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Rationale: Recent studies suggest that people with asthma of different racial backgrounds may respond differently to various therapies.
Objectives: To use data from well-characterized participants in prior Asthma Clinical Research Network (ACRN) trials to determine whether racial differences affected asthma treatment failures.
Methods: We analyzed baseline phenotypes and treatment failure rates (worsening asthma resulting in systemic corticosteroid use, hospitalization, emergency department visit, prolonged decrease in peak expiratory flow, increase in albuterol use, or safety concerns) in subjects participating in 10 ACRN trials (1993–2003). Self-declared race was reported in each trial and treatment failure rates were stratified by race.
Measurements and Main Results: A total of 1,200 unique subjects (whites = 795 [66%]; African Americans = 233 [19%]; others = 172 [14%]; mean age = 32) were included in the analyses. At baseline, African Americans had fewer asthma symptoms (P < 0.001) and less average daily rescue inhaler use (P = 0.007) than whites. There were no differences in baseline FEV1 (% predicted); asthma quality of life; bronchial hyperreactivity; or exhaled nitric oxide concentrations. A total of 147 treatment failures were observed; a significantly higher proportion of African Americans (19.7%; n = 46) experienced a treatment failure compared with whites (12.7%; n = 101) (odds ratio = 1.7; 95% confidence interval, 1.2–2.5; P = 0.007). When stratified by treatment, African Americans receiving long-acting β-agonists were twice as likely as whites to experience a treatment failure (odds ratio = 2.1; 95% confidence interval, 1.3–3.6; P = 0.004), even when used with other controller therapies.
Conclusions: Despite having fewer asthma symptoms and less rescue β-agonist use, African-Americans with asthma have more treatment failures compared with whites, especially when taking long-acting β-agonists.
In Asthma Clinical Research Network trials, a greater proportion of African Americans experienced asthma treatment failures than whites despite having fewer asthma symptoms and less rescue β-agonist use.
The increased rate of treatment failures was related to increased rates of treatment failure occurring in African Americans being treated with long-acting β-agonists, suggesting that these medications should be used with caution in these patients.
Environmental and genetic factors have been shown to significantly influence response to medications in patients with asthma. Among these factors, it has been speculated that race contributes to differential response to pharmacologic therapies. In this regard, several studies have demonstrated that African Americans have worse asthma control than whites, and a disproportionately higher rate of asthma-related emergency department visits, hospitalizations, and deaths (1). Although genetic, environmental, and socioeconomic factors, including disparities in access to care and quality of care, have been implicated in these differential outcomes (2), it is also possible that there are inherent pathophysiologic or even pharmacogenomic differences between whites and African Americans that result in these discrepancies.
Over the last few years, several reports have associated specific asthma therapies with adverse responses including life-threatening asthma and asthma-related deaths, particularly among African Americans (3, 4). Because of these discrepancies in asthma control in patients with asthma of different racial backgrounds, we hypothesized that patients with asthma of different racial backgrounds respond differently to specific asthma pharmacologic therapies.
The Asthma Clinical Research Network (ACRN) is a consortium of asthma clinical research centers across the United States that has been funded by the National Heart, Lung, and Blood Institute since 1993 to perform asthma treatment trials. The diverse and large number of subjects with asthma studied by this network, using several different classes of asthma therapies, coupled with the rigorous standards of quality control, makes this cohort an ideal one to assess the effect of race on response to different therapies. In this analysis of 1,200 patients with asthma in 10 trials, we assessed the effect of race on the response to commonly used asthma medications, as defined by treatment failure.
The study cohort consists of 1,200 unique randomized subjects from six centers across the United States participating in 10 different ACRN treatment trials. Trial subjects had limited comorbidities other than asthma. Socioeconomic status data were not captured but subjects were recruited from diverse neighborhoods and from databases of all of the network's participating asthma research centers, and from diverse practices affiliated with their institutions, which include primary care, hospital-based, academic centers, and specialty practices. Subjects were excluded from these studies if they had an asthma exacerbation within the month preceding the trial; no data were captured regarding exacerbations within the prior year. The studies analyzed had different run-in period durations, duration of therapy, and duration of follow-up; details of these trials can be found at www.acrn.org, at www.clinicaltrials.gov, and in the references (5–14). Table 1 lists the number of unique subjects of each race in each study arm.
For each trial, baseline characteristics for individuals of different self-reported races (based on National Institutes of Health categorization: white, black/African American, Asian, Native American, Hawaiian/Pacific Islander, or other) were examined and included PEF, FEV1, asthma symptoms, asthma quality of life, use of asthma rescue medication, exhaled nitric oxide, and methacholine responsiveness (Table 2). Asthma treatment failure was defined as an asthma exacerbation, worsening lung function, increased use of asthma medication, or physician clinical judgment. Specific treatment failure criteria and types of treatment failure by race are reported in Table 3. Definitions of other specified phenotypes are in the online supplement.
Details of statistical analysis are in the online supplement. Analyses were performed using SAS 9.2 software (SAS Institute, Inc., Cary, NC). Comparisons were made between races in terms of age using an analysis of variance and in terms of sex and treatment failure using a Pearson chi-square test. Comparisons between races at baseline for these outcomes adjusted for age, sex, center, and study were made using a linear mixed-effects model.
A comparison between races (self-reported) in terms of the rate of treatment failure was made using two different methods. Primary analysis involved logistic regression that was used to test the difference in the treatment failure rate between races. This was a cross-sectional analysis that only used one observation per subject. Treatment failure rates, odds ratios, and P values from this analysis are listed in Table 4. A secondary analysis adjusting for baseline characteristics that demonstrated differences between whites and African Americans (i.e., FEV1, body-mass index, daily symptom scores, and daily β-agonist rescue puffs) was completed, but there were no notable differences between the unadjusted and adjusted results. Kaplan-Meier survival curves were constructed and a generalized Wilcoxon test was applied to test the difference in survival curves between races (Figures 1–5).
All observations used in each comparison were from unique subjects over all of the study treatment groups involved in each comparison, with no repeated measures. All of these comparisons were made within treatment types and within combinations of treatments (see Results and Table 4).
A total of 1,200 unique subjects with asthma were enrolled in 10 randomized, double-blind, placebo-controlled trials in the ACRN between 1993 and 2003. Of this group, 795 subjects were self-reported white, 233 were African American, and 172 other races. Other races included American Indian, Asian, South American, mixed races, or unreported; these other races were not analyzed because of small sample size and their broad representation. Demographics are shown in Table 2. Most of the subjects participating in the ACRN trials were female and young to middle age with similar demographic distribution between races. Of note, in the trials reported, adherence rates were 87.5% and 91%, respectively, for African Americans and whites, and there was no difference in adherence between those who had treatment failures and those who did not (90% adherence in both; see online supplement).
In ACRN trials, baseline absolute values for spirometric measurements were lower in African Americans with asthma compared with whites. However, when FEV1 was presented as percent predicted, African Americans showed similar results (82.8%; 95% confidence interval, 81.1–84.4) as whites (81.0%; 95% confidence interval, 79.9–82.1). There was no significant difference in exhaled nitric oxide, methacholine bronchial reactivity, or asthma-related quality of life between whites and African Americans. When adjusted for age, sex, site of enrollment, and trial, daily asthma symptoms and use of supplemental rescue short-acting β-agonists were significantly greater in whites compared with African Americans.
Overall, African Americans were more likely to have a treatment failure than whites (46 of 233 [19.7%] vs. 101 of 795 [12.7%]; P = 0.0074) (Table 4), and also had a shorter time to treatment failure (Figure 1).
Table 4 lists all of the comparisons between African Americans and whites with respect to treatment failure rates for various asthma therapies (P values based on logistic regression analyses). Figures 1–5 display the Kaplan-Meier survival curves of African Americans and whites with respect to time to treatment failure rates for selected asthma therapies (P values based on generalized Wilcoxon tests). The two different analyses yield very similar P values. When stratified by treatment received, there were no differences between races when subjects did not receive long-acting β-agonist (LABA) therapy. However, when individuals with asthma received LABA, African Americans were more than twice as likely to experience a treatment failure (P = 0.0017) despite similar baselines when these subgroups were treated with LABA (data not shown). This difference in both treatment failure rate and time to treatment failure (Figures 2–5)) was apparent when LABA were used concurrently with other asthma controller therapies, including inhaled corticosteroids (ICS) (P = 0.0385 [Wilcoxon]; P = 0.0661 [logistic regression]) and leukotriene receptor antagonists (LTRA) (P = 0.0001 [Wilcoxon]; P = 0.0007 [logistic regression]). There was also a higher rate of asthma treatment failures in African Americans using ICS or LTRA compared with whites. However, this increased rate was only appreciated when individuals were concomitantly receiving LABA, but not when they received ICS or LTRA as monotherapy.
This analysis compared African Americans and whites who participated in clinical trials, and thus had equal access to asthma caregivers and asthma medications. It was found that in controlled clinical trials of adults with asthma, in which individuals were provided free access to clinicians and asthma medications, and in which subjects were monitored for medication adherence (87.5% and 91%, respectively, for African Americans and whites), African Americans experienced a higher rate of asthma treatment failures than whites.
The increased rate of treatment failures seemed to occur in African Americans being treated with LABAs, without a protective effect by the concomitant use of either ICS or LTRA. Indeed, in treatment arms in which LABA were not used, (i.e., when subjects received only ICS, LTRA, or even just placebo), there was no significant difference between African Americans and whites. Although not necessarily causative, the association of increased treatment failures with LABA in African Americans, even in the setting of concurrent controller use, is particularly important given the widespread use of this class of therapy, and the Food and Drug Administration's mandated boxed warning suggesting that this class may pose some increased risks in a subset of the population.
Our data stress the importance of studying response to specific therapies using race as a phenotype. Although differences within racial groups can further discriminate between differential ethnicities, specific phenotypes, and drug responsiveness (15, 16), there has been little study of asthma therapies in study populations limited to African Americans or other ethnicities (17, 18). However, data from the SMART study (a large multicenter trial examining safety of salmeterol) (3) and the current findings suggest that differential response to LABAs in African Americans exist. Indeed, despite the fact that multiple studies of similar and smaller size in predominantly white populations had demonstrated superiority of added salmeterol in exacerbations, symptom control, and medication use (19–21), the only prospective asthma study in African Americans to date (salmeterol or ICS vs. ICS alone in 475 African Americans) (22) revealed a blunted response to LABA in African Americans. That study failed to demonstrate that exacerbations were decreased or that asthma control (except night-time awakenings) was improved by the addition of salmeterol.
The reason for the observed association of differential response to LABAs in African Americans is unclear. Although there was no difference in baseline lung function (FEV1% predicted) between African Americans and whites in these studies, similar to other reports (23), whites had more symptoms and used more rescue inhaler at baseline than African Americans. This difference supports prior reports suggesting that African Americans may have differential perception of their asthma symptoms and perhaps their asthma severity, compared with whites, similar to other ethnicities (18). Because LABA use has been reported to attenuate asthma symptom perception (24), it is possible that in this population of individuals who already report fewer symptoms and use less asthma rescue medication, this class of therapy may be potentially detrimental and put these individuals at increased risk of adverse outcomes. Although use of LABA monotherapy (previously demonstrated in the predominantly white study to be associated with increased asthma treatment failures independent of race ) was not associated with an increased risk of treatment failures in African Americans, the number of African Americans who received LABA monotherapy in these trials (n = 7) was too small to permit us to draw conclusions.
Possible explanations for our findings could include differences in socioeconomic status or geography between subjects, confounding by indication, differential medication adherence, or definitions of race in the studies analyzed. Although access to medications and clinicians was equal for all subjects and subjects were recruited from all center sites using similar recruitment methods, no data regarding household income, socioeconomic status, or baseline exacerbation rate were obtained in ACRN trials, thus limiting the study's generalizability. However, adherence rates in the trials reported were high (87.5% and 91%, respectively, for African Americans and whites), and there was no difference in adherence rates between those who had treatment failures and those who did not (90% adherence in both), suggesting that differential adherence did not play a significant role. Although study populations are often racially admixed, self-identified racial and ethnic categories are crude descriptors of individual genetic ancestry; indeed, recent studies of African Americans suggest that fewer than 5% of self-reported African Americans get misclassified when race is analyzed using ancestry informative markers (15) and that genetic ancestry does not contribute to differences in response to asthma medications among African American patients with asthma (17).
Another possible explanation for the increased asthma treatment failures observed in African Americans receiving LABA is that some African Americans have a pharmacogenomic predisposition to either nonresponse or to adverse response with this class of therapy. Although associations are likely related to multiple loci, this hypothesis is suggested by our recent genotype-stratified randomized-controlled asthma study comparing LABA with placebo in users of ICS, in which African American subjects harboring the Arg/Arg polymorphism at the sixteenth amino acid position of the β-adrenergic receptor demonstrated no incremental benefit of LABA with respect to lung function compared with placebo, whereas Gly/Gly African Americans did improve with LABA (25). This analysis was not designed to evaluate these possibilities, but additional studies evaluating whether these and other factors have an impact on serious asthma outcomes in some African Americans, and efforts to identify genetic loci that correlate with these findings (e.g., β-receptor or other polymorphisms), are currently under way.
Interestingly, although there were several reasons for treatment failures in both groups (Table 3), a greater proportion of African Americans than whites reported increased use of rescue medication (P = 0.01) and there was a trend of a greater proportion of whites than African Americans having treatment failures caused by asthma exacerbations (P = 0.1) or by physician judgment (P = 0.1). However, because many subjects had more than one reason for failing treatment, one cannot extrapolate that treatment failures in whites were more severe; indeed, there were similar proportions of African Americans and whites receiving emergency room care or getting hospitalized.
It remains unclear whether populations other than African Americans, or whether other asthma outcomes besides treatment failures, are differentially affected by different asthma therapies. However, the results shed light onto the novel concept in recent iterations of asthma guidelines recommending individualized treatment paradigms for different patient populations (26). Although pooled analysis of studies with different trial designs and with diverse patient populations, that may not have represented the spectrum of asthma severity, may also limit the generalizability of the findings, until further trials are performed to prospectively assess the risk of LABAs in African Americans, both with and without concomitant use of ICS, these therapies should be used with caution in this patient population, with attentive monitoring and with consideration of alternative treatment options to maximize drug efficacy and patient safety.
All studies that were analyzed were reviewed and approved by the institutional review boards of the respective institutions.
Supported by National Institutes of Health grants 5 U10 HL051810, 5 U10 HL051823, 5 U10 HL051831, 5 U10 HL051834, 5 U10 HL051843, 5 U10 HL051845, 5 U10 HL056443, and U10 HL74227.
Author Contributions: All the authors participated in the study's conception and design, analysis and interpretation of data, preparation and editing of manuscript for important intellectual content, and in recruitment and analysis of the primary research studies.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201103-0514OC on September 1, 2011
Author Disclosure: No author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Forms available with the text of this article at www.atsjournals.org
Asthma Clinical Research Network: Richard J. Martin, M.D., Stanley J. Szefler, M.D., and Reuben Cherniack, M.D., National Jewish Medical Center; Robert F. Lemanske, M.D., Christine A. Sorkness, Pharm.D., and Nizar Jarjour, M.D., University of Wisconsin Medical School; Tim Craig, D.O., and Susan J. Kunselman, M.A., Penn State University College of Medicine; Homer A. Boushey, M.D., and John V. Fahy, M.D., University of California, San Francisco; Monica Kraft, M.D., Duke University Medical Center; Steven Wasserman, M.D., and Joe Ramsdell, M.D., University of California, San Diego; William J. Calhoun, M.D., and Bill Ameredes, Ph.D., University of Texas; Michael Walter, M.D., Washington University School of Medicine; Eugene Bleecker, M.D., Wake Forest University; Emily DiMango, M.D., and Gene R. Pesola, M.D., Columbia University Medical School; and Robert Smith, Ph.D., National Heart, Lung and Blood Institute.