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Long-Acting Inhaled ß-Agonists and Mortality

Earlier in 2006, findings highlighted increased risk for asthma-related deaths; more recently, experts have suggested the risks were due to use of these medications without inhaled steroids.

Results of a large randomized trial published in early 2006 led to an FDA black-box warning that long-acting inhaled ß-agonists (LABAs) could increase the chance of severe asthma and death and should not be used as first-line therapy. In the SMART trial, which involved 26,355 adolescents and adults with asthma, more subjects randomized to salmeterol than to placebo experienced respiratory death or mechanical ventilation (50 vs. 36 events) by 28 weeks, but the difference did not reach statistical significance (Journal Watch Feb 17 2006).

Later in 2006, researchers published a meta-analysis of 19 randomized, placebo-controlled trials (including SMART) that involved 33,826 children and adults (Journal Watch Jul 18 2006). LABAs were significantly associated with asthma hospitalizations, life-threatening asthma exacerbations, and asthma-related deaths.

Some observers have questioned these conclusions. The editorial accompanying SMART pointed out that in clinical trials, combinations of LABAs and inhaled corticosteroids reduced severe asthma exacerbations. In SMART, most patients using LABAs were not receiving inhaled corticosteroids. The editorialists concluded that it was highly improbable that combination therapy carried the same risks as monotherapy (Journal Watch Feb 17 2006).

The Canadian Asthma Guideline Group noted that the previously mentioned meta-analysis included 12 studies that did not require inhaled corticosteroids. Although the meta-analysis found LABAs increased risk for hospitalization even in studies in which most subjects were on inhaled corticosteroids, the guideline group pointed out that the studies did not provide corticosteroids, and adherence was not known (Ann Intern Med Nov 7; 145:692). Also, two Cochrane reviews restricted to studies of patients who received inhaled corticosteroids did not find that LABAs increased the risk for hospitalization or drops in peak flow (http://dx.doi.org/10.1002/14651858.CD005533 and http://dx.doi.org/10.1002/14651858.CD005535).

Writers of letters to the editor raised another question: Why hasn’t the rate of asthma deaths increased since the introduction of LABAs (Ann Intern Med Nov 7; 145:706, 707)? An author of the meta-analysis suggests that such an increase may have been obscured by decreasing deaths from reduced use of short-acting ß-agonist monotherapy (Ann Intern Med Nov 7; 145:708).

It is noteworthy that, of all authors of the works cited in this story, only the meta-analysis authors had no ties to LABA manufacturers. This debate will not end without more study of LABAs in people taking inhaled corticosteroids as maintenance therapy. In the meantime, when LABAs are used for asthma, they should be used in combination with inhaled corticosteroids, and only when inhaled corticosteroids are not providing optimal control.

— Richard Saitz, MD, MPH, FACP, FASAM

Published in Journal Watch General Medicine December 28, 2006

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