Effects of long-acting beta2-agonists compared with anti-leukotrienes when added to inhaled corticosteroids?

Background

People who continue to experience asthma symptoms despite regular use of inhaled corticosteroids (ICS) represent an asthma management challenge. The addition of a long-acting beta2-agonist (LABA) and the addition of an oral anti-leukotriene (LTRA) are two therapeutic options.

Review question

What is the best add-on treatment in adults and children with asthma whose condition is inadequately controlled with ICS alone: LABA or LTRA?

What evidence did we find?

From available evidence until December 2012, we found 16 trials involving 6872 adults and two trials involving 336 children contributing to the review. The risk of asthma exacerbations requiring the use of corticosteroids was lower with the combination of LABA + ICS compared with LTRA + ICS—from 13% to 11%. The choice of LTRA (montelukast or zafirlukast), the dose of ICS and the age of patients did not significantly affect the results. The effect appeared stronger in trials of short duration and in those using a single device to administer both ICS and LABA. Serious adverse events were more common with LABA than with LTRA, particularly in adults. The combination of LABA + ICS was superior to LTRA + ICS in terms of lung function and was modestly superior in other indicators of the control of asthma and quality of life. LTRA was found superior in preventing deterioration during exercise. The risk of withdrawal from a trial for any reason was significantly lower with LABA than with LTRA. More patients were satisfied with the combination of LABA + ICS, and fewer changed therapy if they started with LABA instead of LTRA.

Conclusion

In adults whose asthma is inadequately controlled with ICS, the addition of LABA to ICS was found to be modestly superior to LTRA + ICS. Although both options appeared safe, evidence suggests that slightly more serious adverse events (SAE) may be seen with LABA than with LTRA, particularly when separate devices are used to administer LABA + ICS. Because only two paediatric trials contributed data to the review, the best adjunct strategy to ICS remains uncertain for children.

Quality of the evidence

Our confidence in the quality of evidence is high in the primary efficacy outcome (i.e. patients with exacerbation requiring systemic corticosteroids and high to moderate efficacy and safety measures). One open-label study of adult patients with asthma contributed to certain outcomes that led to downgrading of the quality of evidence from high to moderate. Of note, only two paediatric trials contributed to this review.

Authors' conclusions: 

In adults with asthma that is inadequately controlled by predominantly low-dose ICS with significant bronchodilator reversibility, the addition of LABA to ICS is modestly superior to the addition of LTRA in reducing oral corticosteroid–treated exacerbations, with an absolute reduction of two percentage points. Differences favouring LABA over LTRA as adjunct therapy were observed in lung function and, to a lesser extend, in rescue medication use, symptoms and quality of life. The lower overall withdrawal rate and the higher proportion of participants satisfied with their therapy indirectly favour the combination of LABA + ICS over LTRA + ICS. Evidence showed a slightly increased risk of SAE with LABA compared with LTRA, with an absolute increase of one percentage point. Our findings modestly support the use of a single inhaler for the delivery of both LABA and low- or medium-dose ICS. Because of the paucity of paediatric trials, we are unable to draw firm conclusions about the best adjunct therapy in children.

Read the full abstract...
Background: 

Asthma patients who continue to experience symptoms despite taking regular inhaled corticosteroids (ICS) represent a management challenge. Long-acting beta2-agonists (LABA) and anti-leukotrienes (LTRA) are two treatment options that could be considered as add-on therapy to ICS.

Objectives: 

To compare the safety and efficacy of adding LABA versus LTRA to the treatment regimen for children and adults with asthma who remain symptomatic in spite of regular treatment with ICS. We specifically wished to examine the relative impact of the two agents on asthma exacerbations, lung function, symptoms, quality of life, adverse health events and withdrawals.

Search strategy: 

We searched the Cochrane Airways Group Specialised Register until December 2012. We consulted reference lists of all included studies and contacted pharmaceutical manufacturers to ask about other published or unpublished studies.

Selection criteria: 

We included randomised controlled trials (RCTs) conducted in adults or children with recurrent asthma that was treated with ICS along with a fixed dose of a LABA or an LTRA for a minimum of four weeks.

Data collection and analysis: 

Two review authors independently assessed the risk of bias of included studies and extracted data. We sought unpublished data and further details of study design when necessary.

Main results: 

We included 18 RCTs (7208 participants), of which 16 recruited adults and adolescents (6872) and two recruited children six to 17 years of age (336) with asthma and significant reversibility to bronchodilator at baseline. Fourteen (79%) trials were of high methodological quality.

The risk of exacerbations requiring systemic corticosteroids (primary outcome of the review) was significantly lower with the combination of LABA + ICS compared with LTRA + ICS—from 13% to 11% (eight studies, 5923 adults and 334 children; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 0.99; high-quality evidence). The number needed to treat for an additional beneficial outcome (NNTB) with LABA compared with LTRA to prevent one additional exacerbation over four to 102 weeks was 62 (95% CI 34 to 794). The choice of LTRA, the dose of ICS and the participants' age group did not significantly influence the magnitude of effect. Although results were inconclusive, the effect appeared stronger in trials that used a single device rather than two devices to administer ICS and LABA and in trials of less than 12 weeks' duration.

The addition of LABA to ICS was associated with a statistically greater improvement from baseline in lung function, as well as in symptoms, rescue medication use and quality of life, although the latter effects were modest. LTRA was superior in the prevention of exercise-induced bronchospasm. More participants were satisfied with the combination of LABA + ICS than LTRA + ICS (three studies, 1625 adults; RR 1.12, 95% CI 1.04 to 1.20; moderate-quality evidence). The overall risk of withdrawal was significantly lower with LABA + ICS than with LTRA + ICS (13 studies, 6652 adults and 308 children; RR 0.84, 95% CI 0.74 to 0.96; moderate-quality evidence). Although the risk of overall adverse events was equivalent between the two groups, the risk of serious adverse events (SAE) approached statistical significance in disfavour of LABA compared with LTRA (nine studies, 5658 adults and 630 children; RR 1.33, 95% CI 0.99 to 1.79; P value 0.06; moderate-quality evidence), with no apparent impact of participants' age group.

The following adverse events were reported, but no significant differences were demonstrated between groups: headache (11 studies, N = 6538); cardiovascular events (five studies, N = 5163), osteopenia and osteoporosis (two studies, N = 2963), adverse events (10 studies, N = 5977 adults and 300 children). A significant difference in the risk of oral moniliasis was noted, but this represents a low occurrence rate.

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