Introduction

Studies have demonstrated important disparities in the care of racial and ethnic minority patients with atrial fibrillation (AF) (1–3). Blacks and Hispanics are less likely to receive oral anticoagulation than Whites, even when adjusting for clinical and socioeconomic factors (2–5). When they do receive anticoagulation, the quality of anticoagulant use is lower in racial and ethnic minority patients who spend a greater time outside the therapeutic range compared with White patients (6,7). Blacks and Hispanics are also less likely than Whites to receive direct oral anticoagulants (DOACs) for AF (4–6), despite practice guidelines recommending DOACs over warfarin in eligible patients.

Racial and ethnic minorities, including Blacks and Hispanics, are less likely to be treated with rhythm control strategies, especially catheter ablation (1,2,8–10). In this issue of the Journal, Thomas et al (11) present the first randomized trial data describing outcomes of catheter ablation in racial and ethnic minorities who were enrolled in the CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation; NCT00911508) trial in North America in a pre-specified racial and ethnic subgroup analysis. Of 1,280 participants in North America, 127 (9.9%) were racial and ethnic minorities, as defined by the National Institutes of Health minority classification. Racial and ethnic minorities were younger and more likely than nonminorities to have hypertension, symptomatic heart failure (HF), left ventricular hypertrophy (LVH), and ejection fraction (EF) <40%. Although there was no significant difference in the primary composite endpoint of death, disabling stroke, serious bleeding, or cardiac arrest for ablation and drug therapy groups in the main CABANA trial (12), racial and ethnic minorities treated with ablation demonstrated a 68% relative reduction in the primary endpoint (adjusted hazard ratio [aHR]: 0.32; 95% CI: 0.13-0.78). In racial and ethnic minorities, the primary outcome occurred in 12.9% of those in the ablation arm and 23.1% in the drug therapy arm. In racial and ethnic minorities treated with ablation, there was also a 72% relative reduction in all-cause mortality (aHR: 0.28; 95% CI: 0.10-0.79). This clinical advantage of ablation in minorities was primarily due to substantially worse outcomes in the drug therapy arm. Racial and ethnic minorities in the drug arm had an early acceleration of mortality during the first 12 months following randomization, which accounted for most of the difference.

Why might drug therapy result in worse outcomes in racial and ethnic minorities? One possibility is that antiarrhythmic drugs can lead to proarrhythmia, which may be more likely to occur in the setting of HF, reduced LV function or LVH. This would be consistent with higher occurrence of symptomatic HF, EF <40%, and LVH in racial and ethnic minorities enrolled in CABANA (11). Although cardiac arrest, ventricular fibrillation, or ventricular tachycardia events occurred in 6.3% of racial and ethnic minority patients and in 2.3% of nonminority patients, none of these events were assessed by the investigators as related to drug therapy. In addition, racial and ethnic minorities were less likely to be treated with dronedarone or flecainide and more likely to receive amiodarone, the latter of which is less likely to be associated with adverse effects in HF patients or to result in proarrhythmia compared with other antiarrhythmic agents. Among racial and ethnic minorities with AF, catheter ablation relative to drug therapy produced significant reductions in time to first recurrence of AF (55% relative risk reduction). It is also possible that drug therapy may have been less effective in maintaining sinus rhythm in racial and ethnic minorities based on AF burden, and that adverse effects of recurrent arrhythmia could affect outcomes, but the sample size using the proprietary recording system is too small to investigate this possibility.

Racial differences in arrhythmia substrate may contribute to differences in outcomes. Blacks are more likely to have hypertension and LVH, and the presence of hypertrophy itself may predispose to potentially lethal ventricular arrhythmias. Worse clinical outcomes and early acceleration of mortality during the first 12 months following randomization in racial and ethnic minorities in the drug therapy arm of CABANA could be related to differences in arrhythmia substrate compared with nonminority groups with an interaction between hypertensive heart disease and drug therapy. In the MUSTT (Multicenter Unsustained Tachycardia Trial; NCT00000480), there was a trend toward decreased inducibility of sustained ventricular arrhythmias in Blacks compared with Whites (37% vs 31%; P = 0.054), despite the presence of underlying coronary artery disease and reduced LV function in both racial groups (13). Blacks also had a higher rate of initial drug response at electrophysiology (EP) testing, suggesting potential differences in arrhythmia substrates (13). There was an increased risk of arrhythmic death/cardiac arrest in Blacks treated with EP-guided therapy, suggesting increased risk of proarrhythmia of antiarrhythmic drugs in Blacks (13).

In CABANA, racial and ethnic minorities were more likely to have symptomatic HF and an EF <40% (11). The CASTLE-AF (Catheter Ablation Versus Standard Conventional Treatment in Patients With LV Dysfunction and AF; NCT00643188) trial demonstrated that catheter ablation of AF is associated with a significantly lower rate of death or hospitalization for worsening HF compared with medical therapy in patients with HF and reduced EF (14). A recently published analysis of patients with HF enrolled in CABANA demonstrated that catheter ablation resulted in improvements in survival and freedom from AF occurrence compared with drug therapy (15). The current analysis is consistent with findings from previous studies suggesting improved outcomes of ablation compared with drug therapy in patients with HF and reduced LV function.

The authors point out the possibility that the unexpected higher mortality rate in the racial and ethnic minority drug arm patients may at least partially represent an adverse interaction between rhythm control drugs, hypertensive heart disease, and symptomatic HF. In addition, various racial and ethnic minority groups were combined for the purpose of this analysis according to NIH classification, without any medical or physiological basis for this grouping. Asian race was not included in the racial and ethnic minority group because this is not considered a minority as defined by the NIH classification. Very small numbers of certain racial and ethnic minorities, including American Indian, Alaskan Native, Hawaiian, other Pacific Islanders or multiracial subgroups were included in the minority group, and a homogeneous response in various minority subgroups cannot be presumed. It is also possible that optimizing guideline-directed medical therapy for HF and control of comorbidities, such as treatment of hypertension or diabetes, could have differed between racial and ethnic subgroups, contributing to differential effects of randomized therapy on outcomes. Although the sample size was too small to allow evaluation of the interaction of these factors or to separate examination of various racial and ethnic subgroups, this study represents the most extensive analysis of AF treatment outcomes stratified by race or ethnicity in the literature (16).

Thomas et al (11) should be commended on reporting outcomes in a diverse North American population of patients undergoing ablation versus drug therapy in a large randomized clinical trial. These findings further highlight the importance of enrolling a racially and ethnically diverse group of subjects in clinical trials, because outcomes may not necessarily be generalizable to all subgroups. Gaining a better understanding of racial differences in treatment of AF and its relationship to outcomes is essential for developing comprehensive practice guidelines and eliminating racial disparities in the treatment of underrepresented populations with AF. This paper should be a “call to action” to ensure that all treatment options, including catheter ablation, are widely accessible to provide the highest quality of care for all patients with AF.

Footnotes