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The MHRA has published the findings of its review of LABAs (salmeterol and formoterol) in asthma, in the January issue of Drug Safety Update (7th January 2008).
Background
Concerns were first raised about the safety of LABAs following the SMART study. This was a large, multicentre randomised controlled trial (RCT) in which patients with asthma aged over than 12 years, who had not previously used a LABA were randomised to receive either salmeterol or placebo. Patients in the salmeterol group had a greater risk of respiratory-related deaths, asthma-related deaths, and combined asthma-related deaths or life-threatening experiences. This finding was most prominent among African-American patients, although the reasons for this occurrence are not known. There was a fairly low usage of inhaled steroids alongside salmeterol and patients who were not using inhaled steroids from the outset of treatment had poorer outcomes than those who were using inhaled steroids.
More recently, a meta-analysis of 19 RCTs (both in children and adults) reported that, compared with placebo, salmeterol and formoterol were associated with more frequent worsening of asthma that required admission to hospital or that was life-threatening. This meta-analysis also found a two-fold increased risk of admission to hospital even in trials where more than 75% (mean 90%) of patients were also using an inhaled corticosteroid. Similar risks were found with both LABAs, and in children and adults.
Review conclusions
The MHRA review concluded that:
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Epidemiological data show that since the introduction of LABAs, there has been a decrease in asthma-related hospitalisations in adolescents and a decrease in asthma-related mortality in all ages
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Data from RCTs do not suggest a similar safety concern to that shown in postmarketing studies, probably because of more consistent use of concomitant inhaled corticosteroids in randomised controlled settings. The data support the use of LABAs in conjunction with inhaled corticosteroids in the treatment of moderate to severe asthma consistent with national guidance on management of asthma in children and adults, published jointly by SIGN and the BTS
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To aid compliance with the concomitant use of inhaled corticosteroids and LABAs, a combination inhaler should be used when appropriate
The MHRA states that further epidemiological studies are under way to assess the relation between adverse outcomes and use of LABAs, the results of which are expected before the end of 2008. The MHRA is also reviewing the role of LABAs in the treatment of asthma in children younger than age 12 years. We have recently noted that, in an internal memorandum, drug safety staff at the FDA in the USA have commented that salmeterol “may have an unfavorable risk benefit ratio in the treatment of pediatric asthma” and recommend a “more thoroughgoing, formal risk-benefit analysis of salmeterol” in this indication.
How does this fit with current guidance?
LABAs clearly have an important place in therapy, but it is important that they are used correctly. The current advice from the Commission on Human Medicines (CHM) is that salmeterol and formoterol should:
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be added to therapy only if regular use of standard-dose inhaled steroids has failed to control asthma adequately
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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 an increase in dose is considered
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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 be asked to report any deterioration in symptoms following initiation of a LABA.
This is entirely consistent with national guidance on management of asthma in children and adults, published jointly by SIGN and the BTS. This was last updated in November 2007. There is a strong emphasis in the guidance on achieving control of asthma symptoms by using appropriate treatment, but also on stepping down to the minimum level of treatment required for control and a good quality of life.
Action:
Healthcare professionals should follow current CHM advice and national guidance on management of asthma. LABAs should be initiated (at step 3) only if inhaled corticosteroids at moderate doses are failing to control asthma symptoms adequately. Before initiating a new drug therapy practitioners should recheck compliance, inhaler technique and eliminate trigger factors. If LABAs are introduced this should be in context of a therapeutic trial.
Professionals should take particular note that LABAs should not be initiated in patients with rapidly deteriorating asthma: they are for “stable but poorly controlled” asthma. Practitioners should consider stepping down LABA use when good long term asthma control has been achieved.
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