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* From the National Jewish Medical and Research Center (Dr. Nelson), Denver, CO; Brigham and Women’s Hospital and Harvard Medical School (Dr. Weiss), Boston, MA; Wake Forest University School of Medicine (Dr. Bleecker), Winston Salem, NC; and GlaxoSmithKline (Mr. Yancey and Dr. Dorinsky), Research Triangle Park, NC.
Correspondence to: Paul M. Dorinsky, MD, GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC 27709; e-mail: paul.m.dorinsky{at}gsk.com
Abstract
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 ß2-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.
Key Words: asthma • long-acting ß2-agonist • salmeterol
Published studies1 have suggested a progressive increase in the incidence of asthma-related mortality over the past several decades. Risk factors associated with asthma-related death include overuse of ß-agonists or theophylline, underuse of controller medications, disease severity, pollution, gender, age, substance abuse, and ethnic background.2 Among these risk factors, the link between specific asthma therapies, in particular ß2-agonists, and the rising asthma death rate has been the subject of ongoing debate.
For example, in the 1960s an increase in asthma deaths was reported in countries where a high-dose preparation of isoprenaline aerosol was available.3 After careful review, the researchers concluded that overuse of isoprenaline was the major factor associated with these asthma deaths.4 In the 1970s, an increase in asthma deaths in association with the use of fenoterol, a potent, full ß2-agonist, was reported.567 While these reports567 raised questions about a possible class effect with ß2-agonist bronchodilators, ultimately these reports were ascribed to isolated overuse of ß-agonists for poorly controlled asthma.
Salmeterol and formoterol are highly selective, third-generation ß2-agonists that have been available for use since the early 1990s and were designed to provide long-lasting bronchodilation and improved pharmacokinetic properties to minimize unwanted side effects. In this regard, large-scale clinical and observational studies891011 have supported the profile of this new generation of ß2-agonists relative to their less selective, short-acting predecessors. Nonetheless, in a 16-week, randomized controlled trial12 conducted in the United Kingdom in the mid 1990s, serious exacerbations and asthma deaths were compared in subjects who received salmeterol twice daily or albuterol four times daily. In this study,12 there were significantly fewer withdrawals due to worsening asthma with salmeterol. However, the frequency of asthma-related death, although low in both treatment groups, was numerically but not significantly higher in the salmeterol group. In order to further evaluate the effects of salmeterol on respiratory- and asthma-related deaths or life-threatening episodes, these events were examined in a 28-week study in which salmeterol or placebo was added to usual asthma care.
Materials and Methods
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 ß2-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 risk; history of any adverse reaction (including immediate or delayed hypersensitivity reaction) to any sympathomimetic amine drug; or current use of ß-blockers.
Two methods of recruitment were utilized during the study. Initially, subjects were recruited via print, radio, and television advertising and were assigned to a study investigator by geographic location during 1996 to 1999 (phase 1). However, when recruitment waned, the large-scale advertising campaign was stopped and study investigators were added to facilitate enrollment during from 2000 to 2003 (phase 2). During phase 2, subjects were recruited directly by the study investigators.
Study Design and Intervention
The Salmeterol Multicenter Asthma Research Trial (SMART) was a multicenter, randomized, double-blind, parallel-group, placebo-controlled, observational surveillance study conducted at 6,163 sites in the United States; 1,316 investigators randomized subjects into the trial. SMART was initiated on June 30, 1996. Institutional review boards approved the study protocol, and all subjects signed a written informed consent document prior to enrollment. SMART was designed to compare respiratory-related and asthma-related outcomes in subjects receiving usual asthma pharmacotherapy alone or usual asthma pharmacotherapy plus salmeterol.
The study consisted of a single clinic visit (visit 1) during which eligibility was evaluated, and informed consent and baseline information were obtained. Eligible subjects were randomized to treatment with either salmeterol 42 µg bid via metered-dose inhaler (MDI) or placebo MDI bid (Fig 1 ). At visit 1, subjects were given a 28-week supply of study medication and study procedures were reviewed. Subjects were instructed on the proper use of the MDI. In addition, they were instructed to continue use of current asthma medications, as the study drug was a supplement, not a replacement, for current therapy. Subjects not currently receiving short-acting ß-agonists were supplied albuterol. Short-acting ß-agonist use was recorded at baseline only and not throughout the study. Study medication was to be administered on arising and before bedtime (approximately 12 h apart), and a new inhaler was to be used every 4 weeks.
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Case Adjudication and Data Safety Monitoring
All deaths and life-threatening experiences were reviewed by a Morbidity and Mortality Review Committee (MMRC) to assess if these events were respiratory related. Events adjudicated as respiratory related in nature included events such as pulmonary fibrosis, asthma, and pneumonia. Asthma-related deaths and asthma-related life-threatening events were a subset of respiratory-related events. Both respiratory- and asthma-related events were determined by the clinical judgment of the members of the MMRC. Adjudication materials included death certificates, US Food and Drug Administration MedWatch forms, case summary compiled by the study monitor and, when available, autopsy and hospital records. The MMRC was blinded to study treatment. Blinded results were periodically reviewed by an independent Data Safety Monitoring Board consisting of three physicians, one medical ethicist, and two statisticians. The Data Safety Monitoring Board members received blinded data summaries at least quarterly during the course of the study or on the completion of successive cohorts of approximately 3,000 subjects, whichever came first.
Statistical Methods
The primary end point was the occurrence of combined respiratory-related deaths or respiratory-related life-threatening experiences (defined as intubation and mechanical ventilation). Secondary end points included all-cause deaths, combined asthma-related deaths or life-threatening experiences, asthma-related deaths, respiratory-related deaths, combined all-cause deaths or life-threatening experiences, and all-cause hospitalizations. Other end points included the relative frequency of all-cause serious adverse events.
Hypotheses
The primary hypothesis of this study was that there would be no more than a 40% increase in combined respiratory-related deaths or respiratory-related, life-threatening experiences for subjects receiving salmeterol for 28 weeks as compared with subjects receiving placebo for 28 weeks. A secondary hypothesis concerning asthma-related deaths was that there would be no more than a tripling of asthma-related deaths for subjects receiving salmeterol for 28 weeks as compared with subjects receiving placebo for 28 weeks.
Sample Size
It was determined that approximately 238 primary outcome events would be required to rule out a 40% increase in these events for subjects receiving salmeterol for 28 weeks as compared with subjects receiving placebo for 28 weeks with 80% power. The original sample size necessary to obtain the required number of primary outcome events was determined using the reported prevalence of asthma deaths in the United States in 1994 along with the rate of asthma-related intubations and mechanical ventilation. At study initiation, the yearly asthma death rate was reported as 5,106 per 12 million asthma subjects. It was also estimated that for every death due to asthma, there were five occurrences of asthma-related intubation and mechanical ventilation. These assumptions led to an estimated occurrence rate of 0.007918 for the primary outcome event and a sample size estimate of 30,000. After approximately 15,000 subjects had been enrolled in the study, the actual rate of primary outcome events was found to be approximately one half of the expected rate. Consequently, based on the revised estimation the required sample size was 60,000 subjects.
Interim Analysis
Per the protocol, an interim analysis was planned when approximately one half of the expected number of subjects were enrolled. There were provisions in the protocol for the study to be stopped if there was evidence that salmeterol was causing an increase in the primary outcome or in the secondary outcome of asthma-related deaths. The stopping criteria were based on detecting risk ratios of 1.4 for the primary outcome and 3.0 for asthma-related deaths. Analyses of the data at the interim analysis were conducted with a significance level of 0.01. Statistically, the interim analysis results would be interpreted in terms of stopping or continuing the study through examination of the relative risk (RR) and associated 99% confidence interval (CI) comparing event rates of the primary end point and the secondary end point of asthma-related death for salmeterol vs placebo in the overall population.
Predefined criteria for study termination were not met at the interim analysis. However, the sponsor (GlaxoSmithKline; Research Triangle Park, NC) elected to terminate the study due to preliminary findings in African Americans and difficulties in enrollment. After the interim results were analyzed, information was obtained about eight additional cases that were identified from a National Death Index search. These additional cases were identified from the small cohort of subjects who were unavailable for follow-up and for whom data were not available at the time of study termination.
Population
All analyses were based on the intent-to-treat population, which consisted of all subjects who were randomized to study medication and for whom case report form data were available. All available data are reported.
Statistical Methods for Planned Outcome Events Analysis
Inferential analyses of all outcome events were based on the CI for the RR of each outcome for salmeterol vs placebo. At the planned interim analysis, assessments were made based on a 99% CI. Since the study was stopped after the interim analysis, assessments on final data were made based on 95% CI. Due to extensive censoring in the outcome event data, it was determined that the most appropriate estimates of RR would be derived from life table methodology. Therefore, throughout this article the life table estimates of RR are considered the primary analysis. In addition, Kaplan-Meier estimates of the time to each outcome event (first occurrence if appropriate) were generated. Inferential analyses of the time to each outcome event were based on the log-rank test.
Statistical Methods for Exploratory Outcome Event Analysis
Following the review of the interim analysis, exploratory analyses of each outcome event within subpopulations were conducted. Subpopulations were based on baseline characteristics such as inhaled corticosteroid (ICS) use and study phase. Additionally, outcome events were analyzed separately for white and African-American subjects.
The incidence of serious adverse events (defined as death [from all causes]; life-threatening events, including endotracheal intubation and mechanical ventilation; events that are disabling or incapacitating; events that require or prolonged inpatient hospitalization; significant laboratory abnormalities; any congenital anomaly in the offspring of a subject exposed to study drug in utero; events resulting from an overdose of study drug; and any cancer) was determined for each treatment group, and a plot of Kaplan-Meier estimates of time to first serious event was produced. A log-rank test was used to test for differences between treatment groups in the time to first serious event.
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, 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, with 49% in Caucasians and 38% in African Americans. Data for asthma history and current nocturnal symptoms indicate greater disease severity at baseline in the African-American subgroup as compared with Caucasian subjects (Table 2). For demographic and baseline characteristics, there were no statistically significant differences identified between the salmeterol and placebo groups within the Caucasian and African-American subgroups.
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African Americans:
In the African-American population, there were statistically significant differences in the primary end point and for two of the secondary end points between treatment groups (Table 4). Significantly more subjects receiving salmeterol (n = 20; < 1%) had a respiratory-related death or life-threatening experience compared with the placebo group (n = 5; < 1%). The number of combined asthma-related deaths or life-threatening experiences was significantly greater in subjects receiving salmeterol (n = 19; < 1%) compared with placebo (n = 4; < 1%). The numbers of asthma-related deaths and all-cause deaths were not statistically significantly different in subjects receiving salmeterol compared with placebo (Table 4).
Effects of Concurrent ICS Use:
While SMART was not designed to assess the effect of ICS use on the end points, post hoc analyses were conducted to explore the effect of ICS use on the results of SMART. In the intent-to-treat population, the number of events for the primary outcome and all secondary outcomes was similar for subjects reporting baseline use of ICS in both treatment groups, and no significant differences were found between treatment groups (Table 8
). The number of primary and secondary outcome events for subjects reporting no baseline ICS use was greater in the salmeterol group compared with placebo. However, only asthma-related death and combined asthma-related death or life-threatening experiences were found to be significantly different between the two treatments (Table 8).
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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.
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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 population for the primary end point, the number of subjects with respiratory-related death or life-threatening experiences, showed no significant differences between treatments for the total population. There were small, but significant differences between treatments for respiratory- and asthma-related deaths and combined asthma-related death or life-threatening experiences. Although the study was active from 1996 to 2003, the imbalance in outcomes between treatment groups in respiratory- and asthma-related events was largely isolated to 1998.
To further explore the data, post hoc analyses were conducted. For example, although there was a higher number of respiratory- and asthma-related death or life-threatening experiences in the total population treated with salmeterol compared with placebo, post hoc analyses showed no significant differences between treatments for these outcomes in the Caucasian population.
By comparison, there was a small, but significant increase in several respiratory- and asthma-related secondary outcomes in African Americans treated with salmeterol compared with placebo. When examining subpopulations at screening, African Americans had lower peak expiratory flow, reported less ICS use, and higher percentages of hospitalizations and ED visits compared with Caucasians. Whether these factors or other factors including but not limited to a physiologic treatment effect, a genetic predisposition, or patient behaviors leading to poor outcomes (eg, delay in seeking care, compliance with study treatments or asthma medications) influenced the study outcomes in African Americans remains unknown. For example, it is hypothesized that a genetic variation in the ß-adrenergic receptor may influence the response to ß-adrenergic therapy, and the frequency of genetic variations in the ß-adrenergic receptor are higher in subgroups such as African Americans compared with the overall population.13 However, the effect of these genetic variations in the ß-adrenergic receptor on serious asthma outcomes is unclear, and there are limited data suggesting that genotype does not affect the phenotypic response to salmeterol.14 The current study was not designed to evaluate these possibilities and additional studies are needed to evaluate whether these and other factors have an impact on serious asthma outcomes in African Americans.
While the risk for all-cause death was not statistically different between treatments in African Americans, the risk for all cause hospitalization and the risk for the combined outcome of all cause death or life-threatening experiences were increased for salmeterol recipients in this population. It is not known whether this increase may be the result of a treatment effect, an imbalance between controller treatments, or in treatment for concurrent medical conditions, socioeconomic status, or a result of chance. Detailed information relative to all-cause events and socioeconomic status were not collected during the study; therefore, SMART was unable to determine the cause of this imbalance between treatments.
The effect of ICS in reducing asthma mortality and major morbidity in children and adults is well documented.1516 Determining the effect of ICS use on the outcomes of SMART was not an objective of this study. As such, SMART was not adequate to determine whether or not ICS use affected the incidence of the key outcome events in this study. Nonetheless, the available data from SMART are consistent with prior observational studies1517 with salmeterol indicating that outcomes such as hospitalizations due to asthma and asthma exacerbations are reduced when salmeterol is used in conjunction with an ICS.
The asthma-related death rate for subjects exposed to salmeterol in SMART (1.22 per 1,000 person-years) is lower than that reported previously by Castle at al12 (2.32 per 1,000 person-years), as well as by Martin and Shakir18 (2.76 per 1,000 person-years). These UK studies included a larger proportion of subjects > 60 years old, which may, in part, account for the differences. Asthma-related death rates by race or ethnicity were not reported in these UK studies, and thus a direct comparison with SMART cannot be made.
Other valid methods for studying rare events such as asthma death and asthma morbidity include observational study designs. In such studies, salmeterol use has not been found to be associated with an increased risk of serious asthma outcomes relative to theophylline,10 ipratropium bromide,10 or short-acting ß-agonists,11 even among patient with the most severe asthma. In the largest matched case-control study19 to date (532 patients), salmeterol use in the prior 3 months was not associated with an increased risk of asthma death (odds ratio, 1.05).
As noted previously, SMART was active from 1996 to 2003; for unclear reasons, the imbalance between treatment groups in respiratory- and asthma-related events was largely isolated to 1998 during phase 1. There was a change in patient recruitment strategies between phase 1 (from 1996 to 1999) and phase 2 (from 1999 to 2003). In phase 1, subjects unknown to the study investigator were directed to centralized study clinics via independent telephone screening services in response to subjects’ calls following media advertising. In contrast, phase 2 used the recruitment methodology of enrolling subjects known within the practice of the physician investigator. It is known that an established doctor-patient relationship can impact the quality of overall asthma care for individual subjects.20 To the extent that this was true of phase 1 vs phase 2, it may, in part explain why there were fewer incidences and no imbalances between treatment groups in the number of serious respiratory- and asthma-related events in phase 2 as compared with phase 1.
In summary, the results of SMART indicate that for the primary end point in the total population, there were no significant differences between treatments. However, there were small, but statistically significant increases in respiratory- and asthma-related deaths and combined asthma-related death or life-threatening experiences in the total population in the salmeterol group compared with placebo. The imbalance occurred largely in the African-American subpopulation. Whether this risk in African Americans is due to factors including but not limited to a physiologic treatment effect, genetic factors, or patient-level behaviors leading to poor outcomes remains unknown.
Footnotes
Abbreviations: CI = confidence interval; ED = emergency department; ICS = inhaled corticosteroid; MDI = metered-dose inhaler; MMRC = Morbidity and Mortality Review Committee; RR = relative risk; SMART = Salmeterol Multicenter Asthma Research Trial
These data were presented in part at the American College of Chest Physicians Conference in Orlando, FL, October 25–30, 2003.
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.
Received for publication November 19, 2004. Accepted for publication March 1, 2005.
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