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

Unipolar Voltage-Guided Individualized Substrate Modification Combined With Pulsed Field Ablation-Based Pulmonary Vein Isolation Versus Pulmonary Vein Isolation Alone in Persistent Atrial Fibrillation: A Multicenter, Randomized, Open-Label, Superiority Trial

UNI-PFA is a multicenter, randomized, open-label, superiority trial evaluating whether adding unipolar voltage-guided individualized substrate modification to pulsed field ablation (PFA)-based pulmonary vein isolation (PVI) improves outcomes in patients with persistent atrial fibrillation and a left atrial low-voltage area (LVA) burden of at least 10% of the post-PVI left atrial surface area. Participants are randomized 1:1 to PFA-PVI plus individualized substrate modification (homogenization, box isolation, linear ablation, or a combination) or PFA-PVI alone. 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. Follow-up includes 14-day continuous ECG patch monitoring at 3, 6, and 12 months, symptom-triggered single-lead ECG, and quality-of-life assessments.

Study Overview

• Status: Not yet recruiting
• Conditions: Atrial Fibrillation (AF)
• Intervention / Treatment: Device: VARIPULSE Pulsed Field Ablation System; Procedure: Pulmonary Vein Isolation; Procedure: Individualized Substrate Modification

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 294
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ligang Ding, MD, PhD; Phone Number: +8601088233162; Email: dlgang@163.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100037
      • Fuwai Hospital, Chinese Academy of Medical Sciences
      • Contact: Ligang Ding, MD, PhD; Phone Number: +8601088233162; Email: dlgang@163.com
      • Principal Investigator: Ligang Ding, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. ECG-documented persistent or long-standing persistent atrial fibrillation (ESC definition).
2. Symptoms (palpitations, dyspnea, fatigue, etc.) attributable to atrial fibrillation.
3. Suitable for catheter ablation.
4. At least one class I/III antiarrhythmic drug has been tried, or the patient is unwilling to try.
5. Age 18 years or older.
6. Intraoperative left atrial voltage mapping demonstrating a unipolar low-voltage area (cutoff 2.5 mV) of at least 10% of the post-PVI left atrial surface area (excluding the pulmonary vein antra, left atrial appendage, and fossa ovalis).

Exclusion Criteria:

1. Left atrial diameter >55 mm on echocardiography.
2. Acute coronary syndrome or coronary artery bypass grafting within 12 weeks.
3. Severe aortic or mitral valve disease (ESC definition).
4. Congenital heart disease.
5. Prior surgical or percutaneous atrial fibrillation ablation, or atrioventricular node ablation.
6. Prior left atrial surgery.
7. Comorbidity with expected survival <1 year.
8. NYHA class IV heart failure symptoms.
9. Contraindication to oral anticoagulation.
10. Dialysis-dependent renal failure.
11. Atrial fibrillation due to reversible causes.
12. Pregnancy or women of childbearing potential not using contraception.
13. History of poor treatment adherence.
14. Unable or unwilling to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PFA-PVI Plus Individualized Substrate Modification; Pulsed field ablation (PFA)-based pulmonary vein isolation plus unipolar voltage-guided individualized substrate modification. Substrate modification is selected according to low-voltage area location and may include homogenization, box isolation, linear ablation, or a combination.	Device: VARIPULSE Pulsed Field Ablation System; Pulsed field ablation catheter and generator used to perform pulmonary vein isolation in both study arms.; Procedure: Pulmonary Vein Isolation; Pulsed field ablation-based pulmonary vein antral isolation with confirmation of entrance and exit block in all pulmonary veins; performed in both arms.; Procedure: Individualized Substrate Modification; Unipolar voltage-guided individualized substrate modification selected according to low-voltage area location, including homogenization, box isolation, linear ablation, or a combination. Performed in the experimental arm only.
Active Comparator: PFA-PVI Alone; Pulsed field ablation (PFA)-based pulmonary vein isolation alone, without substrate or prophylactic ablation.	Device: VARIPULSE Pulsed Field Ablation System; Pulsed field ablation catheter and generator used to perform pulmonary vein isolation in both study arms.; Procedure: Pulmonary Vein Isolation; Pulsed field ablation-based pulmonary vein antral isolation with confirmation of entrance and exit block in all pulmonary veins; performed in both arms.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Success at 12 Months After the Index Ablation Procedure	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 (1-2 procedures total). Patients who remain on class I/III antiarrhythmic drugs at 12 months are counted as treatment failures; missing primary outcome data are counted as treatment failures.	12 months after the index ablation procedure

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to First Recurrence After a Single Procedure Off Antiarrhythmic Drugs	12 months after the index procedure
Change in AFEQT Quality-of-Life Score From Baseline to 12 Months	Baseline and 12 months
Incidence of Prespecified Procedure-Related Complications	90 days after ablation; all-cause mortality at 12 months
Freedom From Atrial Arrhythmia at 12 Months After a Single Procedure Off Antiarrhythmic Drugs	12 months
Freedom From Atrial Arrhythmia at 12 Months After a Single Procedure With or Without Antiarrhythmic Drugs	12 months
Freedom From Atrial Arrhythmia at 12 Months After 1-2 Procedures With or Without Antiarrhythmic Drugs	12 months
Freedom From Atrial Fibrillation at 12 Months After 1-2 Procedures Off Antiarrhythmic Drugs	12 months
Atrial Arrhythmia Burden at 3, 6, and 12 Months	14-day period before each follow-up visit
Time to First Recurrence After Any Number of Procedures	12 months
Number of Repeat Ablations Within 12 Months	12 months after the index procedure
Procedure Duration	Index procedure
Total Fluoroscopy Time	Index procedure

Collaborators and Investigators

• Sponsor: China National Center for Cardiovascular Diseases
• Collaborators: The Second Hospital of Hebei Medical University; Guangdong Provincial People's Hospital; Affiliated Hospital of Hebei University; The Second Affiliated Hospital of Chongqing Medical University; Second Affiliated Hospital of Xi'an Jiaotong University; Sir Run Run Shaw Hospital; The University of Hong Kong-Shenzhen Hospital; Shanxi Cardiovascular Hospital
• Investigators: Principal Investigator: Ligang Ding, MD, PhD, Chinese Academy of Medical Sciences, Fuwai Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: November 3, 2026
• First Submitted That Met QC Criteria: November 3, 2026
• First Posted (Actual): November 9, 2026

Study Record Updates

• Last Update Posted (Actual): November 9, 2026
• Last Update Submitted That Met QC Criteria: November 3, 2026
• Last Verified: October 1, 2026

More Information

Terms related to this study

• Keywords: persistent atrial fibrillation pulsed field ablation low-voltage area substrate modification pulmonary vein isolation unipolar voltage mapping
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Pathological Conditions, Signs and Symptoms; Atrial Fibrillation
• Other Study ID Numbers: UNI-PFA-2026-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Individual participant data will not be shared. Aggregate study results will be published and presented. The informed consent and institutional data-governance approvals do not permit public deposition of individual participant data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No