A multicentre, parallel group, two arm, single-blinded randomized clinical trial, assessing the efficacy of a patient-tailored catheter ablation (CA) strategy guided by atrial low voltage area mapping in addition to pulmonary vein isolation (PVI) when compared to PVI alone in patients with persistent atrial fibrillation (AF).

The optimal CA strategy for persistent AF remains unknown. Current data highlight the need for a better understanding of the substrate and mechanisms of arrhythmia maintenance in this population. Atrial low voltage area (LVA)-based catheter ablation has recently emerged as a promising strategy for ablation of AF. However, the available data has limitations that preclude definitive conclusions regarding the utility of this strategy (no data from multicenter, randomized studies available). Further research is needed to assess the role of LVA-based ablation for persistent AF.

The Investigators hypothesize that catheter ablation of persistent AF (PeAF) tailored to abolish abnormal atrial substrate identified by intracardiac atrial (LVA) mapping in addition to pulmonary vein isolation (PVI) will result in higher procedural success rates when compared to PVI alone.

The study will recruit 502 patients with PeAF (251 per treatment arm) who are candidates for CA ablation of AF according to the treating physician (and in agreement with current practice guidelines). Subjects will be recruited over a 42-month period. The total duration of the study is 60 months.

Prior to undergoing catheter ablation subjects will be seen by the investigator/ research assistant and the following data will be collected:

i. Age and sex ii. Structural heart disease if present iii. CHADS2VASc score iv. DR-FLASH score v. NYHA class vi. Current medications vii. Duration of uninterrupted AF viii. Height and weight ix. Echocardiogram and other cardiac imaging results (within previous 24 months, including assessment of left ventricular ejection fraction, left atrial volume and valve function) x. ECG, Holter or loop monitor recording (within past 36 months) documenting AF.

Subjects will be randomly assigned in a 1:1 ratio to undergo wide area circumferential ablation for pulmonary vein isolation (PVI- control arm) or wide area circumferential ablation PVI and atrial LVA ablation (experimental arm). Randomization will be stratified by centre and by sex. Subjects will be randomized prior to the procedure.

Enrolled subjects will have a clinical follow-up visit at 3, 6, 12, 18, 24 and 36 months after the ablation procedure, defined as Holter monitoring with equipment capable of recording 14 days of continuous ambulatory ECG. Patients will be followed for 36 months or until the last recruited patient completes the mandatory 18-month follow-up visit. The results of monitoring will be interpreted at a centralized core lab, and the results will be adjudicated by an arrhythmia specialist blinded to treatment group. A total of three questionnaires will be administered throughout the study, each at a specific time point. The Quality of Life (EQ-5D), CCS-Severity of AF scale, and Atrial Fibrillation Effect on Quality of life (AFEQT) will be completed at baseline, and at the 12-month and 18-month visit.

Concomitant medical therapy will be selected according to the treating physician. All subjects will be maintained on systemic oral anticoagulation for at least 2 months following catheter ablation.

Inclusion Criteria:

1. Age ≥18 years;
2. Subjects with symptomatic persistent AF AND clinically indicated catheter ablation for AF;
3. Persistent AF defined as a sustained episode beyond 3 months in duration;
4. At least one episode of AF must have been documented on 12-lead ECG, Holter monitor, loop monitor or trans-telephonic monitor (TTM) within 36 months of enrollment in the study;
5. Modified DR-FLASH score >=3

4. Subjects must be able to provide informed consent.

Exclusion Criteria:

1. History of previous catheter ablation for AF or left atrial flutter;
2. History of previous surgical ablation for AF;
3. Known intracardiac thrombus;
4. Contraindication to systemic oral anticoagulation therapy;
5. Reversible causes of AF;
6. Hypertrophic cardiomyopathy;
7. Severe valvular disease (mitral/aortic stenosis or regurgitation);
8. Subjects that are pregnant or breastfeeding;
9. Comorbid condition with life expectancy < 1 year

Single-blinded