Drug Safety and Salmeterol: The Controversy Continues

Since their introduction in the 1960s, inhaled β-agonists have been celebrated for their ability to offer dramatic relief of symptoms for persons with asthma. However, they have engendered considerable controversy. Early indications suggested that higher doses of some of the short-acting β-agonists were associated with higher fatal and near-fatal asthma-related events (1). Further research suggested that overuse of even moderate doses of inhaled short-acting β-agonists was associated with a small but definite increase in fatal and near-fatal events (2).

The 1990s provided a major milestone in the advancement of β-agonist therapy—the introduction of long-acting β-agonists (3, 4). These drugs were much more convenient to use, led to even better control of asthma symptoms, and improved quality of life. However, and perhaps not unexpectedly, controversy soon erupted about the safety of long-acting β-agonists (5, 6).

As early as 2003, the concerns about the safety of long-acting β-agonists led the U.S. Food and Drug Administration to require GlaxoSmithKline (Research Triangle Park, North Carolina) to conduct a very large (>26 000 persons), postmarketing, randomized, controlled trial to examine drug safety (7). The SMART (Salmeterol Multicenter Asthma Research Trial) was a randomized, double-blind, placebo-controlled study of drug safety under a “real-world,” effectiveness study design based in the United States. The study allowed concomitant use of inhaled corticosteroids. GlaxoSmithKline ended the study because of preliminary findings and difficulties in reaching target enrollment and published the results in 2006. The trial found no statistically significant differences between treatments in the combined …