Introduction: The Paradox of Multimorbidity in Atrial Fibrillation
Atrial fibrillation (AF) is rarely a solitary diagnosis. In clinical practice, the typical AF patient presents with a constellation of coexisting conditions, including hypertension, heart failure, diabetes, and chronic kidney disease. This state of multimorbidity significantly complicates the management of AF, as the cumulative burden of these conditions often dictates both the progression of the arrhythmia and the patient’s overall prognosis. Historically, clinicians have been more hesitant to recommend invasive procedures like catheter ablation to patients with high comorbidity burdens, often opting for more conservative medical management due to perceived risks and lower expected efficacy. However, emerging evidence suggests that it is precisely these high-risk patients who may stand to gain the most from definitive rhythm control. The Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial was designed to address the comparative effectiveness of these two strategies. This latest post hoc analysis of the CABANA data provides a critical look at how the total burden of comorbidities influences the outcomes of catheter ablation versus medical therapy.
Highlights of the Study
The following points summarize the key insights from this comprehensive analysis:
Differential Clinical Impact
Catheter ablation was associated with a 38 percent reduction in the primary composite endpoint (death, stroke, bleeding, or cardiac arrest) in patients with a high comorbidity burden, whereas no such benefit was observed in those with a low burden.
Rhythm and Quality of Life
While ablation reduced AF recurrence in all patients, the improvements in AF-related quality of life were more sustained and pronounced in those with the highest number of coexisting conditions.
Evidence-Based Shift
The findings challenge the traditional ‘healthy candidate’ bias, suggesting that multimorbidity should serve as an indicator for, rather than a contraindication to, catheter ablation in AF management.
Study Design and Methodology
This study was a post hoc analysis of the landmark CABANA trial, which remains one of the largest randomized controlled trials comparing catheter ablation with drug therapy. The researchers included 2,204 patients from the original cohort, stratifying them based on their overall comorbidity burden. To define this burden, the investigators utilized a data-driven threshold derived from 15 pre-specified clinical conditions, including but not limited to heart failure, hypertension, diabetes, sleep apnea, and vascular disease. Patients were categorized into two groups: those with a ‘high comorbidity burden’ (defined as having 4 or more conditions) and those with a ‘low burden’ (3 or fewer conditions). The primary outcome was a composite endpoint consisting of all-cause mortality, disabling stroke, serious bleeding, or cardiac arrest. Secondary endpoints included cardiovascular hospitalizations and a composite of all-cause mortality or cardiovascular hospitalization. The researchers also examined AF recurrence through longitudinal monitoring and assessed quality of life using standardized instruments within a designated sub-cohort. The median follow-up period was 3.9 years, providing a robust window into the long-term clinical trajectory of these patients.
Key Findings: Does Comorbidity Burden Modify Treatment Effect?
The results of the analysis revealed a striking interaction between comorbidity burden and the effectiveness of catheter ablation. Among the 736 patients identified as having a high comorbidity burden, the adjusted hazard ratio (aHR) for the primary composite outcome was 0.62 (95% CI: 0.42-0.93) in favor of catheter ablation. In contrast, for the 1,468 patients with a low comorbidity burden, the aHR was 1.16 (95% CI: 0.76-1.77). The interaction p-value of 0.038 confirms that the benefit of ablation was significantly modified by the presence of multiple comorbidities.
Reduction in Hospitalizations
The secondary outcomes followed a similar trend. In the high-burden group, catheter ablation was associated with a significant reduction in the composite of all-cause mortality or cardiovascular hospitalization. This suggests that for patients who are frequently in and out of the healthcare system due to their various conditions, successful rhythm control through ablation may provide a much-needed stabilization of their clinical status.
Rhythm Control and AF Recurrence
Interestingly, catheter ablation was highly effective at maintaining sinus rhythm regardless of comorbidity status. The relative risk reduction for AF recurrence was 49 percent in the low-burden group and 40 percent in the high-burden group. While the low-burden group saw a slightly higher relative reduction in recurrence, the absolute benefit in the high-burden group was substantial, considering their higher baseline risk for arrhythmia progression and associated complications.
Sustained Quality of Life Improvements
Perhaps most importantly for the patient experience, the study found that AF-related quality of life improved in both groups after ablation. However, in the high comorbidity group, these benefits were more sustained over the follow-up period. Patients with multiple chronic illnesses often have a lower baseline quality of life; the successful reduction of their AF symptom burden appears to have a disproportionately positive impact on their overall well-being.
Expert Commentary: Mechanistic Insights and Clinical Implications
The findings from this CABANA post hoc analysis are provocative and necessitate a shift in how we approach the multimorbid AF patient. Why would patients with more comorbidities benefit more from ablation? One hypothesis is that in patients with high comorbidity, AF acts as a ‘tipping point’ that exacerbates other conditions, such as heart failure or renal dysfunction. By eliminating AF, clinicians may be removing a significant physiological stressor, allowing for better management of the patient’s other chronic diseases. Furthermore, patients with high comorbidity burdens have a higher absolute risk of adverse events. In the world of clinical trials, a therapy often shows its greatest benefit in the highest-risk populations because there is more ‘room’ for improvement. This is likely what we are seeing here: the absolute risk reduction provided by ablation is more significant when the baseline risk is elevated. It is also worth noting that the ‘low burden’ group in this study did not show a statistically significant benefit for the primary outcome. This does not mean ablation is ineffective for them, but rather that their baseline risk of stroke or death is already low, making it difficult to demonstrate further reduction within the timeframe of the trial. For these patients, the decision to ablate remains primarily driven by symptom management and rhythm control rather than hard clinical endpoints like mortality.
Conclusion and Future Directions
The results of this study support a broader consideration of catheter ablation in AF patients who have traditionally been viewed as ‘too sick’ or ‘too complex’ for the procedure. By demonstrating a 38 percent reduction in major clinical events for those with four or more comorbidities, the data suggest that we should be more proactive in offering ablation to this population. However, it is important to acknowledge the limitations of post hoc analyses. While these findings are robust, they are hypothesis-generating. Future prospective trials specifically targeting multimorbid populations are needed to confirm these results and to help refine patient selection. In the meantime, the CABANA trial continues to provide a wealth of data that moves us toward a more personalized approach to rhythm management. Clinicians should view the presence of multiple comorbidities not as a reason to avoid ablation, but as a potential signal that the patient may derive significant prognostic benefit from the procedure.
Funding and ClinicalTrials.gov Registration
The CABANA trial was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) and through various industry partnerships providing equipment and research support. The trial is registered at ClinicalTrials.gov with the identifier NCT00911508.
References
1. Chen Y, Soler-Espejo E, Zhao M, et al. Association between comorbidity burden and outcomes of catheter ablation vs. medical therapy for atrial fibrillation: insights from the CABANA trial. Europace. 2025 Dec 1;27(12):euaf292. doi: 10.1093/europace/euaf292. PMID: 41213867.
2. Packer DL, Mark DB, Robb RA, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Heart Failure, and Hospitalization Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA. 2019;321(13):1261–1274. doi:10.1001/jama.2019.0693.
3. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2021;42(5):373-498.
