Asthma management guidelines recommend low‐dose inhaled corticosteroids (ICS) as first‐line
therapy for adults and adolescents with persistent asthma. The addition of anti‐leukotriene
agents to ICS offers a therapeutic option in cases of suboptimal control with daily
ICS. To assess the efficacy and safety of anti‐leukotriene agents added to ICS compared
with the same dose, an increased dose or a tapering dose of ICS (in both arms) for
adults and adolescents 12 years of age and older with persistent asthma. Also, to
determine whether any characteristics of participants or treatments might affect the
magnitude of response. We identified relevant studies from the Cochrane Airways Group
Specialised Register of Trials, which is derived from systematic searches of bibliographic
databases including the Cochrane Central Register of Controlled Trials (CENTRAL),
MEDLINE, Embase, PsycINFO, the Allied and Complementary Medicine Database (AMED),
the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the trial
registries clinicaltrials.gov and ICTRP from inception to August 2016. We searched
for randomised controlled trials (RCTs) of adults and adolescents 12 years of age
and older on a maintenance dose of ICS for whom investigators added anti‐leukotrienes
to the ICS and compared treatment with the same dose, an increased dose or a tapering
dose of ICS for at least four weeks. We used standard methods expected by Cochrane.
The primary outcome was the number of participants with exacerbations requiring oral
corticosteroids (except when both groups tapered the dose of ICS, in which case the
primary outcome was the % reduction in ICS dose from baseline with maintained asthma
control). Secondary outcomes included markers of exacerbation, lung function, asthma
control, quality of life, withdrawals and adverse events. We included in the review
37 studies representing 6128 adult and adolescent participants (most with mild to
moderate asthma). Investigators in these studies used three leukotriene receptor antagonists
(LTRAs): montelukast (n = 24), zafirlukast (n = 11) and pranlukast (n = 2); studies
lasted from four weeks to five years. Anti‐leukotrienes and ICS versus same dose of
ICS Of 16 eligible studies, 10 studies, representing 2364 adults and adolescents,
contributed data. Anti‐leukotriene agents given as adjunct therapy to ICS reduced
by half the number of participants with exacerbations requiring oral corticosteroids
(risk ratio (RR) 0.50, 95% confidence interval (CI) 0.29 to 0.86; 815 participants;
four studies; moderate quality); this is equivalent to a number needed to treat for
additional beneficial outcome (NNTB) over six to 16 weeks of 22 (95% CI 16 to 75).
Only one trial including 368 participants reported mortality and serious adverse events,
but events were too infrequent for researchers to draw a conclusion. Four trials reported
all adverse events, and the pooled result suggested little difference between groups
(RR 1.06, 95% CI 0.92 to 1.22; 1024 participants; three studies; moderate quality).
Investigators noted between‐group differences favouring the addition of anti‐leukotrienes
for morning peak expiratory flow rate (PEFR), forced expiratory volume in one second
(FEV 1 ), asthma symptoms and night‐time awakenings, but not for reduction in β 2
‐agonist use or evening PEFR. Anti‐leukotrienes and ICS versus higher dose of ICS
Of 15 eligible studies, eight studies, representing 2008 adults and adolescents, contributed
data. Results showed no statistically significant difference in the number of participants
with exacerbations requiring oral corticosteroids (RR 0.90, 95% CI 0.58 to 1.39; 1779
participants; four studies; moderate quality) nor in all adverse events between groups
(RR 0.96, 95% CI 0.89 to 1.03; 1899 participants; six studies; low quality). Three
trials reported no deaths among 834 participants. Results showed no statistically
significant differences in lung function tests including morning PEFR and FEV 1 nor
in asthma control measures including use of rescue β 2 ‐agonists or asthma symptom
scores. Anti‐leukotrienes and ICS versus tapering dose of ICS Seven studies, representing
1150 adults and adolescents, evaluated the combination of anti‐leukotrienes and tapering‐dose
of ICS compared with tapering‐dose of ICS alone and contributed data. Investigators
observed no statistically significant difference in % change from baseline ICS dose
(mean difference (MD) ‐3.05, 95% CI ‐8.13 to 2.03; 930 participants; four studies;
moderate quality), number of participants with exacerbations requiring oral corticosteroids
(RR 0.46, 95% CI 0.20 to 1.04; 542 participants; five studies; low quality) or all
adverse events (RR 0.95, 95% CI 0.83 to 1.08; 1100 participants; six studies; moderate
quality). Serious adverse events occurred more frequently among those taking anti‐leukotrienes
plus tapering ICS than in those taking tapering doses of ICS alone (RR 2.44, 95% CI
1.52 to 3.92; 621 participants; two studies; moderate quality), but deaths were too
infrequent for researchers to draw any conclusions about mortality. Data showed no
improvement in lung function nor in asthma control measures. For adolescents and adults
with persistent asthma, with suboptimal asthma control with daily use of ICS, the
addition of anti‐leukotrienes is beneficial for reducing moderate and severe asthma
exacerbations and for improving lung function and asthma control compared with the
same dose of ICS. We cannot be certain that the addition of anti‐leukotrienes is superior,
inferior or equivalent to a higher dose of ICS. Scarce available evidence does not
support anti‐leukotrienes as an ICS sparing agent, and use of LTRAs was not associated
with increased risk of withdrawals or adverse effects, with the exception of an increase
in serious adverse events when the ICS dose was tapered. Information was insufficient
for assessment of mortality. Background: A daily low dose of inhaled corticosteroids
(ICS) is the recommended first preventer treatment offered to adults and teenagers
with asthma. Patients with inadequate asthma control are often treated by adding an
anti‐leukotriene (LTRA) or a long‐acting β 2 ‐agonist, or by increasing the dose of
ICS. Review question: Is adding an anti‐leukotriene to ICS better than using an ICS
alone for adults and adolescents 12 years of age and older with persistent asthma?
Study characteristics: We found 37 studies (representing 6128 adults and adolescents).
The people in these trials had mild to moderate asthma. Most (24) studies used the
LTRA called montelukast, 11 studies used zafirlukast and only two studies used pranlukast.
We divided all studies into three categories to help us make sense of the evidence.
• Anti‐leukotrienes and ICS versus same dose of ICS : Ten studies (representing 2364
adults and adolescents) contributed data for analysis. Anti‐leukotrienes given with
ICS reduced by half the number of patients with exacerbations requiring oral steroids
(from 9% to 5% over three months), but we are unsure about effects of this treatment
on quality of life or serious side effects. Anti‐leukotrienes given with ICS improved
lung function and asthma control measures. • Anti‐leukotrienes and ICS versus higher
dose of ICS : Eight studies (representing 2008 adults and adolescents) contributed
data for analysis. Results showed no reduction in the number of patients with exacerbations
requiring oral steroids and no difference in quality of life nor in side effects.
Data showed no improvement in lung function nor in asthma control measures. • Anti‐leukotrienes
and gradual reduction of ICS dose versus gradual reduction of ICS dose alone : Seven
studies (representing 1150 adults and adolescents) evaluated anti‐leukotrienes given
with a gradually reduced dose of ICS compared with a gradually reduced dose of ICS
without use of anti‐leukotriene agents. This approach was not beneficial for % reduction
in the amount of ICS over time. More people receiving anti‐leukotriene and ICS compared
with ICS alone experienced increased serious side effects and showed no improvement
in lung function nor in asthma control measures. Conclusion: For adolescents and
adults with asthma not controlled with daily low‐dose ICS, adding anti‐leukotriene
agents to ICS reduced by half the number of patients with asthma exacerbations requiring
an oral corticosteroid. Anti‐leukotrienes and ICS also improved lung function and
asthma control. However, we are not sure whether the combination of anti‐leukotrienes
and ICS is superior to higher‐dose ICS. Limited available evidence does not support
use of anti‐leukotrienes as a way to decrease ICS dose. In general, addition of anti‐leukotrienes
to ICS therapy was not associated with increased side effects, if the dose of ICS
was maintained. Quality of the results: Our confidence in the evidence was moderate
or low for most outcomes.