Three common asthma inhalers containing the drugs salmeterol or formoterol might be responsible four out of five US asthma-related deaths per year, researchers from Cornell and Stanford universities have concluded after a search of medical literature. They suggest that the medications should be taken off the market. Their findings appear in the June 20 issue of Annals of Internal Medicine.

The researchers base these conclusions on a statistical analysis of 19 published trials involving 33,826 patients. This meta-analysis found that patients who inhaled the long-acting β-agonists salmeterol or formoterol were 3.5 times more likely to die from asthma and 2.5 times more likely to be hospitalized (whether or not death resulted), compared with those taking a placebo.

The reason, say the researchers, is that, although these medications relieve asthma symptoms, they also promote bronchial inflammation and sensitivity without warning.

Despite these findings, asthma deaths in the study were relatively rare—over a 6-month period, 15 patients in the meta-analysis who were taking the β-agonists died, compared with three in the placebo group.

Adding an anti-inflammatory drug to a long-acting β-agonist adds little benefit, report the researchers. One product combines salmeterol with an anti-inflammatory drug to provide some protection against bronchial inflammation associated with β-agonists, even so, hospitalizations still doubled for patients inhaling a long-acting β-agonist combined with an anti-inflammatory drug compared with asthma patients taking a placebo and an anti-inflammatory drug by itself.

Of the 19 studies surveyed in the meta-analysis, the largest—the Salmeterol Multicenter Asthma Research Trial with 26,000 participants—reported a fourfold increased risk for asthma-related deaths and a twofold increase in life-threatening asthma events in patients using salmeterol. If older people who also suffered from chronic obstructive pulmonary disease were removed from the analysis, the researchers report, salmeterol would be associated with a 6 times greater risk for asthma-related deaths.

The meta-analysis found that 53 of 3,083 patients inhaling beta-agonists were hospitalized for an asthma attack compared with 12 of 2,008 patients who received a placebo, meaning that there was one hospitalization for every 71 patients treated with a long-acting beta-agonist per year.

The researchers caution that the small number of deaths limited the reliability of assessing the risk of fatal asthma exacerbations.

Additional information is available at http://www.news.cornell.edu/stories/June06/AsthmaDeaths.kr.html.