The aim is to determine the effect of extended ablation (pre-specified linear PF/RF lesion set) in addition to PVI in symptomatic persistent AF patients on AF/AT/AFL recurrence. The study is designed as multicenter, randomized trial. Eligible patients are patients with persistent AF (but not long-standing persistent AF) planned for a first-ever AF ablation procedure. Patients will be randomly assigned 1:1 either to: i) PVI-only, or ii) PVI-plus arms. Patients in both groups will undergo catheter ablation using an ablation system capable of performing PF and RF ablation (Sphere-9, Affera, Medtronic). Patients randomized to the PVI-only arm will undergo only PVI. Patients randomized to the PVI-plus arm will undergo PVI plus linear lesions (roof, bottom line, lateral or anterior MI line, and septal line in the LA; intercaval line and cavotricuspid line in the RA). The primary endpoint will be freedom from recurrent AF/AT/AFL, assessed as time-to-first recurrence in the period of 12 months after randomization (post 2-month blanking period). Secondary clinical endpoints will be 1) 12-month differences in AF/AT/AFL burden, 2) AF/AFL/AT-related outcomes (hospitalization or emergency visits), 3) Quality of life according to the AFEQT questionnaire score at 12 months, 4) MACE defined as cardiovascular death, stroke, myocardial infarction, or hospitalization for heart failure. Secondary endpoints will be evaluated throughout the entire (minimum 12-month) follow-up period.

BACKGROUND The cornerstone of catheter ablation for AF is pulmonary vein (PV) isolation (PVI). PVI alone is highly effective in patients with paroxysmal AF; however, its efficacy is lower in patients with non-paroxysmal AF (persistent and long-standing persistent). For this reason, additional ablation strategies have been developed and investigated in patients with non-paroxysmal AF. However, results from randomized catheter-based studies comparing PVI alone with extended ablation strategies combining PVI with additional linear lesions have been inconsistent. While some studies showed no improvement in sinus rhythm (SR) maintenance with the addition of linear lesions compared with PVI alone, other studies demonstrated superiority of an extensive ablation approach, including linear lesions over PVI alone. A key determinant of success in these studies is the completeness of the ablation lesion set. . In studies using radiofrequency (RF) energy alone, such as the STAR AF II trial, all planned linear ablation lesions were completed in only 74% of patients during the procedure. Moreover, in the CAPLA study, comparing PVI alone with PVI combined with adjunctive left atrial (LA) posterior wall isolation using roof and inferior lines, posterior wall reconnections were present in 75% of patients. However, the results of older catheter ablation studies that relied solely on RF energy cannot be directly extrapolated to contemporary procedures performed using PF energy or combined PF/RF systems that also enable simultaneous endocardial mapping and thus reliable identification of conduction gaps and completion of ablation lesions. The markedly higher efficacy of these newer energy modalities and their combinations raises the question of whether highly effective comprehensive endocardial ablation, including linear lesions, will be associated with superior sinus rhythm maintenance compared with PVI alone.

The aim of this study is therefore to compare PVI-alone with an extended ablation strategy (PVI plus linear lesions) in patients with persistent AF, using a technology that enables ablation with both PF and RF energy and 3D mapping.

STUDY DESIGN Prospective, randomized controlled trial that will be conducted at 4 sites in the Czechia.

STUDY POPULATION The study focuses on patients with persistent AF as defined in recent ESC guidelines (i.e., with ≥2 AF episodes; ≥1 episode with a duration of >7 days) who are referred the catheter ablation in accordance with the indication criteria outlined in these guidelines.

Inclusion criteria:

• symptomatic persistent AF
• ≥1 episode of persistent AF in the last 12 months
• signed informed consent

Exclusion criteria:

• first-manifested AF, paroxysmal AF, long-standing persistent AF, permanent AF
• SR on admission without Class I/III AADs
• AF of secondary cause (e.g. hyperthyroidism)
• any previous LA ablation
• severe valvular disease (mitral valve insufficiency ≥3+, moderate or severe aortic stenosis) or history of valvular surgery or intervention
• left ventricular ejection fraction ≤40%
• pulmonary hypertension (estimated systolic pulmonary artery pressure ≥40 mm Hg)
• symptomatic coronary artery disease
• pregnancy
• LA anteroposterior diameter ≥55 mm
• body mass index ≥40 kg/m2
• age ≥80 years
• chronic kidney disease stage 3b or higher
• contraindication to anticoagulation
• general contraindications of catheter ablation
• life expectancy <2 years due to other comorbidities RANDOMIZATION AND MASKING Patients will be randomized to the PVI-plus or PVI-only arm. Operators, personnel involved in the procedure, and staff participating in the patient´s clinical follow-up will not be blinded to the treatment allocation.

ECG monitoring will be performed outside the participating centres, and the technicians and physicians analyzing the ECG recordings will be fully blinded to the patient's assignment.

ELECTROPHYSIOLOGICAL STUDY AND ABLATION PROCEDURE Ablation will be performed using an ablation system that enables endocardial mapping and delivery of both PF and RF energy (Affera, Medtronic, USA). The aim of ablation therapy in the PVI-only arm will be PVI alone. The objective in the PVI-plus arm will be, in addition to PVI, the deployment of a comprehensive ablation lesion set designed to block major atrial reentry circuits, including the roof and bottom lines, perimitral (lateral or anterior) line, septal line in the left atrium, and CTI line with intercaval line in the right atrium.

OUT-PATIENT FOLLOW-UP AND BLANKING PERIOD Starting on the day of randomization, out-patient follow-up visits will be scheduled at 2, 6, and 12 months. The first 2 months will serve as a blanking period. In the event of AF/AT/AFL recurrence during the blanking period, management with AADs and/or electrical cardioversion is permitted. In addition, all patients presenting with AF at the 2-month visit, irrespective of symptom burden, will be referred for early electrical cardioversion, so that the majority of patients enter the rhythm analysis period in SR. Five-day ECG monitoring will be performed at 3, 6, 9, and 12 months starting on the day of randomization, and every 6 months thereafter.

ENDPOINTS Primary endpoint The primary outcome is freedom from recurrent AF, AT, or AFL during the first 12 months (post 2-month blanking period), assessed as time to first documented recurrence. An episode of AF/ AT/AFL is defined as either (1) a recording demonstrating at least 30 seconds of continuous interpretable signal during Holter monitoring performed at 3, 6, 9, or 12 months, or (2) a 12-lead ECG demonstrating the arrhythmia throughout the entire tracing, with at least 10 seconds of continuous interpretable signal during scheduled or emergency visits.

Secondary endpoints

• AF/AFL/AT burden according to scheduled 5-day Holter monitoring at 3, 6, 9, or 12 months
• AF-related clinical outcomes, i.e., emergency visits or hospitalizations due to documented recurrence of AF/AFL/AT during the whole study course
• Quality of life assessment using the AFEQT questionnaire (a change between baseline and 12 months evaluation)
• Major adverse clinical outcomes (MACE), a composite of cardiovascular death, stroke, myocardial infarction, or hospitalization for heart failure during the whole study course The study will utilize a CEC to review and adjudicate clinical endpoints and AEs/SAEs.

Data management A tailor-made website will be developed for the study. Each participating medical centre will have access to a dedicated section of the website (data entry and randomization).

Sample size calculation We assume that 60% of patients in the PVI-only group will achieve freedom from AF/AT/AFL during the first year of follow-up. In contrast, freedom from AF/AFL/AT in the PVI-plus group is expected in at least 73% of patients, corresponding to an absolute difference of ≥13%. Assuming a two-sided alpha level of 0.05, a power of 80%, a total of 206 patients per group will be required. With an anticipated dropout rate of <5%, 450 patients are planned to be enrolled.

Statistical analysis and methods Analyses of the primary and secondary endpoints will be based on the intention-to-treat (ITT) principle. Standard descriptive statistical methods will be employed in the analysis. Categorical data will be summarized using absolute and relative frequencies, while continuous data will be described using either the mean with standard deviation (SD) or the median with interquartile range (IQR), depending on data distribution. Kaplan-Meier estimates and Cox proportional hazards regression models will be used for data visualization and analysis of the primary endpoint, as well as the clinical endpoint (AF-related outcomes and MACEs), with treatment group included as a covariate. The superiority of the PVI-plus approach (AF freedom at 12 months) will be evaluated using a two-sided Z-test. The values of AF burden at specific time frames will be evaluated using the Mann-Whitney test with multiplicity adjustment to assess the statistical significance of differences between the two groups. Additionally, the paired Wilcoxon signed-rank test will be used to evaluate the statistical significance of changes in AFEQT within each group between baseline and 12-month values. Secondary endpoints will be tested in a fixed hierarchical sequence.

Inclusion Criteria:

• symptomatic persistent AF
• ≥1 episode of persistent AF in the last 12 months
• signed informed consent

Exclusion Criteria:

• first-manifested AF, paroxysmal AF, long-standing persistent AF, permanent AF
• SR on admission without Class I/III AADs
• AF of secondary cause (e.g. hyperthyroidism)
• any previous LA ablation
• severe valvular disease (mitral valve insufficiency ≥3+, moderate or severe aortic stenosis) or history of valvular surgery or intervention
• left ventricular ejection fraction ≤40%
• pulmonary hypertension (estimated systolic pulmonary artery pressure ≥40 mm Hg)
• symptomatic coronary artery disease
• pregnancy
• LA anteroposterior diameter ≥55 mm
• body mass index ≥40 kg/m2
• age ≥80 years
• chronic kidney disease stage 3b or higher
• contraindication to anticoagulation
• general contraindications of catheter ablation
• life expectancy <2 years due to other comorbidities

Technicians and physicians responsible for Holter monitoring analysis will be fully blinded to treatment allocation.