Pulsed-field Ablation vs. Sham Ablation to Treat AF

The study is planned as a single-blind, multicenter, prospective, randomized study. Sixty sbjects 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). 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 simply undergo approximately 20-30 min of anesthesia with propofol and benzodiazepines in a similar manner as patients in the ablation arm. Primary endpoints will be assessed six months after the procedure. ECGs will be monitored using implantable ECG monitors (ILR) in all patients. There will be two co-primary endpoints (assessed at six months or at cross-over if Early Exit): Freedom from recurrent AF/AT/AFL (post 2-month blanking), assessed as time-to first recurrence; Quality of life according to Atrial Fibrillation Effect on QualiTy of life (AFEQT) score at 6 months (or at cross-over if Early Exit).

INTRODUCTION The performance of a sham trial for AF ablation has previously been problematic on ethical grounds. The landscape has changed because (i) CABANA, the only RCT on catheter ablation inAF, did not demonstrate an improvement in "hard outcomes" in the intention-to-treat analysis, and (ii) other sham-controlled studies in the cardiovascular field such as the ORBITA trial of angina relief from percutaneous coronary intervention and the Symplicity-3 trial of renal sympathetic denervation for hypertension have failed to show positive outcomes. Thus, only performing sham control studies enabled to document the real effect of this method in hypertension treatment. Together, this has prompted a renewed call for a sham-controlled trial of AF ablation to assess the efficacy in arrhythmia freedom and symptom improvement. Indeed, some cardiologists and general internists have questioned if AF ablation has any utility in the absence of a sham trial. Furthermore, the advent of new, faster technology for PVI requiring angiosedation makes the study more feasible. The speed and safety of pulsed-field ablation to treat AF and the need for deep sedation have further changed the ethical and practical considerations for a sham-controlled AF ablation trial. Using the pentaspline PFA catheter (Farawave; Farapulse-BSCI Inc), PVI can reliably be performed in < 30-60 min at experienced centers. For all these purposes, the investigators plan to conduct a prospective, multicenter, single-blinded, randomized trial comparing catheter-based pulsed-field ablation to a sham-control procedure for paroxysmal or persistent AF. 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 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 Age >18 years Paroxysmal or Persistent Atrial Fibrillation (but not long-standing Persistent AF) Screening (qualifying) AFEQT score ≤ 50 Patients with symptomatic paroxysmal or persistent AF will be included. Symptoms will be assessed using the AFEQT questionnaire during screening; the presence of significant symptoms at screening (AFEQT ≤ 50) is a critical component since it will be vital to ensure a sufficiently symptomatic population to avoid a Type 2 error. Patients with long-standing AF or AF-induced cardiomyopathy or LV dysfunction will be also excluded. Patients can have SR or AF on the day of the screening and signed informed consent, but long-standing persistent AF has to be excluded based on patient history. EXCLUSION CRITERIA Any prior AF ablation procedure (or left atrial ablation procedure) Untreated other arrhythmias (e.g. atrial flutter, SVT, VT, frequent PVCs); Long-standing Persistent AF episodes (any continuous episodes lasting > 1 year); Permanent AF; No ECG evidence of AF episode >30 seconds in the 6 months prior to randomization; LA size > 55 mm; Hypertrophic cardiomyopathy; Valve disease (any aortic stenosis, moderate or severe mitral regurgitation); Left ventricular ejection fraction ≤ 35% according to echocardiogram within 6 months of randomization; Moderate or severe pulmonary hypertension History of tachycardia-induced cardiomyopathy; Symptomatic coronary artery disease; Pregnancy; Presence of an artificial valve; Life expectancy less than two years; 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 AFEQT will be used during enrollment to ensure the symptoms of patients, and presents one of the qualifying (inclusion) criterion. AEFQT 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. 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. A combined HADS score ≥ 7 indicates the presence of psychological distress and a score ≥ 15 indicates severe psychological distress. 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 (right or left, right preferred). Femoral access should be performed with ultrasound guidance. One catheter will be inserted in the coronary sinus, the other at the His bundle area (to record atrial His and ventricular activity). SVT and concealed accessory pathway (AP) will be excluded using standard EP protocols: retrograde ventricular pacing to exclude left and right 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. The same vascular (venous) access used in the EP study will be used for catheter insertion. An ICE catheter will be positioned in the right atrium, and a transseptal puncture will be carried out under ICE navigation. In all patients, atropine (1 mg) may be given to avoid a vagal reaction. The ablation will be done using a pentaspline PFA catheter (Farawave; Farapulse-BSCI Inc.); PFA energy will be applied 4 times in the basket and 4 in the flower configuration for each pulmonary vein, plus additional lesions as needed. In patients with persistent AF, an additional posterior wall ablation can be done using a flower configuration of the catheter. 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. 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 DCCV 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. Since the study is open to symptomatic AF patients, early patient cross-over is only allowed in cases of persistent severe symptoms. Early cross-over is allowed only in subjects with documented recurrence of AF/AT/AFL, plus one of the following: AFEQT score at or below their baseline score for 3 consecutive months post-randomization may cross over, or Subjects who have a drop in the AFEQT score of 10 or more points may cross over after 1 month For early cross-over to occur, 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. The reason for the interaction between the follow-up physician and the core lab is to access the ILR interrogations (which would not otherwise be available to the follow-up physician) and to confirm that symptoms are not the result of an unrelated arrhythmia. Of note, since the treating Cardiologist is blinded to the treatment assignment, from their perspective, this could be an actual cross-over or a redo ablation procedure. They will remain blinded to this until after the 6 month timepoint. 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): Freedom from recurrent AF/AT/AFL (post two month blanking period): assessed as time to first recurrence (or to cross-over for Early Exits); 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). Secondary endpoints 6-month differences in AF/AT/AFL burden; 6-month difference in HADS scores; 12-month Freedom from recurrent AF/AT/AFL (post two month blanking period); 12-month AFEQT scores (between treatment and control groups); Correlation of AFEQT score with AF recurrence/burden data; Unplanned Cardiovascular Hospitalization; Procedure-related Major Complications; Time to exit from assigned treatment. AF/AFL/AT: episode of the corresponding arrhythmia that is recorded for review, where the recording contains at least 30 seconds of continuous interpretable signal. An exception is a 12-lead ECG where the arrhythmia occurs during the entire tracing and the continuous interpretable signal is 10 seconds or longer. ADVERSE EVENTS This study will utilize a core lab for the review and adjudication of AEs. All safety analyses will utilize the adjudicated rather than site determination of an AE's characteristics in those instances where the CEC has adjudicated that characteristic to be different than the site's determination. In both the control and treatment groups, the risks of sheath insertion in the femoral vein include access site complications (e.g., hematoma, fistula, pseudo-aneurysm, laceration, bleeding) potentially requiring surgical intervention. Risks of anesthesia in both groups include aspiration pneumonia, allergic reaction to medication, and cardiac arrhythmia. In the treatment group, risks of catheter ablation include the following: Air embolism Anemia Cardiac tamponade or perforation Cardiac arrest or cardiac failure Cardiogenic shock Catheter entrapment potentially requiring endovascular or surgical intervention Conduction system injury, either transient or permanent, potentially requiring pacemaker insertion Coronary artery or vein injury Death Esophageal injury, ulcer or fistula Hemopericardium Hemoperitoneum Hemothorax Myocardial infarction / ischemia Nerve damage Pericardial effusion Pericarditis w Phrenic nerve injury with potential paralysis of the diaphragm and breathing impairment Pneumothorax PV injury, perforation or stenosis Stroke / transient ischemic attack STATISTICAL RATIONALE In previously published clinical studies on catheter ablation, the effect of the ablation on AF-freedom was dependent on 1) ablation technology and 2) the sensitivity of the ECG monitoring. Regarding ablation technology, pulsed field ablation seems to be the most effective technology for the achievement of durable pulmonary vein isolation. Although the number of operators in these studies have been small, the >90% durability of pulmonary vein isolation that has been described with PFA is above the best radiofrequency tools including ablation index etc. Regarding ECG monitoring, it is known that less frequent monitoring (single intermittent 24-Holter recording) is able to record substantially fewer AF recurrences than daily trans-telephonic recording or permanent ILR monitoring. In the recently published EARLY-AF trial comparing cryoablation vs AADs, in which the effect of ablation was monitored using ILRs, one-year AF-freedom was present in 57.1% of ablated patients. In a recent study on PFA, one-year AF freedom (monitored using 24-hours Holter monitoring and weekly ECG transmissions) was achieved in 87.4%. In eight studies comparing AADs with placebo using mixed monitoring methods (but no study used ILRs) with 655 patients, the success in placebo arms was 24.9% (95% CI 15-34). However, as noted, no study used ILR for monitoring, but no study experienced sham-procedure placebo that could be more effective than pharmacological placebo. For the QOL Primary Endpoint, means are compared in independent samples, with the test of equality of means carried out at a 2-sided 0.05 level of significance, with a probability of 90% of rejecting the null hypothesis of equal proportions if the alternative holds. Assuming an AFEQT score of 50 in the Control group (with a S.D. of 20), and improvement to 70 in the Ablation group, a total of 25 patients are required in each group, or 50 patients total. Assuming a 10% crossover (outside the protocol), 55 patients would be required. And finally, assuming minimal loss to follow-up, a total of 60 patients (30 per arm) will be enrolled. For the AF Recurrence Primary Endpoint, in the sham-procedure arm, a maximum of 30% freedom from AF should be expected. In the active-PFA treatment arm, 70% AF freedom is a very conservative expectation. With β=80% and α=0.025, a total of 25 patients are required in each group, or 50 patients total. Assuming a 10% crossover (outside the protocol), 55 patients would be required. And again, assuming minimal loss to follow-up, a total of 60 patients (30 per arm) will be enrolled. Secondary Endpoint of Psychological Distress: As a secondary endpoint, we have planned for sufficient sample size to assess differences in psychological distress at 6 months between groups (using the Hospital Anxiety and Depression score, HADS). Based on the recently-published REMEDIAL study, where the mean baseline HADS score was approximately 12.3, we expect a mean baseline HADS score of 13 in our study since we are enriching for a more symptomatic cohort. We expect a mean HADS score at 6 months post-procedure to be 13 (with S.D. of 6; consistent with that observed in the REMEDIAL study) in the control group and 8 in the treatment group (an improvement by 5 points was observed with ablation in the REMEDIAL study). With β=80% and α=0.025, a total of 28 patients are required in each group, or 56 patients total.

Patients will receive catheter ablation, i.e. pulmonary vein isolation by means of pulsed-field energy

Freedom from recurrent AF/AT/AFL (post two month blanking period): assessed as time to first recurrence (or to cross-over)

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)

The difference in AF burden assessed using ILR. AF burden is expressed as percentage of time spent in AF

Differences in Hospital Anxiety and Depression Score (HADS) between baseline (before randomization) and at 6 months

Quality of life assessed using AFEQT (Atrial Fibrillation Effect on QualiTy of Life ) questionnaire, range 1-20

Correlation between the changes in the quality of life assessed using AFEQT questionnaire with the AF burden

Inclusion Criteria: Age >18 years; Paroxysmal or Persistent Atrial Fibrillation (but not long-standing Persistent AF); AFEQT score ≤ 50. Exclusion Criteria: Any prior AF ablation procedure (or left atrial ablation procedure) Untreated other arrhythmias (e.g. atrial flutter, SVT, VT, frequent PVCs); Long-standing Persistent AF episodes (any continuous episodes lasting > 1 year); Permanent AF; No ECG evidence of AF episode >30 seconds in the 6 months prior to randomization; LA size > 55 mm; Hypertrophic cardiomyopathy; Valve disease (any aortic stenosis, moderate or severe mitral regurgitation); Left ventricular ejection fraction ≤ 35% according to echocardiogram within 6 months of randomization; Moderate or severe pulmonary hypertension; History of tachycardia-induced cardiomyopathy; Symptomatic coronary artery disease; Pregnancy; Presence of an artificial valve; Life expectancy less than two years; Known medical condition or contraindication causing potential complications for interventional procedures or follow up.