Studying COPD in African-Americans: Better Late than Never

In this month's issue of the Journal of COPD, Criner and colleagues publish the results of the first ever randomized placebo-controlled trial of a COPD treatment (inhaled tiotropium) performed exclusively in African-Americans ([1]). Regardless of the results, the Journal, authors, and indeed the sponsor of the study should be congratulated. Despite the increasing impact of COPD among African-Americans ([2]) and evidence that they may be more susceptible to tobacco smoke than Caucasians ([3], [4], [5]); no prior study has examined the effects of a COPD treatment in this subpopulation. The importance of race as a determinant of pharmacologic benefit has been documented in hypertension ([6]) and congestive heart failure ([7], [8]) and a similar phenomenon may exist in asthma ([9], [10], [11]). Examination of this issue in patients with COPD is long overdue.

COPD is currently the fourth-leading cause of death in the United States and mortality continues to increase, more so in African Americans than in Caucasians ([2]). Although this phenomenon has been attributed to changing smoking habits over time, some have argued that African-Americans may be more susceptible to tobacco smoke than Caucasians ([3], [4], [5]). Chatila has shown that despite comparable lung function, African-Americans presenting for lung transplant evaluation were younger and had smoked less than their white counterparts ([3], [4]). We have found similar data across the spectrum of COPD severity ([5]) and indeed the patients enrolled in the Criner study were younger and had fewer pack-years of smoking than the predominantly Caucasian population enrolled in the pivotal placebo-controlled trials of tiotropium ([12]). The explanation for this phenomenon has not been elucidated, though genetic, biologic, behavioral and socioeconomic factors may all be involved.

Just as susceptibility to tobacco smoke may vary by race, the biologic response to treatment may also be different though until recently this has been poorly studied in respiratory disease. The well-publicized results of the Salmeterol Multicenter Asthma Research Trial (SMART) have raised important questions about the safety of long-acting beta-agonists, particularly in African-American asthmatics ([9]). While the study's methodology prevents a “cause-and-effect” conclusion about the risk of these drugs, the uneven racial distribution of certain beta-receptor polymorphisms associated with an altered bronchodilator response provides a genetic basis for the excess adverse events observed in African-Americans ([10], [11]). It has also been shown that T-lymphocytes from African-American asthmatics are less responsive to corticosteroids than those from Caucasian patients and this may in part underlie the excess asthma morbidity in blacks ([13]).

Data such as these are unavailable in COPD and the efficacy and safety of existing therapies including bronchodilators, corticosteroids, vaccination, pulmonary rehabilitation, and lung volume reduction surgery in African-Americans is based on extrapolation of data from Caucasians or from small numbers of African-American trial participants. The study by Criner and colleagues is the first to examine the biologic response to a bronchodilator in African-Americans with COPD and to correlate this with patient reported outcomes ([1]). The results highlight several important limitations to these typically used generalizations.

In this 8-week randomized trial of tiotropium versus placebo, Criner reports spirometric improvements that are comparable to those observed in the general population of previous clinical trials and to a post-hoc analysis of the African-American patients who participated ([1], [12], [14]). However, these improvements produced unexpected effects on patient centered outcomes. Firstly, unlike previous placebo-controlled trials of tiotropium ([12]), the drug did not reduce rescue albuterol use. This is almost certainly explained in part by the fact that unlike prior trials, long acting beta-agonists were permitted and frequently used in the Criner study and that baseline albuterol use was lower. These facts may be causally related though it is also possible that the lower albuterol use was the result of poor beta-agonist responsiveness among African-Americans ([10], [11], [15]). Although permitting the use of long-acting beta-agonists may have reduced the power of the study to detect changes in rescue albuterol use, this does make the trial a better measure of the real-world effectiveness of supplemental tiotropium in moderate to severe COPD. It is important to note that the results may have also been impacted by the mismatch in baseline medication usage between those in the tiotropium and placebo arms as the former were more often prescribed most of the first-line COPD treatments.

Second, again in contrast to previous studies ([12]), no improvements in measures of dyspnea were observed. It should be noted that the metric used in the study, the San Diego Shortness of Breath Questionnaire (SOBQ), has not been validated in African-Americans and the possibility of cultural bias is real. There are no published studies examining racial or ethnic differences in the perception of dyspnea in COPD. Studies in asthmatics suggest that African-Americans and Caucasians equally overestimate their level of asthma control ([16], [17]) and that both poorly perceive resistive loading ([18]). However, African-American children and their parents are more likely to report “non-standard” asthma symptoms than their White counterparts ([16]). In addition, when challenged with methacholine, African-American asthmatics primarily used descriptors of upper airway dysfunction while whites reported lower airway and chest wall symptoms ([19]). Whether the SOBQ or other standard COPD clinical research questionnaires are valid in African-Americans is an unanswered and in fact unstudied question.

Finally, it is notable that in the study by Criner tiotropium was associated with a significant and unexpected reduction in the frequency of exacerbations when compared to placebo and when compared to previous studies ([1], [12], [20]). Although the definition of exacerbation was not prespecified, most events were associated with antibiotic or steroid use. One could speculate that anti-cholinergic therapy may be more beneficial for the prevention of exacerbations in African-Americans. This would be consistent with one report suggesting that this subpopulation may have greater methacholine reactivity ([19]).

Unfortunately, racial disparities in COPD treatment have been documented and African-Americans are less likely than Whites to be counseled against smoking, to receive influenza vaccination, and to receive portable oxygen ([21]). Whether these disparities are driven by physician bias, limitations in access to care or patient preference is unknown though they may have already led to poor outcomes among African-Americans with COPD ([21]). The study by Criner suggests that we might expect racial differences in the clinical response to COPD treatments though it is not clear whether this is based on biologic differences or cultural biases in our measurement tools. Further studies will help clarify these issues and are necessary to prevent the further divergence of COPD outcomes based on race.