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ABSTRACT
Introduction: Inhaled corticosteroids (ICS) are a first-line
treatment for mild persistent asthma, but montelukast
(MON) monotherapy also has been beneficial. The aim of
this review is to evaluate current evidence comparing MON
versus ICS monotherapy in pediatric patients.
Method: A systematic review was conducted of randomized
controlled trials evaluating treatment of mild to moderate
persistent asthma in which MON was compared with ICS
monotherapy in children aged 2 to 18 years. PubMed, the Cumulative Index to Nursing and Allied Health Literature, and
the Institute of Scientific Informations Web of Knowledge
Kristen Massingham, Pediatric Nurse Practitioner, Essex
Pediatrics, Doctor of Nursing Practice Program, Columbia
University School of Nursing, New York, NY.
Shelley Fox, Family Nurse Practitioner, Khasak Dermatology,
Doctor of Nursing Practice Program, Columbia University School
of Nursing, New York, NY.
Arlene Smaldone, Associate Professor of Clinical Nursing,
Columbia University School of Nursing, New York, NY.
Conflicts of interest: None to report.
Correspondence: Kristen Massingham, MS, CPNP, Columbia
University School of Nursing, 630 West 168th St, New York, NY
10032; e-mail: klm2158@columbia.edu.
0891-5245/$36.00
Copyright Q 2014 by the National Association of Pediatric
Nurse Practitioners. Published by Elsevier Inc. All rights
reserved.
Published online January 10, 2013.
http://dx.doi.org/10.1016/j.pedhc.2012.11.005
www.jpedhc.org
were searched using key words asthma, MON, and ICS. Studies that met inclusion criteria were appraised for quality.
Results: Of 214 identified studies, eight met inclusion criteria
and seven were deemed high quality. Study sample sizes
ranged from 62 to 994, 88% were multi-site, and the average
length of follow-up was 8.2 months. Asthma symptoms improved with both therapies. Four studies reported superiority of ICS compared with MON; the remaining studies
showed no differences between therapies.
Discussion: These results are consistent with the National
Asthma Education and Prevention Program (2007) recommendation that ICS therapy should be first-line treatment in
children with mild to moderate persistent asthma. J Pediatr
Health Care. (2014) 28, 51-62.
KEY WORDS
Asthma, inhaled corticosteroids, montelukast
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a spacer is recommended when using medication delivered by a meter dose inhaler to increase the efficiency of
drug delivery. Proper delivery technique of aerosol
medications is extremely important to ensure that the
patient receives the full dose of the prescribed medication. Spacer devices have been shown to increase the
amount of delivered medication and improve lung delivery in children who may lack the ability to cooperate
with treatment because of limited developmental and
cognitive abilities (Myers & Tomasio, 2011). Administration via nebulization is beyond the scope of this review because this method of delivery typically is used
for acute exacerbations and is rarely indicated for
chronic use. Many children with asthma have concurrent rhinitis, a symptom that MON can address directly
(Dahlen, 2006). In addition, MON has fewer safety
concerns and is well tolerated (Knorr et al., 2001).
The most frequently reported adverse events include
headache, pharyngitis, gastrointestinal disorders, and
rash, although rates of these events are similar between
those receiving active medication and placebo
(Montella et al., 2012). Although ICS also have few adverse effects, particular concern exists about delayed
bone growth in children who take ICS on a long-term
basis (Pedersen et al., 2007). Until more is known about
the long-term effects of ICS, MON is considered a safe
alternative pharmacotherapy (Kazani, Ware, Drazen,
Taylor, & Sears, 2010).
This article seeks to systematically review the literature, following the Preferred Reporting Items for
Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Moher, Liberati, Tetzlaff, Altman, & the PRISMA
Group, 2009), to evaluate the effectiveness of asthma
management using MON monotherapy compared
with ICS monotherapy in children between 2 to 18 years
of age with mild to moderate persistent asthma.
METHODS
Search
Before beginning this review, searches of PubMed, the
Cochrane Library, and the Turning Research into Practice (TRIP) database (http://www.tripdatabase.com/)
were conducted to ensure that a comparable systematic
review had not been published. The search for randomized controlled trials (RCTs) on this topic was performed using PubMed, the Cumulative Index to
Nursing and Allied Health (CINAHL), and the Institute
of Scientific Informations Web of Knowledge. Searches
were conducted independently by two reviewers, using the following key words: asthma, MON, and ICS.
To reflect current treatment strategies, we restricted
studies to those published in the past 10 years (January
2002 to November 2011). The reference lists of studies
identified in the search were assessed for additional
studies that met the specified inclusion criteria. Only
RCTs that compared MON monotherapy with ICS
monotherapy were included; all other study designs
Journal of Pediatric Health Care
RESULTS
Study Selection
After the initial search of three databases, 214 records
were identified and duplicates were eliminated, leaving
157 studies. After the initial screening of the title and abstract, 108 studies were eliminated. The primary reason
for exclusion was study design, including combination
therapy. The full text of 49 studies was further evaluated, and 41 studies were eliminated, primarily because
the study design was not an RCT. In total, 8 studies
met all inclusion/exclusion criteria and were included
in the review. The Figure provides detailed results of
the literature search.
Quality Assessment
Seven of the eight studies were deemed to be of high
quality with a score of 8 or higher on the PEDro scale.
Table 1 provides a detailed assessment of each study using the PEDro criteria. Risk of bias primarily was related
to dropout rates greater than 15% in three studies (Kooi
et al., 2008; Ostrom et al., 2005; Szefler, Baker, Uryniak,
Goldman, & Silkoff, 2007) and lack of intention-to-treat
analysis in two studies (Kumar, Ramesh, Lodha,
Pandey, & Kabra, 2007; Szefler et al., 2005). One study
did not use subject and investigator blinding by having
each participant take either a placebo oral tablet or inhaler in addition to the active medication (Szefler
et al., 2007). Four studies specified the method used
to blind patients to active versus placebo MON through
overencapsulated tablets (Sorkness et al., 2007), sugarcoated tablets (Maspero et al., 2008; Ostrom et al.,
2005), and similar appearance of tablets (Kooi et al.,
2008; Kumar et al., 2007), and three studies specified
use of identical diskus devices to blind patients to active
versus placebo ICS (Kooi et al., 2008; Kumar et al., 2007;
Sorkness et al., 2007). Patients lost to follow-up ranged
between 6.9% to 29% across studies. In three studies, attrition rates greater than 15% were reported (Kooi et al.,
2008; Ostrom et al., 2005; Szefler et al., 2007). The study
by Szefler and colleagues (2007) had the greatest dropout rate at 29%.
Study Findings
Table 2 summarizes each of the eight randomized trials included in the review. A total of 2,833 children
(62% male) participated in the studies. Four trials
were conducted in the United States (Ostrom et al.,
2005; Sorkness et al., 2007; Szefler et al., 2005;
Szefler et al., 2007). Of these, participant race and ethnicity characteristics were reported in three studies,
with a total of 70.1% of participants reported as White.
Study participants ranged in age from 2 to 17 years,
with a mean age of 8.6 1.9 years. Only two studies
included children younger than 5 years (Kooi et al.,
2008; Szefler et al., 2007). The sample sizes varied
greatly across studies, as did the study locations and
the length of follow-up. Sample size ranged from 62
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53
FIGURE. Flow diagram of study inclusion process. CINAHL, Cumulative Index to Nursing and Allied
Health Literature; ICS, inhaled corticosteroids; RCT, randomized controlled trial.
Identification
Screening
Eligibility
Studies screened
(n=157)
Included
TABLE 1. Assessment of potential bias in included randomized controlled trials using the PEDro
scoring system
Author
II
III
IV
VI
VII
VIII
IX
XI
Total
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
1
1
1
1
1
1
1
0
1
1
1
1
1
1
0
0
1
0
1
1
0
1
1
0
1
1
0
1
1
1
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
11
10
10
11
10
11
9
7
1, criteria fulfilled, low possibility of bias; 0, criteria not fulfilled, high possibility of bias.
Assessment criteria: I, Eligibility criteria specified; II, random allocation; III, allocation concealed; IV, groups similar at baseline; V, subject
blinding; VI, therapist blinding; VII, assessor blinding; VIII, less than 15% dropout rate; IX, intention-to-treat analysis; X, measurement of difference between groups in outcomes; XI, size of treatment effect and measures of variability (i.e., confidence intervals, standard errors, standard deviations, interquartile ranges, and minimum-maximum range).
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www.jpedhc.org
Multisite (yes/no)
Sample size
Intervention groups
January/February 2014
Study duration
Study findings
Change in RFDs:
MON, 22.4%
ICS, 25.2%
p = NS
Mean change FEV1:
MON, 0.27 L
ICS, 0.30 L
p = .004
$ 3 School days missed:
MON, 1.9%
ICS, 2.1%
Treatment adherence:
MON, 98.1%
ICS, 98%
Change in eosinophils (103 cells per mL)
MON, 0.08
ICS: 0.06
p = NS
Daily symptom score:
Improvement with ICS and MON
p = NS
RFDs:
Significant decrease in both groups
p = NS
Oral corticosteroid use:
MON: 1 child
ICS: 1 child
Change in FEV1:
MON, 1.26 L
ICS, 1.44 L
p = NS
Oral corticosteroid use:
MON, none
ICS, none
Yes
N = 994
Age 6-14 years
12 months
Yes
N = 63
Age 2-5 years
3 months
No
N = 62
Age 5-15 years
3 months
Continued on page 56
55
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TABLE 2. Continued.
Study
Multisite (yes/no)
Sample size
Intervention groups
Study duration
Yes
N = 548
Age 6-14 years
3 months
Yes
N = 342
Age 6-12 years
3 months
Yes
N = 285
Age 6-14 years
11 months
Study findings
Change in evening PEFR:
MON, 28.0 L/min
SFC, 46.2 L/min
FEV1 improvement:
MON, 22.08%
ICS, 33.83%
RFDs:
MON, 15 days
ICS, 24 days
(p < .001)
Treatment adherence:
MON, 84%
ICS, 87%
Change in FEV1:
MON, 4.60%
ICS, 10.62%
RFDs:
MON, 35.0%
ICS, 45.1%
(p = .002)
Oral corticosteroid use:
MON, 4%
ICS, 3%
Treatment adherence:
MON, 97.8%
ICS, 92.8%
Change in asthma
control days:
MON, 52.5%
ICS, 64.2%
PACT, 59.6%
FEV1, % predicted:
MON, 0.58%
ICS, 6.32%
(p < .001)
PACT: 3.62%
Treatment adherence:
Capsule count (MON), 86%
Diskus (ICS and PACT), 90%
www.jpedhc.org
Yes
N = 144
Age 6-17 years
Crossover design
2 months
Yes
N = 395
Age 2-8 years
12 months
FEV1, % predicted:
MON, .20%
ICS, 0.32%
(p = .05)
Oral corticosteroid use:
MON, 10 children
ICS, 2 children
Treatment adherence:
MON, 97% period 1
92% period 2
ICS, 94% period 1
89% period 2
Probability of having
an event:
MON, 9.6%
ICS, 6.6%
p = NS
FEV1:
MON, 0.05 L
ICS, 0.09 L
p = NS
RFDs:
MON, 37.24%
ICS, 38.74%
p = NS
Oral corticosteroid use:
MON, 32%
ICS, 25.5%
Treatment adherence:
MON, 82.8%
ICS, 82.9%
BID, Twice a day; EFD, episode-free day; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; MON, montelukast; RFD, rescue-free day; PEFR, peak expiratory flow rate; NS, no
significant difference; SFC, salmeterol/fluticasone propionate.
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exacerbations that require more intensive management. One of the primary reasons for patient withdrawal in the studies included in this review was
asthma exacerbation. High dropout rates can affect validity; however, it is important to note that each study
reporting a high rate of attrition conducted an
intention-to-treat analysis that minimized
MON may be
bias by including data
particularly
of all enrolled participants in the analysis.
beneficial for
The evidence sumtreatment of
marized in this review
asthma in certain
supports the current
guidelines that ICS
populations such
should be prescribed
as children younger
as first-line for treatthan 5 years.
ment of persistent
asthma (Rachelefsky,
2009). However, MON may be particularly beneficial
for treatment of asthma in certain populations such as
children younger than 5 years. Because most studies included in this review did not include young children in
their samples, this question remains unanswered and
requires further research. In addition, the ability to generalize these findings to African American and Hispanic
children is limited because these children were not well
represented in the included clinical trials.
Limitations
Our systematic review has several limitations. The literature search only included studies published in the English language. Only three large databases were
searched, and thus additional studies not identified
via use of these particular databases potentially were
not included. Although in four of the studies included
in this review no differences were found between treatment groups, it is possible that publication bias may
have led to a failure to publish other studies finding
no significant differences between ICS and MON.
CONCLUSION
In children ages 2 to 18 years with mild to moderate persistent asthma, both MON and ICS monotherapies are
effective options in improving asthma symptoms,
with a somewhat more favorable response to ICS
monotherapy. The findings of this systematic review
are consistent with the recommendation of the
National Asthma Education and Prevention Program
(2007) that ICS therapy should be first-line for all pediatric patients with mild to moderate persistent asthma.
Further studies are needed that include minority children at higher risk for asthma. Examination of the use of
MON and ICS also is needed in preschool children
younger than 5 years, because this population may particularly benefit from MON treatment. Additionally, further research is needed to compare the effectiveness of
Journal of Pediatric Health Care
www.jpedhc.org
and/or chronic asthma in adults and children. Cochrane Database of Systematic Reviews, 1, CD002314.
Fanta, C. (2009). Asthma. New England Journal of Medicine,
360(10), 1002-1014.
Garcia, G. M. L., Wahn, U., Gilles, L., Swern, A., Tozzi, C. A., & Polos,
P. (2005). Montelukast, compared with fluticasone, for control
of asthma among 6- to 14-year-old patients with mild asthma:
The MOSAIC study. Pediatrics, 116(2), 360-369.
Harmanci, K. (2007). Montelukast: Its role in the treatment of children
with asthma. Journal of Therapeutics and Clinical Risk Management, 3(5), 885-892.
Kazani, S., Ware, J. H., Drazen, J. H., Taylor, D. R., & Sears, M. R.
(2010). The safety of long-acting beta-agonists: More evidence
is needed. Respirology, 15(6), 881-886.
Kelly, H. W., Sternberg, A. L., Lescher, R., Fuhlbrigge, A. L., Williams,
P., Zeiger, R. S., . Strunk, R. C. (2012). Effect of inhaled glucocorticoids in childhood on adult height. New England Journal
of Medicine, 367(10), 904-912.
Knorr, B., Franchi, L. M., Bisgaard, H., Vermeulen, J. H., LeSouef, P.,
Santanello, N., . Bratton, D. L. (2001). Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma
in children aged 2 to 5 years. Pediatrics, 108(3), e48-e58.
Kooi, E. M. W., Schokker, S., Boezen, M., de Vries, T. W., VaessenVerbern, A. A. P. H., van der Molen, T., & Duiverman, E. J.
(2008). Fluticasone or montelukast for preschool children with
asthma-like symptoms: Randomized controlled trial. Pulmonary
Pharmacology & Therapeutics, 21(5), 798-804.
Kumar, V., Ramesh, P., Lodha, R., Pandey, R. M., & Kabra, S. K.
(2007). Montelukast vs. inhaled low-dose budesonide as monotherapy in the treatment of mild persistent asthma: A randomized double blind controlled trial. Journal of Tropical
Pediatrics, 53(5), 325-330.
Maher, C. G., Sherrington, C., Herbert, R. D., Moseley, A. M., &
Elkins, M. (2003). Reliability of the PEDro scale for rating quality
of randomized controlled trials. Physical Therapy, 83(8),
713-721.
Makino, S., Ohta, K., Nishima, S., & Morikawa, A. (2005). Pharmacologic control of asthma. International Archives of Allergy and
Immunology, 136, 14-49.
Maspero, J. F., Duenas-Meza, E., Volovitz, B., Daza, C. P., Kosa, L.,
Vrijens, F., & Leff, J. A. (2001). Evaluating long-term safety,
satisfaction, and adherence with therapy. Current Medical
Research and Opinion, 17(2), 96-104.
Maspero, J., Guera, F., Cuevas, F., Gutierrez, J. P., Soto-Ramos, M.,
Anderton, S., . Pedersen, S. (2008). Efficacy and tolerability
of salmeterol/fluticasone versus montelukast in childhood
asthma: A prospective, randomized, double-blind, double
dummy, parallel-group study. Clinical Therapeutics, 30(8),
1492-1504.
McQuaid, E. L., Kopel, S. J., Klein, R. B., & Fritz, G. K. (2003).
Medication adherence in pediatric asthma: Reasoning, responsibility, and behavior. Journal of Pediatric Psychology, 28(5),
323-333.
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G. & the PRISMA
Group. (2009). Preferred reporting items for systematic review
and meta-analyses: The PRISMA statement. PloS Medicine,
6(7), e1000097.
Montella, S., Maglione, M., De Stefano, S., Manna, A., Di Giorgio, A.,
& Santamaria, F. (2012). Update on leukotriene receptor antagonists in preschool children wheezing disorders. Italian Journal
of Pediatrics, 38(1), 29-46.
Myers, T. R., & Tomasio, L. (2011). Asthma: 2105 and beyond.
Respiratory Care, 56(9), 1389-1407.
National Asthma Education and Prevention Program. (2007). Guidelines for the diagnosis and management of asthma (NIH Publication No. 085846). Retrieved from http://www.nhlbi.nih.
gov/guidelines/asthma/asthsumm.pdf
January/February 2014
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