NPC Archive Item: More data on the safety of salmeterol when added to inhaled corticosteroids in asthma

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Bateman E, Nelson H, Bousquet J, et al. Meta-analysis: effects of adding salmeterol to inhaled corticosteroids on serious asthma-related events. Ann Intern Med  2008; 149. Early online publication

The safety of long-term salmeterol remains a concern, despite a recent meta-analysis suggesting that it does not increase the risk of serious asthma-related adverse events when added to inhaled corticosteroids.

Clinicians should continue to be aware of the possible risks associated with the long-term use of long-acting beta-agonists (LABAs, i.e. salmeterol and formoterol). They should be used only in conjunction with inhaled corticosteroids (Step 3) in accordance with recent British Guidelines for the Management of Asthma.

A review of the safety of long-acting beta-agonists is currently being undertaken by the MHRA. To ensure safe use, the CHM has advised that for the management of chronic asthma, LABAs should:

  • be added only if regular use of standard-dose inhaled corticosteroids has failed to control asthma adequately;
  • not be initiated in patients with rapidly deteriorating asthma;
  • be introduced at a low dose and the effect properly monitored before considering dose increase;
  • be discontinued in the absence of benefit;
  • be reviewed as clinically appropriate: stepping down therapy should be considered when good long-term asthma control has been achieved.

Patients should report any deterioration in symptoms following initiation of treatment with a LABA. Any adverse reactions that are thought to occur as a result of treatment for asthma should be reported to the MHRA through the Yellow Card Scheme.

What is the background to this?
The Salmeterol Multicenter Asthma Research Trial (SMART) and a subsequent meta-analysis of randomised controlled trials (see NPC blog 53) raised concerns about the safety of LABAs in asthma, in view of the apparent increased incidence of serious asthma-related adverse events. While a full review of the safety of LABAs is underway, the MHRA have issued advice on how they should be used (see Action above). An analysis of data from randomised clinical studies conducted by GlaxoSmithKline (GSK) has recently been published in attempt to alleviate concerns regarding the safety of salmeterol when used in the recommended manner in combination with inhaled corticosteroids.

What does this study claim?
The analysis identified that salmeterol combined with inhaled corticosteroids did not result in an increased risk of asthma-related hospitalisation compared with inhaled corticosteroids alone, while it decreased the risk of some severe exacerbations.

What are the limitations
Unlike other studies/analyses that have raised concerns over the safety of LABAs in people with asthma, this study only considered people who were included in randomised controlled trials. People with concomitant respiratory conditions, such as COPD, were excluded. Therefore, the study population reflects a selective group of patients who would have been closely monitored as part of the clinical study. The generalisation of the results to the use of LABAs in routine clinical practice is uncertain. An editorial points out that the incidence of adverse events in the GSK studies were very much lower than those seen in the SMART study, suggesting that the study populations were different, or a different level of attention was given to measuring adverse events accurately, or both. It also notes that the study failed to address concerns regarding the apparent higher mortality rates seen in African Americans in the SMART study. There were few long-term studies included in the analysis, the median duration was only 12 weeks, and most were designed to evaluate changes in lung function, rather than more relevant patient-oriented outcomes, such as exacerbations or symptoms.

So what?
In view of the limitations of the study, the results should be interpreted cautiously. The study suggests that if salmeterol is used in combination with inhaled corticosteroids according to British Guidelines, then the incidence of serious adverse events arising from the use of salmeterol in asthma are likely to be very small, at least over the short term. The study does not by itself alleviate the concerns over the long-term safety of LABAs when used in routine clinical practice, and clinicians should continue to bear in mind the possibility of serious adverse events arising from their use, and to advise patients of the risks and monitor them accordingly. LABAs should only be used in patients with asthma whose symptoms are uncontrolled by inhaled corticosteroids alone. Stepping-down therapy should be considered when good long-term asthma control has been achieved.

The study was sponsored by GSK. Authors of the paper are consultants or employees of GSK.

Study details

Patients – Data from 66 trials involving a total of 20 966 participants with persistent asthma were summarised quantitatively. These ranged from 1 to 52 weeks in duration (median 12 weeks), and only 26 trials were longer than 12 weeks.

Intervention and comparator – Randomised controlled trials were identified systematically, from the literature and from the GSK database that compared inhaled corticosteroids plus salmeterol (administered as fluticasone propionate/salmeterol by means of a single device or concomitant administration of inhaled corticosteroids and salmeterol) versus inhaled corticosteroids alone in participants with asthma. All studies included in the analysis were conducted by GSK. Three physicians independently reviewed and adjudicated blinded case narratives on serious adverse events that were reported in the trials

Outcomes – Only 35 and 34 asthma-related hospitalisations were identified in the salmeterol plus inhaled corticosteroids and corticosteroid alone groups, respectively. The summary risk difference was 0.0002 (95% CI –0.0019 to 0.0023; P=0.84), i.e. a 95% confidence interval of 19 in 10,000 patients deriving benefit to 23 in 10,000 deriving harm from the salmeterol. There was one asthma-related intubation and one asthma-related death among participants receiving inhaled corticosteroids with salmeterol; no such events occurred among participants receiving inhaled corticosteroids alone. A subset of 24 trials (conducted in the US, n=7549) showed a statistically significant decreased risk for severe asthma-related exacerbations for inhaled corticosteroids plus salmeterol versus inhaled corticosteroids alone (risk difference, –0.025 [95%CI –0.036 to –0.014; P<0.001]).

You can find further information on the treatment of asthma on the respiratory tract section of NPC

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