Randomised, double-blind, placebo-controlled safety trial, terminated early
Treatment
Salmeterol 42 microg twice daily added to usual asthma therapy
Control
Placebo added to usual asthma therapy
Population
26,355 subjects with asthma, enrolled in usual community practice
Follow-up
28 weeks
Primary endpoint
Respiratory-related deaths or life-threatening experiences
Result
The primary endpoint occurred in 50 versus 36 subjects — relative risk 1.40 (95% CI 0.91 to 2.14), not significant. Respiratory-related deaths were higher with salmeterol, 24 versus 11 (relative risk 2.16, 95% CI 1.06 to 4.41), as were asthma-related deaths, 13 versus 3 (relative risk 4.37, 95% CI 1.25 to 15.34). The trial was terminated at interim analysis because of findings in African American participants and difficulties in enrolment.
Secondary endpoints
Respiratory-related deaths, asthma-related deaths, combined asthma-related death or life-threatening experience, subgroup by race
For the primary end point in the total population, there were no significant differences between treatments. There were small, but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol. Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects.
The trial authors, in the published abstract
How it has aged
The trial behind the long-acting beta agonist black-box warning and, indirectly, behind every subsequent combination inhaler. The crucial detail is that salmeterol was added to *usual therapy*, which for many participants meant no inhaled steroid at all. Later trials in which the LABA is always paired with a steroid found no excess mortality, which is why LABA monotherapy in asthma is now considered indefensible while combination therapy is standard. Absolute numbers are small and the excess concentrated in African American participants, unexplained to this day.
Publications
The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol
Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006 Jan;129(1):15-26.
Primary composite endpoint not significantly different
Asthma-related deaths 13 versus 3, relative risk 4.37
Salmeterol was added to usual therapy, often without an inhaled steroid