Unipolar Voltage-Guided Substrate Modification Plus Pulsed Field Ablation Pulmonary Vein Isolation Versus Pulmonary Vein Isolation Alone in Persistent Atrial Fibrillation (UNI-PFA)

Background: Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation for atrial fibrillation, but outcomes in persistent atrial fibrillation remain suboptimal, with approximately 50% freedom from recurrence in unselected patients. Left atrial low-voltage areas (LVAs) are an electrical surrogate for atrial fibrosis and predict recurrence after PVI. Unipolar voltage mapping may detect intramural or epicardial fibrosis that bipolar mapping misses. Pulsed field ablation (PFA) provides preferential myocardial ablation with a favorable safety profile. Whether adding unipolar voltage-guided individualized substrate modification to PFA-PVI improves outcomes in patients with a substantial LVA burden is unknown.

Design: UNI-PFA is a multicenter, randomized, open-label, superiority trial. Approximately 294 participants with persistent or long-standing persistent atrial fibrillation and a unipolar LVA burden of at least 10% of the post-PVI left atrial surface area (excluding the pulmonary vein antra, left atrial appendage, and fossa ovalis) will be randomized 1:1. Randomization is stratified by sex and LVA proportion category (10-20%, 20-30%, and >30%). The experimental arm receives PFA-PVI plus individualized substrate modification selected according to LVA location (homogenization, box isolation, linear ablation, or a combination); the active comparator arm receives PFA-PVI alone. All participants receive 14-day continuous ECG patch monitoring at 3, 6, and 12 months, symptom-triggered single-lead ECG, and unscheduled ECG/Holter/telemetry when clinically indicated.

Endpoints: The primary endpoint is treatment success at 12 months, defined as freedom from documented atrial fibrillation, atrial tachycardia, or atrial flutter lasting more than 30 seconds after a 90-day blanking period while off class I/III antiarrhythmic drugs, allowing up to one repeat ablation within 6 months of the index procedure. Patients who remain on class I/III antiarrhythmic drugs at 12 months are counted as treatment failures. Twelve prespecified secondary endpoints include arrhythmia-free survival, quality of life (AFEQT), arrhythmia burden, repeat ablation, procedure duration, and fluoroscopy time. Sixteen prespecified safety endpoints are adjudicated by an independent, blinded clinical events committee.

Eligibility: Adults aged 18 years or older with symptomatic persistent or long-standing persistent atrial fibrillation, suitable for catheter ablation, who have tried at least one class I/III antiarrhythmic drug or are unwilling to do so, and who meet the intraoperative unipolar LVA criterion. Key exclusions include left atrial diameter >55 mm, recent acute coronary syndrome or coronary artery bypass grafting, severe valvular disease, prior atrial fibrillation ablation or left atrial surgery, NYHA class IV heart failure, contraindication to oral anticoagulation, dialysis-dependent renal failure, and pregnancy.