Long-acting beta-agonists linked to life-threatening asthma attacks

[Anil Tuladhar]

Use of the long-acting inhaled beta-agonists, salmeterol and formoterol, appears to increase the risk of severe asthma complications, including asthma-related death, investigators report in the Annals of Internal Medicine for June 6.

Patients are sometimes put on long-acting beta-agonist therapy if inhaled corticosteroids alone fail to control their asthma, Dr. Shelley R. Salpeter and associates note, but mortality due to asthma has increased in the US over the past 10 years, during the time that these drugs were put on the market.

Because severe asthma attacks are relatively rare, Dr. Salpeter, from Santa Clara Valley Medical Center in San Jose, California, and her colleagues performed a meta-analysis to better quantify the risks associated with the use of salmeterol or formoterol.

Their literature search turned up 19 randomized, double-blind trials in which long-acting beta-agonists were compared with placebo, published between 1966 and 2005. The subjects were followed for an average of 6 months. Approximately half of the subjects were using concomitant inhaled corticosteroids, and all were allowed the use of short-acting beta-agonists as needed.

The odds ratio for hospitalization due to asthma was 2.6 for long-acting beta-agonists compared with placebo, while combination for life-threatening attacks was 1.8. Only one trial was large enough to document a substantive number of deaths, in which the OR was 3.5 (13 deaths in the beta-agonist group versus 3 in the placebo group, from a total of 26,000 participants).

Subgroup analyses revealed similar results for adults and children, and for treatment with salmeterol and formoterol.

Dr. Salpeter's group notes that negative feedback can worsen asthma control while patients are on long-acting beta-agonist therapy, and that regular use increases bronchial hyperreactivity. Therefore, they add, "these effects, along with a reduction in response to subsequent rescue beta-agonist use, may worsen asthma control without giving any warning of increased symptoms."

To put their findings into clinical perspective, they found that the increased number of asthma-related deaths was approximately 0.06% to 0.07% over 6 months, translating to an excess of about 1 death per 1000 person-years of use. In other words, these drugs appear to be responsible for 80% of the 5000 asthma-related deaths that occur in the US each year.

Despite the fact that FDA-mandated black-box warnings have been added to the drugs' labels, physicians' prescribing practices have not changed, the authors point out. Therefore, they write, "This information could be used to reassess whether these agents should be withdrawn from the market."

In a related editorial, Dr. Jeffrey Glassroth advises physicians to first maximize the dose of inhaled corticosteroid if patients' asthma is not sufficiently controlled. Then, if further treatment is needed, they can add a long-acting beta-agonist to the treatment regimen, but he reminds them to carefully monitor patients who do not respond or whose condition worsens.

If withdrawal of the agent is required, then Dr. Glassroth, from Tufts University School of Medicine in Boston, suggests switching patients to an inhaled anticholinergic agent.