iCLAS* for Persistent Atrial Fibrillation

Atrial fibrillation (AF) remains the most commonly treated sustained arrhythmia
affecting approximately 1% to 2% of the general population worldwide. It is a
major public health concern in the United States and in 2001, it was reported
to be affecting an estimated 2.3 million Americans.
By the year 2050 this may reach 12-million. Age adjusted population trending
projects 17.9 million people in the European Union will have AF by 2060. AF is
associated with a five-fold risk of stroke, a three-fold incidence of
congestive heart failure, and higher mortality.
Several factors have been associated with an increased risk of AF. The
prevalence of AF increases with age and affects eight to ten percent of
patients older than 80 years of age. AF is also more common in males. Data from
the Framingham Heart Study suggest that men are 1.5 times more likely to
develop AF than are women after controlling for age and comorbidities. Obesity
increases the risk of developing AF. Data from community-based cohorts suggest
that obese persons have a 1.5 to 2.3 greater risk of developing AF.
Furthermore, obesity increases the likelihood that AF will progress from
paroxysmal to permanent AF. Additional factors that have been associated with
an increased risk of AF include smoking, hypertension, hyperthyroidism,
obstructive sleep apnea, diabetes, myocardial infarction, heart failure, and
cardiac surgery.
Atrial fibrillation is currently classified by the duration of the episode
documented by ECGs, cardiac rhythm strips, loop recorders or intracardiac
electrogram monitoring. The following definitions are used for AF
classification:
Paroxysmal AF Defined as AF that terminates spontaneously
or with intervention within 7 days of onset.
Persistent AF Defined as continuous AF that is
sustained beyond 7 days.
Long-standing Persistent AF Defined as continuous AF of greater than 12
months* duration.
Permanent AF Permanent AF is defined as the presence of
AF that is accepted by the patient and physician, and for which no further
attempts to restore or maintain sinus rhythm will be undertaken. The term
permanent AF represents a therapeutic attitude on the part of the patient and
physician rather than an inherent pathophysiological attribute of AF. The term
permanent AF should not be used within the context of a rhythm control strategy
with antiarrhythmic drug therapy or AF ablation.
The heart*s normal conduction pathway (sinus rhythm) typically begins in the
right atrium and proceeds in a single, orderly wave front at rates of 60 to 100
beats per minute. Atrial fibrillation disrupts normal rhythm by creating
multiple wave fronts e from a rapid ventricular response leading to an
irregular pulse as well as diminished cardiac output related to these
uncoordinated contractions. Pooling of blood in areas of the atria (i.e.
atrial appendage) may allow clots to form and lead to thromboembolic events
such as stroke and transient ischemic attacks (TIAs).
Atrial fibrillation is characterized by a chaotic contraction of the atrium in
which an electrocardiogram (ECG) recording is necessary to diagnose the
arrhythmia. Any arrhythmia that has the ECG characteristics of AF and lasts
sufficiently long for a 12-lead ECG to be recorded, or at least 30 seconds on a
rhythm strip, should be considered an AF episode. The diagnosis requires an ECG
or rhythm strip demonstrating: (1) Irregular RR
intervals (in the absence of complete AV block), (2) no distinct P waves on the
surface ECG, and (3) an atrial cycle length (when visible) that is usually
variable and less than 200 milliseconds. For many years, three major schools of
thought competed to explain the mechanism(s) of AF: multiple random propagating
wavelets, focal electrical discharges, and localized reentrant activity with
fibrillatory conduction.
Significant progress has been made in defining the mechanisms of initiation and
perpetuation of AF. One of the most important breakthroughs was the
recognition that, in a subset of patients, AF was triggered by a rapidly firing
focus and could be *cured* with a localized catheter ablation procedure. This
landmark observation caused the EP community to refocus their attention on the
pulmonary veins (PVs) and the posterior wall of the left atrium (LA), as well
as the autonomic innervation in that region. It also reinforced the concept
that the development of AF requires *trigger* and an anatomic or functional
substrate capable of both initiation and perpetuation of AF.

The management of AF involves rate control, rhythm control with antiarrhythmic
drugs (AADs), and more recently catheter ablation. The 2017
HRS/EHRA/ECAS/APHRS/SOLACE expert consensus has stated: *The role of catheter
ablation as first-line therapy, prior to a trial of a Class I or III
antiarrhythmic agent, is an appropriate indication*. The most commonly used
catheter ablation approaches to treat AF are pulmonary vein isolation (PVI) and
pulmonary vein antrum isolation (PVAI). Isolation of the pulmonary veins may
also be achieved through wide area circumferential ablation
(WACA). If the pulmonary veins are targeted, complete electrical isolation
should be the desired endpoint.

As AF progresses into a more persistent state, additional non-PV targets may be
included in the ablation strategy. In a recent land-mark clinical study, Verma,
et al randomized the persistent AF population into three treatment groups.
• PVI
• PVI plus a roof line and a mitral isthmus line
• PVI plus ablation of complex fractionated electrograms
Single treatment efficacy results demonstrated the PVI only group had improved
longer-term outcomes although the sample size was much smaller than the other
groups (67 versus 259 versus 263). There was no statistical difference in
outcomes between the latter two groups.
In 2008, Hummel, et al investigated a persistent and long-standing persistent
AF population with a treatment strategy that included PVI plus elimination of
fractionated electrograms on the left atrial septum and posterior wall.
A two- treatment efficacy was reported to be 55.8% as measured by a 48-hour
Holter at 6-months. Cryoablation of AF Two major multi-center studies have been
published where cryoenergy was used for the isolation of PVs. The Fire and Ice
study prospectively randomized to two comparative arms including the Artic
Front Cryoballoon (Medtronic, Minneapolis,MN) and RF ablation while the STOP-AF
was the initial IDE study leading to the cryoballoon approval.
Both treated the PAF population and the study was limited to PVI as the only
ablation strategy.

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The objective of the clinical study is to evaluate the safety and efficacy of
the Adagio Cryoablation System (iCLAS*) in the ablation treatment of persistent
atrial fibrillation (PsAF). Data will be used to support a pre-market
application (PMA).

A prospective, single-arm, multi-center, open-label, controlled, premarket,
clinical study designed to provide safety and efficacy data regarding the use
of the Adagio System in the treatment of PsAF. For the purposes of this study,
PsAF is defined as:
• Continuous AF that is sustained beyond 7 days and <= 12months.
Enrolled subjects will be treated (ablation) with the Adagio System. Treatment
will include the isolation of all assessible pulmonary veins (PVI), isolation
of the left atrial posterior wall (PWI), and a right atrial cavo-tricuspid line
for bi-directional block.
Data will be collected at procedure, discharge, 1-, 3-, 6-, and 12 months to
assess safety and efficacy of the device. Testing for recurrence of atrial
arrhythmias will include 12-lead ECGs and a 24-h continuous ECG recording at
3-, 6-, and 12-months post ablation.
Symptom triggered rhythm monitoring will be used throughout the post-ablation
period.
A subset of forty (40) subjects will be randomly selected and consented to a
sub-study evaluating the evidence of discrete lesions in the PV. Subjects in
the PV sub-study will be required to complete a CTA or MRA at baseline
(pre-ablation) and again during the 3month
follow-up (post ablation). A centralized core lab will interpret the presence
and degree of PV stenosis.

A de novo endocardial ablation of symptomatic, drug-refractory PsAF, followed
by clinical follow up visits at discharge, 7 days, 1 month, 3 months, 6 months
and 12Months.

For patients participating in the substudy the baseline visit and the clinical
follow up visits at 3 months will also include a CTA or MRA.

Patient burden includes additional hospital contacts beyond the standard of
care for ablations. Those visits are at 7 days (by phone), 1 month and 6
months (at the hospital). There is additional burden for wearing a rhythm
monitor to record individual events and for 24-hour recordings at the follow up
time points. There is another burden for those selected to participate in the
PV sub-study because they will need a baseline and 3-month CTA or MRA. The
risks associated with the iCLAS ablation procedure are the same as for any
ablation procedure. There is minimal risk of radiation exposure and contrast
allergy for those who are selected for the PV sub-study and receive CTA scans.
The benefits include the potential to reduce or eliminate, either temporarily
or permanently, the symptoms of atrial fibrillation.