Title:
Addition of anti-leukotriene agents to inhaled corticosteroids for adults and adolescents with persistent asthma.

Abstract:
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 ICSOf 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), asthma symptoms and night-time awakenings, but not for reduction in β-agonist use or evening PEFR. Anti-leukotrienes and ICS versus higher dose of ICSOf 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 nor in asthma control measures including use of rescue β-agonists or asthma symptom scores. Anti-leukotrienes and ICS versus tapering dose of ICSSeven 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.