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Friday, December 23, 2005

Long acting beta-agonist (LABAs) and the dilemma of "coarse grain" data

The FDA has recently issued an advisory saying that LABAs may increase the chance of severe asthma episodes and death when those episodes occur,this warning appearing more than 10 years after salmeterol was first approved for use in the U.S. Formoterol ,another LABA is used less widely in this country but the combination of salmeterol and a steroid sold as Advair is very widely used by allergists, pulmonologists and family practice doctors.The warning does not apply to LABA use in COPD.
As early as 1994 some increase in asthma deaths was attributed to salmeterol. A Lancet article
by Castle et. al which was designed to compare albuterol with salmeterol showed a non significant increase in death by a factor of 3 in the salmeterol group while asthma control seemed better in those treated with salmeterol. Even though the increased number of deaths was not statistically significant, the FDA's concern lead GSK to initiate the SMART trial, the interim analysis of which has lead to further concern and the warning issued by the FDA. In this trial salmeterol was compared to placebo and after 26,000 patients were enrolled, data indicated that asthma related deaths were 4.4 times higher in the treatment group. The reason that I call the data coarse grained is that neither the Lancet paper or SMART have adequate data regarding which patients were also receiving inhaled steroids (ICS) to make a determination regarding whether steroids will mitigate or eliminate any increased risk from salmeterol.This is important as standard therapy consists of adding an ICS for asthma as severe as"mild persistent", so we need to know the risk of adding a LABA to ICS for the more severe degrees of asthma. Two large RCTs do not provide that critical information because there is not enough detail and/or statistical power available to indicate if there were increased deaths occurring in patients receiving ICS plus LABA.A post hoc analysis suggested that the risk was greater in African-Americans.
It has been the experience of pulmonary docs and allergists that for most patients the addition of a LABA to ICS is beneficial yet there may well be the possibility of a rare serious side effect.
LABAs , to a greater degree than short acting beta agonists have been accused of down regulating the beta 2 adrenoreceptor and inducing subtherapeutic response to the rescue inhalers which is a proposed mechanism for the worsening of asthma. It may well be that genetic polymorphism in these receptors may account for a small subset of patients who are at risk of worsening asthma if treated with LABAs.The coarse grain data we currently obtain from epidemiologic methods cannot tell us who they are. Should we change our practice in light of the FDA warning? I continue to believe LABAs are appropriate to add on to the asthma patient's regimen when ICS and rescue inhalers are not enough. Theophylline preparations and leukotriene antagonists may be used instead but the ease of use,the low incidence of acute side effects and the patient acceptance of the LABAs make me think there will be little change in the number of prescriptions written. This belief is strengthened by the MEDSCAPE review of the Harvard study suggesting that many physicians do not pay that much attention to the black Box warnings anyway. The National Jewish website has this page that should reassure their asthma patients and at least gives the impression that they plan no major changes in their treatment approach.This page from the CMA journal give a good overview and some common sense recommendations with which most would agree.These include:LABAs are not to be used as rescue inhalers,be sure the patient is taking an ICS before LABAs are added to the treatment plan, and use the lowest dose when possible and if symptoms worsen contact your physician.

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