Rethinking Rhythm Control for Secondary Stroke Prevention: Insights from the STABLED Randomized Clinical Trial

Highlights

• The STABLED trial demonstrates that adding catheter ablation to edoxaban therapy did not significantly reduce recurrent stroke or heart failure hospitalization in patients with nonvalvular atrial fibrillation (AF) and a recent stroke.
• The trial reported a primary composite endpoint hazard ratio (HR) of 1.11, indicating no superiority of the invasive strategy over standard anticoagulation alone.
• Observed event rates were lower than anticipated in both study arms, suggesting that modern Direct Oral Anticoagulants (DOACs) like edoxaban provide robust protection, making incremental gains from ablation difficult to statistically isolate.
• Safety data confirm that catheter ablation can be performed with high procedural safety (0.8% complication rate) even in patients with a recent history of ischemic stroke.

Background

Atrial fibrillation (AF) remains a leading cause of ischemic stroke, accounting for approximately 20-30% of all cases. For patients who have already experienced an index stroke, the risk of recurrence is markedly elevated, especially within the first year. Standard care for these patients centers on lifelong oral anticoagulation (OAC), with DOACs such as edoxaban currently preferred over vitamin K antagonists due to a superior safety profile regarding intracranial hemorrhage.

While anticoagulation addresses the thromboembolic mechanism, it does not mitigate the underlying arrhythmia or the associated risks of heart failure (HF) and atrial remodeling. Catheter ablation has emerged as a gold standard for rhythm control, demonstrating superiority over antiarrhythmic drugs (AADs) in maintaining sinus rhythm. Pivotal trials such as CASTLE-AF have suggested mortality and HF benefits in specific populations, yet the specific role of catheter ablation in secondary stroke prevention—beyond what is achieved by OAC—remains a subject of intense clinical debate. The Stroke Secondary Prevention With Catheter Ablation and Edoxaban for Patients With Nonvalvular Atrial Fibrillation (STABLED) trial was designed to address this critical gap in evidence.

Key Content

The STABLED Trial: Methodology and Findings

The STABLED study (NCT03777631) was a multicenter, open-label, randomized clinical trial conducted across 45 sites in Japan. It targeted a high-risk cohort: patients aged 20-85 with nonvalvular AF and a recent history of ischemic stroke (mRS ≤ 3). All patients received edoxaban, but the intervention group underwent catheter ablation within 1 to 6 months of the index stroke.

Over a median follow-up of 3 years, the results (published in JAMA Neurology, 2026) showed that the primary composite endpoint (stroke, systemic embolism, death, HF hospitalization) occurred in 4.9% per person-year in the standard therapy group compared to 5.6% in the ablation group (HR 1.11; 95% CI, 0.62-2.01). Mortality rates were similarly undistinguished, at 1.0 and 2.8 per 100 person-years, respectively. Crucially, the trial was underpowered because the actual event rates were significantly lower than the 15% predicted during the design phase.

Contextualizing STABLED: Evolution of Rhythm Control Evidence

To understand the STABLED results, it is necessary to examine the broader landscape of rhythm control trials:

1. The Legacy of CABANA (2019): The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial was the largest RCT to compare ablation with medical therapy. While the primary intention-to-treat analysis for the composite endpoint of death, disabling stroke, serious bleeding, or cardiac arrest was neutral (HR 0.84, p=0.30), the per-protocol analysis suggested a potential benefit. However, the specific stroke rate was notably low in both arms, mirroring the findings in STABLED.

2. The Paradigm Shift of EAST-AFNET 4 (2020): This trial provided the strongest evidence for early rhythm control. It demonstrated that initiating rhythm control (ablation or AADs) within a year of AF diagnosis reduced cardiovascular death and stroke. Unlike STABLED, EAST-AFNET 4 included a broader AF population, not just post-stroke patients. The contrast suggests that while rhythm control is beneficial early in the AF disease course, its incremental value in a population already stabilized on high-quality anticoagulation post-stroke may be smaller than expected.

3. CASTLE-AF and HF Populations: In patients with AF and reduced ejection fraction, catheter ablation has shown clear benefits in reducing death and HF hospitalizations. STABLED’s cohort was older (mean age 71.7) and primarily focused on stroke recurrence, perhaps suggesting that in the absence of severe HF, the drive for sinus rhythm has less impact on survival and stroke than the baseline quality of anticoagulation.

Safety and Procedural Considerations

A significant concern in post-stroke patients is the safety of invasive procedures requiring periprocedural heparinization and transseptal puncture. STABLED reported an exceptionally low complication rate (0.8% for cardiac tamponade and 0.8% for procedural stroke). This reinforces the safety of catheter ablation in the subacute phase after a stroke, provided the patient has been stabilized on DOACs for at least 4 weeks.

Expert Commentary

The “Power” Paradox and the Efficacy of DOACs

The primary takeaway from STABLED is not necessarily that ablation is ineffective, but that edoxaban is highly effective. When the control group performs better than historical averages, demonstrating a statistically significant improvement with any additional intervention becomes mathematically challenging. In STABLED, the annual stroke rate in the control group was surprisingly low, suggesting that adherence to edoxaban in a clinical trial setting may provide a ceiling for stroke prevention that rhythm control cannot easily break.

Mechanistic Insights: AF Burden vs. Atrial Cardiopathy

There is an increasing focus on the concept of “atrial cardiopathy,” where the stroke risk is tied to the fibrotic state of the atrium rather than the arrhythmia itself. If the index stroke was caused by a substrate that remains even after successful rhythm control, ablation may prevent the “trigger” (AF) but not the “substrate” (thrombus formation in a diseased atrium). This might explain why ablation reduces symptoms but did not significantly alter stroke outcomes in the STABLED population.

Clinical Applicability

For clinicians, these findings suggest that catheter ablation should continue to be prioritized for symptom management and potentially for patients with concomitant heart failure. However, for the specific goal of secondary stroke prevention, it cannot yet be recommended as a replacement for, or a necessary addition to, rigorous anticoagulation. The “wait and see” approach for rhythm control post-stroke appears safe, provided the patient remains asymptomatic and adequately anticoagulated.

Conclusion

The STABLED trial provides high-quality, randomized evidence that catheter ablation added to edoxaban does not further reduce the composite risk of stroke, death, or heart failure in patients with a recent history of stroke. While the study was underpowered due to low event rates, it underscores the formidable efficacy of modern anticoagulation. Future research should focus on identifying specific subgroups—perhaps those with high AF burden or progressive heart failure—who might derive a more clear-cut benefit from an early invasive rhythm control strategy after a cerebrovascular event.

References

• Kimura K, et al. Catheter Ablation and Oral Anticoagulation for Secondary Stroke Prevention in Atrial Fibrillation: The STABLED Randomized Clinical Trial. JAMA Neurol. 2026. PMID: 41770549.
• Packer DL, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA. 2019;321(13):1261-1274. PMID: 30874756.
• Kirchhof P, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020;383(14):1305-1316. PMID: 32865375.
• Marrouche NF, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med. 2018;378(5):417-427. PMID: 29412959.
• Di Biase L, et al. Ablation Versus Amiodarone for Treatment of Atrial Fibrillation in Patients With Left Ventricular Ejection Fraction Less Than 40% and an Implantable Cardioverter Defibrillator: The AATAC Multicenter Randomized Trial. J Am Coll Cardiol. 2016;67(16):1891-1903. PMID: 27012404.