Therapeutics

Long acting β2 agonists in adult asthma

BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f4662 (Published 6 August 2013)
Cite this as: BMJ 2013;347:f4662

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Friday, 25 October 2013

To the editor,

We thank Professor Hasford for his comments on our article1 and in particular those relating to the Salmeterol Multicenter Asthma Research Trial (SMART).2 It is, however, very clear from the study that “Occurrence of the primary outcome (respiratory related deaths or life threatening experience) was low and not significantly different for salmeterol vs. placebo (50 vs. 36; relative risk 1.40)”.2 Moreover, only 47% of individuals in both the active treatment and placebo groups were receiving regular therapy with inhaled corticosteroids, meaning that salmeterol was being used inappropriately in the majority; this may be one of the explanations behind the increased incidence of adverse events in those receiving active treatment.

In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) advise that long acting β2-agonists (LABAs) should only be started in patients with persistent asthma who remain sub-optimally controlled on inhaled corticosteroids (with the latter being continued)3. Moreover, there is overwhelming evidence that regular use of LABAs only when used in conjunction with inhaled corticosteroids improves control for adult patients with moderately severe asthma. We therefore agree with Professor Hasford that the addition of a LABA in adults with asthma should be for those only not controlled on inhaled corticosteroids as monotherapy.

Graeme P Currie
Graham Douglas

References
1. Currie GP, Small I, Douglas G. Long acting β2 agonists in adult asthma. BMJ. 2013 Aug 6;347:f4662. doi: 10.1136/bmj.f4662
2. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129: 15-26.
3. Medicine and Healthcare products Regulatory Agency (MHRA). Long-acting β2-agonists: reminder for use in children and adults. 2010. www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON093845.

Competing interests: None declared

Graeme p Currie, Chest Physician

Graham Douglas

Aberdeen Royal infirmary, Foresterhill

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As asthma is a very common disease it is important to review from time to time the pros and cons of current medicines against asthma. Unfortunately the authors when reviewing the value of long acting ß2 agonists did not properly report the results of one of the major studies done, the Salmeterol Multi-centre Asthma Research Trial(SMART)(1).

When salmeterol was approved in the USA in 1994 the FDA asked the manufacturer to run a large scale placebo-controlled safety trial due to the accumulating concerns regarding the safety of long acting ß2 agonists (LABA) and in particular of salmeterol(2). In contrast to the authors, SMART showed statistically significant differences in major endpoints in favour of placebo(3). According to the SMART protocol, an interim analysis was to be performed after 30,000 patients were recruited. The protocol called for SMART to be terminated if evidence was found that salmeterol led to an increase in either the primary end-point or asthma-related death. The termination criteria were defined as a Relative Risk of 1.4 for the primary end-point and a RR of 3.0 for asthma-related deaths(3). SMART was prematurely terminated on January 23, 2003, and 26,355 patients were included in the final analysis.

The following end-points occurred statistically significantly (p<0.05) more frequently in the salmeterol group: i) respiratory-related deaths (Relative Risk 2.16); ii) combined asthma-related death or life-threatening experiences (RR 1.70); and iii) asthma-related deaths (RR 4.37). Thus there is no doubt that the prespecified early termination criteria had been reached. In view of previous findings it would have been unethical to recruit additional patients simply to confirm the excess salmeterol-associated mortality for the primary endpoint with statistical significance(2). The FDA has even prepared a nice little video to publicise these results of SMART(4). The number needed to harm for death of any cause was 1,316 for patients treated for 28 weeks with salmeterol. The excessive risks seen in African Americans which are emphasized by the authors are a result of a subgroup analysis not prespecified in the trial protocol.

Finally one has to state that convincing evidence that concurrent treatment with inhalative corticosteroids nullifies LABA-related risks is missing(5). Thus the use of LABA for asthma should definitely be restricted to patients with asthma that cannot be controlled otherwise.

References:
1) Curry GP et al. BMJ 2013;347Aug 6;347:f4662. doi: 10.1136/bmj.f4662.
2)Hasford J et al.Eur Respir J 2006;28:900-902.
3) Nelson HS et al. Chest 2006;139:15-26.
4)http://www.accessdata.fda.gov/cdrh_docs/psn/video/mpeg/FDA-SHOW21-SEG3.MPG . Last access 16/08/2013
5)http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4398s1-03-Mosholder.pdf . Last access 16/08/2013

Competing interests: None declared

Joerg Hasford, Professor for Medical Biometry and Epidemiology

IBE, Ludwig-Maximilians-Universitaet Muenchen, Marchioninistr.15 D-81377 Munich, Germany

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