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
), there has been little study of asthma therapies in study populations limited to African Americans or other ethnicities (17
). 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
), 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 [6
]) 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 (), 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.