhaled beclomethasone 200 mcg bid
CONTROL GROUP 2
-Placebo + Placebo (not used in this review)
DEVICE
- Aero-Chamber spacer device
CO-INTERVENTION:
not specified
Outcomes ANALYSIS ( Intention-to-treat)

OUTCOMES reported at 6 and 16 weeks
-Change from baseline Am PEFR
SYMPTOM SCORES
-Change from baseline daytime asthma symptoms scores (6-point scale)
FUNCTIONAL STATUS
-% Change from daily mean use of beta2-agonists
-Change from baseline nocturnal awakenings (nights/week)
-Change from baseline peripheral blood eosinophil counts
ADVERSE EVENTS
reported
WITHDRAWALS
reported
* Primary outcome
children (Review)
Laviolette 1999 (Continued)
Notes -Full Text publication (1999)

-Funded by Merck
-Confirmation of methodology and data received from Reiss 01 Sept 1999
400 (daily dose of beclomethasone = 400)
Risk of bias
Malmstrom 1999
Methods DESIGN
-parallel-group
ALLOCATION
-Random
-mode of allocation not described
BLINDING
-double-blind
-double-dummy -identical placebo
WITHDRAWAL/DROPOUT
-described

RANDOMISED
-N = 895
M:387
BDP:251
PLACEBO:257
WITHDRAWALS:
M: 33 (8.5%)
BDP:18 (7.2%)
AGE:
M:35 (15-78)
BDP: 35 (15-74)
GENDER (% male)
M: 40%
BDP: 35%
-%PRED FEV1 (mean, SD)
M : 65 10
BDP: 65 10
children (Review)
Malmstrom 1999 (Continued)
M: 5.4 3.4
BDP: 5.5 4.2
ATOPY:
M: 62 %
BDP:61 %
ASTHMA DURATION (years)
M: 17 (1-67)
BDP: 18 (0.5-65)
-Age: >=15 years old
-history of chronic asthma for >= one year
-50-85% FEV1 Pred
-average daily use of >= one puff of beta-agonist
-minimal predefined daytime asthma symptom score (64 of a possible of 336)
EXCLUSION:
-inhaled or oral steroids, cromolyn, or nedocromil in <4 weeks
-use of long-acting beta2-agonist, antimuscarinic or new tx with theophylline in < 2 weeks
Duration
-Wash-out Period: 3 weeks
TEST GROUP
-Montelukast 10 mg die at bedtime p.o.
CONTROL GROUP 1
-Beclomethasone 200 ug bid
CONTROL GROUP 2
DEVICE
-spacer for Beclomethasone
CO-INTERVENTION:
theophylline (10%)
Outcomes ANALYSIS ( ITT not specified)

OUTCOMES reported at 6 and 12 weeks
-*% Change from baseline FEV1
-Change from baseline AM PEFR
SYMPTOM SCORES
-Change from baseline daytime symptom scores
FUNCTIONAL STATUS
-Change from baseline nocturnal awakenings (nights/week)
-Change from baseline quality of life scores (Juniper)
-% Change from baseline mean daily B2-agonist use (puffs/day)
-Change from baseline peripheral blood eosinophil counts
ADVERSE EVENTS
children (Review)
Malmstrom 1999 (Continued)
reported
WITHDRAWALS
reported
* Primary outcome

-funded by Merck
-Confirmation of methodology and data extraction obtained.
Risk of bias
Maspero 2001
Methods DESIGN
-parallel-group
ALLOCATION
-Random
-opaque consecutive-numbered envelopes
BLINDING
-open-label
-no placebo
WITHDRAWAL/DROPOUT
-described

RANDOMISED
N = 124
M: 83
BDP: 41
WITHDRAWALS:
M: 5 (6%)
BDP: 3 (7%)
AGE: 6-11 years
M: 9.5 1.8 (6-12) years
BDP:9.7 1.4 (7-12) years
GENDER (% male):
M: 64 %
BDP: 51%
BASELINE SEVERITY:
moderate
children (Review)
Maspero 2001 (Continued)
Mean % Predicted FEV1

M: 82 13
BDP:82 17
ATOPY/ALLERGEN TRIGGERS:
M: 66%
BDP:61%
not described
not reported
-Age: 6-11 years
-within 40% pf tje 5 to 95% weight range
-non smoker
-baseline FEV1 >=60 and<=85% predicted
-Improvement >=12% after beta2-agonist
-need for rescue beta2-agonist 7/14 days of the run-in
EXCLUSION:
-ED asthma visit in past month
-Admission for asthma in past 3 months
-prior intubation
-unresolved URTI in past 3 weeks
-significant sinus infection
-cromolyn use within 1 month
-inhaled or systemic steroids use in past 2 weeks or >= 3 short courses of systemic steroids in past 6 months
-long-acting beta2-agonist, anticholinergics, long-acting anti-histamine, theophylline in past 2 weeks
Duration
-Run-in Period: unspecified
-Primary RCT Period: 10 weeks
-Extension Period: 6 months
TEST GROUP
CONTROL GROUP
-Inhaled BPD 100 mcg tid
DEVICE
-MDI, spacer optional
CO-INTERVENTION:
not specified
Outcomes ANALYSIS by Intention-to-treat

OUTCOMES reported at 12, 24 weeks
SYMPTOM SCORES
not reported
FUNCTIONAL STATUS
-days off work for parents
-days off school for children
children (Review)
Maspero 2001 (Continued)
-Number of exacerbations requiring systemic steroids

-Number of exacerbations requiring admission
-*LTC4 in nasal wash
ADVERSE EVENTS
reported
WITHDRAWALS
reported
* Primary outcome
Notes -Full-text publication of primary and extension study (1999)

-Funded by Merck Frosst
-confirmation of methodology and data extraction obtained
Risk of bias
Meltzer 2002
Methods DESIGN
-parallel group
-multicentre trial
ALLOCATION
-Random
-Computer-generated allocation in blocks of 4
-mode of allocation: not described
BLINDING
-Double-blind
-Double-dummy
-Identical placebo
WITHDRAWAL/DROPOUT
-described
by group and by reason
-Confirmation of methodology: not obtained

RANDOMISED: N = 522
M= 264
FP= 258
WITHDRAWALS; N(%)
M: 67(25%)
FP: 60 (23%)
AGE: mean ( SD) years
children (Review)
Meltzer 2002 (Continued)
M: 35.4 (15-77) years

FP: 36.2 (15-73) years
GENDER (% male):
M: 41 %
FP: 51 %
BASELINE SEVERITY:
moderate
% Predicted FEV1 (Mean SE)
M: 65.9 9.1
FP: 65.6 8.9
not reported
M: 74% for >=10 years
FP: 78% for >=10 years
-Non-smoking male and female
-Age: >=15 years old
-diagnosis of asthma as per the ATS criteria for >= 6 months
-use of an inhaled or oral short-acting beta-agonist on a regular or as-needed basis during the preceding
3 months
-50-80% FEV1 Pred pre-bronchodilator
-improvement >=15% FEV1 after 200 mcg of B2-agonist use
At the end of the run-in period:
-unmedicated FEV1 of 50-80% that was within 15% of the FEV1 at screening
-use of albuterol to relieve asthma symptom on at least 6 to 7 days before randomisation
-an asthma symptom score of 2 or more (based on a 1-5-point scale) on at least 4 of the 7 days
EXCLUSION:
-history of life-threatening or unstable asthma
-known hypersensitivity to study medication
-respiratory tract infections within 4 weeks of screening
-pregnancy
-smoking history of more than 10 pack-years
-inhaled or systemic steroids, inhaled cromolyn or nedocromil, leukotriene modifiers, anticholinergics,
and theophylline products
Duration
-Intervention: 24 weeks
TEST GROUP
CONTROL GROUP
-Inhaled FP 100 mcg bid
DEVICE
-MDI with spacer
CO-INTERVENTION:
Rx permitted: antihistamines, nasal decongestants, intranasal medications (including corticosteroids)for
the treatment of rhinitis
children (Review)
Meltzer 2002 (Continued)
Outcomes ANALYSIS by intention-to-treat

OUTCOMES reported at 24 weeks or endpoint
-*% Change from baseline FEV1
-Change from baseline PM PEFR
-Change in mean diurnal variation in PEF
SYMPTOM SCORES
-Change from baseline daytime symptom scores (scale of 0 to 5)
-change in nighttime awakening (specify /week or /night) (scale of 0 to 5)
-% symtom-free days
-% symptom-free nights
FUNCTIONAL STATUS
-Exacerbations requiring systemic steroids
-Exacerbations requiring admission
-Global assessment of medication effectiveness
-Patient satisfaction
-Change in AQLQ
-not reported
ADVERSE EVENTS
-not reported
WITHDRAWALS
reported
* Primary outcome
Notes -Full-text publication (2002)

-Funded by GlaxoSmithKline
USER-DEFINED ORDER: 400 (daily dose of BDP-equivalent=200 x 2)
Risk of bias
children (Review)
Nathan 2001
Methods DESIGN
-parallel groups
-involving 25 sites in USA
ALLOCATION
-Random
method of randomization:
-not reported
means of assignment: not reported
BLINDING
-double-blind
-double-dummy
-placebo
WITHDRAWAL/DROPOUT
-described

RANDOMISED:
N =294
Z=150
FP= 144
WITHDRAWALS; N(%)
Z: 12 (8%)
FP: 5 (3%)
AGE: Mean ( years, range)
Z: 32 (12-70)
FP: 31 (12-54)
GENDER (% male):
Z: 65 (43%)
FP: 65 (45%)
BASELINE SEVERITY:
-not mentioned
% Pred. FEV1 (Mean SD)
Z: 68.9 7.6
FP: 68 8.5
Z=4.4 2.7
FP=4.4 2.6
ATOPY:
-not reported
ASTHMA DURATION
-not reported
->= 12 years old
-histroy of asthma according to ATS
-50-80% FEV1 pred.
-reversibility >= 12% after 2 puffs of albuterol
-using inhaled or oral short acting beta2-agonist for longer than 6 weeks
children (Review)
Nathan 2001 (Continued)
-not using inhaled corticosteroids within 30 days

EXCLUSION:
-life-threatening or unstable asthma
-significant uncontrolled disease other than asthma
-URTI within 2 weeks
-used oral or parenteral corticosteroids within 60 days
-used an investigational medication within 30 days
Duration
TEST GROUP
-zafirulast 20 mg bid
CONTROL GROUP
-fluticasone 100 mcg bid
DEVICE
-not reported
CO-INTERVENTION:
none permitted
Outcomes PER PROTOCOL ANALYSIS (not ITT)

OUTCOMES reported at 4 and endpoint
-*change from baseline in morning predose FEV1 (L)
-Change from baseline PM PEFR
SYMPTOM SCORES
-Change from baseline in symptom score
(scale of 0 to 4)
-% symtom-free days
-asthma exacerbations defined as worsening of asthma requiring a change in patients asthma therapy other
than increased use of supplemental albuterol
FUNCTIONAL STATUS
-% Change from baseline mean daily B2-agonist use (puffs/day
-not reported
ADVERSE EVENTS
reported
WITHDRAWALS
reported
* Primary outcome

-Funded by add cie (Glaxo Wellcome)
-confirmation of methodology and data extraction obtained/not requested/not obtained ?????????????
USER-DEFINED ORDER: 400 (daily dose of BDP-equivalent=usually 400 mcg )
Risk of bias
children (Review)
Nathan 2001 (Continued)
Riccioni 2001
Methods DESIGN
-parallel group
ALLOCATION
-Random
-method of randomization: computer generated
-method of assessment: not mentioned
BLINDING
-described as double-blind (patient and assessor) but no placebo
WITHDRAWAL/DROPOUT
-described
-Confirmation of methodology: obtained (Oct 2003)

RANDOMISED:
N = 48
Z= 12
BUD= 12
Z+BUD= 12
Control= 12
WITHDRAWALS;
Z=2 (16%)
BUD= 1 (8%)
Z+BUD= 2 (16%)
Z:
33.75 (11.24)
BUD:
32.15 (10.27)
Z+BUD:
33.44 (11.12)
Control:
29.15 (10.34)
GENDER (% male):
Z: 6 (50)
BUD: 6 (50)
Z+BUD: 6 (50)
Control: 6 (50)
BASELINE SEVERITY:
-mild persistent
% Predicted FEV1 (Mean +- SD)
Z:
children (Review)
Riccioni 2001 (Continued)
94.75 7.68
BUD:
92.75 9.87
Z+BUD:
92.16 5.06
Control:
95.75 5.84
-not reported
-1 year
-1 year of mild persistent bronchial asthma
-PEF >80% pred. and PEF daily variability in 20-30% range with positive salbutamol reversibility test
EXCLUSION:
-URTI in last 3 weeks
-hospitalization for asthma in the last 3 months
-treatment with antihistamines, anticholinergics, teophyllinic drugs
-presence of autoimmune, hepatic, or renal disorders
-malabsorbtion, drug or alchohol addiction
-pregnancy or lactation
Duration
-run-in Period: 2 weeks
TEST GROUP:
TEST GROUP 2
-Zafirlukast 20 mg bid + Budesonide
400 g bid
CONTROL GROUP
-Budesonide 400 g bid
CONTROL GROUP 2
-Placebo
DEVICE:
-not reported
CO-INTERVENTION:
-not reported
Outcomes ANALYSIS PER PROTOCOL

(not by ITT)
OUTCOMES
PULMONARY FUNCTION TEST
-pre- and post FVC values
-pre- and post FEV1
-pre- and post PC20
SYMPTOM SCORES
children (Review)
Riccioni 2001 (Continued)
-not reported
FUNCTIONAL STATUS
-not reported
-not reported
ADVERSE EVENTS
-not mentioned
WITHDRAWALS
-not reported
Primary outcome not specified

Funded by University
-confirmation of methodology and data extraction: obtained from Graziano Riccioni, Oct 2003
Risk of bias
Allocation concealment? No C - Inadequate
Riccioni 2002a
Methods DESIGN
-parallel group
ALLOCATION
-random
BLINDNG
WITHDRAWALS/DROPOUTS
-described
obtained (Oct 2003)

RANDOMISED (N=40)
M=20
BUD=20
WITHDRAWALS:
-reported
AGE ( SD)
M= 25.16 7.68
BUD=26.18 6.15
GENDER (% male)
children (Review)
Riccioni 2002a (Continued)
M= 11 (55)
BUD= 10 (50)
ASTHMA SEVERITY:
-mild and persistent
ASTHMA DURATION:
-not mentioned
% Pred. FEV1
M=93.15 12.17
BUD=94.73 10.18
Mean (+-SD) beta2agonist use (puffs per day)
-not described
ATOPY:
M= 12 (60%)
BUD= 10 (40%)
PARTICIPANTS WITH ALLERGIC RHINITIS:
M: 2 (10%)
BUD: 2 (10%)
ELIGIBILITY
CRITERIA
-FEV1 >80%
-daily variability of 20-30% in PEF
-diagnosed with asthma by a specialist
EXCLUSION
-URTI in last 3 weeks
-hospitalization for asthma in last 3 months
-inhaled and systemic corticosteroids
Duration
-Run-in: 2 weeks
TEST GROUP
-10 mg montelukast od
CONTROL GROUP
-400 Budesonide bid
DEVICE
-turbuhaler
CRITERIA FOR WITHDRAWAL
-mentioned
CO-INTERVENTION:
-not permitted
Outcomes ANALYSIS probably PER PROTOCOL

(no ITT analysis mentioned)
OUTCOMES
-change from baseline in FVC
children (Review)
Riccioni 2002a (Continued)
-change from baseline in FEV1

-change from baseline in PC20
SYMPTOM SCORES
-not reported
FUNCTIONAL STATUS
-not mentioned
-not reported
ADVERSE EVENTS
-reported
overall, not in details
WITHDRAWALS
-reported
Primary outcome:
not specified

Funded by the University G. DAnnunzio
-confirmation of methodology and data extraction : not obtained
Risk of bias
Riccioni 2002b
Methods DESIGN
-parallel-group
ALLOCATION
-random
-method of assessment: not described
BLINDING
WITHDRAWAL/DROPOUT
-described
JADAD = 3
CONFIRMATION OF METHODOLOGY: obtained (Oct 2003)

RANDOMISED (N=45)
M=15
BUD=15
M+BUD=15
WITHDRAWALS:
children (Review)
Riccioni 2002b (Continued)
M=1 (7%)
BUD=1 (7%)
M+BUD=1 (7%)
AGE ( SD)
M= 26.7 8.6
BUD=26.9 12.3
M+BUD=28.2 10
GENDER (% male)
M= 9 (60)
BUD=8 (53.3)
M+BUD=5(33.7)
ASTHMA SEVERITY:
-mild
ASTHMA DURATION:
-1 year
% Pred. FEV1
M=97 (85-123)
BUD=97 (76-123)
M+BUD=99 (84-131)
Mean (+-SD) beta2agonist use (puffs per day)
-not described
ATOPY:
-100% (Definition not mentioned)
ELIGIBILITY
CRITERIA
-asthma as per ATS criteria
-confirmation of the presence of BHR by methacholine on the initial visit
-regular attendance of the outpatient clinic over 4 months from the initial visit
-PEF >= 80% of predicted
-PEF variability <=20% as per NIH criteria
EXCLUSION:
-ER visit for asthma exacerbation within 1 month
- URTI in the past 4 weeks
-hospitalization for asthma in past 6 months
-treatment with antihistamines, anticholinergics, theophylline and cromones, LABA, inhaled and oral
corticosteroids
-bronchiectasies
-gastroesophageal reflux
-poor knowledge of the italian language
Duration
-Run-in: 4 weeks
TEST GROUP 1
-10 mg montelukast once daily
TEST GROUP 2
10 mg Montelukast once daily +
400 ug budesonide bid
children (Review)
Riccioni 2002b (Continued)
CONTROL GROUP
-400 Budesonide bid
DEVICE
-turbohaler
CRITERIA FOR WITHDRAWAL
-not described
CO-INTERVENTION:
-none permitted
Outcomes ANALYSIS PER PROTOCOL

(not by ITT)
OUTCOMES
-change from baseline in FVC
-change from baseline in FEV1
-change from baseline in PC20
SYMPTOM SCORES
-not reported
FUNCTIONAL STATUS
-Change in AQOL (Asthma Quality of Life Questionnaire - Juniper) in each of 4 domains
-Asthma exacerbations (defined as requiring systemic steroids or hospital admission or ED treatment for
worsening asthma or decrease in morning PEF >25%
-not reported
ADVERSE EVENTS
-not mentioned
WITHDRAWALS
-reported

Funded by University
-confirmation of methodology and data extraction: obtained by Graziono Riccioni, Oct 2003
-confirmation of methodology and data obtained
Risk of bias
children (Review)
Sheth 2001a
Methods DESIGN
-parallel group
ALLOCATION
-Random
-method of assessment: not mentioned
BLINDING
-double-blind -double-dummy
WITHDRAWAL/DROPOUT
-not described

RANDOMISED:
unclear if stratified randomisation on baseline FEV1 value
FEV1 >70%
N = 152
Z= 55
FP= 51
Placebo=46
FEV1 <70%
N=177
Z=52
FP=60
Placebo=65
WITHDRAWALS;
-not reported
-not reported
GENDER (% male):
-not reported
BASELINE SEVERITY:
-not reported
% Predicted FEV1
(FEV1 >70%)
Z: 75%
FP:76%
Placebo: 76%
(FEV1 <70%)
Z: 63%
FP: 62%
Placebo: 63%
-not reported
-not reported
->= 12 years old
children (Review)
Sheth 2001a (Continued)
-symptomatic on beta-agonists
EXCLUSION:
-not reported
Duration
TEST GROUP
CONTROL GROUP
DEVICE
-not mentioned
CRITERIA FOR WITHDRAWAL:
-not mentioned
CO-INTERVENTION:
-not mentioned

-Change from baseline in morning PEF (L/s)
SYMPTOM SCORES
-Change in symptom-free days (%)
FUNCTIONAL STATUS
-Change from baseline in rescue beta2-agonist use (puffs/day)
-not reported
ADVERSE EVENTS
-not reported
WITHDRAWALS
-not reported
* Primary outcome
Notes -Abstract
Funding not mentioned, probably by GSK
-confirmation of methodology and data extraction: not obtained
USER-DEFINED ORDER: 400 (daily dose of BDP-equivalent=FP 200 x 2 )
Risk of bias
children (Review)
Sheth 2001b
Methods Same as above
Participants Same as above
Interventions Same as above
Outcomes Same as above
Notes Same as above
Risk of bias
Skalky 1999
Methods DESIGN
-parallel-group
ALLOCATION
-Computer generated randomisation
-means of assignment not described
BLINDING
-triple-blind
-identical placebo
WITHDRAWAL/DROPOUT
-described

RANDOMISED:
M:337
BDP:329
WITHDRAWALS:
M: 11 (3%)
BDP: 14 (4%)
AGE ( SD):
M: 33.5 12.1 (15-71) years
BDP: 33.9 12.7 (15-74) years
GENDER (% male)
M: 48%
BDP: 47%
ASTHMA SEVERITY:
not described
M: 67.4 11.11 BDP:65.9 11.69
children (Review)
Skalky 1999 (Continued)
M: 5.6 2.85
BDP: 5.8 2.94
ATOPY or ALLERGIC RHINITIS:
M: 90%
BDP: 89%
-age >=15 years
->=50 and <=85 % pred FEV1 at least twice
-history of asthma for >= 1 year
->=15% improvement after inhaled beta-agonist
-minimal predefined level of beta-agonist use (daily average over a week of >=2 puffs/day)
-no concurrent tx other than rescue beta2-agonist (no ICS < 2 weeks, no cromolyn, nedocromil, AL,
anticholinergic, xanthine or long-acting beta2-agonist <1 week.
-non smoker (for at least 1 year)
-no recent (<1month) tx in the Emergency room
-no recent (<3 months) admission for asthma
-no recent URTI in past 3 weeks
-no clinically significant sinus disease
Duration
TEST GROUP
-Montelukast 10 mg qd p.o.
CONTROL GROUP 1
-Beclomethasone dipropionate 200 ug bid
CONTROL GROUP 2:
placebo (not used)
DEVICE
CO-INTERVENTION:
none permitted other than rescue beta2-agonist and oral steroids.
Outcomes ANALYSIS by Intention-to-treat

SYMPTOM SCORES
not reported
FUNCTIONAL STATUS
-*Change from baseline percentage of asthma control days (2 puffs of albuterol, no nighttime awaken-
ings, no systemic steroid use, and no unscheduled physician visit for asthma)
-% patients with asthma attacks (systemic steroid use or unscheduled physician visit for asthma)
-change from baseline eosinophils
ADVERSE EVENTS
children (Review)
Skalky 1999 (Continued)
reported
WITHDRAWALS
reported
* *Primary outcome
Notes -Abs (1999)

-Funded by Merck
-confirmation of methodology and data obtained
Risk of bias
Stelmach 2002a
Methods DESIGN
-parallel-group
ALLOCATION
-Random
-Means of assignment by coded puffers/pill containers supplied by pharmacy
BLINDING
-double-blind
-identical placebo
WITHDRAWAL/DROPOUT
-described by group but not with reasons by group

RANDOMISED
N = 91
M: 18
Triamcinolone: 19
Formoterol: 18
Placebo: 36
WITHDRAWALS
M: 3 (17%)
Triamcinolone: 3 (17%)
AGE (SD): (without withdrawals)
M: 11.1 1.8 yr
Triamcinolone:12.2 2.1 yr
GENDER (% male)
M: 60%
Triamcinolone:55%
children (Review)
Stelmach 2002a (Continued)
ASTHMA SEVERITY:
moderate
% Pred. FEV1 % (SD)
M: 78.1 3.1
Triamcinolone:73.5 4.3
not described
ALLERGIC RHINITIS:
M: 15%
Triamcinolone: 10%
ATOPY (to dust mites):
M: 100%
Triamcinolone: 100%
DURATION OF ASTHMA:
M: 3.8 0.6
-Age: 6-18 years
-Asthma definition as per the NIH 1997
-Improvement in FEV1 >=15% after 200 mcg salbutamol
-current tx with only beta2-agonist
-use of beta2-agonist daily, attacks that limit daily activity, nighttime symptoms >1 / week, PEF 60-80%
of predicted, PEF variability >30%
EXCLUSION:
Co-existent diseases (hepatic, gastrointestinal, renal, endocrine, neurologic, cardiovascular, malignancy,
other pulmonary or hematologic disease, active upper respiratory tract infections.?
-medication: B-blockers, astemizole, oral corticosteroids, immunotherapy.
Duration
TEST GROUP
-Montelukast 5 mg die if <=14 years (10 mg die, otherwise)
CONTROL GROUP 1
-Inhaled Triamcinolone acetonide 100ug/day qid
CONTROL GROUP 2
CONTROL GROUP 3
-Formoterol 12 ug bid (not used in this review)
DEVICE
CO-INTERVENTION:
No other Rx allowed other than rescue b2-agonists or rescue oral steroids
Outcomes ANALYSIS per protocol

-Change from baseline FEV1 -Change from baseline in PC 20
children (Review)
Stelmach 2002a (Continued)
SYMPTOM SCORES
-total score (3-point for daytime symptoms + 3-point for nighttime symptoms + 3 points for use of rescue
beta2-agonists)
?not reported
FUNCTIONAL STATUS
- change from baseline in serum IL-10
- change from baseline in serum ECP
ADVERSE EVENTS
-reported
WITHDRAWALS
reported
* Primary outcome not specified

-Self-funded by authors
-Confirmation of methodology and data obtained from I. Stelmach June 2003
200 (daily dose of triamcinolone (400) x 0.5 = 200)
Risk of bias
Stelmach 2002b
Methods DESIGN
-parallel-group
ALLOCATION
-Random
-Assignment by coded puffers/pill containers supplied by pharmacy
BLINDING
-double-blind
-identical placebo
WITHDRAWAL/DROPOUT
-described by group but not with reasons by group

RANDOMISED
N =154
M: 27
children (Review)
Stelmach 2002b (Continued)
Triamcinolone: 28
Formoterol: 28
Nedocromil:26
Placebo: 45
WITHDRAWALS (N=14)
M: 11% (3/27)
Triamcinolone: 11 % (3/28)
Formoterol: 11% (3/28)
Nedocromil: 0%
Placebo: 12% (40/45)
AGE (SD):
M: 12.8 1.7 yr
Triamcinolone:13,1 2.4 yr
GENDER (% male)
M: 48.1%
Triamcinolone:53.6 %
ASTHMA SEVERITY:
moderate asthma
% Pred. FEV1 % (SD) - after withdrawals
M: 73.7 5.4
not described
ATOPY (described as chronic atopic):
M: 100%
Triamcinolone: 100%
ALLERGIC RHINITIS:
Montelukast: 7.1%
Triamcinolone:10.7%
DURATION OF ASTHMA (years):
M: 3.8 0.5
Triamcinolone: 3.7 0.6
ASTHMA SYMPTOMS:
M: 6.2 1.0
Triamcinolone: 7.1 0.9 (score of 0-9)
-Age= 9-17 years
-Asthma definition according to NIH 1997
-Reversibility: improvement in FEV1 >=15% after 200 mcg salbutamol
-use of beta2-agonist daily, attacks that limit daily activity, nighttime symptoms >1 / week, PEF 60-80%
of predicted, PEF variability >30%
EXCLUSION:
Co-existent diseases (hepatic, gastrointestinal, renal, endocrine, neurologic, cardiovascular, malignancy,
other pulmonary or hematologic disease, active upper respiratory tract infections.
Duration
children (Review)
Stelmach 2002b (Continued)
TEST GROUP
Montelukast 5 mg die if <=14 years (10 mg die, otherwise)
CONTROL GROUP 1
-Inhaled Triamcinolone acetonide 200ug bid
CONTROL GROUP 2
CONTROL GROUP 3
-Formoterol 12 ug bid (not used in this review)
CONTROL GROUP 4
-Nedocromil 0.002 g/inhalation 2 inhalations qid (not used in this review)
DEVICE
CO-INTERVENTION:
no other Rx allowed other than rescue beta2-agonist or rescue systemic steroids.
Outcomes ANALYSIS per protocol

-Change from baseline FEV1 -Change from baseline in PC 20
SYMPTOM SCORES
-total score (3-point for daytime symptoms + 3-point for nighttime symptoms + 3 points for use of rescue
beta2-agonists)
not reported?
FUNCTIONAL STATUS
?-patients with exacerbations requiring systemic steroids
- change from baseline in serum ECP
ADVERSE EVENTS
-not reported
WITHDRAWALS
reported overall (not by group)

-Self-Funded
-Confirmation of methodology and data obtained from I. Stelmach June 2003
200 (daily dose of triamcinolone (400) x 0.5 = 200)
Risk of bias
Allocation concealment? Unclear B - Unclear
children (Review)
Williams 2001
Methods DESIGN
-parallel-group
ALLOCATION
-Computer generated random
numbers (but same randomisation as for the primary study despite large number of drop-outs:
M: 30%(118/387) BDP: 33% (84/251)
-supplied by numbered coded medications
BLINDING
-triple-blind
-identical placebo
WITHDRAWAL/DROPOUT
-described
-Confirmation of methodology obtained: 08/01

RANDOMISED:
N = 436 (extension period) of 895 patients of the primary RCT
M: 269
BDP: 167
WITHDRAWALS:
M: 32 (12%)
BDP:23 (14%)
AGE (SD) years:
M: 37.8 15.5
BDP: 36.4 14.6
GENDER (% male)
M: 39%
BDP: 35%
ASTHMA SEVERITY:
not described
% Pred. FEV1 % (mean SD)
Not described
Baseline FEV1 (L)
M: 2.1 L
BPD: 2.1 L
Not described
ATOPY:
M: 63 %
BDP: 62 %
not reported
-Age 15-85 years
-50-85% Pred FEV1
-history of asthma
->=15% improvement in FEV1 after inhaled beta-agonist
-predefined level of daytime symptoms and beta-agonist use (not specified)
children (Review)
Williams 2001 (Continued)
-competence in performance in study procedures

EXCLUSION CRITERIA:
not described
Duration
-Run-in Period: none
-Primary RCT period: 12 weeks
-Wash-out Period: none
-Extension Period: 37 weeks
TEST GROUP
CONTROL GROUP
-Inhaled Beclomethasone 200 ug/day bid
DEVICE
-MDI with spacer
CO-INTERVENTION:
Theophylline
M: 11%
BCP: 10%
Outcomes ANALYSIS ( ITT for efficacy and safety measures)

OUTCOMES reported at 8, 16, 24, 37 weeks
-Change in morning and evening PEFR (L/min)
SYMPTOM SCORES
-Change in daytime symptoms (scale: 0 to 6) (/day)
-Change in nocturnal asthma symptom score (0-3 point scale)
FUNCTIONAL STATUS
-Change from baseline in nocturnal awakenings (nights/week)
-Number of exacerbations requiring hospital admission
-serum eosinophil counts
ADVERSE EVENTS
Headache, elevated liver enzymes, nausea, death
WITHDRAWALS
reported
*Primary outcome
Notes -Full-text publication of three trials (2001)

-Funded by Merck Frosst
-Confirmation of data and methodology requested
USER-DEFINED ORDER: 400 (daily dose of BDP=400 mcg)
Risk of bias
children (Review)
Williams 2001 (Continued)
Yamauchi 2001
Methods DESIGN
-parallel-group
ALLOCATION
-Random allocation
-means of allocation not described
BLINDING
-not reported
WITHDRAWAL/DROPOUT
-not described
-Confirmation of methodology not obtained

RANDOMISED:
N = 30
P: 10
BDP: 10
Placebo: 10 (not used)
WITHDRAWALS:
not reported
AGE (SD) years:
P: 40.6 2.02
BDP: 42.2 3.32
GENDER (% male)
M: 60%
BDP: 70%
ASTHMA SEVERITY:
mild persistent or mild intermittent
P: 91.8 3.21
BDP: 92.0 2.18
not described
ATOPY:
P: 60 %
BDP: 60 %
not reported
-Age years
-% Pred FEV1
children (Review)
Yamauchi 2001 (Continued)
-<15% variability in PEF over preceding 2 weeks

-no upper respiratory tract infection in preceding 4 weeks
-tx with inhaled beta2-agonist on demand or oral slow-release theophylline or oral beta2-agonist
-no inhaled or systemic steroids
EXCLUSION CRITERIA:
not described.
Duration
-Run-in Period: not described if any
TEST GROUP
-Pranlukast 450 mg/day
CONTROL GROUP
-Inhaled Beclomethasone 400 ug/day die
DEVICE
-not reported
CO-INTERVENTION:
Theophylline
M: 11%
BCP: 10%

-Change in morning and evening PEFR
SYMPTOM SCORES
-not reported
FUNCTIONAL STATUS
not reported
-sputum eosinophil (%)
-exhaled NO2 concentration (ppb)
ADVERSE EVENTS
not reported
WITHDRAWALS
not reported

-Funded by the Ministry of Education, Science, Sports and Culture in Japan
-Confirmation of data and methodology requested
USER-DEFINED ORDER: 400 (daily dose of BDP=400 mcg)
Risk of bias
children (Review)
Zieger
Methods DESIGN
-parallel group
-multicentre
ALLOCATION
-Random
method of randomization:
-not reported
means of assignment: not reported
BLINDING
-double blind
WITHTHDRAWAL/DROPOUT
-described

RANDOMISED:
N =380
M=189
FP=191
WITHDRAWALS; N(%)
M: 25 (12.5%)
FP: 28 (14%)
AGE: Mean ( years, +SD)
M: 33.9 (14.8)
FP: 36.5 (13.8)
GENDER (% male):
M: 58 (30.2%)
FP: 59 (30.9%)
BASELINE SEVERITY:
-mild and moderate
% Pred. FEV1 (Mean SD)
M: 93 8.9
FP: 94.8 10.8
M= 3.4 1.2
FP= 3.6 1.4
ATOPY:
-not reported
ASTHMA DURATION
- >=4 months
-asthmatic outpatients 15 to 85 years old
-clinical history of asthma >= 4 months
-average baseline FEV1 >= 80% pred. with no qualifying value below 70%
-daytime symptoms and B-agonist use on an average of >= and <= 6 days per week in the last 2 weeks of
the run-in period
-reversibility by one of the following methods during baseline: FEV1 or PEFR, methacholine PC20 or
exercise challenge
children (Review)
Zieger (Continued)
EXCLUSION:
-not reported
Duration
TEST GROUP
-montelukast 10 mg od
CONTROL GROUP
-fluticasone 100 mcg bid
DEVICE
-not reported
CO-INTERVENTION:
-not reported

-change from baseline in FEV1 (L)
-Change from baseline PEFR
SYMPTOM SCORES
-not reported
FUNCTIONAL STATUS
-*% Change from baseline asthma rescue free days
-% change from baseline in days with B-agonist use
-Methacholine PC20
ADVERSE EVENTS
-reported
WITHDRAWALS
-reported
* Primary outcome
Notes -Abstract (1998)

-Funded by Merck & Co. Inc
USER-DEFINED ORDER: 400
(FP 200 x 2 )
Risk of bias
children (Review)
Characteristics of excluded studies [ordered by study ID]
Abbott Pharma 1996 Not a randomized controlled trial
Allen 1997 Not a randomized controlled trial
Altman 1998 Control intervention was not inhaled corticosteroids
Anonymous 1997 Not a randomized controlled trial
Barnes 1996 Control intervention was not inhaled corticosteroids
Barnes 1997 Not a randomized controlled trial
Barnes 1997b Control intervention was not inhaled corticosteroids
Barnes 2001 Not a randomized controlled trial (meta-analysis)
Bateman 1995 Control intervention was not inhaled corticosteroids
Baumgartner 1999 Duplicate of published paper in Eur Respir J 2003;21:123-128.
Bilancia 2000 control intervention was not placebo
Bisgaard 1999 Control intervention was not inhaled corticosteroids

Subjects received additional non-permitted co-interventions (inhaled steroids) other than short-acting
beta2-agonists
Outcomes did not reflect control of asthma (airway inflammation)
Intervention < 4 weeks
Bisgaard 2000 Control intervention was not inhaled corticosteroids
Bjermer 2002 control intervention were not placebo
Brannan 2001 Intervention < 4 weeks

Control intervention was not inhaled corticosteroids
Brocks 1996 Subjects were not asthmatics
Bronsky 1997 Subjects were not asthmatics
Bruce 2002 Outcome measures did not reflect asthma control
Busse 1999 Control intervention was not inhaled corticosteroids

beta2-agonists
Outcomes did not reflect control of asthma (provocation challenge)
Cakmak 2000 control intervention was not placebo
children (Review)
(Continued)
Calhoun 1997 Control intervention was not inhaled corticosteroids
Calhoun 2001 Use of other non permitted drug
Camargo 2002 Acute asthma setting
Capella 2001 Subjects non-asthmatics (atopic dermatitis)
Chiba 1997 Not a randomized controlled trial
Chuchalin 2002 Intervention was not anti-leukotrienes
Claesson 1998 Not a randomized controlled trial
Cloud 1989 Control intervention was not inhaled corticosteroids
Currie 2003 (B) control intervention was not placebo
Cylly 2003 ongoing trials
Dahlen In Press Control intervention was not inhaled corticosteroids

beta2-agonists
Daikh 2003 Subjects were not asthmatics
Dempsey 1999 tested intervention administered for < 4 weeks.
Dempsey 2000 Intervention lasted <4 weeks
Dempsey 2000 (B) control intervention was not placebo
Dempsey 2002b Control intervention was not placebo
Demuro-Mercon 2001 control intervention was not placebo
Dessanges 1999 Subjects received additional non-permitted co-interventions (inhaled steroids) other than short-acting
beta2-agonists
Intervention lasted <4 weeks
Outcomes did not reflect control of asthma (provocation challenge)
Diamant 1997 Control intervention was not inhaled corticosteroids

Intervention was administered for less than a four-week period
Outcomes were solely the result of provocation
Dicpinigaitis 2002 Outcome measures did not reflect asthma control
children (Review)
(Continued)
Dockhorn 2000 Control intervention was not inhaled corticosteroids

Intervention administered for less than 4 weeks
Eliraz 2001 Tested intervention is not anti-leukotrienes
Fabbri 1996 Not a randomized controlled trial
Faul 2002 Outcome measures did not reflect asthma control
Findlay 1992 Control intervention was not inhaled corticosteroids

Intervention was administered for less than a four week period
Finn 2000 control intervention was not inhaled steroids (but placebo). A small number of placebo-treated patients
also received co-intervention with inhaled steroids (N=42), but co-intervention with inhaled steroids was
not randomily assigned.
Fischer 1995 Control intervention was not inhaled corticosteroids

Fischer 1997 Control intervention was not inhaled corticosteroids
Fish 1997 Control intervention was not inhaled corticosteroids
Fish 2001 Co-intervention with inhaled corticosteroids

Control intervention was not inhaled corticosteroids (it was long-acting beta2-agonists)
Franzen 1994 Not a randomized controlled trial
Fujimura 1993 Control intervention was not inhaled corticosteroids
Gaddy 1990 Control intervention was not inhaled corticosteroids

Intervention was administered for less than a four-week period, intravenously
Geha 2001 Tested intervention was not anti-leukotrienes
Georgiou 1997 Control intervention was not inhaled corticosteroids

Subjects were not asthmatics
Ghiro 2002 Outcome measures did not reflect asthma control
Gold 2001 Control intervention was not placebo
Gold 2001 1 Control intervention was not placebo
Green 2002 control intervention was not placebo

co-intervention with inhaled steroids in all patients
children (Review)
(Continued)
Green 2002 1 Intervention was not anti-leukotrien
Grossman 1995 Control intervention was not inhaled corticosteroids
Grossman 1997 Control intervention was not inhaled corticosteroids
Haahtela 1994 Intervention was not anti-leukotrienes
Hamilton 1998 Control intervention was not inhaled corticosteroids

Hassall 1998 Control intervention was not inhaled corticosteroids
Hay 1997 Not a randomized controlled trial
Henderson 1994 Not a randomized controlled trial
Hood 1999 Subjects non-asthmatics

Tested intervention was not anti-leukotrienes
Intervention lasted <4 weeks
Howland 1994 Control intervention was not inhaled corticosteroids
Hsieh 1996 Intervention was not anti-leukotrienes
Hui K 1991 Control intervention was not inhaled corticosteroids

Ikeda 1997 Not a randomized controlled trial
Israel 1990 Control intervention was not inhaled corticosteroids

Johnson 1999 Abstract of included full text publication:

Busse W, Wolfe J, Storms W, Srebro S, Edwards L, Johnson M, Bowers BW, Rogenes PR, Rickard K .
Fluticasone propionate compared to Zafirlukast in controlling persistent asthma: A randomised double-
blind, placebo-controlled trial. J Fam Pract 2001;50:595-602
Juniper 1995 Control intervention was not inhaled corticosteroids
Kalberg 1999 Control intervention was not inhaled corticosteroids
children (Review)
(Continued)
Kane 1994 Not a randomized controlled trial
Kanniess 2002 1 control intervention were not placebo
Kemp 1995 Control intervention was not inhaled corticosteroids
Kemp 1996 Not a randomized controlled trial


Kemp 1999 Not a randomized controlled trial (meta-analysis of RCT)
Ketchell 2002 intervention was not anti-leukotrienes
Kips 1991 Control intervention was not inhaled corticosteroids

Intervention was administered for less than a four-week period, intravenously
Knorr 1998 Subjects received additional non-permitted co-interventions other than short-acting 2-agonists
Knorr 1999 Control intervention were not placebo
Knorr 2001
Kohrogi 1997 Not a randomized controlled trial
Korenblat 1998 Use of higher than licensed dose of leukotriene receptor antagonists (Pranlukast 600 mcg/day vs. 450
mcg/day)
Kuna 1997 Control intervention was not inhaled corticosteroids
Kylstra 1998 Control intervention was not inhaled corticosteroids
Laitinen 1995 Control intervention was not inhaled corticosteroids
Leff 1998 Control intervention was not inhaled corticosteroids

Leigh 2002 Tested intervention administrated for less than 4 weeks
Leigh 2002 (B) Use of other non permitted drug
Li 2001 control intervention was not placebo
children (Review)
(Continued)
Liebke 2001 Control intervention was not placebo (it was sodium cromoglycate)
Lipworth 1999 Ongoing trial
Liu 1996 Control intervention was not inhaled corticosteroids
Lockey 1995 Control intervention was not inhaled corticosteroids
Lofdahl 1999 Subjects received additional non-permitted co-interventions (inhaled steroids) other than short-acting 2-
agonists
Malerba 2002 use of other non permitted drug
Marchese 1998 Not a randomized controlled trial
Margolskee 1991 Control intervention was not inhaled corticosteroids
McGill 1996 Not a randomized controlled trial
Menendez 2001 Duplicate publication of :

Bleecker ER, Welch MJ, Weinstein SF et al. Low dose inhaled fluticasone propionate vs oral Zafirlukast in
the treatment of persistant asthma. J Allergy Clin Immunol 2000; 105 :1123-9.
Outcomes did not reflect control of chronic or acute asthma
Micheletto 1997 Control intervention was not inhaled corticosteroids
Minkwitz 1998 Control intervention was not inhaled corticosteroids
Miyamoto 1999 control intervention was not placebo
Nakagawa 1992 Not a randomized controlled trial
Nathan 1998 Control intervention was not inhaled corticosteroids
Nayak 1998 Control intervention was not inhaled corticosteroids
Negro 1997 Not a randomized controlled trial
Nelson 2001 Control intervention were not placebo
Nelson 2001 1 Control intervention were not placebo
Nishimura 1999 control intervention were not placebo
Nishizawa 2002 Intervention was not anti-leukotrienes
Nishizawa 2002 1 Intervention was not anti-leukotrien
children (Review)
(Continued)
Noonan 1998 Control intervention was not inhaled corticosteroids
Noonan 1999 Not a randomized controlled trial
Nsouli 2000 control intervention was not placebo
Nsouli 2001 Control group was not placebo
OByrne 1997 Not a randomized controlled trial
OByrne 1997b Not a randomized controlled trial
OByrne 1997c Not a randomized controlled trial
OConnor 1994 Not a randomized controlled trial
OShaughnessy 1996 Subjects were not asthmatics

OSullivan 2003 control intervention was not placebo
Obase 2001 Subjects received additional non-permitted drugs (maintenance systemic steroids)
Obata 1992 Not a randomized controlled trial
Okudaira 1997 Not a randomized controlled trial
Oosaki 1997 Not a randomized controlled trial
Oosaki 1997b Not a randomized controlled trial
Overbeek 2002 outcomes measures did not reflect asthma control
Panettieri 1997 Not a randomized controlled trial
Paterson 1999 Tested intervention administrated for less than 4 weeks
Pearlman 1999 Control intervention was not inhaled corticosteroids

Pearlman 2002 use of other non permitted drug
Pereira 1989 Subjects non-asthmatics
Pizzichini 1999 Control intervention was not inhaled corticosteroids
Price 1999 Control intervention was not inhaled corticosteroids
children (Review)
(Continued)
Price 2002 control intervention were not placebo
Pullerits 1999 Subjects non-asthmatics (allergic rhinitis)
Pullerits 2001 Subjects were not asthmatics
Pullerits 2002 Subjects were not asthmatics
Rachelefsky 1997 Not a randomized controlled trial
Ramsay 1997 Control intervention was not inhaled corticosteroids
Ramsay 1998 Control intervention was not inhaled corticosteroids
Reiss 1996 Subjects received additional non-permitted co-interventions other than short-acting 2-agonists
Reiss 1997 Control intervention was not inhaled corticosteroids

Subsequently published as: Subsequently published as Williams B, Noonan G, Reiss TF, Knorr B, Guerra
J, White R, Matz J. Long-term asthma control with oral montelukast and inhaled beclomethasone. Clin
Exp Allergy:2001;31:1-10 (Study B)
Reiss 1997b Subjects received additional non-permitted co-interventions other than short-acting 2-agonists
Reiss 1997c Subjects received additional non-permitted co-interventions other than short-acting 2-agonists
Reiss 1998 Control intervention was not inhaled corticosteroids
Rickard 1999 control intervention was not placebo
Ringdal 1997 Outcomes did not reflect control of chronic or acute asthma
Robinson 2001 Subjects received additional non-permitted co-interventions (inhaled steroids) other than short-acting 2-
agonists
Treatment for < 4 weeks
Rosenhall 2003 Intervention was not anti-leukotrienes
Sahn 1997 Control intervention was not inhaled corticosteroids
Schwartz 1995 Control intervention was not inhaled corticosteroids
Sheth 2002 use of other non permitted drugs
Shingo 2001 Control intervention was not inhaled corticosteroids
Simons 2001 Control intervention was not inhaled corticosteroids
children (Review)
(Continued)
Smith 1993 Control intervention was not inhaled corticosteroids

Smith 1998 Control intervention was not inhaled corticosteroids

Spahn 1996a Not a randomized controlled trial
Spector 1992 Control intervention was not inhaled corticosteroids
Spector 1996 Not a randomized controlled trial
Stanford 2002 non-permitted drugs
Suguro 1997 Not a randomized controlled trial
Suissa 1997 Control intervention was not inhaled corticosteroids
Suzuki 1997 Not a randomized controlled trial
Svensson 1994 Control intervention was not inhaled corticosteroids
Tamaoki 1997 Control intervention was not inhaled corticosteroids
Tashkin 1998 Control intervention was not inhaled corticosteroids
Terzano 2001 Intervention was not anti-leukotrienes
Tohda 2002 control intervention was not placebo
Tomari 2001 control intervention was not placebo
Tomita 1999 Subjects received additional non-permitted co-interventions (inhaled steroids; some on oral steroids) other
than short-acting beta2-agonists
Townley 1995 Control intervention was not inhaled corticosteroids
Tukiainen 2002 Intervention was not anti-leukotrienes
Vaquerizo 2003 control intervention was not placebo
Verhoeven 2001 Subjects non-asthmatics (COPD)
children (Review)
(Continued)
Vethanayagam 2002 Tested intervention administrated for less than 4 weeks
Vidal 2001 Intervention administered for < 4 weeks
Vidal 2001 1 Intervention administered for < 4 weeks
Virchow 1997 Control intervention was not inhaled corticosteroids
Volovitz 1999 First partial publication of eligible RCT subsequently accepted for publication in full as:
Maspero JF, Duenas-Meza E, Volovitz B, Daza CP Kosa L, Vrijens F, Leff JA. Oral Montelukast versus
inhaled beclomethasone in 6- to 11- year-old children with asthma: results of an open-label extension study
evaluating the long-term safety, satisfaction, and adherence with therapy. Current Medical Research and
Opinion (In Press, 2001)
Von Berg 2002 Intervention was not anti-leukotrienes
Wada 2000 Subjects received additional non-permitted co-interventions (inhaled steroids) other than short-acting
beta2-agonists
Wahedna 1999 Intervention was administered for less than a four-week period
Wechsler 1998 Not a randomized controlled trial
Weinberg 1998 Outcomes did not reflect control of chronic or acute asthma
Welch 1994 Control intervention was not inhaled corticosteroids

Wenzel 1994 Control intervention was not inhaled corticosteroids
Wenzel 1995 Control subjects were not asthmatics

Wenzel 1997 Duplicate data from Korenblat
Westbroek 1998 tested intervention administered for less than 4 weeks
Westbroek 2000 Intervention administered for less than 4 weeks
Williams 2001Study C Some subjects received non-permitted co-interventionwith inhaled steroids (64% of those assigned to anti-
leukotrienes and 21% of those assigned to BPD)
Williams 2001StudyB Some subjects received non-permitted co-intervention with inhaled steroids (43% of those assigned to anti-
leukotrienes and 12% of those assigned to BPD 400 mcg/day)
Wilson 1999 (b) Control intervention was not placebo
children (Review)
(Continued)
Wilson 2000 Control intervention was not inhaled corticosteroids

Intervention < 4 weeks
Wilson 2001 Intervention < 4 weeks
Wilson 2001 (c) Subjects were not asthmatics
Wilson 2001 1 Outcome measures did not reflect asthma control
Wilson 2001b Intervention < 4 weeks
Xiang 2001 control intervention was not placebo
Yamamoto 1994 Control intervention was not inhaled corticosteroids

Yildirim 2001 control intervention was not placebo
Yoo 2001 Subjects received additional non-permitted co-interventions (inhaled steroids) other than short-acting
beta2-agonists
Yoshida 2000 Tested intervention asministrated for less than 4 weeks
Yoshida 2002 Tested intervention asministrated for less than 4 weeks
Zeneca Accolate 1998 Not a randomized controlled trial (product monograph)
Zhang 1999 1 No co-treatment with inhaled corticosteroids
Zorc 2003 Intervention was not anti-leukotrienes
children (Review)
DATA AND ANALYSES
Comparison 1. Anti-leukotriene (AL) vs. Inhaled glucocorticoids (in CFC-BDP equivalent)
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Change from baseline FEV1 at 6 13 3574 Std. Mean Difference (IV, Fixed, 95% CI) -0.26 [-0.33, -0.20]
+/- 2 weeks
1.1 Montelukast 5 mg die (10 2 79 Std. Mean Difference (IV, Fixed, 95% CI) -0.01 [-0.45, 0.43]
mg for children aged 15 years
and over) - % predicted FEV1
1.2 Montelukast 10 mg die - 6 1841 Std. Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.29, -0.10]
FEV1 (L)
1.4 Zafirlukast 20 mg bid - 5 1654 Std. Mean Difference (IV, Fixed, 95% CI) -0.35 [-0.45, -0.26]
FEV1 (L)
2 Change from baseline FEV1 10 3206 Std. Mean Difference (IV, Random, 95% CI) -0.25 [-0.40, -0.11]
( L or %) pre or post
bronchodilator at 12 +/- 4
weeks
2.1 Montelukast 5 mg die 1 123 Std. Mean Difference (IV, Random, 95% CI) -0.03 [-0.41, 0.34]
2.2 Montelukast 10 mg die 5 2202 Std. Mean Difference (IV, Random, 95% CI) -0.19 [-0.35, -0.03]
2.3 Zafirlukast 20 mg bid 4 881 Std. Mean Difference (IV, Random, 95% CI) -0.49 [-0.64, -0.33]
3 Change from baseline FEV1 (L) 4 1576 Mean Difference (IV, Fixed, 95% CI) -0.13 [-0.18, -0.08]
at 24 +/- 4 weeks
3.1 Montelukast 5 mg die 1 123 Mean Difference (IV, Fixed, 95% CI) -0.01 [-0.14, 0.12]
3.2 Montelukast 10 mg die 3 1453 Mean Difference (IV, Fixed, 95% CI) -0.15 [-0.20, -0.10]
4 Change from baseline FEV1 (L) 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
at 40 +/- 8 weeks
4.1 Montelukast 10 mg die 1 Mean Difference (IV, Fixed, 95% CI) Not estimable
5 Change from baseline AM PEFR 10 2713 Mean Difference (IV, Fixed, 95% CI) -19.11 [-23.15, -
(L/min) at 6 +/- 2 weeks 15.06]
5.1 Montelukast 10 mg die 5 1030 Mean Difference (IV, Fixed, 95% CI) -22.10 [-29.56, -
14.64]
5.2 Zafirlukast 20 mg bid 5 1683 Mean Difference (IV, Fixed, 95% CI) -17.86 [-22.67, -
13.05]
6 Change from baseline AM PEFR 8 2742 Mean Difference (IV, Random, 95% CI) -22.13 [-31.69, -
(L/min) at 12 +/- 4 weeks 12.57]
6.1 Montelukast 10 mg die 4 1860 Mean Difference (IV, Random, 95% CI) -16.32 [-24.55, -
8.09]
6.2 Zafirlukast 20 mg bid 4 882 Mean Difference (IV, Random, 95% CI) -35.64 [-46.27, -
23.00]
7 Change from baseline in AM 3 1451 Mean Difference (IV, Fixed, 95% CI) -27.14 [-34.63, -
PEFR (L/min) at 24 +/- 4 19.66]
weeks
19.66]
children (Review)
8 Change from baseline in AM 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
PEFR (L/min) at 40 +/- 8
weeks
9 Change from baseline daytime 8 2651 Std. Mean Difference (IV, Fixed, 95% CI) 0.23 [0.16, 0.31]
symptom scores at 6 +/- 2
weeks
9.1 Montelukast 10 mg die 3 971 Std. Mean Difference (IV, Fixed, 95% CI) 0.20 [0.07, 0.33]
9.2 Zafirlukast 20 mg bid 5 1680 Std. Mean Difference (IV, Fixed, 95% CI) 0.25 [0.16, 0.35]
weeks
weeks
12 Change from baseline daytime 1 Std. Mean Difference (IV, Fixed, 95% CI) Totals not selected
weeks
12.1 Montelukast 10 mg die 1 Std. Mean Difference (IV, Fixed, 95% CI) Not estimable
13 Change from baseline in night- 7 2172 Std. Mean Difference (IV, Random, 95% CI) 0.09 [-0.09, 0.28]
time awakenings (awakenings/
night or awakenings/week-
>williams) at 6 +/- 2 week
13.1 Montelukast 10 mg die 3 786 Std. Mean Difference (IV, Random, 95% CI) 0.18 [0.03, 0.32]
13.2 Zafirlukast 20 mg bid 4 1386 Std. Mean Difference (IV, Random, 95% CI) 0.04 [-0.26, 0.34]
14 Change from baseline in night- 6 1995 Std. Mean Difference (IV, Fixed, 95% CI) 0.21 [0.13, 0.30]
time awakenings (awakenings/
night or /week->Williams) at
12 +/- 4 weeks
15 Change from baseline in night- 3 1451 Std. Mean Difference (IV, Fixed, 95% CI) 0.19 [0.09, 0.29]
time awakenings (# or %) at 24
+/- 4 weeks
16 Change from baseline in night- 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
time awakenings (awakenings
per week) at 40 +/- 8 weeks
17 Change from baseline mean 12 3990 Std. Mean Difference (IV, Random, 95% CI) 0.24 [0.15, 0.34]
daily use of B2-agonists (puffs/
day or % ) at 6
17.1 Montelukast 10 mg die 7 2309 Std. Mean Difference (IV, Random, 95% CI) 0.16 [0.07, 0.24]
17.2 Zafirlukast 20 mg bid 5 1681 Std. Mean Difference (IV, Random, 95% CI) 0.36 [0.23, 0.48]
18 Change from baseline mean 8 2733 Std. Mean Difference (IV, Fixed, 95% CI) 0.28 [0.20, 0.36]
day) at 12 +/- 4 weeks
children (Review)
19 Change from baseline mean 3 1453 Mean Difference (IV, Fixed, 95% CI) 0.74 [0.44, 1.04]
19.1 Montelukast 10 mg die 3 1453 Mean Difference (IV, Fixed, 95% CI) 0.74 [0.44, 1.04]
20 Change from baseline mean 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
21 Change in proportion of 5 1856 Mean Difference (IV, Fixed, 95% CI) -9.90 [-13.05, -6.76]
symptom-free days (%) at 6 +/-
2 weeks
6.66]
22 Change in proportion of 5 1328 Mean Difference (IV, Fixed, 95% CI) -11.47 [-15.72, -
symptom-free days (%) at 12 7.23]
+/- 4 weeks
22.1 Montelukast 10 mg 1 446 Mean Difference (IV, Fixed, 95% CI) -10.8 [-17.20, -4.40]
6.32]
23 Change in proportion of 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
symptom-free days (%) at 24
+/- 4 weeks
24 Change in rescue-free days (%) 6 1624 Mean Difference (IV, Fixed, 95% CI) -12.74 [-16.40, -
at 6 +/-2 weeks 9.08]
5.78]
8.54]
25 Change in rescue-free days (%) 3 1110 Mean Difference (IV, Fixed, 95% CI) -13.92 [-18.32, -
at 12 +/-4 weeks 9.51]
25.1 Montelukast 10 mg 1 446 Mean Difference (IV, Fixed, 95% CI) -12.60 [-19.67, -
5.53]
9.12]
26 Change in rescue-free days (%) 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
at 24 +/- 4 weeks
27 Days off work or school at 6 +/ 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
- 2 weeks
28 Days off work or school at 12 2 610 Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.03, 0.15]
+/- 4 weeks
28.1 Montelukast 10 mg die 1 386 Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.03, 0.15]
28.2 Zafirlukast 20 mg die 1 224 Mean Difference (IV, Fixed, 95% CI) -0.13 [-1.51, 1.25]
29 Days off work or school at 24 2 606 Mean Difference (IV, Fixed, 95% CI) 0.12 [-0.01, 0.26]
+/- 4 weeks
29.2 Montelukast 10 mg die 1 482 Mean Difference (IV, Fixed, 95% CI) 0.13 [-0.00, 0.26]
children (Review)
30 Change from baseline quality 3 1105 Mean Difference (IV, Fixed, 95% CI) -0.36 [-0.50, -0.22]
of life (QOL) at 6 +/- 2 weeks
30.2 Zafirlukast 20 mg bid 2 641 Mean Difference (IV, Fixed, 95% CI) -0.40 [-0.60, -0.20]
31.2 Pranlukast 300 mg bid 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
33 Change from baseline blood 4 1294 Mean Difference (IV, Fixed, 95% CI) 0.06 [0.03, 0.08]
eosinophils at 6 +/- 2 weeks
33.1 Montelukast 10 mg die 4 1294 Mean Difference (IV, Fixed, 95% CI) 0.06 [0.03, 0.08]
34 Change from baseline blood 2 1013 Mean Difference (IV, Fixed, 95% CI) -0.00 [-0.03, 0.02]
35 Change from baseline blood 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
36 LTC4 concentration (ng/mL) 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
in nasal wash at 12 +/- 4 weeks
37 LTC4 concentration (ng/mL) 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
in nasal wash at 24 +/- 4 weeks
38 Patients with at least 1 18 4965 Risk Ratio (M-H, Fixed, 95% CI) 1.65 [1.36, 2.00]
exacerbation requiring systemic
steroids
38.1 Montelukast 5 mg (10 3 216 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.32, 1.85]
mg for children 15 years and
over)
38.2 Montelukast 10 mg die 10 3173 Risk Ratio (M-H, Fixed, 95% CI) 1.56 [1.25, 1.94]
38.3 Pranlukast 300 mg bid 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
38.5 Zafirlukast 20 mg bid 5 1576 Risk Ratio (M-H, Fixed, 95% CI) 2.62 [1.57, 4.38]
39 Patients with at least 1 13 3189 Risk Ratio (M-H, Fixed, 95% CI) 1.62 [0.64, 4.15]
exacerbation requiring
admission
39.1 Montelukast 5 mg (10 3 216 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
over)
39.3 Pranlukast 300 mg bid 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
40 Overall Withdrawals 19 6666 Risk Ratio (M-H, Random, 95% CI) 1.29 [1.08, 1.56]
40.1 Montelukast 5 mg (10 3 216 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.38, 1.96]
over)
40.2 Montelukast 10 mg die 9 4258 Risk Ratio (M-H, Random, 95% CI) 1.07 [0.93, 1.24]
40.3 Zafirlukast 20 mg bid 7 2192 Risk Ratio (M-H, Random, 95% CI) 1.87 [1.45, 2.42]
41 Withdrawal due to poor asthma 17 6221 Risk Ratio (M-H, Fixed, 95% CI) 2.58 [1.95, 3.42]
control/exacerbations
children (Review)
41.1 Montelukast 5 mg die 1 124 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
42 Withdrawals due to adverse 16 6277 Risk Ratio (M-H, Fixed, 95% CI) 1.15 [0.86, 1.54]
effects
43 Overall Adverse effects 15 5648 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.93, 1.04]
44 Elevated liver enzymes 8 2193 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.69, 2.32]
45 Headache 16 5928 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.77, 1.08]
46 Nausea 14 5031 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.68, 1.49]
47 Oral candidiasis 2 757 Risk Ratio (M-H, Fixed, 95% CI) 0.15 [0.02, 1.18]
48 Death 13 4935 Risk Ratio (M-H, Fixed, 95% CI) 3.10 [0.13, 75.82]
48.1 Montelukast 5 mg die 1 124 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
48.3 Zafirlukast 20 mg bid 4 1434 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
49 Patient satisfied with treatment 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
49.1 Zafirlukast 20 mg bid 1 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
50 Main outcome - stratified on 18 4965 Risk Ratio (M-H, Fixed, 95% CI) 1.65 [1.36, 2.00]
age
50.1 Children 3 216 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.32, 1.85]
50.2 Adults 15 4749 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [1.40, 2.09]
51 Main outcome - stratified on 18 4965 Risk Ratio (M-H, Random, 95% CI) 1.60 [1.18, 2.18]
methodological quality
51.1 Poor reported 7 669 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.43, 1.59]
methodological quality (Jadad
score <=3)
51.2 High reported 11 4296 Risk Ratio (M-H, Random, 95% CI) 1.83 [1.29, 2.60]
methodological quality (Jadad
score >=4)
52 Main outcome - stratified on 12 4655 Risk Ratio (M-H, Random, 95% CI) 1.79 [1.29, 2.48]
ICS
52.1 Beclomethasone or 5 2154 Risk Ratio (M-H, Random, 95% CI) 1.54 [0.92, 2.56]
budesonide 400 mcg die
52.2 Fluticasone 200 mcg die 7 2501 Risk Ratio (M-H, Random, 95% CI) 2.11 [1.39, 3.21]
53 Main outcome - stratified on 18 4965 Risk Ratio (M-H, Fixed, 95% CI) 1.65 [1.36, 2.00]
duration of intervention
children (Review)
53.1 4-8 weeks 9 2346 Risk Ratio (M-H, Fixed, 95% CI) 1.73 [1.09, 2.74]
53.2 12-16 weeks 6 1526 Risk Ratio (M-H, Fixed, 95% CI) 2.28 [1.62, 3.21]
53.3 24 to 37 weeks 3 1093 Risk Ratio (M-H, Fixed, 95% CI) 1.25 [0.95, 1.65]
54 Main outcome -stratified on 17 4529 Risk Ratio (M-H, Fixed, 95% CI) 1.88 [1.47, 2.40]
asthma severity
54.1 Mean FEV1 50-79% of 10 3860 Risk Ratio (M-H, Fixed, 95% CI) 2.15 [1.64, 2.81]
predicted
54.2 Mean FEV1 >=80% of 7 669 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.43, 1.58]
predicted
55 Main outcome- stratified on 18 4965 Risk Ratio (M-H, Random, 95% CI) 1.60 [1.18, 2.18]
publication status
55.1 Published trials 15 4514 Risk Ratio (M-H, Random, 95% CI) 1.62 [1.17, 2.24]
55.2 Unpublished trials 3 451 Risk Ratio (M-H, Random, 95% CI) 1.26 [0.34, 4.63]
56 Main outcome- stratified on 18 4965 Risk Ratio (M-H, Random, 95% CI) 1.60 [1.18, 2.18]
funding source
56.1 funded by producers of 7 2156 Risk Ratio (M-H, Random, 95% CI) 2.24 [1.44, 3.49]
ICS
56.2 funded by producers of 6 2623 Risk Ratio (M-H, Random, 95% CI) 1.38 [0.90, 2.12]
AL
56.3 No industry funding 5 186 Risk Ratio (M-H, Random, 95% CI) 0.57 [0.12, 2.61]
57 Change (%) from baseline in 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
serum IL-10 (pg/mL) at 6 +/- 2
weeks
57.1 Montelukast 5 mg (10 0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable
over)
58 % Asthma control days during 3 1815 Mean Difference (IV, Random, 95% CI) -8.06 [-15.01, -1.10]
intervention period at 6 +/- 2
weeks
58.1 Montelukast 10 mg die 3 1815 Mean Difference (IV, Random, 95% CI) -8.06 [-15.01, -1.10]
59 Hoarseness 2 734 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.03, 2.24]
60 % Change in sputum 1 80 Mean Difference (IV, Fixed, 95% CI) -1.30 [-4.89, 2.29]
eosinophils
61 Change in PC20 2 85 Mean Difference (IV, Fixed, 95% CI) -1.18 [-1.60, -0.76]
62 % rescue - free days 2 876 Mean Difference (IV, Fixed, 95% CI) -8.67 [-14.31, -3.02]
children (Review)
Analysis 1.1. Comparison 1 Anti-leukotriene (AL) vs. Inhaled glucocorticoids (in CFC-BDP equivalent),
Outcome 1 Change from baseline FEV1 at 6 +/- 2 weeks.
Review: Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children
Comparison: 1 Anti-leukotriene (AL) vs. Inhaled glucocorticoids (in CFC-BDP equivalent)
Outcome: 1 Change from baseline FEV1 at 6 +/- 2 weeks
Study or subgroup Anti-leukotrienes Inhaled steroids Std. Mean Difference Weight Std. Mean Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Montelukast 5 mg die (10 mg for children aged 15 years and over) - % predicted FEV1
Stelmach 2002a 15 23.32 (12.7) 15 22.75 (14.48) 0.9 % 0.04 [ -0.68, 0.76 ]
Stelmach 2002b 24 22.8 (12.4) 25 23.4 (14.1) 1.4 % -0.04 [ -0.60, 0.52 ]
Subtotal (95% CI) 39 40 2.3 % -0.01 [ -0.45, 0.43 ]

Heterogeneity: Chi2 = 0.03, df = 1 (P = 0.85); I2 =0.0%
Test for overall effect: Z = 0.05 (P = 0.96)
2 Montelukast 10 mg die - FEV1 (L)
Williams 2001 259 0.19 (0.49) 158 0.29 (0.52) 11.2 % -0.20 [ -0.40, 0.00 ]
Baumgartner 2003 303 0.25 (0.39) 304 0.3 (0.44) 17.3 % -0.12 [ -0.28, 0.04 ]
Kanniess 2002 40 0.37 (0.44) 40 0.5 (0.44) 2.3 % -0.29 [ -0.73, 0.15 ]
Israel 2002 337 0.24 (0.55) 329 0.38 (0.55) 18.9 % -0.25 [ -0.41, -0.10 ]
Hughes 1999 (BDP) 12 0.1 (0.38) 23 0.3 (0.5) 0.9 % -0.42 [ -1.13, 0.28 ]
Hughes 1999 (FP) 13 0.1 (0.38) 23 0.1 (0.56) 0.9 % 0.0 [ -0.68, 0.68 ]
Subtotal (95% CI) 964 877 51.4 % -0.20 [ -0.29, -0.10 ]

4 Zafirlukast 20 mg bid - FEV1 (L)
Busse 2001a 111 0.31 (0.42) 113 0.52 (0.53) 6.2 % -0.44 [ -0.70, -0.17 ]
Laitinen 1997 136 0.07 (0.34) 135 0.18 (0.46) 7.7 % -0.27 [ -0.51, -0.03 ]
Brabson 2002 216 0.08 (0.5) 224 0.24 (0.37) 12.3 % -0.36 [ -0.55, -0.18 ]
Nathan 2001 150 0.33 (0.46) 144 0.39 (0.5) 8.4 % -0.12 [ -0.35, 0.10 ]
Kim 2000 210 0.03 (0.44) 215 0.22 (0.29) 11.7 % -0.51 [ -0.70, -0.32 ]
Subtotal (95% CI) 823 831 46.4 % -0.35 [ -0.45, -0.26 ]

Heterogeneity: Chi2 = 7.21, df = 4 (P = 0.13); I2 =45%
Test for overall effect: Z = 7.10 (P < 0.00001)
Total (95% CI) 1826 1748 100.0 % -0.26 [ -0.33, -0.20 ]
Test for subgroup differences: Chi2 = 6.45, df = 2 (P = 0.04), I2 =69%
-4 -2 0 2 4
Favours ICS Favours LTRA
children (Review)
Outcome 2 Change from baseline FEV1 ( L or %) pre or post bronchodilator at 12 +/- 4 weeks.
Outcome: 2 Change from baseline FEV1 ( L or %) pre or post bronchodilator at 12 +/- 4 weeks
Study or subgroup Anti-leukotrienes Inhaled steroids Std. Mean Difference Std. Mean Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
1 Montelukast 5 mg die
Maspero 2001 83 0.3 (0.29) 40 0.31 (0.3) -0.03 [ -0.41, 0.34 ]
Subtotal (95% CI) 83 40 -0.03 [ -0.41, 0.34 ]

Heterogeneity: not applicable
Laviolette 1999 199 -0.01 (0.29) 198 0.03 (0.25) -0.15 [ -0.34, 0.05 ]
Malmstrom 1999 375 7.49 (17.01) 246 13.3 (19.72) -0.32 [ -0.48, -0.16 ]
Busse 2001b 204 15.52 (20.57) 207 24.45 (21) -0.43 [ -0.62, -0.23 ]
Williams 2001 251 0.21 (0.48) 155 0.25 (0.47) -0.08 [ -0.28, 0.12 ]
Zieger 183 13.4 (10.5) 184 13 (9.7) 0.04 [ -0.17, 0.24 ]
Subtotal (95% CI) 1212 990 -0.19 [ -0.35, -0.03 ]

Heterogeneity: Tau2 = 0.02; Chi2 = 14.19, df = 4 (P = 0.01); I2 =72%
3 Zafirlukast 20 mg bid
Sheth 2001a 55 0.38 (0) 51 0.6 (0) 0.0 [ 0.0, 0.0 ]
Sheth 2001b 52 0.28 (0) 60 0.55 (0) 0.0 [ 0.0, 0.0 ]
Bleecker 2000 213 0.2 (0.45) 226 0.42 (0.46) -0.48 [ -0.67, -0.29 ]
Busse 2001a 111 0.33 (0.42) 113 0.57 (0.53) -0.50 [ -0.77, -0.23 ]
Subtotal (95% CI) 431 450 -0.49 [ -0.64, -0.33 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.01, df = 1 (P = 0.92); I2 =0.0%
Total (95% CI) 1726 1480 -0.25 [ -0.40, -0.11 ]
-1 -0.5 0 0.5 1
children (Review)
Outcome 3 Change from baseline FEV1 (L) at 24 +/- 4 weeks.
Outcome: 3 Change from baseline FEV1 (L) at 24 +/- 4 weeks
Study or subgroup Anti-leukotrienes Inhaled steroids Mean Difference Weight Mean Difference
Maspero 2001 83 0.33 (0.31) 40 0.34 (0.35) 14.0 % -0.01 [ -0.14, 0.12 ]
Subtotal (95% CI) 83 40 14.0 % -0.01 [ -0.14, 0.12 ]

Busse 2001b 262 0.33 (0.49) 271 0.51 (0.49) 32.7 % -0.18 [ -0.26, -0.10 ]
Meltzer 2002 264 0.32 (0.49) 258 0.48 (0.48) 32.7 % -0.16 [ -0.24, -0.08 ]
Williams 2001 245 0.19 (0.53) 153 0.27 (0.51) 20.7 % -0.08 [ -0.18, 0.02 ]
Subtotal (95% CI) 771 682 86.0 % -0.15 [ -0.20, -0.10 ]

Total (95% CI) 854 722 100.0 % -0.13 [ -0.18, -0.08 ]
Test for subgroup differences: Chi2 = 3.90, df = 1 (P = 0.05), I2 =74%
-1 -0.5 0 0.5 1
Outcome 4 Change from baseline FEV1 (L) at 40 +/- 8 weeks.
Outcome: 4 Change from baseline FEV1 (L) at 40 +/- 8 weeks
Study or subgroup Anti-leukotrienes Inhaled steroids Mean Difference Mean Difference

Williams 2001 237 0.2 (0.48) 144 0.3 (0.46) -0.10 [ -0.20, 0.00 ]
-1 -0.5 0 0.5 1
children (Review)
Outcome 5 Change from baseline AM PEFR (L/min) at 6 +/- 2 weeks.
Outcome: 5 Change from baseline AM PEFR (L/min) at 6 +/- 2 weeks
Hughes 1999 (FP) 13 9 (81.03) 23 35.7 (95.12) 0.5 % -26.70 [ -85.45, 32.05 ]
Hughes 1999 (BDP) 12 9 (81.03) 23 22.9 (95.85) 0.4 % -13.90 [ -74.20, 46.40 ]
Busse 2001b 235 33.75 (53.96) 243 55.52 (60.33) 15.6 % -21.77 [ -32.02, -11.52 ]
Williams 2001 259 24.74 (56.62) 158 45.39 (65.4) 10.8 % -20.65 [ -32.96, -8.34 ]
Kanniess 2002 32 14 (40.2) 32 46.7 (69.6) 2.1 % -32.70 [ -60.55, -4.85 ]
Subtotal (95% CI) 551 479 29.4 % -22.10 [ -29.56, -14.64 ]

Nathan 2001 150 18.3 (38.6) 144 29.3 (48.1) 16.4 % -11.00 [ -20.99, -1.01 ]
Laitinen 1997 153 20.3 (43.04) 149 37.8 (55.69) 12.9 % -17.50 [ -28.75, -6.25 ]
Kim 2000 209 3.11 (53.62) 214 17.8 (53.54) 15.7 % -14.69 [ -24.90, -4.48 ]
Busse 2001a 111 18 (47.41) 113 43.4 (71.22) 6.5 % -25.40 [ -41.22, -9.58 ]
Brabson 2002 216 6 (48) 224 30 (51) 19.1 % -24.00 [ -33.25, -14.75 ]
Subtotal (95% CI) 839 844 70.6 % -17.86 [ -22.67, -13.05 ]

Total (95% CI) 1390 1323 100.0 % -19.11 [ -23.15, -15.06 ]
Test for subgroup differences: Chi2 = 0.88, df = 1 (P = 0.35), I2 =0.0%
-100 -50 0 50 100

children (Review)
Outcome 6 Change from baseline AM PEFR (L/min) at 12 +/- 4 weeks.
Outcome: 6 Change from baseline AM PEFR (L/min) at 12 +/- 4 weeks

Laviolette 1999 200 -4.49 (24.86) 197 3.51 (23.82) -8.00 [ -12.79, -3.21 ]
Williams 2001 248 26.26 (55.47) 154 46.81 (65.35) -20.55 [ -32.97, -8.13 ]
Malmstrom 1999 372 25.03 (46.24) 244 40.12 (46.89) -15.09 [ -22.62, -7.56 ]
Busse 2001b 218 37.99 (62.6) 227 65.83 (76.24) -27.84 [ -40.78, -14.90 ]
Subtotal (95% CI) 1038 822 -16.32 [ -24.55, -8.09 ]

Busse 2001a 111 15.2 (61.1) 113 46.7 (69.1) -31.50 [ -48.57, -14.43 ]
Sheth 2001a 55 7.9 (0) 51 45.3 (0) 0.0 [ 0.0, 0.0 ]
Sheth 2001b 52 22.8 (0) 60 47.9 (0) 0.0 [ 0.0, 0.0 ]
Bleecker 2000 215 11.68 (64.82) 225 49.94 (80.25) -38.26 [ -51.86, -24.66 ]
Subtotal (95% CI) 433 449 -35.64 [ -46.27, -25.00 ]

Total (95% CI) 1471 1271 -22.13 [ -31.69, -12.57 ]
-100 -50 0 50 100

children (Review)
Outcome 7 Change from baseline in AM PEFR (L/min) at 24 +/- 4 weeks.
Outcome: 7 Change from baseline in AM PEFR (L/min) at 24 +/- 4 weeks
Meltzer 2002 264 37.6 (74.75) 258 63.7 (81.9) 30.9 % -26.10 [ -39.56, -12.64 ]
Busse 2001b 262 34.1 (67.98) 271 68.5 (85.6) 32.6 % -34.40 [ -47.50, -21.30 ]
Williams 2001 244 28.24 (58.54) 152 49.78 (62.74) 36.5 % -21.54 [ -33.93, -9.15 ]
Total (95% CI) 770 681 100.0 % -27.14 [ -34.63, -19.66 ]

-100 -50 0 50 100

Outcome 8 Change from baseline in AM PEFR (L/min) at 40 +/- 8 weeks.
Outcome: 8 Change from baseline in AM PEFR (L/min) at 40 +/- 8 weeks
Study or subgroup Treatment Control Mean Difference Mean Difference

Williams 2001 233 29.8 (60.82) 144 52.1 (60.27) -22.30 [ -34.87, -9.73 ]
-100 -50 0 50 100

children (Review)
Outcome 9 Change from baseline daytime symptom scores at 6 +/- 2 weeks.
Outcome: 9 Change from baseline daytime symptom scores at 6 +/- 2 weeks
Kanniess 2002 38 0.44 (0.8) 38 0.4 (0.7) 2.9 % 0.05 [ -0.40, 0.50 ]
Busse 2001b 235 -0.6 (0.77) 243 -0.77 (0.78) 18.2 % 0.22 [ 0.04, 0.40 ]
Williams 2001 259 -0.64 (1.08) 158 -0.86 (0.99) 15.0 % 0.21 [ 0.01, 0.41 ]
Subtotal (95% CI) 532 439 36.1 % 0.20 [ 0.07, 0.33 ]

Kim 2000 208 0.08 (0.73) 212 -0.13 (0.59) 15.9 % 0.32 [ 0.12, 0.51 ]
Busse 2001a 111 -0.4 (0.84) 113 -0.61 (0.74) 8.5 % 0.26 [ 0.00, 0.53 ]
Brabson 2002 216 -0.01 (0.64) 224 -0.16 (0.53) 16.7 % 0.26 [ 0.07, 0.44 ]
Laitinen 1997 153 -0.47 (0.64) 149 -0.73 (0.78) 11.4 % 0.36 [ 0.14, 0.59 ]
Nathan 2001 150 -1.2 (2.26) 144 -1.27 (2.09) 11.3 % 0.03 [ -0.20, 0.26 ]
Subtotal (95% CI) 838 842 63.9 % 0.25 [ 0.16, 0.35 ]

Total (95% CI) 1370 1281 100.0 % 0.23 [ 0.16, 0.31 ]
-1 -0.5 0 0.5 1
Favours LTRA Favours ICS
children (Review)
Laviolette 1999 200 0.15 (0.54) 200 -0.02 (0.53) 16.0 % 0.32 [ 0.12, 0.51 ]
Busse 2001b 219 -0.64 (0.89) 227 -0.82 (0.9) 18.0 % 0.20 [ 0.01, 0.39 ]
Williams 2001 259 -0.64 (1.08) 158 -0.86 (0.99) 15.8 % 0.21 [ 0.01, 0.41 ]
Malmstrom 1999 372 -0.49 (0.81) 244 -0.7 (0.08) 23.6 % 0.33 [ 0.17, 0.49 ]
Subtotal (95% CI) 1050 829 73.5 % 0.27 [ 0.18, 0.36 ]

Busse 2001a 111 -0.36 (1.05) 113 -0.65 (0.74) 9.0 % 0.32 [ 0.06, 0.58 ]
Bleecker 2000 215 -0.19 (0.74) 225 -0.46 (0.76) 17.6 % 0.36 [ 0.17, 0.55 ]
Subtotal (95% CI) 326 338 26.5 % 0.35 [ 0.19, 0.50 ]

Total (95% CI) 1376 1167 100.0 % 0.29 [ 0.21, 0.37 ]
-1 -0.5 0 0.5 1
children (Review)
Meltzer 2002 264 -0.57 (0.81) 258 -0.91 (0.96) 49.2 % 0.38 [ 0.21, 0.56 ]
Busse 2001b 262 -0.6 (0.97) 271 -0.85 (0.99) 50.8 % 0.25 [ 0.08, 0.43 ]
Total (95% CI) 526 529 100.0 % 0.32 [ 0.20, 0.44 ]

-1 -0.5 0 0.5 1
Williams 2001 233 -0.72 (1.13) 144 -0.87 (0.94) 0.14 [ -0.07, 0.35 ]
-1 -0.5 0 0.5 1
children (Review)
Outcome 13 Change from baseline in night-time awakenings (awakenings/night or awakenings/week->williams)
at 6 +/- 2 week.
Outcome: 13 Change from baseline in night-time awakenings (awakenings/night or awakenings/week->williams) at 6 +/- 2 week
Kanniess 2002 38 0.27 (0.5) 38 0.19 (0.5) 8.8 % 0.16 [ -0.29, 0.61 ]
Williams 2001 259 -2.18 (2.79) 158 -2.67 (2.62) 15.7 % 0.18 [ -0.02, 0.38 ]
Busse 2001b 144 -0.54 (0.72) 149 -0.67 (0.73) 14.8 % 0.18 [ -0.05, 0.41 ]
Subtotal (95% CI) 441 345 39.3 % 0.18 [ 0.03, 0.32 ]

Kim 2000 209 0.11 (0.29) 214 0.02 (0.15) 15.9 % 0.39 [ 0.20, 0.58 ]
Brabson 2002 216 -5 (21) 224 0 (16) 16.1 % -0.27 [ -0.46, -0.08 ]
Laitinen 1997 152 -1.8 (4.7) 147 -2.1 (4.97) 14.9 % 0.06 [ -0.16, 0.29 ]
Busse 2001a 111 -0.29 (0.53) 113 -0.28 (0.53) 13.8 % -0.02 [ -0.28, 0.24 ]
Subtotal (95% CI) 688 698 60.7 % 0.04 [ -0.26, 0.34 ]

Total (95% CI) 1129 1043 100.0 % 0.09 [ -0.09, 0.28 ]
-1 -0.5 0 0.5 1
children (Review)
Outcome 14 Change from baseline in night-time awakenings (awakenings/night or /week->Williams) at 12 +/- 4
weeks.
Outcome: 14 Change from baseline in night-time awakenings (awakenings/night or /week->Williams) at 12 +/- 4 weeks
Busse 2001b 137 -0.52 (0.82) 137 -0.66 (0.7) 14.0 % 0.18 [ -0.05, 0.42 ]
Malmstrom 1999 285 -2.03 (2.16) 203 -2.68 (2.29) 24.1 % 0.29 [ 0.11, 0.47 ]
Williams 2001 248 -2.2 (2.82) 154 -2.49 (2.57) 19.5 % 0.11 [ -0.10, 0.31 ]
Laviolette 1999 93 0.12 (1.41) 74 -0.44 (1.51) 8.3 % 0.38 [ 0.07, 0.69 ]
Subtotal (95% CI) 763 568 66.0 % 0.23 [ 0.12, 0.34 ]

Busse 2001a 111 -0.23 (0.63) 113 -0.32 (0.63) 11.5 % 0.14 [ -0.12, 0.40 ]
Bleecker 2000 215 -0.15 (0.59) 225 -0.28 (0.61) 22.5 % 0.22 [ 0.03, 0.40 ]
Subtotal (95% CI) 326 338 34.0 % 0.19 [ 0.04, 0.34 ]

Total (95% CI) 1089 906 100.0 % 0.21 [ 0.13, 0.30 ]
-1 -0.5 0 0.5 1
children (Review)
Outcome 15 Change from baseline in night-time awakenings (# or %) at 24 +/- 4 weeks.
Outcome: 15 Change from baseline in night-time awakenings (# or %) at 24 +/- 4 weeks
Williams 2001 244 -2.18 (2.94) 152 -2.42 (2.74) 26.3 % 0.08 [ -0.12, 0.29 ]
Meltzer 2002 264 -47.1 (87.75) 258 -72 (80.3) 36.3 % 0.30 [ 0.12, 0.47 ]
Busse 2001b 262 -0.48 (0.97) 271 -0.64 (0.99) 37.4 % 0.16 [ -0.01, 0.33 ]
Total (95% CI) 770 681 100.0 % 0.19 [ 0.09, 0.29 ]

-1 -0.5 0 0.5 1
Outcome 16 Change from baseline in night-time awakenings (awakenings per week) at 40 +/- 8 weeks.
Outcome: 16 Change from baseline in night-time awakenings (awakenings per week) at 40 +/- 8 weeks

Williams 2001 233 -2.3 (2.77) 144 -2.51 (2.67) 0.21 [ -0.35, 0.77 ]
-1 -0.5 0 0.5 1
children (Review)
Outcome 17 Change from baseline mean daily use of B2-agonists (puffs/day or % ) at 6.
Outcome: 17 Change from baseline mean daily use of B2-agonists (puffs/day or % ) at 6
Williams 2001 259 -2.27 (3.33) 158 -2.88 (3.05) 10.3 % 0.19 [ -0.01, 0.39 ]
Baumgartner 2003 308 -35.69 (42.61) 305 -45.68 (41.6) 12.1 % 0.24 [ 0.08, 0.40 ]
Hughes 1999 (BDP) 11 -43.7 (52.97) 22 3.3 (157.72) 1.7 % -0.34 [ -1.07, 0.39 ]
Hughes 1999 (FP) 10 -43.7 (52.97) 16 -41.8 (59.68) 1.4 % -0.03 [ -0.82, 0.76 ]
Busse 2001b 235 -2.08 (3.07) 243 -2.78 (2.65) 11.1 % 0.24 [ 0.06, 0.42 ]
Israel 2002 337 -30.3 (44.2) 329 -31.9 (46) 12.5 % 0.04 [ -0.12, 0.19 ]
Kanniess 2002 38 1 (1.8) 38 0.8 (1.7) 3.8 % 0.11 [ -0.34, 0.56 ]
Subtotal (95% CI) 1198 1111 52.9 % 0.16 [ 0.07, 0.24 ]

Busse 2001a 111 -1.9 (2.53) 113 -2.7 (2.66) 7.8 % 0.31 [ 0.04, 0.57 ]
Kim 2000 209 0.27 (1.88) 214 -0.66 (1.61) 10.5 % 0.53 [ 0.34, 0.72 ]
Brabson 2002 216 0.1 (1.8) 224 -0.6 (1.5) 10.7 % 0.42 [ 0.23, 0.61 ]
Laitinen 1997 152 -1.3 (2.57) 148 -1.8 (2.99) 9.1 % 0.18 [ -0.05, 0.41 ]
Nathan 2001 150 -1.1 (2.2) 144 -1.8 (2.7) 9.0 % 0.28 [ 0.05, 0.51 ]
Subtotal (95% CI) 838 843 47.1 % 0.36 [ 0.23, 0.48 ]

Total (95% CI) 2036 1954 100.0 % 0.24 [ 0.15, 0.34 ]
-4 -2 0 2 4
children (Review)
Outcome 18 Change from baseline mean daily use of B2-agonists (puffs/day) at 12 +/- 4 weeks.
Outcome: 18 Change from baseline mean daily use of B2-agonists (puffs/day) at 12 +/- 4 weeks
Malmstrom 1999 371 -28.3 (48.56) 242 -43.9 (40.12) 0.34 [ 0.18, 0.51 ]
Busse 2001b 219 -2.32 (2.37) 227 -2.98 (2.71) 0.26 [ 0.07, 0.44 ]
Laviolette 1999 196 18.69 (65.19) 194 2.64 (66.7) 0.24 [ 0.04, 0.44 ]
Williams 2001 248 -2.37 (3.09) 154 -2.84 (2.83) 0.16 [ -0.04, 0.36 ]
Subtotal (95% CI) 1034 817 0.26 [ 0.17, 0.35 ]

Sheth 2001b 52 -2.1 (0) 60 -3.1 (0) 0.0 [ 0.0, 0.0 ]
Sheth 2001a 55 -1.7 (0) 51 -2.5 (0) 0.0 [ 0.0, 0.0 ]
Busse 2001a 111 -1.9 (2.84) 113 -2.8 (2.87) 0.31 [ 0.05, 0.58 ]
Bleecker 2000 215 -1.45 (2.82) 225 -2.39 (2.89) 0.33 [ 0.14, 0.52 ]
Subtotal (95% CI) 433 449 0.32 [ 0.17, 0.48 ]

Total (95% CI) 1467 1266 0.28 [ 0.20, 0.36 ]
-1 -0.5 0 0.5 1
children (Review)
Busse 2001b 262 -2.31 (2.75) 271 -3.1 (2.8) 40.6 % 0.79 [ 0.32, 1.26 ]
Williams 2001 245 -2.34 (3.25) 153 -2.66 (2.97) 23.3 % 0.32 [ -0.30, 0.94 ]
Meltzer 2002 264 -2.25 (2.76) 258 -3.21 (3.05) 36.1 % 0.96 [ 0.46, 1.46 ]
Total (95% CI) 771 682 100.0 % 0.74 [ 0.44, 1.04 ]

-4 -2 0 2 4
Study or subgroup Treatment Control Mean Difference Mean Difference

Williams 2001 234 -2.39 (3.41) 144 -2.85 (2.81) 0.46 [ -0.17, 1.09 ]
-10 -5 0 5 10
children (Review)
Outcome 21 Change in proportion of symptom-free days (%) at 6 +/- 2 weeks.
Outcome: 21 Change in proportion of symptom-free days (%) at 6 +/- 2 weeks
Busse 2001b 235 15.8 (27.59) 243 24.5 (34.29) 31.8 % -8.70 [ -14.27, -3.13 ]
Subtotal (95% CI) 235 243 31.8 % -8.70 [ -14.27, -3.13 ]

Kim 2000 208 7.1 (42) 212 16.2 (35.19) 17.9 % -9.10 [ -16.52, -1.68 ]
Busse 2001a 111 14.1 (34.77) 113 24.6 (42.5) 9.6 % -10.50 [ -20.66, -0.34 ]
Nathan 2001 150 11.6 (27.3) 144 19.8 (32.8) 20.6 % -8.20 [ -15.11, -1.29 ]
Brabson 2002 216 8 (36) 224 22 (39) 20.1 % -14.00 [ -21.01, -6.99 ]
Subtotal (95% CI) 685 693 68.2 % -10.47 [ -14.27, -6.66 ]

Total (95% CI) 920 936 100.0 % -9.90 [ -13.05, -6.76 ]
-100 -50 0 50 100

children (Review)

1 Montelukast 10 mg
Busse 2001b 219 16.8 (31.08) 227 27.6 (37.67) -10.80 [ -17.20, -4.40 ]
Subtotal (95% CI) 219 227 -10.80 [ -17.20, -4.40 ]

Bleecker 2000 215 15.6 (34.11) 225 28.5 (39.52) -12.90 [ -19.79, -6.01 ]
Sheth 2001b 52 19.8 (0) 60 29.3 (0) 0.0 [ 0.0, 0.0 ]
Sheth 2001a 55 17.6 (0) 51 28.1 (0) 0.0 [ 0.0, 0.0 ]
Busse 2001a 111 18.7 (33.7) 113 28.8 (42.5) -10.10 [ -20.14, -0.06 ]
Subtotal (95% CI) 433 449 -12.00 [ -17.68, -6.32 ]

Total (95% CI) 652 676 -11.47 [ -15.72, -7.23 ]
-100 -50 0 50 100

children (Review)

Busse 2001b 262 18.4 (33.99) 271 32 (41.16) -13.60 [ -20.00, -7.20 ]
-100 -50 0 50 100

Outcome 24 Change in rescue-free days (%) at 6 +/-2 weeks.
Outcome: 24 Change in rescue-free days (%) at 6 +/-2 weeks
Hughes 1999 (FP) 11 67.1 (85.37) 16 36.5 (41.93) 0.5 % 30.60 [ -23.87, 85.07 ]
Hughes 1999 (BDP) 10 67.1 (85.37) 22 99.2 (231.12) 0.1 % -32.10 [ -142.22, 78.02 ]
Busse 2001b 235 25.5 (33.73) 243 38.3 (38.97) 31.4 % -12.80 [ -19.33, -6.27 ]
Subtotal (95% CI) 256 281 32.0 % -12.25 [ -18.72, -5.78 ]

Kim 2000 209 9.3 (34.78) 214 23.4 (36.66) 28.9 % -14.10 [ -20.91, -7.29 ]
Busse 2001a 111 33.5 (40.04) 113 43.7 (40.39) 12.1 % -10.20 [ -20.73, 0.33 ]
Brabson 2002 216 10 (39) 224 23 (36) 27.1 % -13.00 [ -20.02, -5.98 ]
Subtotal (95% CI) 536 551 68.0 % -12.97 [ -17.40, -8.54 ]
-100 -50 0 50 100

(Continued . . . )
children (Review)
(. . . Continued)
Total (95% CI) 792 832 100.0 % -12.74 [ -16.40, -9.08 ]
-100 -50 0 50 100

Outcome 25 Change in rescue-free days (%) at 12 +/-4 weeks.
Outcome: 25 Change in rescue-free days (%) at 12 +/-4 weeks
1 Montelukast 10 mg
Busse 2001b 219 29.8 (37) 227 42.4 (39.17) 38.8 % -12.60 [ -19.67, -5.53 ]
Subtotal (95% CI) 219 227 38.8 % -12.60 [ -19.67, -5.53 ]

Busse 2001a 111 37.5 (40) 113 48.9 (38.27) 18.5 % -11.40 [ -21.65, -1.15 ]
Bleecker 2000 215 24.2 (34.11) 225 40.4 (38) 42.7 % -16.20 [ -22.94, -9.46 ]
Subtotal (95% CI) 326 338 61.2 % -14.75 [ -20.38, -9.12 ]

Total (95% CI) 545 565 100.0 % -13.92 [ -18.32, -9.51 ]
-100 -50 0 50 100

children (Review)
Outcome 26 Change in rescue-free days (%) at 24 +/- 4 weeks.
Outcome: 26 Change in rescue-free days (%) at 24 +/- 4 weeks

Busse 2001b 262 31.2 (37.23) 271 45.9 (41.16) -14.70 [ -21.36, -8.04 ]
-100 -50 0 50 100

Outcome 27 Days off work or school at 6 +/- 2 weeks.
Outcome: 27 Days off work or school at 6 +/- 2 weeks

Busse 2001b 195 0.12 (0.7) 208 0.17 (1.01) -0.05 [ -0.22, 0.12 ]
-1 -0.5 0 0.5 1
children (Review)
Busse 2001b 187 0.08 (0.55) 199 0.02 (0.28) 99.6 % 0.06 [ -0.03, 0.15 ]
Subtotal (95% CI) 187 199 99.6 % 0.06 [ -0.03, 0.15 ]

2 Zafirlukast 20 mg die
Busse 2001a 111 0.13 (7.37) 113 0.26 (0.96) 0.4 % -0.13 [ -1.51, 1.25 ]
Subtotal (95% CI) 111 113 0.4 % -0.13 [ -1.51, 1.25 ]

Total (95% CI) 298 312 100.0 % 0.06 [ -0.03, 0.15 ]
-4 -2 0 2 4
children (Review)
Maspero 2001 83 0.7 (2.26) 41 0.94 (3.12) 1.5 % -0.24 [ -1.31, 0.83 ]
Subtotal (95% CI) 83 41 1.5 % -0.24 [ -1.31, 0.83 ]

Busse 2001b 238 0.22 (0.93) 244 0.09 (0.47) 98.5 % 0.13 [ 0.00, 0.26 ]
Subtotal (95% CI) 238 244 98.5 % 0.13 [ 0.00, 0.26 ]

Total (95% CI) 321 285 100.0 % 0.12 [ -0.01, 0.26 ]
-4 -2 0 2 4
children (Review)
Outcome 30 Change from baseline quality of life (QOL) at 6 +/- 2 weeks.
Outcome: 30 Change from baseline quality of life (QOL) at 6 +/- 2 weeks
Busse 2001b 225 1.01 (1.05) 239 1.33 (1.08) 50.5 % -0.32 [ -0.51, -0.13 ]
Subtotal (95% CI) 225 239 50.5 % -0.32 [ -0.51, -0.13 ]

Kim 2000 207 0.1 (1.44) 210 0.6 (1.45) 24.7 % -0.50 [ -0.78, -0.22 ]
Busse 2001a 111 0.8 (1.05) 113 1.1 (1.06) 24.8 % -0.30 [ -0.58, -0.02 ]
Subtotal (95% CI) 318 323 49.5 % -0.40 [ -0.60, -0.20 ]

Total (95% CI) 543 562 100.0 % -0.36 [ -0.50, -0.22 ]
-1 -0.5 0 0.5 1
children (Review)
Busse 2001b 200 1.12 (0.99) 207 1.49 (1.15) 39.6 % -0.37 [ -0.58, -0.16 ]
Malmstrom 1999 375 0.81 (1.06) 245 1.06 (1.04) 60.4 % -0.25 [ -0.42, -0.08 ]
Subtotal (95% CI) 575 452 100.0 % -0.30 [ -0.43, -0.17 ]

2 Pranlukast 300 mg bid
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Test for overall effect: not applicable
Total (95% CI) 575 452 100.0 % -0.30 [ -0.43, -0.17 ]
-1 -0.5 0 0.5 1
Busse 2001b 245 1.04 (1.25) 261 1.46 (1.13) 63.5 % -0.42 [ -0.63, -0.21 ]
Meltzer 2002 264 1 (1.6) 258 1.3 (1.6) 36.5 % -0.30 [ -0.57, -0.03 ]
Total (95% CI) 509 519 100.0 % -0.38 [ -0.54, -0.21 ]

-1 -0.5 0 0.5 1
children (Review)
Outcome 33 Change from baseline blood eosinophils at 6 +/- 2 weeks.
Outcome: 33 Change from baseline blood eosinophils at 6 +/- 2 weeks
Baumgartner 2003 289 -0.08 (0.62) 293 -0.06 (0.72) 5.9 % -0.02 [ -0.13, 0.09 ]
Hughes 1999 (FP) 13 0 (0.11) 24 -0.1 (0.16) 9.1 % 0.10 [ 0.01, 0.19 ]
Israel 2002 327 -0.02 (0.18) 313 -0.07 (0.22) 71.7 % 0.05 [ 0.02, 0.08 ]
Hughes 1999 (BDP) 12 0 (0.11) 23 -0.1 (0.09) 13.4 % 0.10 [ 0.03, 0.17 ]
Total (95% CI) 641 653 100.0 % 0.06 [ 0.03, 0.08 ]

-1 -0.5 0 0.5 1
children (Review)
Malmstrom 1999 373 -0.08 (0.3) 246 -0.07 (0.25) 29.0 % -0.01 [ -0.05, 0.03 ]
Laviolette 1999 199 0.04 (0.16) 195 0.04 (0.12) 71.0 % 0.0 [ -0.03, 0.03 ]
Total (95% CI) 572 441 100.0 % 0.00 [ -0.03, 0.02 ]

-0.5 -0.25 0 0.25 0.5

Favours LTRA Favours BDP

Williams 2001 228 -0.1 (0.35) 136 -0.09 (0.32) -0.01 [ -0.08, 0.06 ]
-0.5 -0.25 0 0.25 0.5

Favours LTRA Favours ICS alone
children (Review)
Outcome 36 LTC4 concentration (ng/mL) in nasal wash at 12 +/- 4 weeks.
Outcome: 36 LTC4 concentration (ng/mL) in nasal wash at 12 +/- 4 weeks

Maspero 2001 6 0.8 (1.72) 6 1.5 (1.47) -0.70 [ -2.51, 1.11 ]
-10 -5 0 5 10
Outcome 37 LTC4 concentration (ng/mL) in nasal wash at 24 +/- 4 weeks.
Outcome: 37 LTC4 concentration (ng/mL) in nasal wash at 24 +/- 4 weeks

Maspero 2001 6 1 (0.73) 6 1.5 (2.45) -0.50 [ -2.55, 1.55 ]
-10 -5 0 5 10
children (Review)
Outcome 38 Patients with at least 1 exacerbation requiring systemic steroids.
Outcome: 38 Patients with at least 1 exacerbation requiring systemic steroids
Study or subgroup Anti-leukotrienes Inhaled steroids Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Montelukast 5 mg (10 mg for children 15 years and over)

Stelmach 2002b 0/27 0/28 0.0 [ 0.0, 0.0 ]
Stelmach 2002a 0/18 0/19 0.0 [ 0.0, 0.0 ]
Maspero 2001 11/83 7/41 0.78 [ 0.32, 1.85 ]
Subtotal (95% CI) 128 88 0.78 [ 0.32, 1.85 ]

Total events: 11 (Anti-leukotrienes), 7 (Inhaled steroids)
Zieger 5/189 4/191 1.26 [ 0.34, 4.63 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Williams 2001 85/269 42/167 1.26 [ 0.92, 1.72 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Baumgartner 2003 15/308 9/308 1.67 [ 0.74, 3.75 ]
Laviolette 1999 61/201 22/200 2.76 [ 1.77, 4.31 ]
Busse 2001b 16/262 10/271 1.65 [ 0.77, 3.58 ]
Israel 2002 10/337 12/329 0.81 [ 0.36, 1.86 ]
Riccioni 2002b 1/15 1/15 1.00 [ 0.07, 14.55 ]
Riccioni 2002a 1/20 2/20 0.50 [ 0.05, 5.08 ]
Subtotal (95% CI) 1626 1547 1.56 [ 1.25, 1.94 ]

Subtotal (95% CI) 0 0 0.0 [ 0.0, 0.0 ]
Bleecker 2000 14/220 8/231 1.84 [ 0.79, 4.29 ]
0.01 0.1 1 10 100

(Continued . . . )
children (Review)
(. . . Continued)
Kim 2000 12/216 4/221 3.07 [ 1.01, 9.37 ]
Busse 2001a 13/111 5/113 2.65 [ 0.98, 7.18 ]
Brabson 2002 10/216 1/224 10.37 [ 1.34, 80.32 ]
Riccioni 2001 0/12 1/12 0.33 [ 0.01, 7.45 ]
Subtotal (95% CI) 775 801 2.62 [ 1.57, 4.38 ]

Total (95% CI) 2529 2436 1.65 [ 1.36, 2.00 ]
0.01 0.1 1 10 100

Outcome 39 Patients with at least 1 exacerbation requiring admission.
Outcome: 39 Patients with at least 1 exacerbation requiring admission


Stelmach 2002b 0/27 0/28 0.0 [ 0.0, 0.0 ]
Stelmach 2002a 0/18 0/19 0.0 [ 0.0, 0.0 ]
Maspero 2001 0/83 0/41 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 128 88 0.0 [ 0.0, 0.0 ]

Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%
Williams 2001 1/269 3/167 0.21 [ 0.02, 1.97 ]
0.001 0.01 0.1 1 10 100 1000

(Continued . . . )
children (Review)
(. . . Continued)
Zieger 0/189 0/191 0.0 [ 0.0, 0.0 ]
Busse 2001b 2/262 0/271 5.17 [ 0.25, 107.20 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Laviolette 1999 4/201 1/200 3.98 [ 0.45, 35.30 ]
Riccioni 2002a 1/20 1/20 1.00 [ 0.07, 14.90 ]
Subtotal (95% CI) 966 895 1.34 [ 0.49, 3.67 ]

Subtotal (95% CI) 0 0 0.0 [ 0.0, 0.0 ]
Kim 2000 0/216 0/221 0.0 [ 0.0, 0.0 ]
Busse 2001a 0/111 0/113 0.0 [ 0.0, 0.0 ]
Bleecker 2000 2/220 0/231 5.25 [ 0.25, 108.72 ]
Subtotal (95% CI) 547 565 5.25 [ 0.25, 108.72 ]

Total (95% CI) 1641 1548 1.62 [ 0.64, 4.15 ]
0.001 0.01 0.1 1 10 100 1000

children (Review)
Outcome 40 Overall Withdrawals.
Outcome: 40 Overall Withdrawals
Study or subgroup Anti-leukotrienes Inhaled steroids Risk Ratio Weight Risk Ratio
n/N n/N M-H,Random,95% CI M-H,Random,95% CI

Stelmach 2002b 3/27 3/28 1.4 % 1.04 [ 0.23, 4.70 ]
Stelmach 2002a 3/18 4/19 1.7 % 0.79 [ 0.21, 3.06 ]
Maspero 2001 5/83 3/41 1.6 % 0.82 [ 0.21, 3.28 ]
Subtotal (95% CI) 128 88 4.6 % 0.87 [ 0.38, 1.96 ]

Malmstrom 1999 41/387 24/251 7.3 % 1.11 [ 0.69, 1.79 ]
Baumgartner 2003 22/313 19/314 5.8 % 1.16 [ 0.64, 2.10 ]
Israel 2002 11/339 14/332 4.1 % 0.77 [ 0.35, 1.67 ]
Meltzer 2002 67/264 60/258 10.3 % 1.09 [ 0.81, 1.48 ]
Zieger 25/200 28/200 6.9 % 0.89 [ 0.54, 1.48 ]
Williams 2001 32/269 23/167 7.0 % 0.86 [ 0.52, 1.42 ]
Laviolette 1999 42/201 22/200 7.3 % 1.90 [ 1.18, 3.06 ]
Busse 2001b 75/262 77/271 10.9 % 1.01 [ 0.77, 1.32 ]
Riccioni 2002b 1/15 1/15 0.5 % 1.00 [ 0.07, 14.55 ]
Subtotal (95% CI) 2250 2008 59.9 % 1.07 [ 0.93, 1.24 ]

Bleecker 2000 50/220 31/231 8.4 % 1.69 [ 1.13, 2.55 ]
Laitinen 1997 14/162 13/160 4.5 % 1.06 [ 0.52, 2.19 ]
Kim 2000 46/216 19/221 7.0 % 2.48 [ 1.50, 4.09 ]
Nathan 2001 12/150 5/144 2.7 % 2.30 [ 0.83, 6.38 ]
Brabson 2002 45/216 17/224 6.6 % 2.75 [ 1.62, 4.64 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
children (Review)
(. . . Continued)
Busse 2001a 21/111 16/113 5.7 % 1.34 [ 0.74, 2.42 ]
Riccioni 2001 2/12 1/12 0.6 % 2.00 [ 0.21, 19.23 ]
Subtotal (95% CI) 1087 1105 35.5 % 1.87 [ 1.45, 2.42 ]

Total (95% CI) 3465 3201 100.0 % 1.29 [ 1.08, 1.56 ]
0.1 0.2 0.5 1 2 5 10

Outcome 41 Withdrawal due to poor asthma control/exacerbations.
Outcome: 41 Withdrawal due to poor asthma control/exacerbations

Maspero 2001 0/83 0/41 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 83 41 0.0 [ 0.0, 0.0 ]

Laviolette 1999 23/201 8/200 2.86 [ 1.31, 6.24 ]
Meltzer 2002 17/264 11/258 1.51 [ 0.72, 3.16 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Israel 2002 5/339 3/332 1.63 [ 0.39, 6.78 ]
Malmstrom 1999 4/387 1/251 2.59 [ 0.29, 23.08 ]
0.01 0.1 1 10 100

(Continued . . . )
children (Review)
(. . . Continued)
Williams 2001 8/269 3/167 1.66 [ 0.45, 6.15 ]
Baumgartner 2003 0/313 1/314 0.33 [ 0.01, 8.18 ]
Busse 2001b 26/262 15/271 1.79 [ 0.97, 3.31 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Riccioni 2002b 1/15 1/15 1.00 [ 0.07, 14.55 ]
Subtotal (95% CI) 2075 1854 1.85 [ 1.29, 2.64 ]

Kim 2000 31/216 5/221 6.34 [ 2.51, 16.01 ]
Brabson 2002 29/216 5/224 6.01 [ 2.37, 15.25 ]
Laitinen 1997 1/162 2/160 0.49 [ 0.05, 5.39 ]
Nathan 2001 4/150 1/144 3.84 [ 0.43, 33.95 ]
Bleecker 2000 14/220 6/231 2.45 [ 0.96, 6.26 ]
Busse 2001a 6/111 2/113 3.05 [ 0.63, 14.81 ]
Subtotal (95% CI) 1075 1093 4.16 [ 2.60, 6.65 ]

Total (95% CI) 3233 2988 2.58 [ 1.95, 3.42 ]
0.01 0.1 1 10 100

children (Review)
Outcome 42 Withdrawals due to adverse effects.
Outcome: 42 Withdrawals due to adverse effects

Maspero 2001 0/83 1/41 0.17 [ 0.01, 4.00 ]
Subtotal (95% CI) 83 41 0.17 [ 0.01, 4.00 ]

Laviolette 1999 27/201 9/200 2.99 [ 1.44, 6.19 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Zieger 1/189 5/191 0.20 [ 0.02, 1.71 ]
Israel 2002 6/339 8/332 0.73 [ 0.26, 2.09 ]
Baumgartner 2003 0/313 3/314 0.14 [ 0.01, 2.76 ]
Busse 2001b 4/262 10/271 0.41 [ 0.13, 1.30 ]
Williams 2001 11/269 6/167 1.14 [ 0.43, 3.02 ]
Meltzer 2002 5/264 5/258 0.98 [ 0.29, 3.34 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Malmstrom 1999 8/387 5/251 1.04 [ 0.34, 3.14 ]
Subtotal (95% CI) 2249 2030 1.08 [ 0.75, 1.55 ]

Kim 2000 9/216 6/221 1.53 [ 0.56, 4.24 ]
Bleecker 2000 12/220 8/231 1.58 [ 0.66, 3.78 ]
Busse 2001a 3/111 4/113 0.76 [ 0.17, 3.33 ]
Laitinen 1997 6/162 5/160 1.19 [ 0.37, 3.81 ]
Brabson 2002 4/216 2/224 2.07 [ 0.38, 11.21 ]
Subtotal (95% CI) 925 949 1.40 [ 0.84, 2.32 ]

0.001 0.01 0.1 1 10 100 1000

(Continued . . . )
children (Review)
(. . . Continued)
Total (95% CI) 3257 3020 1.15 [ 0.86, 1.54 ]
0.001 0.01 0.1 1 10 100 1000

Outcome 43 Overall Adverse effects.
Outcome: 43 Overall Adverse effects
Maspero 2001 60/83 34/41 3.8 % 0.87 [ 0.72, 1.06 ]
Subtotal (95% CI) 83 41 3.8 % 0.87 [ 0.72, 1.06 ]

Zieger 96/189 105/191 8.8 % 0.92 [ 0.76, 1.12 ]
Hughes 1999 (BDP) 1/12 6/23 0.3 % 0.32 [ 0.04, 2.36 ]
Busse 2001b 178/262 192/271 15.9 % 0.96 [ 0.86, 1.07 ]
Baumgartner 2003 121/313 132/314 11.1 % 0.92 [ 0.76, 1.11 ]
Williams 2001 195/269 115/167 12.0 % 1.05 [ 0.93, 1.19 ]
Malmstrom 1999 253/387 160/251 16.4 % 1.03 [ 0.91, 1.15 ]
Israel 2002 161/339 152/332 13.0 % 1.04 [ 0.88, 1.22 ]
Hughes 1999 (FP) 1/13 6/23 0.4 % 0.29 [ 0.04, 2.19 ]
Subtotal (95% CI) 1784 1572 77.9 % 0.98 [ 0.93, 1.04 ]
0.01 0.1 1 10 100

(Continued . . . )
children (Review)
(. . . Continued)
Busse 2001a 77/111 76/113 6.4 % 1.03 [ 0.86, 1.23 ]
Nathan 2001 15/150 6/144 0.5 % 2.40 [ 0.96, 6.01 ]
Brabson 2002 8/216 16/224 1.3 % 0.52 [ 0.23, 1.19 ]
Laitinen 1997 80/162 67/160 5.7 % 1.18 [ 0.93, 1.50 ]
Bleecker 2000 23/220 23/231 1.9 % 1.05 [ 0.61, 1.82 ]
Kim 2000 15/216 30/221 2.5 % 0.51 [ 0.28, 0.92 ]
Subtotal (95% CI) 1075 1093 18.3 % 1.01 [ 0.87, 1.17 ]

Total (95% CI) 2942 2706 100.0 % 0.99 [ 0.93, 1.04 ]
0.01 0.1 1 10 100

children (Review)
Outcome 44 Elevated liver enzymes.
Outcome: 44 Elevated liver enzymes

Maspero 2001 1/79 1/39 0.49 [ 0.03, 7.68 ]
Subtotal (95% CI) 79 39 0.49 [ 0.03, 7.68 ]

Malmstrom 1999 8/382 7/249 0.74 [ 0.27, 2.03 ]
Laviolette 1999 7/199 4/196 1.72 [ 0.51, 5.79 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Williams 2001 7/268 2/164 2.14 [ 0.45, 10.19 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 874 655 1.24 [ 0.63, 2.43 ]

Laitinen 1997 3/162 1/160 2.96 [ 0.31, 28.19 ]
Busse 2001a 1/111 1/113 1.02 [ 0.06, 16.07 ]
Subtotal (95% CI) 273 273 2.00 [ 0.37, 10.86 ]

Total (95% CI) 1226 967 1.27 [ 0.69, 2.32 ]
0.01 0.1 1 10 100

children (Review)
Outcome 45 Headache.
Outcome: 45 Headache
Maspero 2001 11/83 6/41 3.3 % 0.91 [ 0.36, 2.28 ]
Subtotal (95% CI) 83 41 3.3 % 0.91 [ 0.36, 2.28 ]

Williams 2001 34/269 27/167 13.6 % 0.78 [ 0.49, 1.25 ]
Laviolette 1999 52/201 42/200 17.2 % 1.23 [ 0.86, 1.76 ]
Busse 2001b 3/262 8/262 3.3 % 0.38 [ 0.10, 1.40 ]
Hughes 1999 (BDP) 0/12 1/23 0.4 % 0.62 [ 0.03, 14.06 ]
Meltzer 2002 2/264 2/258 0.8 % 0.98 [ 0.14, 6.89 ]
Malmstrom 1999 68/387 47/251 23.3 % 0.94 [ 0.67, 1.31 ]
Hughes 1999 (FP) 0/13 1/23 0.5 % 0.57 [ 0.02, 13.10 ]
Israel 2002 22/339 20/332 8.3 % 1.08 [ 0.60, 1.94 ]
Baumgartner 2003 31/313 34/314 13.9 % 0.91 [ 0.58, 1.45 ]
Riccioni 2002a 1/20 1/20 0.4 % 1.00 [ 0.07, 14.90 ]
Subtotal (95% CI) 2080 1850 81.7 % 0.96 [ 0.80, 1.15 ]

Bleecker 2000 3/220 7/231 2.8 % 0.45 [ 0.12, 1.72 ]
Laitinen 1997 9/162 12/160 4.9 % 0.74 [ 0.32, 1.71 ]
Kim 2000 7/216 10/221 4.0 % 0.72 [ 0.28, 1.85 ]
Busse 2001a 2/111 3/113 1.2 % 0.68 [ 0.12, 3.98 ]
Brabson 2002 4/216 5/224 2.0 % 0.83 [ 0.23, 3.05 ]
Subtotal (95% CI) 925 949 15.0 % 0.69 [ 0.42, 1.13 ]

0.01 0.1 1 10 100

(Continued . . . )
children (Review)
(. . . Continued)
Total (95% CI) 3088 2840 100.0 % 0.92 [ 0.77, 1.08 ]
0.01 0.1 1 10 100

Outcome 46 Nausea.
Outcome: 46 Nausea

Maspero 2001 1/83 0/41 1.50 [ 0.06, 36.04 ]
Subtotal (95% CI) 83 41 1.50 [ 0.06, 36.04 ]

Laviolette 1999 12/201 11/200 1.09 [ 0.49, 2.40 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Busse 2001b 14/262 13/271 1.11 [ 0.53, 2.32 ]
Israel 2002 0/339 3/332 0.14 [ 0.01, 2.70 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Baumgartner 2003 5/313 4/314 1.25 [ 0.34, 4.63 ]
Williams 2001 2/269 1/167 1.24 [ 0.11, 13.59 ]
Subtotal (95% CI) 1409 1330 1.02 [ 0.64, 1.64 ]

0.001 0.01 0.1 1 10 100 1000

(Continued . . . )
children (Review)
(. . . Continued)
Kim 2000 1/216 5/221 0.20 [ 0.02, 1.74 ]
Laitinen 1997 3/162 4/160 0.74 [ 0.17, 3.26 ]
Nathan 2001 3/150 0/144 6.72 [ 0.35, 129.00 ]
Busse 2001a 2/111 2/113 1.02 [ 0.15, 7.10 ]
Brabson 2002 0/216 2/224 0.21 [ 0.01, 4.29 ]
Bleecker 2000 3/220 0/231 7.35 [ 0.38, 141.45 ]
Subtotal (95% CI) 1075 1093 0.94 [ 0.45, 1.97 ]

Total (95% CI) 2567 2464 1.00 [ 0.68, 1.49 ]
0.001 0.01 0.1 1 10 100 1000

children (Review)
Outcome 47 Oral candidiasis.
Outcome: 47 Oral candidiasis
Busse 2001b 0/262 3/271 49.8 % 0.15 [ 0.01, 2.85 ]
Subtotal (95% CI) 262 271 49.8 % 0.15 [ 0.01, 2.85 ]

Busse 2001a 0/111 3/113 50.2 % 0.15 [ 0.01, 2.78 ]
Subtotal (95% CI) 111 113 50.2 % 0.15 [ 0.01, 2.78 ]

Total (95% CI) 373 384 100.0 % 0.15 [ 0.02, 1.18 ]
0.001 0.01 0.1 1 10 100 1000

children (Review)
Outcome 48 Death.
Outcome: 48 Death

Maspero 2001 0/83 0/41 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 83 41 0.0 [ 0.0, 0.0 ]

Baumgartner 2003 0/313 0/314 0.0 [ 0.0, 0.0 ]
Williams 2001 0/269 0/167 0.0 [ 0.0, 0.0 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Laviolette 1999 0/201 0/200 0.0 [ 0.0, 0.0 ]
Malmstrom 1999 0/387 0/251 0.0 [ 0.0, 0.0 ]
Israel 2002 0/339 0/332 0.0 [ 0.0, 0.0 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Busse 2001b 1/262 0/271 3.10 [ 0.13, 75.82 ]
Subtotal (95% CI) 1796 1581 3.10 [ 0.13, 75.82 ]

Laitinen 1997 0/162 0/160 0.0 [ 0.0, 0.0 ]
Kim 2000 0/216 0/221 0.0 [ 0.0, 0.0 ]
Busse 2001a 0/111 0/113 0.0 [ 0.0, 0.0 ]
Bleecker 2000 0/220 0/231 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 709 725 0.0 [ 0.0, 0.0 ]

Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%
Total (95% CI) 2588 2347 3.10 [ 0.13, 75.82 ]
0.001 0.01 0.1 1 10 100 1000

children (Review)
Outcome 49 Patient satisfied with treatment.
Outcome: 49 Patient satisfied with treatment

Busse 2001a 61/111 77/113 0.81 [ 0.65, 1.00 ]
0.1 0.2 0.5 1 2 5 10

Outcome 50 Main outcome - stratified on age.
Outcome: 50 Main outcome - stratified on age
Study or subgroup LTRA Inhaled steroids Risk Ratio Risk Ratio

1 Children
Stelmach 2002b 0/27 0/28 0.0 [ 0.0, 0.0 ]
Stelmach 2002a 0/18 0/19 0.0 [ 0.0, 0.0 ]
Maspero 2001 11/83 7/41 0.78 [ 0.32, 1.85 ]
Subtotal (95% CI) 128 88 0.78 [ 0.32, 1.85 ]

Total events: 11 (LTRA), 7 (Inhaled steroids)
2 Adults
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Bleecker 2000 14/220 8/231 1.84 [ 0.79, 4.29 ]
Israel 2002 10/337 12/329 0.81 [ 0.36, 1.86 ]
Brabson 2002 10/216 1/224 10.37 [ 1.34, 80.32 ]
0.01 0.1 1 10 100

(Continued . . . )
children (Review)
(. . . Continued)
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Laviolette 1999 61/201 22/200 2.76 [ 1.77, 4.31 ]
Williams 2001 85/269 42/167 1.26 [ 0.92, 1.72 ]
Busse 2001b 16/262 10/271 1.65 [ 0.77, 3.58 ]
Zieger 5/189 4/191 1.26 [ 0.34, 4.63 ]
Baumgartner 2003 15/308 9/308 1.67 [ 0.74, 3.75 ]
Busse 2001a 13/111 5/113 2.65 [ 0.98, 7.18 ]
Kim 2000 12/216 4/221 3.07 [ 1.01, 9.37 ]
Riccioni 2002b 1/15 1/15 1.00 [ 0.07, 14.55 ]
Riccioni 2002a 1/20 2/20 0.50 [ 0.05, 5.08 ]
Riccioni 2001 0/12 1/12 0.33 [ 0.01, 7.45 ]
Subtotal (95% CI) 2401 2348 1.71 [ 1.40, 2.09 ]

Total (95% CI) 2529 2436 1.65 [ 1.36, 2.00 ]
0.01 0.1 1 10 100

children (Review)
Outcome 51 Main outcome - stratified on methodological quality.
Outcome: 51 Main outcome - stratified on methodological quality

1 Poor reported methodological quality (Jadad score <=3)

Maspero 2001 11/83 7/41 0.78 [ 0.32, 1.85 ]
Zieger 5/189 4/191 1.26 [ 0.34, 4.63 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Riccioni 2002a 1/20 2/20 0.50 [ 0.05, 5.08 ]
Riccioni 2002b 1/15 1/15 1.00 [ 0.07, 14.55 ]
Riccioni 2001 0/12 1/12 0.33 [ 0.01, 7.45 ]
Subtotal (95% CI) 344 325 0.83 [ 0.43, 1.59 ]

2 High reported methodological quality (Jadad score >=4)
Stelmach 2002a 0/18 0/19 0.0 [ 0.0, 0.0 ]
Stelmach 2002b 0/27 0/28 0.0 [ 0.0, 0.0 ]
Baumgartner 2003 15/308 9/308 1.67 [ 0.74, 3.75 ]
Busse 2001a 13/111 5/113 2.65 [ 0.98, 7.18 ]
Laviolette 1999 61/201 22/200 2.76 [ 1.77, 4.31 ]
Williams 2001 85/269 42/167 1.26 [ 0.92, 1.72 ]
Bleecker 2000 14/220 8/231 1.84 [ 0.79, 4.29 ]
Israel 2002 10/337 12/329 0.81 [ 0.36, 1.86 ]
Busse 2001b 16/262 10/271 1.65 [ 0.77, 3.58 ]
Kim 2000 12/216 4/221 3.07 [ 1.01, 9.37 ]
Brabson 2002 10/216 1/224 10.37 [ 1.34, 80.32 ]
Subtotal (95% CI) 2185 2111 1.83 [ 1.29, 2.60 ]

0.01 0.1 1 10 100

(Continued . . . )
children (Review)
(. . . Continued)
Total (95% CI) 2529 2436 1.60 [ 1.18, 2.18 ]
0.01 0.1 1 10 100

Outcome 52 Main outcome - stratified on ICS.
Outcome: 52 Main outcome - stratified on ICS

1 Beclomethasone or budesonide 400 mcg die

Williams 2001 85/269 42/167 1.26 [ 0.92, 1.72 ]
Laviolette 1999 61/201 22/200 2.76 [ 1.77, 4.31 ]
Israel 2002 10/337 12/329 0.81 [ 0.36, 1.86 ]
Baumgartner 2003 15/308 9/308 1.67 [ 0.74, 3.75 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 1127 1027 1.54 [ 0.92, 2.56 ]

2 Fluticasone 200 mcg die
Zieger 5/189 4/191 1.26 [ 0.34, 4.63 ]
Busse 2001a 13/111 5/113 2.65 [ 0.98, 7.18 ]
Bleecker 2000 14/220 8/231 1.84 [ 0.79, 4.29 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Kim 2000 12/216 4/221 3.07 [ 1.01, 9.37 ]
0.01 0.1 1 10 100

(Continued . . . )
children (Review)
(. . . Continued)
Busse 2001b 16/262 10/271 1.65 [ 0.77, 3.58 ]
Brabson 2002 10/216 1/224 10.37 [ 1.34, 80.32 ]
Subtotal (95% CI) 1227 1274 2.11 [ 1.39, 3.21 ]

Total (95% CI) 2354 2301 1.79 [ 1.29, 2.48 ]
0.01 0.1 1 10 100

Outcome 53 Main outcome - stratified on duration of intervention.
Outcome: 53 Main outcome - stratified on duration of intervention

1 4-8 weeks
Stelmach 2002b 0/27 0/28 0.0 [ 0.0, 0.0 ]
Stelmach 2002a 0/18 0/19 0.0 [ 0.0, 0.0 ]
Israel 2002 10/337 12/329 0.81 [ 0.36, 1.86 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Baumgartner 2003 15/308 9/308 1.67 [ 0.74, 3.75 ]
Kim 2000 12/216 4/221 3.07 [ 1.01, 9.37 ]
Brabson 2002 10/216 1/224 10.37 [ 1.34, 80.32 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Riccioni 2001 0/12 1/12 0.33 [ 0.01, 7.45 ]
Subtotal (95% CI) 1159 1187 1.73 [ 1.09, 2.74 ]
0.01 0.1 1 10 100

(Continued . . . )
children (Review)
(. . . Continued)
2 12-16 weeks
Laviolette 1999 61/201 22/200 2.76 [ 1.77, 4.31 ]
Zieger 5/189 4/191 1.26 [ 0.34, 4.63 ]
Busse 2001a 13/111 5/113 2.65 [ 0.98, 7.18 ]
Bleecker 2000 14/220 8/231 1.84 [ 0.79, 4.29 ]
Riccioni 2002a 1/20 2/20 0.50 [ 0.05, 5.08 ]
Riccioni 2002b 1/15 1/15 1.00 [ 0.07, 14.55 ]
Subtotal (95% CI) 756 770 2.28 [ 1.62, 3.21 ]

3 24 to 37 weeks
Maspero 2001 11/83 7/41 0.78 [ 0.32, 1.85 ]
Williams 2001 85/269 42/167 1.26 [ 0.92, 1.72 ]
Busse 2001b 16/262 10/271 1.65 [ 0.77, 3.58 ]
Subtotal (95% CI) 614 479 1.25 [ 0.95, 1.65 ]

Total (95% CI) 2529 2436 1.65 [ 1.36, 2.00 ]
0.01 0.1 1 10 100

children (Review)
Outcome 54 Main outcome -stratified on asthma severity.
Outcome: 54 Main outcome -stratified on asthma severity

1 Mean FEV1 50-79% of predicted

Stelmach 2002b 0/27 0/28 0.0 [ 0.0, 0.0 ]
Stelmach 2002a 0/18 0/19 0.0 [ 0.0, 0.0 ]
Laviolette 1999 61/201 22/200 2.76 [ 1.77, 4.31 ]
Brabson 2002 10/216 1/224 10.37 [ 1.34, 80.32 ]
Kim 2000 12/216 4/221 3.07 [ 1.01, 9.37 ]
Israel 2002 10/337 12/329 0.81 [ 0.36, 1.86 ]
Busse 2001a 13/111 5/113 2.65 [ 0.98, 7.18 ]
Baumgartner 2003 15/308 9/308 1.67 [ 0.74, 3.75 ]
Busse 2001b 16/262 10/271 1.65 [ 0.77, 3.58 ]
Bleecker 2000 14/220 8/231 1.84 [ 0.79, 4.29 ]
Subtotal (95% CI) 1916 1944 2.15 [ 1.64, 2.81 ]

2 Mean FEV1 >=80% of predicted
Maspero 2001 11/83 7/41 0.78 [ 0.32, 1.85 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Zieger 5/189 4/191 1.26 [ 0.34, 4.63 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Riccioni 2002a 1/20 2/20 0.50 [ 0.05, 5.08 ]
Riccioni 2002b 1/15 1/15 1.00 [ 0.07, 14.55 ]
Riccioni 2001 0/12 1/12 0.33 [ 0.01, 7.45 ]
Subtotal (95% CI) 344 325 0.83 [ 0.43, 1.58 ]

Total (95% CI) 2260 2269 1.88 [ 1.47, 2.40 ]
0.01 0.1 1 10 100

(Continued . . . )
children (Review)
(. . . Continued)
0.01 0.1 1 10 100

Outcome 55 Main outcome- stratified on publication status.
Outcome: 55 Main outcome- stratified on publication status

1 Published trials
Stelmach 2002a 0/18 0/19 0.0 [ 0.0, 0.0 ]
Stelmach 2002b 0/27 0/28 0.0 [ 0.0, 0.0 ]
Maspero 2001 11/83 7/41 0.78 [ 0.32, 1.85 ]
Kim 2000 12/216 4/221 3.07 [ 1.01, 9.37 ]
Baumgartner 2003 15/308 9/308 1.67 [ 0.74, 3.75 ]
Israel 2002 10/337 12/329 0.81 [ 0.36, 1.86 ]
Busse 2001a 13/111 5/113 2.65 [ 0.98, 7.18 ]
Williams 2001 85/269 42/167 1.26 [ 0.92, 1.72 ]
Brabson 2002 10/216 1/224 10.37 [ 1.34, 80.32 ]
Bleecker 2000 14/220 8/231 1.84 [ 0.79, 4.29 ]
Laviolette 1999 61/201 22/200 2.76 [ 1.77, 4.31 ]
Busse 2001b 16/262 10/271 1.65 [ 0.77, 3.58 ]
Riccioni 2002b 1/15 1/15 1.00 [ 0.07, 14.55 ]
Riccioni 2002a 1/20 2/20 0.50 [ 0.05, 5.08 ]
Riccioni 2001 0/12 1/12 0.33 [ 0.01, 7.45 ]
0.01 0.1 1 10 100

(Continued . . . )
children (Review)
(. . . Continued)
Subtotal (95% CI) 2315 2199 1.62 [ 1.17, 2.24 ]
2 Unpublished trials
Zieger 5/189 4/191 1.26 [ 0.34, 4.63 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 214 237 1.26 [ 0.34, 4.63 ]

Total (95% CI) 2529 2436 1.60 [ 1.18, 2.18 ]
0.01 0.1 1 10 100

children (Review)
Outcome 56 Main outcome- stratified on funding source.
Outcome: 56 Main outcome- stratified on funding source

1 funded by producers of ICS

Hughes 1999 (BDP) 0/12 0/23 0.0 [ 0.0, 0.0 ]
Hughes 1999 (FP) 0/13 0/23 0.0 [ 0.0, 0.0 ]
Bleecker 2000 14/220 8/231 1.84 [ 0.79, 4.29 ]
Busse 2001b 16/262 10/271 1.65 [ 0.77, 3.58 ]
Busse 2001a 13/111 5/113 2.65 [ 0.98, 7.18 ]
Brabson 2002 10/216 1/224 10.37 [ 1.34, 80.32 ]
Kim 2000 12/216 4/221 3.07 [ 1.01, 9.37 ]
Subtotal (95% CI) 1050 1106 2.24 [ 1.44, 3.49 ]

2 funded by producers of AL
Maspero 2001 11/83 7/41 0.78 [ 0.32, 1.85 ]
Baumgartner 2003 15/308 9/308 1.67 [ 0.74, 3.75 ]
Laviolette 1999 61/201 22/200 2.76 [ 1.77, 4.31 ]
Israel 2002 10/337 12/329 0.81 [ 0.36, 1.86 ]
Williams 2001 85/269 42/167 1.26 [ 0.92, 1.72 ]
Zieger 5/189 4/191 1.26 [ 0.34, 4.63 ]
Subtotal (95% CI) 1387 1236 1.38 [ 0.90, 2.12 ]

3 No industry funding
Stelmach 2002b 0/27 0/28 0.0 [ 0.0, 0.0 ]
Stelmach 2002a 0/18 0/19 0.0 [ 0.0, 0.0 ]
Riccioni 2001 0/12 1/12 0.33 [ 0.01, 7.45 ]
Riccioni 2002b 1/15 1/15 1.00 [ 0.07, 14.55 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
children (Review)
(. . . Continued)
Riccioni 2002a 1/20 2/20 0.50 [ 0.05, 5.08 ]
Subtotal (95% CI) 92 94 0.57 [ 0.12, 2.61 ]

Total (95% CI) 2529 2436 1.60 [ 1.18, 2.18 ]
0.1 0.2 0.5 1 2 5 10

Outcome 58 % Asthma control days during intervention period at 6 +/- 2 weeks.
Outcome: 58 % Asthma control days during intervention period at 6 +/- 2 weeks
Baumgartner 2003 313 50.7 (37.1) 314 57.9 (36.1) 41.3 % -7.20 [ -12.93, -1.47 ]
Israel 2002 337 41.4 (75.1) 329 41.1 (77.2) 22.2 % 0.30 [ -11.27, 11.87 ]
Meltzer 2002 264 20.2 (37.38) 258 34.3 (43.36) 36.5 % -14.10 [ -21.05, -7.15 ]
Total (95% CI) 914 901 100.0 % -8.06 [ -15.01, -1.10 ]

-100 -50 0 50 100

children (Review)
Outcome 59 Hoarseness.
Outcome: 59 Hoarseness
Nathan 2001 0/150 1/144 38.4 % 0.32 [ 0.01, 7.79 ]
Brabson 2002 0/216 2/224 61.6 % 0.21 [ 0.01, 4.29 ]
Total (95% CI) 366 368 100.0 % 0.25 [ 0.03, 2.24 ]

0.01 0.1 1 10 100

Outcome 60 % Change in sputum eosinophils.
Outcome: 60 % Change in sputum eosinophils
Kanniess 2002 40 -2.7 (8.2) 40 -1.4 (8.2) 100.0 % -1.30 [ -4.89, 2.29 ]
Total (95% CI) 40 40 100.0 % -1.30 [ -4.89, 2.29 ]

-10 -5 0 5 10
children (Review)
Outcome 61 Change in PC20.
Outcome: 61 Change in PC20

Zieger 4 6.9 (5.9) 1 13.9 (0) 0.0 [ 0.0, 0.0 ]
Kanniess 2002 40 0.15 (1.08) 40 1.33 (0.82) -1.18 [ -1.60, -0.76 ]
Total (95% CI) 44 41 -1.18 [ -1.60, -0.76 ]

-10 -5 0 5 10
Outcome 62 % rescue - free days.
Outcome: 62 % rescue - free days
Study or subgroup LTRA Inhaled steroids Mean Difference Weight Mean Difference
Zieger 176 73.1 (46) 178 74.9 (47) 34.0 % -1.80 [ -11.49, 7.89 ]
Meltzer 2002 264 33.4 (39) 258 45.6 (41.9) 66.0 % -12.20 [ -19.15, -5.25 ]
Total (95% CI) 440 436 100.0 % -8.67 [ -14.31, -3.02 ]

-100 -50 0 50 100

children (Review)
WHATS NEW
Last assessed as up-to-date: 16 October 2003.
30 June 2008 Amended Converted to new review format.
HISTORY
Protocol first published: Issue 2, 1999
Review first published: Issue 3, 2000
17 October 2003 New citation required and conclusions have changed Substantive amendment
CONTRIBUTIONS OF AUTHORS
Prof Francine Ducharme conceived the protocol, requested the literature search, identified and contacted the corresponding authors
and/or the pharmaceutical companies to solicity their collaboration in this review and in the identification of other possibly relevant
trials, created the methodology and data extraction forms, reviewed all citations for relevance with research assitants, reviewed all
included trials for methodology and data extraction, corresponded with authors or pharmaceutical companies to verify methodology
and data extraction, verified all references, description of studies and data entry, analysed and interpreted results of the meta-analysis.
Giselle Hicks participated in the following aspects of the review from November 1999 to February 2000; she reviewed several citations
for relevance, extracted the methodology and data, and entered data for several trials.
Franco Di Salvio assisted in the August 2003 update. He extracted the methodology and data for the new identified trials, identified
missing information for, and completed the table of characteristics of, included studies, and entered the references for all excluded
studies with their reason for exclusion. Justin Grondines, data manager, tallied the reasons for exclusion for the literature search.
DECLARATIONS OF INTEREST
Francine Ducharme has received travel support, research funds and fees for speaking from both Zeneca Pharma Inc. producer of
zafirlukast and from Merck Frosst Inc, producer of montelukast. She has received some travel support for meeting attendance, research
grant and consulting fee from Glaxo Wellcome Inc, producer of some inhaled corticosteroids preparation to which anti-leukotriene
agents have been compared. Franco DiSalvio and Giselle Hicks : None declared.
children (Review)
SOURCES OF SUPPORT
Internal sources
No sources of support supplied
External sources
Francine Ducharme is supported by a National Researcher Award from the Fonds de la Sant du Qubec, Canada.
INDEX TERMS
Medical Subject Headings (MeSH)

Administration, Inhalation; Anti-Asthmatic Agents [ therapeutic use]; Anti-Inflammatory Agents [ therapeutic use]; Asthma [ drug
therapy]; Chronic Disease; Leukotriene Antagonists [ therapeutic use]; Randomized Controlled Trials as Topic; Recurrence; Steroids
[therapeutic use]; Treatment Outcome
MeSH check words

Adult; Child; Humans
children (Review)

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Anti-leukotriene agents compared to inhaled corticosteroids

in the management of recurrent and/or chronic asthma in

Anti-leukotriene agents compared to inhaled corticosteroids

Francine Ducharme1 , Franco di Salvio2

Editorial group: Cochrane Airways Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Anti-leukotriene agents compared to inhaled corticosteroids for people with asthma

Criteria for considering studies for this review

Assessment of risk of bias in included studies

Intervention duration: The trials varied in the duration of in-

Characteristics of included studies [ordered by study ID]

Participants SYMPTOMATIC PARTICIPANTS

Outcomes ANALYSIS (ITT)

Notes -Abs (2001)

Item Authors judgement Description

Allocation concealment? Unclear D - Not used

Participants SYMPTOMATIC PARTICIPANTS

Outcomes ANALYSIS BY MODIFIED INTENTION-TO-TREAT

- change from baseline in serum eosinophils

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Participants SYMPTOMATIC PARTICIPANTS

Outcomes ANALYSIS ( ITT )

-Change from baseline mean daily beta2-agonist use (puffs/day)

Notes -Full-text publication

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Participants SYMPTOMATIC PARTICIPANTS

Outcomes ANALYSIS (ITT)

Notes -Full-text publication

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Participants SYMPTOMATIC PARTICIPANTS

-Age: >=12 years

Outcomes ANALYSIS ( ITT )

Notes -Full-text publication

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Participants SYMPTOMATIC PARTICIPANTS

Outcomes ANALYSIS ( ITT )

Notes -Full-text publication

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Participants SYMPTOMATIC PARTICIPANTS

Outcomes ANALSIS (ITT)

Notes Abs 2001

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Hughes 1999 (BDP)

Participants SYMPTOMATIC PARTICIPANTS

Outcomes ANALYSIS ( ITT)

PULMONARY FUNCTION TESTS

Notes -Abstract & Poster (1999)

Item Authors judgement Description

Allocation concealment? Unclear D - Not used

Hughes 1999 (FP)

Item Authors judgement Description

Allocation concealment? Unclear D - Not used

Participants SYMPTOMATIC PARTICIPANTS

-FEV1 between 50%-80%

Outcomes ANALYSIS (ITT)

Notes -Full-text publication