John M. Fontaine, MD, MBA, FACC, FHRS

The article by Thomas et al and the CABANA trial investigators published in the July issue of the Journal of the American College of Cardiology compares the responses of racial and ethnic minorities to treatment of AF via catheter ablation vs. medical treatment strategies. This trial focused on 127 patients from a self-identified cohort of African American and Hispanic patients (with a small number of other minority groups added in) in North America who were enrolled in the CABANA trial and followed for a median period of 54.9 months. The results showed that the catheter ablation procedure was superior to medical therapy in this group of patients characterized by a significantly younger age (mean age, 65.6 vs. 68.5 years), with more hypertension, cardiac hypertrophy, symptomatic HF and reduced left ventricular ejection fraction (< 40%) compared with their white counterparts. We are aware that this report is a subgroup analysis, and the primary CABANA trial did not show any significant difference in outcomes between the treatment strategies, catheter ablation and medical treatment. Part of that reason was that in the intention-to-treat analysis, there was a 27% crossover from the medical arm to the ablation arm, but intention-to-treat requires that you keep the study subjects in their original group when you do the analysis. In the on-treatment analysis, there was a difference in the primary endpoint, being CV events, including CV death and overall mortality, which was affected by the intention-to-treat analysis methodology. The on-treatment analysis showed that there was benefit in the primary endpoint and a reduction in recurrence of AF in favor of catheter ablation. The investigators concluded that there is still no difference in the primary outcome for the main study that would apply to patients in the subgroup as the latter analysis is underpowered.

The main point of this article is that a notable difference in outcomes between the catheter ablation arm and the medical treatment arm was observed. A 68% relative reduction in the primary endpoint and 72% reduction in all-cause mortality were noted among underrepresented racial and ethnic groups benefiting the ablation arm vs. the medical treatment arm; whereas no difference in outcomes was noted in the ablation arm between racial and ethnic groups and non-Hispanic white or Asian patients.

Concerningly, patients from underrepresented racial and ethnic group experienced significantly greater incidence of cardiac arrest (6.3 vs. 2.3%), and the reason was not elucidated but speculative. I was surprised by that. The researchers did discuss the potential role of LV hypertrophy, symptomatic HF and comorbidity conditions. But these conditions render antiarrhythmic therapy unsafe, as opposed to catheter ablation. Underrepresented racial and ethnic groups in the medical treatment arm of this study were predisposed to complications, meaning that antiarrhythmic drugs provided in the medical treatment arm would confer more adverse events in patients with ventricular hypertrophy, HF or low EF. In this study, underrepresented racial and ethnic groups had a larger proportion of people with EF less than 40% compared with non-Hispanic white or Asian patients. When LVEF is low, the response to antiarrhythmic therapy might result in an adverse outcome.

This CABANA subgroup analysis informs us that, in utilizing medical therapy in any group of patients with AF, if a comorbid condition exists such as symptomatic HF, low EF or LV hypertrophy, it may mitigate against the use of a medical treatment strategy and in favor of catheter ablation.

Now, if one also looks at the Kaplan-Meier curve for this analysis, it is concerning that after 30 months, racial and ethnic group event rates begin to increase irrespective of treatment arm. I was surprised the researchers did not mention which method of analysis of the Kaplan-Meier curve was used, meaning log-rank test, the most commonly used. Log rank looks at the totality of the time under evaluation, from zero to 48 months, as opposed to Breslow, which emphasizes early periods. That is concerning because that curve rises much more than that for non-Hispanic white or Asian patients. What is the significance of that? Are these patients not being followed carefully? Are they getting away from the medical treatment that has been prescribed? Is there an access-related issue?

The medical therapy arm is potentially problematic, but even in the ablation arm, we know that up to 30% of AF ablation procedures may need to be redone within 2 years or so. In the presence of comorbidities, what happens to the cardiac substrate that is responsible for the AF? That substrate may be changing, or maybe there is some remodeling that would allow progression from paroxysmal to persistent or permanent AF. If there is ongoing substrate or electrical remodeling because of factors such as cardiac hypertrophy, uncontrolled hypertension, etc, then AF recurrence will be more difficult to manage. The implications from the findings in this study support the use of catheter ablation in underrepresented racial and ethnic groups, medical treatment of patients for rhythm control of AF should be guided by a safety-first approach along with careful assessment of the cardiac substrate and for the presence of comorbid conditions.