Adagio Medical Pulsed Field Ablation (PFA) and Pulsed Field Cryoablation (PFCA) Systems for persistent Atrial Fibrillation (PsAF)

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 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 firstline
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.

First-In-Human Clinical Investigation to evaluate the safety and performance of
the Adagio Medical PFA and PFCA Systems in the ablation treatment of
symptomatic Persistent Atrial Fibrillation (PsAF).

A prospective, two-arm, multi-center, randomized, open-label, pre-market,
First-in-Human clinical study designed to provide safety and performance data
regarding the use of the Adagio PFA and PFCA Systems in the treatment of PsAF.

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

Patient burden includes additional hospital contacts beyond the standard of
care for ablations. Those visits are at 7 days (by phone), 1 month (by phone)
and 6 months (at the hospital). There is additional burden for wearing a rhythm
monitor to record individual events and for 48-hour recordings at the follow up
time points.