A prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in Subjects with Persistent Atrial Fibrillation

Atrial Fibrillation
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia,
affecting approximately 2.2 million people in the United States and 4.5 million
in the European Union. The incidence increases with advancing age, affecting 6%
of the population over age 60 and 10% of the population over age 80. Among
Medicare beneficiaries, AF incidence is common and increases as individuals
age, with incidence rates per 1,000 person-years reported at ages 70-74 of
18.8, increasing to 28.8 for persons 75-79 and 38.3 for persons 80-84.
Similarly, the overall prevalence among Medicare beneficiaries age 70-74 is
about 6% increasing to over 13% for individuals 80 years of age and older.
Age-adjusted population trending projects 16 million people in the United
States will have AF by 2050.

Atrial fibrillation remains a significant cause of morbidity and mortality in
industrialized societies. The annual risk of AF related stroke is 5% per year
and one of every six strokes diagnosed occurs in the presence of AF. Therefore,
patients with AF require long-term anticoagulation to prevent embolic events.
Failure to manage AF may also lead to anatomic and electrical remodeling of the
left atrium, tachycardia-induced cardiomyopathy, and reduced left ventricular
function (heart failure). AF remains an extremely costly public health burden,
with annual per patient cost of care approaching approximately USD 3200 or
¤3000.

The Heart Rhythm Society (HRS) 2017 Consensus Statement on Catheter and
Surgical Ablation of Atrial Fibrillation8 defines several different stages of
AF based on its duration and include:
• Paroxysmal AF (PAF): AF that terminates spontaneously or with intervention
within 7 days of onset
• Persistent AF (PersAF): continuous AF that is sustained beyond 7 days
• Long-standing PersAF: continuous AF of greater than 12 months* duration

Several studies have demonstrated that AF catheter ablation is a safe and
superior alternative to anti-arrhythmic drugs (AADs) for maintenance of sinus
rhythm and symptom improvement. In particular, the isolation of the pulmonary
veins (PVI), where the majority of arrhythmogenic triggers is found, has been
shown to be a safe and effective technique to reduce arrhythmia recurrence and
related symptoms. Over the last 20 years PVI has remained the cornerstone
catheter ablation technique for AF ablation in subjects with recurrent and
symptomatic PAF refractory or intolerant to AADs. More recently, PVI for the
treatment of PAF is increasingly being performed as first line therapy, and
clinical evidence is accruing that this may well become an accepted first line
treatment.

Persistent Atrial Fibrillation Ablation
Persistent AF (PersAF) represents approximately 25% of all AF cases. In
comparison to patients with PAF, patients with PersAF are at a significantly
greater risk for both cardiac mortality and all-cause mortality. The recent
update of the 2020 ESC Guidelines for the diagnosis and management of atrial
fibrillation AF supports catheter ablation for maintaining sinus rhythm in
patients with both PAF and PersAF, with the eligibility to treat PersAF
patients with ablation being weighted by additional elements, including risk
factors for recurrence (left atrial [LA] size, AF duration, patient age, renal
dysfunction, and substrate visualization by means of MRI), heart failure with
reduced ejection fraction, and patient choice. This recommendation is currently
reflected in practice as approximately one third of all catheter ablation cases
are performed on either persistent or long-standing persistent patients.

There are currently two catheters approved in the US to treat PersAF, supported
by data obtained from the PRECEPT (Biosense Webster, Thermocool SmartTouch® SF
catheter) and STOP Persistent AF trials (Medtronic, ArcticFront Advance®
Cryoballoon), respectively. These trials showed that safety and effectiveness
profile of catheter ablation for PersAF is well-established, with slight
variations in rates depending upon the patient population and technology
utilized. Although the PVs have been identified as the main triggers
responsible for AF, PVI alone for the treatment of PersAF is less effective
than for PAF, and PersAF ablation may require additional lesion sets beyond the
PVs to achieve greater success.

PersAF ablation success is challenged by the heterogeneity of the underlying
pathophysiologic mechanisms, and multiple ablation strategies have evolved in
the attempt to improve long-term outcomes in this population. These include
left atrial lines (roof, mitral isthmus), right atrial lines (superior vena
cava, cavo-tricuspid isthmus) other techniques aimed at suppressing additional
triggers outside the PV. To date, limited data from randomized trials exist on
the effectiveness of these techniques compared to PVI alone. However, recent
studies have suggested a benefit associated with PVI and concomitant isolation
of the portion the left atrial posterior wall (LAPW) lying between the PVs. The
rationale for this ablation technique stands in the common embryological origin
of this anatomical area in the PVs and the peculiar electrophysiological and
structural characteristics of this region that give rise to its arrhythmogenic
potential.

Specifically, spontaneous triggers located in the LAPW have been reported in
previous studies, establishing ablation of this area in addition to PVI being a
potential adjuvant strategy in ablation of PersAF. Several studies have been
recently published adding a dedicated LAPW ablation strategy together with PVI,
including different available energy sources for ablation. A recent systematic
review and meta-analysis showed that LAPW isolation can be successfully
achieved in a large proportion of patients and is associated with a low risk of
major-procedure related complications.

Irreversible Electroporation
Al-Sakere 2007 described irreversible electroporation (IRE) as a non-thermal
tissue ablation technique in which intense short duration electrical fields are
used to permanently open pores in cell membranes, thus producing non-thermal
tissue ablation. Their study, using a mouse model, showed complete regression
in 92% of treated tumors. IRE ablation has a tissue-specific mechanism of
ablation. The tissue injury from IRE ablation occurs at the cellular level with
loss of homeostasis leading to necrosis or apoptosis. IRE ablation typically
spares the extracellular matrix, which facilitates rapid wound healing.
With respect to cardiac tissue, multiple studies have been described reporting
the effects of IRE in a porcine model. Across the studies, no stenosis was
observed at 3-weeks and 3-months of follow-up, and the lesion depth was further
characterized in the proximity of the phrenic nerve and coronary arteries, with
no damage to the adjacent structures or tissues noted. These animal studies
suggest that IRE can safely create deep lesions in heart tissue without harming
adjacent tissues.

FARAPULSE Pulsed Field Ablation System
Preclinical animal studies investigating the safety and efficacy of the
FARAPULSE Pulsed Field Ablation (PFA) System have been performed to demonstrate
that PFA using the FARAPULSE PFA Catheter reliably produces homogeneous,
well-demarcated and transmural lesions in porcine atrial tissue. Seven- and
30-day studies show mild to moderate inflammatory and healing responses
consistent with radiofrequency ablation lesions, and importantly demonstrated
no tissue injury with respect to the esophagus or phrenic nerve as well as no
degree of narrowing or flow impairment of the pulmonary veins.

Paroxysmal Atrial Fibrillation:
Initial safety and feasibility human clinical studies of the FARAWAVE PFA
Catheter were conducted in Europe in a PAF population, including the IMPULSE,
PEFCAT, and PEFCAT II trials. All studies supported the safety and feasibility
of the FARAPULSE PFA System using the FARAWAVE PFA Catheter in the treatment of
patients with PAF, with a low rate of acute and long-term primary safety
endpoint events and a high rate (100%) of acute procedural success resulting in
CE Mark approval for the treatment of PAF in early 2021.

The randomized ADVENT Trial (A Prospective Randomized Pivotal Trial of the
FARAPULSE PFA System Compared with Standard of Care Ablation in Patients with
Paroxysmal Atrial Fibrillation) is being conducted in the United States to
establish the safety and effectiveness of the FARAPULSE PFA System using the
FARAWAVE PFA Catheter in a drug refractory symptomatic PAF patient population.
Subjects in the study are either randomized to catheter ablation with the
FARAPULSE PFA system or conventional thermal ablation (radiofrequency or
cryoballoon ablation). The data will be used to gain initial market approval of
the FARAPULSE PFA System using the FARAWAVE PFA Catheter in the US for the PAF
population.

Persistent Atrial Fibrillation:
Initial data on treatment of PersAF with the FARAPULSE PFA System using the
FARAWAVE PFA Catheter has been collected in the PersAFOne feasibility study
(Feasibility Study of the FARAPULSE Endocardial Multi Ablation System in the
Treatment of Persistent Atrial Fibrillation). The objective of the PersAFOne
Study is to demonstrate that the endocardial creation of electrically isolating
lesions in cardiac tissue via PFA using the FARAPULSE PFA System is a feasible
and safe treatment for PersAF. Patients in the PersAFOne study, after the
isolation of the PVs, received an additional set of lesions along the posterior
wall region between the PVs, performed with the same FARAWAVE PFA Catheter used
for PVI during the ablation procedure.

Reliable and safe electrical isolation of the left atrial posterior wall was
confirmed via electro-anatomical mapping. Reddy et al reported 100% acute PV
isolation, no primary safety events, and chronic isolation of the PVs (82 / 85)
and LAPW (100% with the pentaspline catheter) after remapping at 82 days
post-procedure in 25 subjects. The data collected in the study demonstrated
that the approach proposed in the ADVANTAGE AF Study to ablate the left atrial
posterior wall in addition to creating PVI using the FARAPULSE PFA System is
feasible, leading to an acceptable safety and feasibility profile for the study
device to date.

One of the acknowledged challenges to LAPW ablation is the risk of collateral
damage to the esophagus, given the repeated and additional ablation
applications in addition to the PVs that are delivered to an anatomical area
close to the esophagus. Using PFA for LAPW ablation has the potential to
substantially mitigate this risk, given the marked reduced risk of collateral
damage to adjacent structures with the energy source noted above.

Although AF and CTI-dependent atrial flutter (AFL) are different arrhythmias
with their own mechanisms and electrophysiologic presentation, their
interrelationship has long been recognized and they coexist in a significant
percentage of patients. The relationship is reciprocal since patients diagnosed
with AFL may develop AF after CTI ablation and patients with AF often go on to
develop AFL. In particular, the presentation of AFL in the context of AF may be
the sign of additional atria remodeling or the presence of non-PV triggers.

Accordingly, a strategy that includes both PVI and CTI ablation has become an
established practice in the percutaneous ablative treatment of patients with
AF. The current guidelines for the management of AF indicate that CTI ablation
may be beneficial during procedures of AF ablation, in particular for those
patients with history of typical AFL and where AFL is induced at the time of AF
ablation. The present IDE study incorporates the treatment strategy for PersAF
ablation utilized in PersAFOne using the FARAWAVE PFA Catheter for electrical
isolation of the PV and isolation of the LAPW region between the PVs. In the
PersAFOne II study, LAPW ablation was performed using the FARAWAVE Catheter in
the fully deployed configuration. Consistent with the proposed treatment, two
applications at 2000V at each catheter location was performed, with
approximately 50% overlap between adjacent catheter positions. These catheter
positions along the posterior wall linked the PVI lesion to create a continuous
lesion set encompassing the PVs and LAPW, between the superior and inferior
insertions of the left and right PV pairs. As of the date of the PersAFOne II
interim clinical study report, 17 subjects have returned for the invasive
remapping procedure. Sixty-four of sixty-eight (94.2%) of PVs and sixteen of
seventeen (94%) of LAPWs remained durably isolated. Again, two SAEs in two
patients, both pericardial effusions, were reported, related to the required
remapping procedure.

Expanding the indication of the FARAPULSE PFA System for approval to treat
PersAF patients would fulfill a clinical need in a growing population of
subjects indicated to receive a catheter ablation. The present single arm,
prospective cohort IDE study has been designed to demonstrate safety and
effectiveness of the FARAPULSE PFA System in treating symptomatic
drug-refractory PersAF patients.

The objective of the ADVANTAGE AF Study is to establish the safety and
effectiveness of the FARAPULSE Pulsed Field Ablation System (FARAPULSE PFA
System) for treatment of drug resistant, symptomatic persistent atrial
fibrillation (PersAF).

The FARAPULSE ADVANTAGE AF Study is a prospective, single arm, open label,
multi-center IDE pivotal study utilizing the FARAPULSE PFA System in the
treatment of patients with PersAF.
After ablative isolation of the pulmonary veins (PVs), the left atrial
posterior wall (PW) and if warranted the cavotricuspid isthmus (CTI), subjects
will be followed at Pre-Discharge, Day 7, Day 30, Day 90, Day 180, and Day 360.
The Blanking Period will include Days 0 through 90, after which subjects will
be monitored twice per month plus symptom-driven event monitoring, as well as
Day 180 and Day 360 24-hour Holter monitoring.

Pulmonary Vein Isolation (PVI): PVI will be achieved in target veins using the
FARAWAVE PFA Catheter.
Posterior Wall Isolation (PWI): PWI will be achieved in the left atrial
posterior wall between the PVs using the FARAWAVE PFA Catheter.
CTI: Ablation of the CTI will be performed using a commercially available BSC
RF catheter in the following situations:
• Required: For subjects with a history of CTI-mediated (typical) AFL and
o Who have not had a CTI ablation procedure, or
o Who have had a CTI ablation procedure but have recurrent CTI conduction.
• Required: subjects who manifest CTI-mediated AFL (spontaneous or induced)
during the Index Procedure, or
• At Investigator discretion: subject welfare indicates that CTI ablation
should be performed.
Other Ablation: When the Investigator determines that subject welfare requires
intervention for either an accessory pathway, AVNRT or spontaneously occurring
treatment-emergent AFL or AT, ablation for these arrhythmias may be performed
using any commercially available RF ablation catheter. These permitted
ablations and the associated data will be documented in the CRF and do not
constitute Persistent AF Acute Procedural Failure.
Ablation for an arrhythmia that is provoked only by catheter manipulation or is
only inducible by pacing or pharmacologic stimulation is not permitted.

Patients who take part in this study are subject to similar risks shared by all
patients who have an ablation procedure but are not in this study.