Pulsed field ablation versus conventional radiofrequency catheter ablation for repeat pulmonary vein isolation in patients with paroxysmal atrial fibrillation

Atrial fibrillation is a condition where the heart beats irregularly at times.
Abnormal impulses originate in the pulmonary veins, and these can cause atrial
fibrillation. Fortunately, there is a treatment that can help: an ablation.
During an ablation, a thin tube, also called a catheter, is inserted through
the groin into the heart. Using this catheter, a scar is created at the
junction of the four pulmonary veins and the left atrium through heating,
freezing, or an electrical pulse (ablation). This scar prevents any potential
heart rhythm disturbances and other electrical signals from the pulmonary veins
from reaching the heart.

Sometimes, atrial fibrillation can return. This can have various reasons. In
most patients (around 85% of people), we observe that electrical conduction has
reoccurred at the site of the previous ablation. This allows electrical signals
to reach the heart again and cause atrial fibrillation once more.

During the execution of the second ablation, the cardiologist creates a
detailed map of the heart's electrical conduction and the pulmonary veins. If
conduction from the pulmonary veins is detected again, the cardiologist will
eliminate it using radiofrequency ablation. This involves heating the tip of
the catheter, effectively burning away the connection.

For the past few years, another commonly used ablation technique called 'pulsed
field ablation' has been available. With this technique, heart muscle cells are
rendered inactive by a brief but strong electric shock. The corresponding
catheter can investigate each pulmonary vein for new connections to the atrium
without the need for an extensive map. If a new connection is discovered, the
cardiologist can eliminate it with an electric shock. Pulsed field ablation is
a fast technique that achieves the same goal with less information. However, it
is currently unknown which technique produces the best results.

In this study, we aim to compare two different techniques for the second
ablation in patients who have previously undergone an unsuccessful ablation.
The first technique is called "radiofrequency ablation," and the second
technique is called "pulsed field ablation."

We want to determine which of these two techniques works best to reduce atrial
fibrillation and prevent its recurrence after treatment. Both techniques have
already been proven safe for this procedure, but we now want to investigate
which of the two is most effective for individuals who have had a prior
ablation. This has not been studied before.

During the research, we will examine various aspects. The main objective of
this study is to discover which technique best ensures that atrial fibrillation
remains absent in the two years following treatment. We will continuously
monitor this using a small implantable heart rhythm monitor. Additionally, we
will assess the patients' quality of life, whether any extra hospital
admissions are required, the duration of both procedures, the need for a
potential third ablation, and whether additional medication is necessary.

With the results of this study, we hope to make better decisions in the future
for patients undergoing a second ablation for atrial fibrillation.

This multicentre, national, randomised, open-label, parallel group, phase 3
study aims to compare the effectiveness of two different techniques for the
second ablation in patients who have previously undergone an unsuccessful
ablation for atrial fibrillation (AF). The two techniques being compared are
"radiofrequency ablation" (RF) and "pulsed field ablation" (PFA).

Patients will undergo screening evaluations, including a review of medical
history, medication assessment, AF documentation, echocardiogram, and
evaluation by a cardiac electrophysiologist. Eligible patients will provide
written informed consent according to national regulations. Confidentiality
measures will be implemented, using deidentified subject identification codes
to secure data. Results reporting will be anonymised.

The trial will be conducted at 5 clinical centres in the Netherlands.
Additional sites may be added if needed. Enrolled patients meeting inclusion
and exclusion criteria will be randomised 1:1 to either PFA or RF using a tool
within the Netherlands Heart Registration (NHR) database. Randomization will
occur 1 month prior to the ablation.

Patients will be evaluated for PV isolation at the start of the ablation. Those
with isolated PVs will be withdrawn and followed in an observational registry.

Implantable heart rhythm monitor will be implanted in all randomised patients
at least 1 month prior to repeat ablation and explanted at 24 months or earlier
if needed. Patients will be on uninterrupted oral anticoagulation therapy
before the procedure. Heparin will be administered during the procedure. OACs
will continue post-procedure for at least 3 months.

The study aims to determine which technique better reduces and prevents atrial
fibrillation recurrences. The primary endpoint is the absence of atrial
fibrillation in the two years following treatment. Secondary endpoints include
quality of life, hospitalization rates, procedure duration, need for a third
ablation, and medication requirements. The results will guide treatment choices
for future patients undergoing repeat ablation for atrial fibrillation.

Patients will be randomised in a 1:1 ratio to RF ablation or PFA.

PFA ablation arm
All enrolled patients will be sedated either with general anaesthesia or
(conscious) sedation according to institutional protocol. Intravenous heparin
will be administered as boluses and continuous infusions to obtain activated
clotting time 300 s prior to the first ablation lesion and throughout the
procedure.
Femoral vein access will be obtained, and a single transseptal puncture will be
performed with an 8.5-F sheath and exchanged for a 13-F sheath in the left
atrium. A baseline electrophysiological assessment of PV connection will be
made with the FARAWAVE catheter in each PV. If PV reconnection is detected in
more than 1 PV with diagnostic catheters, then the patient will undergo PFA
re-ablation, as per trial protocol. If PV reconnection is not detected in any
PV with diagnostic catheters (100% PV isolation/ durable PVI), then the patient
will be withdrawn from the study and followed in an observational registry.
Withdrawn patients will be treated according to treating EPs discretion (either
with the FARAWAVE catheter or RF ablation) and will no longer adhere to the
trial protocol.
Propofol boluses synchronized to PFA applications: a 0.035-inch, 180-cm
extra-stiff, straight or j-shape guidewire will be used to cannulate each vein.
A multielectrode FARAWAVE ablation catheter will be advanced over the guidewire
to the left atrium. The guidewire will be advanced into the target PV, the
catheter splines will be deployed to fit anatomy (retracting the deployment
knob), and the deployed catheter will be advanced to the ostium of the target
PV. Positioning of PFA ablation catheter in the ostium will be monitored with
ICE imaging and/or fluoroscopy. An ablation dose of 2kv will be delivered in
accordance with the guidelines for FARASTAR. All PVs, regardless of
reconnection, will be re-ablated/re-isolated and re-antralized with PFA (i.e.
repeat PVI). Number of pulses delivered, waveforms (monophasic/biphasic),
output of generator, and number of applications (minimum 8 per PV) delivered
with the FARAWAVE ablation catheter determined by individual investigator.
Cavotricuspid isthmus (CTI) ablation may be performed with an RF ablation
catheter, if warranted. Investigators are deterred from performing additional
ablations lesions for non-PV triggers, unless necessary. Patients with atrial
flutter and atrial tachycardia were excluded at baseline to minimize ablations
of non-PV triggers.
Acute isolation of the treated PVs will be determined by mapping electrodes on
each spline of the PFA catheter. In addition, pacing will be performed at each
bipolar electrode pair (1-2 of spline 1 and 2, 2-3 of spline 2 and 3, etc). No
waiting period is allowed.
Post-ablation testing for phrenic nerve injury is recommended using fluoroscopy
detecting movement of the diaphragm.

PFA catheter system
Two components from the PFA system will be used for this study: custom PFA
generator (Farastar, Farapulse, Menlo Park, California), over-the-wire 12-F
multielectrode PFA catheter (Farawave, Farapulse; and the 13-F steerable sheath
(Faradrive, Farapulse)
The Farawave *single-shot* multielectrode PFA catheter is the primary ablation
catheter used for PV isolation in this trial. It consists of 5 splines with 4
electrodes per spline and 1 electrode available for electroanatomic
visualization. In this trial, both diameter sizes of the fully deployed
*flower* configuration of the Farawave ablation catheter, 31 or 35 mm, can be
used based on physician preference.

RF point-by-point ablation arm (control)
All enrolled patients will be sedated either with general anaesthesia or
(conscious) sedation according to institutional protocol. Intravenous heparin
will be administered as boluses and continuous infusions to obtain activated
clotting time of 300 s prior to the first ablation lesion and throughout the
procedure.
Repeat PVI with RF ablation will be performed according to standard practice.
Following double transseptal puncture, a detailed activation map of the left
atrium will be performed with a multipolar high density mapping catheter. All
commercially available mapping systems are allowed. RF ablation will be
performed with contact force sensing cooled tip RF ablation catheters. The PV
reconnection site will be identified, and focal RF ablation lesions will be
delivered at sites of PV reconnection. Figure 2 indicates the sites for
re-ablation in the point-by-point RF arm. Ablation lesions should be targeted
to the PVs. Low voltage areas in the carina and ostia may also be re-isolated.
CTI ablation may be performed, if warranted. Investigators are deterred from
performing additional ablations lesions for non-PV triggers, unless necessary.
Patients with atrial flutter and atrial tachycardia were excluded at baseline
to minimize ablations of non-PV triggers. If atypical flutter or AT occurs
during the procedure, it is recommended not to ablate these arrhythmias.
Post-ablation testing for phrenic nerve injury is recommended using fluoroscopy
detecting movement of the diaphragm.

Implantable loop recorder (ILR) implants and explants
ILRs will be implanted in all randomised patients at least 1 month prior to
repeat ablation. ILRs will be implanted in the EP lab and will be implanted
according to standard procedures.
ILR explantation will occur at 24-months follow-up according to standard
practice. Earlier explantation may occur in the case of infection or adverse
event and will be based on treating clinician*s discretion.

The only additional risk that this study entails compared to a regular ablation
is the placement of the implantable heart rhythm monitor. The complications
that may arise from this are low and consist of temporary sensitivity around
the injection site after placement or a local infection. The latter is rare
(<1%), but does require the removal of the IHM and treatment with antibiotics.