Pulsed-field Ablation Vs. Sham Ablation to Treat AF

PURPOSE The purpose of PFA-Sham is to determine the relative efficacy of catheter ablation for symptomatic paroxysmal/persistent AF, when compared against a sham-ablation control procedure. This is a prospective, multi-center, single-blind, randomized trial.

There are two co-primary hypotheses. First, we hypothesize that patients in the catheter ablation group will experience greater freedom from recurrent AF/AT/AFL at 6 months post-procedure. There will be a two-month post-procedure blanking period in both groups. Freedom from AF/AT/AFL will be assessed as time to first recurrence (or to cross-over if earlier).

Second, compared with those in the sham-ablation control group, patients in the catheter ablation group will report higher quality of life as measured by the Atrial Fibrillation Effect on QualiTy of life (AFEQT) score, at 6 months post-procedure (or at cross-over if Early Exit).

METHODS The study will be a single-blind, multicenter, prospective, randomized control study. Subjects will be randomized 1:1 to either: (i) EP study + PFA, or (ii) EP study + Sham ablation control.

After informed consent is obtained, an implantable loop recorder (ILR) will be implanted within seven days, and an EP study will be scheduled for 30±5 days after ILR implantation.

Patients in both groups will first undergo an EP study to rule out a concealed AV bypass tract and supraventricular tachycardia (SVT), and catheter ablation of this substrate if present. Patients will not be randomized if SVT or concealed AV bypass tract is found during the EP study.

Once an SVT or bypass tract is excluded, randomization will be performed. Patients randomized to Ablation will undergo PVI using the commercially-available pentaspline PFA catheter (Farawave, Farapulse-BSCI Inc). Patients randomized to the Sham-ablation Control group will undergo approximately 20-30 min of anesthesia with propofol and benzodiazepines in a similar manner as patients in the ablation arm.

INCLUSION CRITERIA

1. Age \>18 years 2. Paroxysmal or Persistent Atrial Fibrillation (but not long-standing Persistent AF) 3. Screening (qualifying) AFEQT score ≤ 50

AF symptoms will be assessed using the AFEQT questionnaire during screening. AFEQT is a 20-item questionnaire, and provides a 4-item Symptoms score, an 8-item Daily Activities score, a 6-item Treatment Concerns score, and a 2-item Treatment Satisfaction scale. Overall and subscale scores range from 0 to 100. A score of 0 corresponds to complete disability, while a score of 100 describes the highest level of QOL.In the study, screening (qualifying) AFEQT score has to be less than 50.

EXCLUSION CRITERIA

1. Any prior AF ablation procedure (or left atrial ablation procedure) 2. Untreated other arrhythmias (e.g. atrial flutter, SVT, VT, frequent PVCs); 3. Long-standing Persistent AF episodes (any continuous episodes lasting \> 1 year); 4. Permanent AF; 5. No ECG evidence of AF episode \>30 seconds in the 6 months prior to randomization; 6. LA size \> 55 mm; 7. Hypertrophic cardiomyopathy; 8. Valve disease (any aortic stenosis, moderate or severe mitral regurgitation); 9. Left ventricular ejection fraction ≤ 35% according to echocardiogram within 6 months of randomization; 10. Moderate or severe pulmonary hypertension 11. History of tachycardia-induced cardiomyopathy; 12. Symptomatic coronary artery disease; 13. Pregnancy; 14. Presence of an artificial valve; 15. Life expectancy less than two years; 16. Known medical condition or contraindication causing potential complications for interventional procedures or follow up

ENROLLMENT AND ILR IMPLANT

Data will be gathered including the following:

* Demographics including gender, height and weight * Pertinent medical and cardiovascular history, CHA2DS2-VASc * AAD and anticoagulation medication history * 12-lead ECG * TTE within 6 months * The Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life assessment at enrollment

EP STUDY, AFEQT and HADS Before randomization, all patients will undergo an electrophysiology (EP) study. An EP study will be scheduled at 30 days after ILR implantation. Within 1 day of the procedure, all patients will have assessment of the baseline AFEQT and Hospital Anxiety and Depression Scale (HADS), and atrial arrhythmia burden by interrogation of their ILR. (The HADS scale is a 14-item instrument that evaluates symptoms of anxiety and depression in medical populations, on a 4-point scale from 0 to 3. These data (baseline AFEQT, baseline HADS, and ILR interogation) will constitute baseline measurements for the purpose of endpoint estimation.

The EP study will be done using standard techniques; two EP catheters will be inserted via one femoral vein. Femoral access should be performed with ultrasound guidance. One catheter will be inserted in the coronary sinus, the other at the His bundle area. SVT and concealed accessory pathway (AP) will be excluded using standard EP protocols (retrograde ventricular pacing to exclude concealed AP, programmed atrial stimulation to exclude dual AV node physiology, and AV nodal reentry initiation). If concealed AP or inducible AVNRT is present, the arrhythmia will be targeted, but the patient cannot be randomized. These patients will be further monitored in the outpatient clinic as NON-randomized patients. These patients that sign consent but undergo SVT ablation do not count to the 60-patient enrollment goal.

If SVT or concealed AP are excluded, patients will be randomized to the catheter ablation group (CA) or Control Sham group) in a 1:1 ratio.

Group 1: catheter ablation; or Group 2: sham ablation (control group).

RANDOMIZATION will be done using web-based randomization software at the end of the EP procedure. The software will be designed to account for gender and the type of AF (paroxysmal/non-paroxysmal), with the goal of having comparable groups regarding the type of AF. The randomization process will be done outside all participating centers using an electronic web-based CRF; therefore, it will be independent of study subjects and site personnel. No physicia at later out-patient controls will have information on the arm in which the patient was randomized.

TREATMENTS Ablation Arm: after the EP study, patients will undergo pulmonary vein isolation (PVI) using a PFA catheter (Farawave; Farapulse-BSCI Inc.). The same vascular (venous) access used in the EP study will be used for catheter insertion. PFA energy will be applied according to the recommendation of the manufactureur. At the end of the procedure, a single figure-of-eight suture can be placed to achieve hemostasis. The whole procedure will be done under analgosedation (propofol, benzodiazepines, ketamine, opioids) and with the guidance of an anesthesiologist, or as per the center standard of care.

Control arm: after the EP study, patients should undergo approximately 20-30 min of anesthesia with propofol and benzodiazepines in a similar manner as patients in the ablation arm. An anesthesiologist will guide the analgosedation, or as per the center standard of care. At the end of the procedure, a figure-of-eight suture will be placed.

After the procedure, patients will be monitored in the hospital, followed by a TTE to rule out a pericardial effusion. Patients will be discharged the day after the procedure.

Before hospital discharge (ideally the day after the procedure), patients will complete the baseline Blinding Questionnaire.

In-person assessments at months 2, 3, 6 and 12 months post-procedure

* ECG * Adverse events * AAD and anticoagulation medication use * Recurrent arrhythmia, cardioversions, ablations, hospital admissions * AF/AT/AFL burden assessment at 6 months and 12 months only (ILR interrogation to core lab) * The Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life assessment * Hospital Anxiety and Depression Scale (HADS) score (at 2 and 6 months only) * Blinding Questionnaire (at 2 and 6 months only)

Assessments at months 1, 4, 5, 9 post-procedure

These will be performed by phone, and will include the following elements:

* Adverse events * AAD and anticoagulation medication use * Recurrent arrhythmia, cardioversions, ablations, hospital admissions * The Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life assessment AAD use: Class I/III AAD use will be permitted during the first two months post-ablation, during the post-procedure blanking period. At 2 month visit, AADs will be stopped in all patients. After the 2-month blanking period, AAD use will represent a treatment failure.

Cardioversions: Electrical/chemical cardioversions may be performed during the 2 month blanking period. If a subject is in AF near the completion of the blanking period at 2 months, a cardioversion should be performed so that the patient "exits" the Blanking period in sinus rhythm. After the 2-month blanking period, cardioversion will represent a treatment failure.

Early Exit: Any subject may cross over at 6 months. Early cross-over is allowed only in subjects with documented recurrence of AF/AT/AFL, plus one of the following:

1. AFEQT score at or below their baseline score for 3 consecutive months post-randomization may cross over, or 2. Subjects who have a drop in the AFEQT score of 10 or more points may cross over after 1 month

The treating cardiologist in follow-up, who is blinded to treatment assignment, will assess the persistence/worsening of symptoms and contact the core lab to confirm that AF/AT/AFL has recurred. After this confirmation, ablation will then be scheduled.

At the point of decision to cross-over / redo ablation, the patient will again take the AFEQT, HADS and Blinding questionnaire (this will serve in lieu of the 6 month assessments). Cross-over patients will be scheduled for PVI using pulsed-field ablation technology in the same manner as in the active ablation group. Beta-blockers and Ca-channel blockers will be preferentially used for symptom relief until the procedure.

Blinding

* Investigators: The operating physicians (electrophysiologists and anesthetists) will not be blinded to treatment assignment. As much as possible, site based study personnel who perform follow-up evaluations will remain blinded to subject treatment assignment. * Subjects: Study personnel will be trained to avoid disclosing treatment status to study subjects. Study subjects will sign an informed consent that states that they will not be informed of their treatment status until the conclusion of their participation in the study. * Core lab: The core lab, which will analyze ILR data, will remain blinded as much as possible consistent with accurate adjudication. * Data and Safety Monitoring Board (DSMB): In general, the DSMB will review unblinded results in order to perform their function of protecting the integrity of the study and the rights, safety and welfare of study subjects.

Subjects will undergo a blinding assessment on day 1 post procedure, and at the 2 and 6 month visits. They will be asked whether they think they were assigned to the ablation group, the control group, or if they do not know. They will be asked to rate their degree of confidence in their answer on a scale of 1 to 5, with 5 pertaining to certainty.

ENDPOINTS

There will be two co-primary endpoints (assessed at six months):

1. Freedom from recurrent AF/AT/AFL (post two month blanking period): assessed as time to first recurrence (or to cross-over for Early Exits); 2. Quality of life according to the Atrial Fibrillation Effect on QualiTy of life (AFEQT) score at six months post ablation (or at cross-over for Early Exits).

• AF burden [Срок оценки: 6 months]
• Hospital Anxiety and Depression Score [Срок оценки: 6 months]
• 12-month Freedom from recurrent AF [Срок оценки: 12 months]
• 12-month differences in quality of life [Срок оценки: 12 months]
• Unplanned Cardiovascular Hospitalization [Срок оценки: 12 month]
• Procedure-related Major Complications [Срок оценки: 2 months]