Chest
Volume 129, Issue 1, January 2006, Pages 15-26
Journal home page for Chest

Original Research: Asthma
The Salmeterol Multicenter Asthma Research Trial: A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol

https://doi.org/10.1378/chest.129.1.15Get rights and content

Study objective

To compare the safety of salmeterol xinafoate or placebo added to usual asthma care.

Design

A 28-week, randomized, double-blind, placebo-controlled, observational study.

Setting

Study subjects were seen once in the study physician’s office for screening and were provided all blinded study medication for the entire study period. Follow-up by telephone was scheduled every 4 weeks.

Participants

Subjects (> 12 years old) with asthma as judged by the study physician were eligible. Individuals with a history of long-acting β2-agonist use were excluded.

Interventions

Salmeterol, 42 μg bid via metered-dose inhaler (MDI), and placebo bid via MDI.

Measurements and results

Following an interim analysis in 26,355 subjects, the study was terminated due to findings in African Americans and difficulties in enrollment. The occurrence of the primary outcome, respiratory-related deaths, or life-threatening experiences was low and not significantly different for salmeterol vs placebo (50 vs 36; relative risk [RR] = 1.40; 95% confidence interval [CI], 0.91 to 2.14). There was a small, significant increase in respiratory-related deaths (24 vs 11; RR, 2.16; 95% CI, 1.06 to 4.41) and asthma-related deaths (13 vs 3; RR, 4.37; 95% CI, 1.25 to 15.34), and in combined asthma-related deaths or life-threatening experiences (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89) in subjects receiving salmeterol vs placebo. The imbalance occurred largely in the African-American subpopulation: respiratory-related deaths or life-threatening experiences (20 vs 5; RR, 4.10; 95% CI, 1.54 to 10.90) and combined asthma-related deaths or life-threatening experiences (19 vs 4; RR, 4.92; 95% CI, 1.68 to 14.45) in subjects receiving salmeterol vs placebo.

Conclusions

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. Whether this risk is due to factors including but not limited to a physiologic treatment effect, genetic factors, or patient behaviors leading to poor outcomes remains unknown.

Section snippets

Patient Selection

Male and female subjects aged ≥ 12 years were eligible if they had a diagnosis of asthma (per investigator clinical judgement) and were currently receiving a prescription asthma medication. However, subjects could not have previously used inhaled long-acting β2-agonists. Concurrent use of other prescription asthma medication(s) was permitted. Exclusion criteria included pregnancy and/or lactation, or any significant systemic disease that in the opinion of the investigator may place a subject at

Results

There were 26,355 subjects randomized to study treatment. Demographic characteristics and asthma history were similar between treatment groups and are summarized in Tables 1 ,Table 2. In the previous 12 months, asthma emergency department (ED) visits and hospitalizations were reported by 26% and 8% of all subjects, respectively, while at least weekly symptoms of nocturnal asthma were reported by approximately 61% of all subjects. Baseline ICS use was reported by 47% of the overall population,

Total Population

The primary and secondary end point results are shown in Table 4. For the primary end point, there were no significant differences between treatment groups in the number of subjects with respiratory-related death or life-threatening experiences over the 28-week treatment period. There were small, but statistically significant differences between salmeterol and placebo for secondary end points associated with asthma-related and respiratory-related deaths and combined asthma-related death or

Kaplan-Meier Survival Analysis

Log-rank tests found no significant differences for time to primary end point, time to withdrawal related to a medical condition other than asthma, time to all-cause death, or time to first all-cause hospitalization (data not shown). Figures 3, 4 show that there were significant increases in time to withdrawal due to worsening asthma (p < 0.001), and time to withdrawal not related to a medical condition (p = 0.016) for salmeterol compared with placebo.

Adverse Events

Overall, 1,093 subjects (4% in each treatment group) had serious adverse events during the study. The most common serious adverse events, which occurred in 2% of all subjects, were events classified as lower respiratory tract in nature. All other serious adverse events occurred at an incidence of < 1%. Based on Kaplan-Meier analyses, there were statistically significant differences between the treatment groups for time to first serious adverse event causing discontinuation (salmeterol survival

Discussion

This randomized, double-blind, clinical trial was planned for 60,000 subjects, or 238 primary events, but was terminated following a planned interim analysis when approximately one half of the subjects were enrolled, subsequently providing 86 primary events. Predefined criteria for study termination were not met at the interim analysis. However, the study was terminated by GlaxoSmithKline due to preliminary findings in African Americans and difficulties in enrollment.

The results in the total

References (20)

There are more references available in the full text version of this article.

Cited by (0)

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

Dr. Nelson is a consultant, speaker, and recipient of research grants from GlaxoSmithKline, and was also a member of the MMRC for this study. Dr. Weiss is a consultant for GlaxoSmithKline, and was also a member of the MMRC for this study. Dr. Bleecker is a consultant, speaker, and recipient of research grants from GlaxoSmithKline, and was a member of the MMRC for this study. Mr. Yancey is an employee of GlaxoSmithKline. Dr. Dorinsky is an employee of GlaxoSmithKline.

These data were presented in part at the American College of Chest Physicians Conference in Orlando, FL, October 25–30, 2003.

View full text