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Review: adding antileucotrienes to inhaled corticosteroids reduces exacerbations in symptomatic chronic asthma
  1. P John Rees, MD
  1. Guy's, King's and St Thomas's School of Medicine
 London, UK

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 QUESTION: In patients with chronic asthma, how effective and safe is daily antileucotriene (AL) treatment plus inhaled corticosteroids (ICS) compared with ICS alone?

    Data sources

    Studies were identified by searching 4 electronic databases up to September 2001; scanning the reference lists of articles and reviews; reviewing meeting abstracts (1998 to 2000); and contacting the international headquarters of AL manufacturers.

    Study selection

    Studies were selected if they were randomised controlled trials evaluating the effectiveness of AL for ≥ 1 month in patients with asthma who were ≥ 2 years of age.

    Data extraction

    Data were extracted independently by 2 reviewers on study quality, patient characteristics, intervention type and duration, and main outcome measures.

    Main results

    13 trials (12 in adults and 1 in children) were included. Combining data from 2 of the 6 trials in symptomatic patients and after 4 to 16 weeks of treatment showed that the addition of higher-than-licensed AL doses to ICS reduced the risk for exacerbations requiring systemic corticosteroids (table). The addition of higher-than-licensed doses also led to an improvement in FEV1 (weighted mean difference [WMD] 0.10 litre, 95% CI 0.01 to 0.20), peak expiratory flow rate (WMD 27.2 l/min, CI 18.6 to 35.8), asthma symptom scores (standardised mean difference [SMD] –0.46, CI –0.25 to –0.66), and mean use of β2 agonists (SMD –0.43 puffs/d, CI –0.22 to –0.63). The groups did not differ for any other outcomes. The addition of licensed doses led to non-statistically significant reductions in the risk for exacerbations requiring systemic steroids (relative risk reduction 39%, CI –5% to 64%).

    Antileukotriene (AL) agents (higher-than-licensed dose) plus inhaled corticosteroids (ICS) v ICS alone for symptomatic chronic asthma at 4 to 16 weeks*

    2 trials that compared ICS plus AL at higher-than-licensed doses with double dose ICS in symptomatic patients showed no differences between groups for the number of exacerbations requiring systemic steroids or for any other outcome.

    4 trials that compared AL (at licensed doses) plus ICS with the same dose of ICS in well controlled patients showed no difference in reduction in ICS dose after 12 to 20 weeks and no difference in the lowest tolerated dose of ICS.

    Conclusions

    In patients with chronic asthma who are symptomatic while receiving moderate to high doses of inhaled beclomethasone, the addition of 2 to 4 times the licensed dose of antileucotriene agents reduces the rate of exacerbations that require systemic corticosteroids. Insufficient evidence exists that antileucotriene confers benefit over doubling the dose of corticosteroids or that it has an inhaled corticosteroid-sparing effect.

    
 
 QUESTION: In patients with chronic asthma, how effective and safe is daily antileucotriene (AL) treatment plus inhaled corticosteroids (ICS) compared with ICS alone?

    Commentary

    AL agents provide the first new treatment option in asthma for some time. ALs might be helpful as alternatives to ICS in patients starting regular treatment and as an addition to ICS.

    The review by Ducharme et al deals with the latter, when control is inadequate with ICS or as a method of reducing the ICS dose. The reported results are disappointing. In short term studies, exacerbations were reduced and control was slightly improved with the addition of AL, but some doses were greater than current licences allow. No difference existed between adding AL to ICS and doubling the dose of ICS, although steroids have been found to have a rather flat dose response, and the introduction of AL did not allow for a reduction in ICS dose in these studies.

    2 large studies1,2 have examined the effects of adding long acting inhaled β agonists (LABAs) at the same point and have shown that LABAs add to the benefits of ICS and are more effective than doubling the steroid dose. LABAs also reduce exacerbations.1 In the studies reviewed by Ducharme et al, patients were not taking LABAs. The clinical implications would seem to be that LABAs should be the first option for patients who are not well controlled with ICS or who require high doses for control. AL might be considered after assessing the response in each patient.

    The use of AL as a first prophylactic agent has been assessed in a Cochrane review.3 AL agents were inferior to ICS for effects on lung function, symptoms, and quality of life, although again they were not statistically different for exacerbations.

    New drugs for asthma must contend with the fact that ICSs are very effective in asthma and have few side effects at usual doses. AL agents, at the higher doses seen in this review, were found to affect liver function tests, but they are generally safe drugs in asthma; however, their effectiveness is limited and indications for their use have not been broadened by this review.

    References

    View Abstract

    Footnotes

    • Source of funding: in part, Canadian Cochrane Network.

    • For correspondence: Dr F M Ducharme, McGill University, Montreal, Quebec, Canada. Francine.ducharme{at}muhc.mcgill.ca.

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