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This systematic review found that, in patients with asthma poorly controlled with inhaled corticosteroids, the long-term safety profile of montelukast was better than that of salmeterol. Montelukast appeared to be less effective than salmeterol for controlling asthma symptoms and preventing exacerbations over 12 weeks, but over 48 weeks the proportion of patients who suffered exacerbations was not significantly different between the groups.
What is the background to this?
A Cochrane Review (11 randomised controlled trials [RCTs], n=6,030) compared the efficacy and safety profiles of long-acting β2-agonists (LABAs) and leukotriene receptor antagonists (LTRAs) in adults with moderate asthma inadequately controlled on low doses of inhaled corticosteroids (ICS). It concluded that, although both treatments improved asthma control, the addition of a LABA was superior to a LTRA for preventing exacerbations requiring systemic steroids, and for improving lung function, symptoms, and the use of rescue β2-agonists. The number needed to treat [NNT] with a LABA compared to a LTRA was 38 (95% CI: 23 to 247) to prevent one exacerbation over 48 weeks. The risk of overall adverse effects was similar in both groups, although the confidence interval for severe adverse events was wide and required further investigation in a larger study.
What does this study claim?
This systematic review (13 RCTs) evaluated the evidence for the risks and benefits of medium to long-term use (12–48 weeks) of oral montelukast 10mg as add-on therapy to ICS in adolescents and adults with mild to moderate asthma, compared with placebo and active treatments. Seven studies, including tapered or constant doses of ICS, compared montelukast/ICS with ICS monotherapy (with or without placebo). Six studies compared montelukast/ICS with salmeterol/ICS.
In a meta-analysis of the 12 week trials that compared montelukast/ICS with salmeterol/ICS, with regard to the proportion of patients with exacerbations, salmeterol was significantly more effective than montelukast (relative risk [RR] 2.03, 95% CI 1.23 to 3.37, P=0.006). However, in an analysis of the 48 week trials, the difference between the montelukast/ICS and salmeterol/ICS groups was not significant (RR 1.12, 95% CI 0.96 to 1.30, P=0.142).
As in the Cochrane review, the overall adverse event rates were comparable between the groups. However, a meta-analysis of the 48 week trials found that there were significantly more serious adverse events (not defined) in the salmeterol/ICS group than in the montelukast/ICS group (RR 0.68, 95% CI 0.49 to 0.94, P=0.021).
The authors concluded that montelukast as add-on therapy to ICS is less effective than the addition of salmeterol for most clinical outcomes, at least in the medium term, but that montelukast may have a more favourable long-term safety profile. They advised that montelukast may be considered as add-on therapy in patients sub-optimally controlled with an ICS.
How does this relate to existing recommendations?
The Scottish Intercollegiate Guidelines Network (SIGN) and the British Thoracic Society have recently updated the British Guideline on the Management of Asthma (PDF). The guideline recommends that ICSs are the first choice preventer treatment at step 2 in adults and children. For patients who are inadequately controlled, the first choice add-on therapy at step 3 in adults and children 5 years and over is an inhaled LABA, before, if necessary, increasing the dose of ICS. For asthma which remains suboptimally controlled, LTRAs are suggested as an option for add-on therapy at steps 3 and 4, alongside theophyllines and slow-release β2-agonist tablets. For children aged 2 to 5 years, LTRAs are recommended at step 2 if an ICS cannot be used, and also at step 3 as first choice add-on therapy, instead of a LABA.
So what?
There have been concerns over the safety of LABAs since the Salmeterol Multicenter Asthma Research Trial (SMART) found small, but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the population receiving salmeterol. This systematic review suggests that long-term treatment with LABAs may increase the risk of serious adverse events and adds to previous concerns over their safety.
The Medicines and Healthcare products Regulatory Agency (MHRA) is assessing the risks and benefits associated with LABAs. At the current time they consider that the benefits of LABA therapy outweigh the risks. The Commission on Human Medicines (CHM) recommends that, in the management of chronic asthma, LABAs should:
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Only be added if regular doses of standard dose ICS have adequately failed to control asthma
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Not be initiated in patients with rapidly deteriorating asthma
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Be introduced at a low dose and the effect properly monitored before considering a dose increase
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Be discontinued in the absence of benefit
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Be reviewed as clinically appropriate: stepping down therapy should be considered when good long-term asthma control has been achieved.
Patients should also be encouraged to report any deterioration in symptoms following initiation of treatment with a LABA.
Action
Health care professionals who are involved in the management of asthma patients should familiarise themselves with the updated British Guideline on the Management of Asthma. In addition, they should be aware of the safety concerns over LABAs and continue to follow CHM recommendations when prescribing them in the management of chronic asthma. Despite the data from this study, it seems premature to use montelukast routinely instead of a LABA at step 3, provided the CHM guidance is followed.
Study details
Design: Systematic review of RCTs (>12 weeks duration). Thirteen studies fulfilled the inclusion criteria (n=30 to 1,490). A table in the paper summarises the methodological quality of the included trials. Common short-comings included deficiencies in randomisation and allocation concealment, missing sample size calculations, and incomplete description of dropouts.
Patients: Studies in adults and adolescents (mean age ranged from 38 to 45 years) with mild to moderate asthma (mean FEV1 at baseline was between 70% and 99% of predicted) were included.
Intervention: The systematic review evaluated the evidence for the benefits and risks associated with medium to long-term use of montelukast 10mg as add-on therapy to ICS.
Comparison: Seven studies, including tapered or constant doses of ICS, compared montelukast/ICS with ICS monotherapy (with or without placebo). Six studies compared montelukast/ICS with salmeterol/ICS.
Outcomes: Predefined outcomes included asthma symptoms, exacerbations with or without emergency treatment, hospitalisation and/or outpatient treatment, adverse effects, asthma-related mortality and total mortality.
Results: Overall, the data indicated that montelukast/ICS was more effective than ICS monotherapy and safety profiles of the two groups were similar.
In a meta-analysis of the 12 week trials that compared montelukast/ICS with salmeterol/ICS, with regard to the proportion of patients with exacerbations, salmeterol was significantly more effective than montelukast (RR 2.03, 95% CI 1.23 to 3.37, P=0.006). However, in an analysis of the 48 week trials, the difference between the montelukast/ICS and salmeterol/ICS groups was not significant (RR 1.12, 95% CI 0.96 to 1.30, P=0.142). The overall adverse event rates were comparable between the groups. However, a meta-analysis of the 48 week trials found that there were significantly more serious adverse events (not defined in the paper) in the salmeterol/ICS group than in the montelukast/ICS group (RR 0.68, 95% CI 0.49 to 0.94, P=0.021).
Sponsorship: This systematic review formed part of a health technology appraisal carried out by the German Institute for Quality and Efficiency in Health Care.
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