Beyond Sinus Rhythm: Rhythm Control and Mechanism-Based Secondary Prevention in Atrial Fibrillation-Related Stroke

Atrial fibrillation is one of the most important causes of ischemic stroke and it is strongly associated with recurrent stroke, systemic embolism, heart failure, cognitive decline, and mortality. Oral anticoagulation, preferably direct oral anticoagulants, remains the cornerstone of secondary stroke prevention in patients with atrial fibrillation and a history of ischemic stroke. However, ischemic stroke may still occur despite appropriate anticoagulation therapy, a condition often referred to as breakthrough ischemic stroke. This residual risk reflects heterogeneous mechanisms, including inadequate anticoagulant exposure, atrial cardiomyopathy, left atrial appendage thrombus, large-artery atherosclerosis, small-vessel disease, cancer-associated thrombosis, and other competing etiologies. Rhythm control has re-emerged as a disease-modifying strategy after the EAST-AFNET 4 trial, and its prespecified subgroup analysis suggested a potential benefit in patients with prior stroke. However, the recently reported STABLED randomized clinical trial, which specifically evaluated catheter ablation in addition to edoxaban-based standard therapy after a recent ischemic stroke, did not demonstrate a significant reduction in recurrent ischemic stroke, systemic embolism, all-cause mortality, or hospitalization for heart failure. These findings do not negate the value of rhythm control for symptom relief, atrial fibrillation burden reduction, and selected cardiovascular outcomes; however, they challenge the assumption that the restoration of sinus rhythm alone is sufficient for secondary stroke prevention. Future strategies should integrate optimized anticoagulation and early rhythm control when appropriate, with a systematic evaluation of competing stroke mechanisms, vascular risk factor control, and selected left atrial appendage interventions. The next frontier is not rhythm control alone but rhythm control embedded within mechanism-based secondary stroke prevention.