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 aim of the project: to determine the effect of PVI using a commercially-available PFA catheter (vs. sham therapy) in symptomatic paroxysmal or persistent AF patients on (1) AF recurrence and (2) quality-of-life.~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 simply receive propofol anesthesia for ~20-30 min.~Inclusion criteria:~Age >18 years~Paroxysmal or Persistent Atrial Fibrillation (but not long-standing Persistent AF)~Baseline 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 baseline (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 arrhythmias (e.g., atrial flutter, SVT, VT, frequent PVCs)~Long-standing Persistent AF episodes (any continuous episodes lasting > 1 year)~LA size > 55 mm~Hypertrophic cardiomyopathy~Valve disease (any aortic stenosis, moderate or severe mitral regurgitation)~Permanent AF~LV EF < 35%~Moderate or severe pulmonary hypertension (sPAP ≥ 30 mm Hg)~History of tachycardia-induced cardiomyopathy~Symptomatic coronary artery disease~Pregnancy~Presence of an artificial valve~Life expectancy of less than two years~Before randomization, all patients will undergo an EP study. The EP study will be done using standard techniques; two EP catheters will be inserted via one femoral vein (right or left, right preferred). One catheter will be inserted in the coronary sinus, the other on the His bundle area (top record atrial His and ventricular activity). SVT and concealed AP will be excluded using standard EP protocols: retrograde ventricular pacing to exclude left and right concealed AP, programmed atrial stimulation to exclude AV node duality, and AN 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 randomized patients.~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; randomization will be done using web-based randomization software at the end of the EP procedure.~Treatments I. Active catheter ablation arm Ablation Arm: after the EP study, patients will undergo PVI using a PFA catheter (see below). 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) will 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 4x times in the basket and 4x in the flower configuration for each pulmonary vein.~II. Control (Sham procedure) arm Sham-Ablation 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.~Outpatient follow-up and endpoint monitoring Primary endpoints will be assessed six months after the procedure; however, the overall follow-up is 12 months. Outpatient follow-up will be done as clinic visits at 2, 3, 6, and 12 months, and as phone calls at 1, 4, 5, and 9 months.~The occurrence of arrhythmias during the first two months (Blanking period) will be censored. ECGs will be monitored using implantable ECG monitors (ILR) in all patients.~Early Exit (this is discouraged, but if a patient insists on a cross-over, the following criteria will apply):~Since the study is open to symptomatic AF patients, early patient cross-over is allowed in cases of persistent severe symptoms. Early crossover is allowed in subjects with documented recurrence of AF/AT plus, and~Subjects who remain at/below their baseline AFEQT 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~Primary endpoints:~There will be two co-primary endpoints (assessed at six months):~Freedom from recurrent AF/AT/AFL (post blanking, two months): assessed both as time-to first recurrence, and AF burden at six months post-ablation~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); compared between groups Secondary endpoints 1) 12-month Freedom from recurrent AF/AT/AFL (post blanking, two months) 2) 12-month differences in AFEQT scores 3) Correlation of AFEQT score with AF recurrence/burden data 4) Unplanned Cardiovascular Hospitalization 5) Procedure-related Major Complications 6) Time to exit from assigned treatment Statistical analysis~Statistical Rationale:~Proportions are compared in independent samples, with the test of equality of proportions carried out at a 0.025 level of significance, with a probability of 90% of rejecting the null hypothesis of equal proportions if the alternative holds.~For the AF Recurrence endpoint, a maximum of 25% freedom from AF should be expected in the sham-procedure arm. In the active-PFA treatment arm, 65% AF freedom is a very conservative expectation in paroxysmal patients. With β = 80% and α = 0.025, a total of 25 patients are required in each group, or 50 patients total. Assuming a 10% cross-over (outside the protocol), 56 patients would be required. For the QoL endpoint, assuming an AFEQT score of 50 in the Control group (with an S.D. of 20) and an improvement to 70 in the Ablation group, a total of 25 patients are required per group, or 50 patients
The study is planned as 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). 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 receive propofol anesthesia for ~20-30 min.~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):~Freedom from recurrent AF/AT/AFL (post blanking, two months): assessed both as time-to first recurrence, and AF burden at six months post-ablation~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); compared between groups