Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group. Chest. 2006;129:15–26
PURPOSE OF THE STUDY. To compare the safety of salmeterol or placebo added to usual asthma care.
STUDY POPULATION. Subjects who were >12 years old with asthma (as judged by the study physician) and were currently receiving a prescription asthma medication.
METHODS. This was a multicenter, randomized, double-blind, parallel group, placebo-controlled observational surveillance study conducted at 6163 US sites with 1316 investigators between 1996 and 1999 (phase 1) and 2000 and 2003 (phase 2). The primary purpose was to compare respiratory and asthma-related outcomes in subjects who were receiving usual asthma pharmacotherapy plus placebo or usual care plus salmeterol. Subjects were recruited by large-scale advertisement and assigned geographically to the closest site (phase 1) and directly by study investigators (phase 2). A single clinic visit was performed to determine eligibility, obtain consent and baseline data, and dispense a 28-week supply of study medications and instructions. Subjects were told to continue their baseline asthma medications, and those without a short-acting β agonist were given albuterol. Telephone follow-up was obtained every 4 weeks. Adherence was not measured or reinforced.
RESULTS. Almost 25% of the subjects dropped out of the study before 28 weeks. At baseline, nearly all of the subjects were taking short-acting β agonists, but only 47% were taking inhaled corticosteroids (ICSs) (49% of white subjects and 38% of black subjects). The study was terminated in 2003 because of safety concerns and difficulty with recruitment (of planned 60 000 subjects). There were 50 combined respiratory-related deaths or life-threatening experiences in the salmeterol group versus 36 in the placebo group (relative risk [RR]: 1.4; 95% confidence interval [CI]: 0.91–2.14). There were 24 respiratory-related deaths in the salmeterol group and 11 in the placebo group (RR: 2.16; 95% CI: 1.06–4.41). There were 13 asthma-related deaths in the salmeterol group (6 white and 7 black) and 3 in the placebo group (RR: 4.37; 95% CI: 1.25–15.34). The increased risk was primarily in black subjects with combined asthma-related deaths or life-threatening experiences of 19 in the salmeterol group versus 4 in the placebo group (RR: 4.92; 95% CI: 1.68–14.45). Half of the black subjects and 71% of the white subjects who had asthma-related deaths were not on ICS at baseline, but the impact of ICS on prevention of asthma or respiratory death or life-threatening experiences could not be analyzed because of the study design. The death rate for subjects exposed to salmeterol in the Salmeterol Multicenter Asthma Research Trial was 1.98 per 1000 person-years.
CONCLUSIONS. The authors concluded that there were small but statistically significant increases in respiratory- and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population in the salmeterol group compared with placebo. The risk was greater in the black subjects.
REVIEWER COMMENTS. This study was difficult to interpret, because the differentiation between respiratory-related versus asthma-related deaths was not clearly defined. The reasoning behind separating the analysis by study phase is also unclear. Health care providers should discuss the Food and Drug Administration's long-acting β-agonist black-box warning (see www.fda.gov/cder/drug/infopage/LABA/default.htm) with patients and caregivers before and while on therapy. Primary care providers should consider specialty evaluation before starting long-acting β agonists to ascertain necessity. Additional studies are ongoing to assess the safety of combined products such as fluticasone/salmeterol and mometasone/formoterol. Long-acting β agonists should not be used as first-line therapy for asthma treatment and should only be used in combination with ICSs.
- Copyright © 2007 by the American Academy of Pediatrics