Every package insert of a medication containing salmeterol (Serevent) or formoterol (Foradil), including the very popular and effective bronchodilator-steroid combinations, Advair, Symbicort, and Dulera, includes a black-box warning about serious potential risks from these long-acting beta-agonist bronchodilators. In persons with asthma, the warning notes, use of these medications is associated with an increased risk of death and near-death (requiring ICU care) from an asthma attack.
Therein lies a major dilemma. Highly effective medications used to control asthma, recommended by national and international panels of experts in their Guidelines for optimal management of asthma, may pose a risk of causing a fatal or near-fatal asthma attack. Why do we say “may” pose a risk? Evidence from a large study (26,000 subjects) indicated an increase in asthma deaths and near-fatal asthma attacks among persons treated with salmeterol compared to placebo, but it did not control what other medications persons participating in this study were taking. Most of the subjects were not taking an inhaled steroid. It is well accepted that a long-acting beta agonist without a medication to control the inflammation of the bronchial tubes in asthma is a bad idea. But what about patients who take an inhaled steroid (such as those combined with a long-acting bronchodilator in Advair, Symbicort, and Dulera)? Are they then safe from any increased risk of severe asthma attacks?
This question is central to the future of asthma care. The answer is too important to leave to speculation and opinion. So the FDA has mandated that a large-scale study be performed in which all subjects (more than 45,000 to be recruited) will receive an inhaled steroid. In addition, half will also receive a long-acting beta-agonist bronchodilator and half will receive a placebo. Participants will be observed for 6 months to determine whether the two groups have any differences in their rates of hospitalization, respiratory failure, or death from asthma. And then – around 2017 – we will know the answer.
In the meantime, we rely on hunch, intuition, and best guess based on information currently available. Our bias is that the long-acting beta-agonist bronchodilators when used in combination with an inhaled steroid will prove to be safe as well as effective.
P.S. Long-acting beta-agonists in patients with COPD are not associated with any increase in respiratory-related deaths or near-deaths from COPD.