\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{One-year outcomes of Pulmonary Vein Isolation with a novel cryoballoon:
Primary results of the FROZEN AF Trial}



\author[1]{Ellenbogen KA}%
\author[2]{Mittal S}%
\author[3]{Niraj Varma}%
\author[4]{Arash Aryana}%
\author[5]{Nassir Marrouche}%
\author[6]{Ante Anic}%
\author[7]{Devi Nair}%
\author[8]{Jean Champagne}%
\author[9]{Saverio Iacopino}%
\author[10]{Carlo de Asmundis}%
\author[11]{Stanislav Weiner}%
\author[12]{Makati K}%
\author[13]{Jon Raybuck}%
\author[13]{Elizabeth Richards}%
\author[14]{Wilber Su}%
\affil[1]{VA Richmond Medical Center}%
\affil[2]{Valley Hospital}%
\affil[3]{Cleveland Clinic}%
\affil[4]{Mercy General Hospital}%
\affil[5]{Tulane University School of Medicine}%
\affil[6]{Klinicki Bolnicki Centar Split Krizine}%
\affil[7]{Saint Bernards Medical Center}%
\affil[8]{Institut Universitaire de Cardiologie et de Pneumologie de Quebec - Universite Laval}%
\affil[9]{Maria Cecilia Hospital SpA}%
\affil[10]{Universitair Ziekenhuis Brussel Orthopedie}%
\affil[11]{Christus Trinity Mother Frances Hospital Winnsboro}%
\affil[12]{St Joseph's Hospitals Foundation}%
\affil[13]{Boston Scientific Corp Arden Hills}%
\affil[14]{Banner - University Medical Center Phoenix}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} Cryoablation therapy for pulmonary vein isolation
(PVI) to treat paroxysmal atrial fibrillation (PAF) is well established.
A novel 28 mm cryoballoon system designed to operate under low pressure
to safely reach a lower nadir temperature and maintain constant balloon
size during cooling has not been prospectively studied in a large
patient population for safety and efficacy. The FROZEN AF (NCT04133168)
trial was an international multi-center, open-label, prospective,
single-arm study on the safety and performance of a novel cryoballoon
system for treatment of PAF. \textbf{Methods and Results:} The study
enrolled patients at 44 sites in 10 countries across North America,
Europe, and Asia. Subjects were indicated for PVI treatment of PAF and
had failed or were intolerant of 1 or more antiarrhythmic drugs.
Procedural outcomes were defined based on the 2017 HRS consensus
statement. Follow-up was performed at 7 days, 3, 6, and 12 months. Data
are reported as mean\selectlanguage{ngerman}±SD or Median (IQR). PVI was performed with a 28mm
cryoballoon in 325 drug refractory PAF patients. Complete PVI was
achieved in 95.7\% of patients. In cryoablation lesions longer than 60s,
60.1\% of PV isolations required only a single cryoballoon application.
Procedure related complications included: phrenic nerve palsy
{[}transient 4 (1.2\%), persistent 0 (0.0\%){]}, cardiac
tamponade/perforation 2 (0.6\%), and air embolism 1 (0.3\%). Freedom
from documented atrial arrhythmia recurrence at 12 months was 79.9\% (AF
82.7\%, AFL 96.5\%, AT 98.1\%), Antiarrhythmic drugs (AAD) were
continued or re-initiated in 26.8\% of patients after the 3-month
blanking period. Additionally, an extension arm enrolled 50 pts for
treatment with 28/31mm variable size cryoballoon. A single temporary PNP
occurred in this group, which resolved prior to discharge. Freedom from
documented recurrence at 12 months in these pts was 82.0\%.
\textbf{Conclusions:} This novel cryoballoon may facilitate PVI to treat
PAF, providing more options to address the variety of anatomy present in
patients with PAF. This cryoballoon system was safe and effective for
treatment of patients with drug refractory or drug intolerant PAF.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction:}

Cryoablation to achieve pulmonary vein isolation (PVI) to treat
paroxysmal atrial fibrillation (PAF) is well
established.\textsuperscript{1} Cryoballoon treatment has been available
for PVI since the Arctic Front\textsuperscript{Tm} (Medtronic, MN, USA)
was launched over 15 years ago.\textsuperscript{2} STOP-AF demonstrated
first generation cryoballoon superiority to AADs,\textsuperscript{3} and
later Fire and ICE demonstrated comparable efficacy of cryoballoon to RF
ablation.\textsuperscript{4} FIRE and ICE showed comparable efficacy of
radiofrequency and cryoballoon but cryoablation has a distinct safety
profile compared to RF, shifting primary safety events from heat
associated pericarditis/perforation to cold associated phrenic nerve
impairment and PV stenosis.\textsuperscript{4} Despite over a decade of
use the safety profile of cryoablation remains relatively
unchanged.\textsuperscript{5-10}

Recently a novel 28 mm cryoballoon system that operates under markedly
lower pressure and maintains constant balloon size during cooling became
available for clinical studies.\textsuperscript{11} Additionally, a
second generation of this novel cryoballoon that allows inflation and
ablation at 2 sizes, 28mm or 31mm, has also become
available.\textsuperscript{12} At present there is limited long-term
(1yr) outcome data on this novel cryoballoon, and little data available
on the safety or effectiveness of the novel variable size
cryoballon\textsuperscript{12} While multiple studies have reported both
acute procedural data,\textsuperscript{13-16} and chronic 1 year
outcomes,\textsuperscript{17-19} only a few reports of large patient
cohorts exist.\textsuperscript{13,14,18,20,21}

FROZEN AF is an international multi-center, open-label, prospective,
single-arm study to determine the safety and performance of a novel
cryoballoon system for treatment of PAF, and an extension arm which
examined the safety and performance of a novel variable size cryoballon.

\textbf{Methods:}

\textbf{Design:} FROZEN-AF is a prospective, non-randomized,
multi-center, investigation conducted to establish the safety and
effectiveness of the POLARx cryoablation system in subjects with
symptomatic, drug refractory, recurrent, paroxysmal atrial fibrillation.
The trial was registered at clinical trials.gov (NCT04133168). All
patients provide written informed consent to participate in the trial
and all centers obtained approval by their local IRB.

\textbf{Subjects:} Subjects were indicated for PVI treatment of PAF and
had failed or were intolerant of 1 or more antiarrhythmic drugs. To
allow orientation to the new investigational system and minimize
potential learning curve bias each ablating physician was required to
treat one ``roll-in'' patient. Sixty-three total roll-in patients were
treated, their data is not reported here. Briefly, patients were
indicated for PVI to treat recurrent symptomatic AF and had failed at
least one Class I or III antiarrhythmic drug (AAD) and had not been on
amiodarone for at least 90 days. Patients were excluded if they had
contraindications for AF ablation (or anticoagulants), continuous AF
(longer than 7 days), a history of prior left atrial ablation for
AF/AFL/AT, structural heart disease of implanted cardiac devices. For
full inclusion and exclusion criteria, see supplement.

All subjects fitting the enrollment criteria, signing the consent and
undergoing the index procedure with the study devices were followed for
up to 12 months after the index procedure. FROZEN-AF was conducted as a
post market study in those regions where the device was already
approved, including Europe.

\textbf{Site description} : Investigators and sites were selected based
on prior experience with cryoablation, ensuring that sites had adequate
access to subject population, staff, and documentation practices. In
total, 44 sites participated in the study, 30 in the United States, 6 in
Europe, 4 in Canada, and 4 in Asia/ Pacific.

\textbf{Patient Flow:} In total, 404 subjects were enrolled across 44
centers (30 in the US, 6 in Europe, 4 in Canada, and 4 in Asia/
Pacific). Of these 385 subjects received treatment with the
investigational device, 60 treatment subjects were classified as roll-In
subjects and 325 as non-roll-in subjects. Fifteen treatment patients and
4 ``roll-in'' patients withdrew consent from the study, which was in
line with the protocol assumed 10\% attrition. Additionally, as part of
an extension arm, 54 patients were enrolled to examine the safety and
effectiveness of the novel variable size cryoballoon POLARx
FIT\textsuperscript{Tm} (Boston Scientific, MN, USA). Of these, there
was 1 consent ineligible, 3 intent to treat, and 50 treatment patients.

\textbf{Cryoballoon Ablation Procedure}

\textbf{Index Procedure:} Procedural guidance (described here) was
provided to inform use of the novel study device, but in general
procedures were performed in accordance with local standard of care at
physician discretion.

\textbf{Dosing recommendation:} Cryoapplications were recommended based
on an algorithm measuring time to isolation (TTI), with a 180s
application where TTI occurred in less than 60s and a 240s application
where TTI occurred after 60s or was not detected, but the duration and
number of cryoapplications was at physician discretion.

\textbf{Esophageal management:} Esophageal monitoring was required with
a recommended cut-off temperature of 20\selectlanguage{ngerman}°C.

\textbf{Phrenic Monitoring:} Phrenic nerve monitoring with the
integrated DMS (Diaphragm Movement Sensor) was recommended, in
conjunction with local standard of care monitoring. The integrated DMS
allows the physician to monitor the amplitude of paced electromyogram
like potential based movement recorded from an external sensor and
visible as real time changes in amplitude on the cryoablation system,
with an adjustable threshold and automatic recommendations to stop the
cryoablation if the electrogram amplitude decreases by a pre-set
percentage, see Supplement. In this study the DMS was recommended to be
set at 65\%. Phrenic nerve impairment was confirmed with a ``sniff
test'' or radiography during the index procedure, discharge, and
follow-up visits until resolved.

\textbf{PVI Procedure:} Procedural guidance (described here) was
provided to inform use of the novel study device, but in general
procedures were performed in accordance with local standard of care at
physician discretion. Cardioversion was performed at operator
discretion. Anti-coagulation was recommended to be uninterrupted or
minimally interrupted prior to procedure. PVI procedures were conducted
based on local standard of care and cryoablation system instruction for
use. Acute success was confirmed by entrance and exit block, lack of
confirmed or recorded block was reported as acute procedural failure.

\textbf{Additional ablations:} Additional ablation of non-PV foci that
initiate AF (including locations in the left atria, right atrium, or
superior vena cava), targeting complex fractionated electrograms or
ganglionated plexi or performing LA mitral isthmus or roof lines was not
allowed. Additional ablation of the cavo-tricuspid isthmus (CTI) with a
market approved RF catheter was allowed in cases where typical atrial
flutter was documented by patient history or occurred during the case
(either spontaneously or inducible).

\textbf{Redo Ablations:} One repeat ablation was allowed during
blanking, use of `non-study' device for redo was considered a failure.

\textbf{Follow-Up:} Follow-up was performed at discharge, 7 days, 3
months, 6 months, and 12 months post index procedure. Trans telephonic
monitoring (TTM) was collected by patients 2 times per month (either
symptomatic or asymptomatic) from 3 to 12m post procedure. Only 43
subjects had monitoring related deviations. 24h Holter monitoring was
provided at the 12m FU visit.

\textbf{Study Endpoints}

\textbf{Endpoint definitions:} Procedural outcomes were defined based on
the 2017 HRS consensus statement. Full endpoint definitions are included
in the Supplement.

\textbf{Primary Efficacy Endpoint:} Failure free rate at 12 months post
procedure, with failure defined as occurrence of any of the following
events; acute procedural failure, surgical treatment for AF/AFL/AT, use
of non-study catheter for AF targets, more than 1 repeat during
blanking, repeat or surgical treatment after blanking, documented
recurrence of AF, AFL, or AT after blanking; electrical or
pharmacological cardioversion after blanking, use of Class I/III AADs or
any other AADs for control of AF/AFL/AT, any use of amiodarone (pre or
post blanking).

\textbf{Primary Safety Endpoint:} Primary safety event free rate at 12
months post procedure. Event free rate was defined as a composite of the
following acute and chronic procedure-related and device-related adverse
events: Acute primary safety endpoint events, events occurring up to 7
days post index or hospital discharge, whichever is later, include:
Death; myocardial infarction (MI); transient ischemic attack (TIA);
stroke/ cerebrovascular accident (CVA); vascular access complications;
mitral or tricuspid valvular damage; thromboembolism/ air embolism
(leading to a life-threatening event such as a ventricular arrhythmia,
stroke, pulmonary embolism, or myocardial infarction and, thromboembolic
events that result in permanent injury, require intervention for
treatment, or prolongs/requires hospitalization for more than 48 hours);
gastroparesis/injury to vagal nerve; pneumothorax; pulmonary edema/heart
failure; atrioventricular block; cardiac tamponade/perforation
(occurring up to 30 days post index procedure). chronic primary safety
endpoint events, events occurring through 12 months post procedure,
include: atrial esophageal fistula; severe PV stenosis (\selectlanguage{english}[?] 70\% reduction
in the diameter of the PV or PV branch from baseline); persistent
phrenic nerve palsy. Safety events, including but not limited to the
predefined safety endpoint, were reviewed by an independent Clinical
Events Committee.

\textbf{Stenosis Sub-study:} Fifty treatment patients were assessed for
stenosis associated with cryoablation. Patients PVs were imaged by
CT/MRI at baselines and 3 to 6 months post procedure. The degree of
narrowing (mild \textless{}50\%, moderate 50-70\%, severe \selectlanguage{english}[?]70\%) from
the 3 to 6 months follow-up scan compared to baseline was assessed by a
central lab.

\textbf{FIT Extension:} In addition to the primary study arm, an
extension arm to FROZEN AF treated 50 pts to assess safety of novel
variable size balloon that allows inflation and ablation at both 28mm
and 31mm. Patients received at least one PV cryoablation with the 31mm
sized cryoballoon, otherwise pts treatment and design were similar to
the larger cohort.

\textbf{Statistical Analysis:} The primary arm of this study was
designed around an expected event-free rates of 94\% (Safety) 60\%
(Effectiveness), targeting 90\% power to compare to performance goals of
89\% (Safety) and 50\% (Effectiveness) with a 95\% one-sides confidence
limit. The FIT extension arm was designed with a primary safety endpoint
based on 3-month follow-up and acute success, with the same performance
goal as the parent study (89\% freedom from safety events), while the
effectiveness endpoint did not have a designated acceptance criteria.
For ease of comparison, the pre-defined primary effectiveness endpoint
of the initial study was also calculated for the 50 patient FIT
extension arm. Secondary analysis reported here include survival
analysis to efficacy component events. Analyses were performed with SAS
version 9.4 (SAS Institute Software Company). Data are reported as mean
+- standard deviation, median (IQR, or N (\%) as appropriate.

\textbf{Results:}

\textbf{Patient Disposition} : The study enrolled 404 patients, of which
5 were consent ineligible, 63 were `roll-in' pts, and 336 non roll-in.
Of the non roll-in pts there were 10 intention to treat (enrolled after
study met treatment goals), 1 attempt to treat, and 325 treatment
subjects (Supplemental Figure 1). A PV stenosis sub-study enrolled 55
pts, of which 50 contributed to the PV stenosis analysis. These patients
underwent MRI or CTA to measure pulmonary veins size pre procedure and
then a repeat study 3 months after ablation. Additionally, an extension
arm enrolled 54 pts to examine the performance of the variable size
POLARx FIT catheter, 0f these 1 was consent ineligible, 3 were Intention
to treat, and 50 received treatment with the 31mm inflation size in at
least one PV.

\textbf{Patient Demographics:} Characterization of patient demographics
is provided in Table 1. Briefly, patients in the primary cohort were 62
+- 11 yrs old on average, 38.2\% (124/325) were females, average BMI was
29. Patients had an average CHADS\textsubscript{2}-VA\textsubscript{2}SC
score of 1.7 +- 1.3, LVEF of 58.6\% +- 5.8\%. Patients were enrolled an
average of 3.0 yrs post initial diagnosis, and an average of 87 days
since their most recent episode. Similar demographics were seen in the
FIT extension arm, though patients had a shorter time since AF diagnosis
(Mean 1.6yrs; Median 0.4, IQR 0.2, 1.0) and higher
CHADS\textsubscript{2}-VA\textsubscript{2}SC scores (2.2).

\textbf{Procedural performance:} Recommended dosing strategy was based
on TTI timing (See Supplement), strategy was not followed in 206/325
pts. General anesthesia was used in a majority of pts (255/325),
conscious sedation was used in (70/325), esophageal temperature
monitoring was used in 311/325 cases. 3D mapping was used in 184/325
cases. Average procedure, LA dwell, and Fluoroscopy times were 91, 59,
and 13 minutes, respectively. Acute success was achieved in 311 cases
(95.7\%). Fourteen subjects (14) were acute procedural failures due to
not achieving entrance block and/or exit block in one or more pulmonary
veins, usage of a non-study catheter or not performing the entrance and
exit block testing. In the FIT extension arm general anesthesia was used
in all patients, 3D mapping had higher utilization (98\%), and
fluoroscopy time was shorter (7 min). The 31 mm balloon size was used in
approximately 64\% of ablations. Additionally, in the FIT arm acute
success was achieved in all 50 patients for a rate of 100\% with a
92.9\% lower confidence interval.

\textbf{Biophysical data:} Biophysics data is reported in Table 2.
Complete PVI, confirmed with exit and entrance block, was achieved in
95.7\% of patients. On average PVs received 1.8 +- 1.3 ablations (IQR
1-2), with a total duration of 4.46 +- 2.7 min (IQR 3-5 min) per PV.
Occlusion score of 3 or 4 was reported in 95.9\% of PVs. Overall single
shot success was achieved in 55.9\% of PVs (726/1299), in cryoablations
longer than 60s the single-shot rate was 60.1\%. The mean nadir
temperature for ablations was 56.4 +- 6.9degC. TTI was available from 1044
ablations and averaged 45.1 +- 25.3 s. Biophysical and performance data
by PV are reported in Table 2. Biophysical data from the 50 patient FIT
extension arm are also reported in Table 2, however as usage of the
larger 31mm balloon configuration was at operator discretion, it is
challenging to directly compare data. Though, it is notable that nadir
temperatures, and time-to-isolation appear relatively similar. See
Figure 1 for visual comparison aggregate freeze curves from all `first
ablation' uses of the 28mm and 31mm balloon sizes.

\textbf{Safety:} The primary safety endpoint was a composite of multiple
acute and chronic safety events. Safety events occurred in 4.0\% of
patients, resulting in a KM freedom from occurrence rate of 96.0\%,
which met the study safety goal of 89.0\% (Figure 2). One death occurred
in a treatment patient during the course of the study at approximately 6
months post ablation due to a non-healing foot wound but was adjudicated
to be unrelated to the study device or the procedure. Primary safety
events included: 5 vascular access complications, 3 gastroparesis, 2
tamponade, 1 air embolism, 1 pulmonary edema, and 1 myocardial
infarction. In addition to prespecified endpoints, 4 patients had
phrenic nerve palsy (temporary phrenic nerve impairment present at the
end of procedure), all of which resolved by the end of the study. See
Figure 1 for list of study safety endpoint events.

\textbf{PV Stenosis Sub study:} A subset of 50 patients in the primary
cohort enrolled in an MRI sub-study to examine occurrence of PV
stenosis. Core lab analysis of 3 and 6 month MRI (1.5 or 3T) images
revealed mild stenosis in the LIPV of 2 patients, and no instances of
moderate or severe stenosis.

\textbf{Effectiveness:}

Effectiveness endpoint, which incorporated atrial arrythmia recurrence,
AAD usage, acute procedural failure, cardioversion, repeat procedures,
was met in 59.9\% of patients (Figure 3), this met the study performance
goal of 50\%, which was based on similar prior trials. Examination of
individual components revealed that the primary endpoint contributors
were AAD usage and documented recurrence. Overall freedom from
recurrence of atrial arrythmia was confirmed in 79.9\% of patients.
Documented recurrence of atrial arrhythmias occurred in 20.1\% of
patient as of 12m follow-up, with recurrence of AF in 17.3\%, AFL 3.5\%,
and AT 1.9\%), Figure 3. Kaplan Meier analysis of AAD usage revealed a
sharp drop in freedom from AADs shortly following blanking, which was
partly attributable to relatively high AAD usage. Notably, 38 of the 46
patients that had treatment failure only due to AAD usage, i.e., with no
documented recurrence or other events, received AADs at the same dose or
lower than baseline. Examination of AAD usage across follow-up, suggests
a marked decrease in AAD usage over the course of the trial, from 60.1\%
of patients on Class I/III AADs (typical for control of AF)
pre-discharge to only 10.1\% on Class I/III AADs at 12m follow-up, 13
pts on Class I (11 flecainide, 2 propafenone, 18 pts on Class III (6
amiodarone, 2 dofetilide, 3 dronedarone, 7 sotalol), Figure 3C.

\textbf{FIT Extension ARM:}

\textbf{Safety:} In the FIT extension arm, as of 3-month FU, there were
no primary safety events resulting in a 100\% (LCL 92.9\%) freedom from
occurrence rate, meeting the safety goal of 89\% (Figure 4). There was a
single transient PNI which resolved prior to discharge.

\textbf{Effectiveness:} In the FIT extension arm, analysis based on the
per protocol endpoint resulted in a freedom from event rate of 78\%
(66.5\% LCL), which meets the study performance goal, Figure 4. Eleven
subjects in this extension arm had failures for documented recurrence
(9), AAD use (5), and repeat procedures (3), in total, with some
subjects contributing multiple categories. Additional analysis showed an
84\% freedom from recurrence of AF, 94\% freedom from AFL, and 100\%
freedom from AT. Though AAD usage was considerably lower in the
extension arm a pattern similar to the larger study was apparent with
AAD usage for atrial arrythmia reducing from 60\% at baseline to only
8.2\% at 12m FU, with only a single pt on Class 1 and 2pts on Class 3
AADs. Electroanatomic mapping data was available from only a sub-set of
patients across both study arms. Figure 5 presents two representative
cases, one of a patient where the 28mm balloon size was used in all PVs
and one of a different patient from the FIT extension where the 31mm
balloon size was used in all PVs. Fractional antral scar is calculated
to facilitate comparison of lesion extent in these two representative
patient cases.

\textbf{Repeat Procedures:} Repeat ablation procedures were performed in
a total of 26 patients, 11 were performed during the blanking period,
and 15 (4.6\%) were performed post-blanking. In the FIT extension arm
there were 4 total repeat procedures 3 (6\%) of which were performed
post blanking.

\textbf{Discussion:}

The FROZEN AF study demonstrates the safety and effectiveness of the
POLARx cryoballoon, the trial met effectiveness and safety endpoints in
patients with drug-refractory paroxysmal atrial fibrillation, with a
high 1-year recurrence free rate or 79.9\% and 0\% phrenic nerve palsy.
Additionally, the FIT extension arm demonstrates the promise of the
variable size cryoballoon, with 84\% freedom from AF recurrence and a
promising safety profile.

\textbf{Safety}

The present study reports a safety event free rate of 96\% in the
primary cohort, and 100\% in the extension arm. The landscape of adverse
events associated with cardiac ablation procedures has consistently
improved from radiofrequency ablation, to irrigated RF, cryoablation,
and pulsed field ablation. Early, landmark cryoablation trials
demonstrated that though RF and cryoablation have similar overall
adverse event rates, the primary adverse events in cryoablation were PV
stenosis and phrenic nerve impairment, but more serious extremely rare
events , like atrioesophageal fistula, could
occur.\textsuperscript{3,4}Technical and procedural advancements have
reduced PV stenosis to negligible levels and use of esophageal
temperature monitoring has significantly reduced esophageal damage (as
well as AE fistula). Phrenic nerve impairment remains at an incidence of
2-4\%,\textsuperscript{5}varying based on definition (transient,
temporary, chronic, or permanent), with permanent phrenic nerve palsy
thought to occur in less than 1\% of patients.\textsuperscript{5} The
present study saw zero permanent phrenic nerve palsy , with all patients
recovering, and a lower rate of temporary phrenic nerve impairment in
the FIT extension arm. This observation may be attributable to multiple
factors. One, DMS was recommended in this study, the integrated DMS
sensor may allow better detection of early transient PNI during
ablation, resulting in lower overall rates of PNP. Two, the lower
pressure and controlled pressure during ablation of this cryoablation
system may allow better contact to PV tissue avoiding seating of the
balloon deep into the PVs. Three, the 31mm configuration in particular
may allow a more antral positioning and thus further from the phrenic
nerve.

\textbf{Efficacy}

The 79.9\% recurrence rate reported here is higher than reports from
recent meta-analysis of treatment success for PAF, cryoablation (28\%
recurrence) AADs (45\% recurrence).\textsuperscript{22} Additionally,
the current data are promising in light of historic studies of the
effectiveness of cryoablation.\textsuperscript{1} Though it used
different endpoints, FIRE and ICE reported cryoballoon effectiveness of
65\%, with 87/376 pts (23\%) having documented recurrence of atrial
arrythmia.\textsuperscript{23} STOP AF reported a 69\% overall
effectiveness of cryoablation\textsuperscript{3} though that study
allowed continued treatment with the same dose of previously ineffective
AADs but used a first generation cryoballoon. Cryo-First reported
similar outcomes to the current study, with an 82.2\% freedom from
recurrence of atrial arrythmia in early PAF patients with no AAD
history.\textsuperscript{24} It should be noted that outcomes might be
improved in patients undergoing ablation prior to trials of
antiarrhythmic drugs and thus early in the course of their disease.. A
recent study of a pulsed field ablation (PFA) system of 150 paroxysmal
AF patients had a markedly higher rate of documented recurrence (33.8 vs
the present 19.1) and more repeat ablations (8\% vs the present
4.4\%).\textsuperscript{25} A recent randomized controlled trial
comparing PFA to thermal (Cryo and RF) ablation modalities also aids in
putting this data in perspective, ADVENT reported a 73\% and 71\%
effectiveness for PFA and thermal ablation,
respectively.\textsuperscript{26} The effectiveness of thermal ablation
in that trial was comparable to the present findings, though the
Bayesian analysis used in ADVENT makes direct comparison to traditional
KM analysis challenging. Further insights into the relative
effectiveness of cryoablation and novel PFA systems may have significant
impact on the landscape of AF treatment.

\textbf{Limitations:}

FROZEN AF is a large, multicenter, multicountry prospective trial to
assess the safety and effectiveness of POLARx for cryoablation of PAF in
drug-refractory patients. While all endpoints were met and the study
conclusions are clear, the trial design has limitations: 1) This study
enrolled drug refractory PAF patients, thus did not directly address use
in other patient populations, such as those with persistent AF or
patients with early AF that have not yet been on AADs, 2) Though the
study was conducted with a primary arm of 325 patients that received PVI
with POLARx and an extension arm of 50 pts treated with the variable
size POLARx FIT, it was essentially a single arm design and did not
directly compare cryoablation to alternative therapies, 3) The trial was
run across 55 centers with a wide range of patients treated per center
with a minimum of 1 and a maximum of 48. Thus, many operators were
relatively inexperienced with the device. While this precluded
examination of learning curves, as few operators treated enough patients
to make examination of procedure times or outcomes over time meaningful,
the high freedom from recurrence with so little device use speaks to the
ease of use of the device. 4) Additionally, the size of the extension
arm limits the conclusions that can be reached about the novel variable
size cryoballoon, which allows ablation at either 28mm or 31mm without
catheter change out. To better understand how this new option may
transform workflow and patient outcomes, future studies should examine
acute and chronic endpoints in larger patient cohorts.

\textbf{Conclusions:}

The present findings suggest an excellent safety and performance profile
for the novel 28mm cryoablation system, with safety and effectiveness
comparable to other ablation therapy. Additionally, the development of a
variable sized balloon may further increase safety and effectiveness of
PVI cryoablation. Considering recent findings that support early rhythm
control, single shot technologies, such as cryoballoon ablation, may see
increased utilization as first line treatment for PAF.

\textbf{Acknowledgments:} The Authors would like to acknowledge the
Investigators of FROzEN AF, Beth Albrecht (BSC, Sci Comm), Binh Tran
(BSC, RD), and Torri Schwartz (BSC, Statistics) as well as supporting
clinic staff and patients, without whom this work would not have been
possible.

\textbf{Funding:} This study was funded by Boston Scientific

\textbf{Data Availability:} The data from this clinical trial may be
made available to other researchers in accordance with Boston
Scientific's Data Sharing Policy
(http://www.bostonscientific.com/en-US/data-sharing-requests.html).



\textbf{References:}

1. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ,
Blomstrom-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, et
al. 2020 ESC Guidelines for the diagnosis and management of atrial
fibrillation developed in collaboration with the European Association
for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis
and management of atrial fibrillation of the European Society of
Cardiology (ESC) Developed with the special contribution of the European
Heart Rhythm Association (EHRA) of the ESC. \emph{Eur Heart J} .
2021;42:373-498. doi: 10.1093/eurheartj/ehaa612

2. Neumann T, Vogt J, Schumacher B, Dorszewski A, Kuniss M, Neuser H,
Kurzidim K, Berkowitsch A, Koller M, Heintze J, et al. Circumferential
pulmonary vein isolation with the cryoballoon technique results from a
prospective 3-center study. \emph{J Am Coll Cardiol} . 2008;52:273-278.
doi: 10.1016/j.jacc.2008.04.021

3. Packer DL, Kowal RC, Wheelan KR, Irwin JM, Champagne J, Guerra PG,
Dubuc M, Reddy V, Nelson L, Holcomb RG, et al. Cryoballoon ablation of
pulmonary veins for paroxysmal atrial fibrillation: first results of the
North American Arctic Front (STOP AF) pivotal trial. \emph{J Am Coll
Cardiol} . 2013;61:1713-1723. doi: 10.1016/j.jacc.2012.11.064

4. Kuck KH, Brugada J, Furnkranz A, Metzner A, Ouyang F, Chun KR, Elvan
A, Arentz T, Bestehorn K, Pocock SJ, et al. Cryoballoon or
Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. \emph{N Engl
J Med} . 2016;374:2235-2245. doi: 10.1056/NEJMoa1602014

5. Heeger CH, Sohns C, Pott A, Metzner A, Inaba O, Straube F, Kuniss M,
Aryana A, Miyazaki S, Cay S, et al. Phrenic Nerve Injury During
Cryoballoon-Based Pulmonary Vein Isolation: Results of the Worldwide
YETI Registry. \emph{Circ Arrhythm Electrophysiol} . 2022;15:e010516.
doi: 10.1161/CIRCEP.121.010516

6. Tsiachris D, Antoniou CK, Doundoulakis I, Manolakou P, Sougiannis D,
Kordalis A, Gatzoulis KA, Chierchia GB, de Asmundis C, Stefanadis C, et
al. Best Practice Guide for Cryoballoon Ablation in Atrial Fibrillation:
The Compilation Experience of More than 1000 Procedures. \emph{J
Cardiovasc Dev Dis} . 2023;10. doi: 10.3390/jcdd10020055

7. Tokuda M, Yamashita S, Shiomi S, Sakurai R, Sato H, Oseto H, Yokoyama
M, Tokutake K, Kato M, Narui R, et al. Pulmonary Vein Stenosis After
Catheter Ablation of Atrial Fibrillation Using a Cryoballoon, Hot
Balloon, or Laser Balloon. \emph{Circ J} . 2023;87:1711-1719. doi:
10.1253/circj.CJ-23-0048

8. Su W, Aryana A, Passman R, Singh G, Hokanson R, Kowalski M, Andrade
J, Wang P. Cryoballoon Best Practices II: Practical guide to procedural
monitoring and dosing during atrial fibrillation ablation from the
perspective of experienced users. \emph{Heart Rhythm} .
2018;15:1348-1355. doi: 10.1016/j.hrthm.2018.04.021

9. Su W, Kowal R, Kowalski M, Metzner A, Svinarich JT, Wheelan K, Wang
P. Best practice guide for cryoballoon ablation in atrial fibrillation:
The compilation experience of more than 3000 procedures. \emph{Heart
Rhythm} . 2015;12:1658-1666. doi: 10.1016/j.hrthm.2015.03.021

10. Chen S, Schmidt B, Bordignon S, Bologna F, Nagase T, Perrotta L,
Julian Chun KR. Practical Techniques in Cryoballoon Ablation: How to
Isolate Inferior Pulmonary Veins. \emph{Arrhythm Electrophysiol Rev} .
2018;7:11-17. doi: 10.15420/aer.2018;1;2

11. Anic A, Lever N, Martin A, Breskovic T, Sulkin MS, Duffy E, Saliba
WI, Niebauer MJ, Wazni OM, Varma N. Acute safety, efficacy, and
advantages of a novel cryoballoon ablation system for pulmonary vein
isolation in patients with paroxysmal atrial fibrillation: initial
clinical experience. \emph{Europace} . 2021;23:1237-1243. doi:
10.1093/europace/euab018

12. Isonaga Y, Miyazaki S, Nitta J, Shirai Y, Inamura Y, Sagawa Y,
Yamauchi Y, Sasaki T, Inaba O, Sasano T. Acute procedural efficacy and
safety of a novel expandable diameter cryoballoon in atrial fibrillation
ablation: Early results from a multicenter ablation registry. \emph{J
Cardiovasc Electrophysiol} . 2023. doi: 10.1111/jce.16135

13. Honarbakhsh S, Martin CA, Mesquita J, Herlekar R, Till R, Srinivasan
NT, Duncan E, Leong F, Dulai R, Veasey R, et al. Atrial fibrillation
cryoablation is an effective day case treatment: the UK PolarX vs.
Arctic Front Advance experience. \emph{Europace} . 2023;25. doi:
10.1093/europace/euad286

14. Martin CA, Tilz RRR, Anic A, Defaye P, Luik A, de Asmundis C,
Champ-Rigot L, Iacopino S, Sommer P, Albrecht EM, et al. Acute
procedural efficacy and safety of a novel cryoballoon for the treatment
of paroxysmal atrial fibrillation: Results from the POLAR ICE
study.\emph{J Cardiovasc Electrophysiol} . 2023;34:833-840. doi:
10.1111/jce.15861

15. Mojica J, Lipartiti F, Al Housari M, Bala G, Kazawa S, Miraglia V,
Monaco C, Overeinder I, Strazdas A, Ramak R, et al. Procedural Safety
and Efficacy for Pulmonary Vein Isolation with the Novel Polarx
Cryoablation System: A Propensity Score Matched Comparison with the
Arctic Front Cryoballoon in the Setting of Paroxysmal Atrial
Fibrillation. \emph{J Atr Fibrillation} . 2021;14:20200455. doi:
10.4022/jafib.20200455

16. Assaf A, Bhagwandien RE, Szili-Torok T, Yap SC. Comparison of the
acute outcome of two cryoballoon technologies for pulmonary vein
isolation: An updated systematic review and meta-analysis. \emph{Int J
Cardiol Heart Vasc} . 2022;42:101115. doi: 10.1016/j.ijcha.2022.101115

17. Bianchi S, De Simone A, Iacopino S, Fassini G, Malacrida M, Rossi P,
Stabile G, Petretta A, Tundo F, Cauti FM, et al. Pulmonary vein
isolation by means of a novel cryoballoon technology in paroxysmal
atrial fibrillation patients: 1-year outcome from a large Italian
multicenter clinical registry. \emph{Pacing Clin Electrophysiol} .
2023;46:1302-1309. doi: 10.1111/pace.14839

18. Guckel D, Lucas P, Isgandarova K, Hamriti ME, Bergau L, Fink T,
Sciacca V, Braun M, Khalaph M, Imnadze G, et al. Impact of pulmonary
vein variant anatomy and cross-sectional orifice area on freedom from
atrial fibrillation recurrence after cryothermal single-shot guided
pulmonary vein isolation. \emph{J Interv Card Electrophysiol} .
2022;65:251-260. doi: 10.1007/s10840-022-01279-w

19. Heeger CH, Popescu SS, Inderhees T, Nussbickel N, Eitel C, Kirstein
B, Phan HL, Hatahet S, Subin B, Traub A, et al. Novel or established
cryoballoon ablation system for pulmonary vein isolation: the
prospective ICE-AGE-1 study. \emph{Europace} . 2023;25. doi:
10.1093/europace/euad248

20. Martin A, Fowler M, Breskovic T, Ouss A, Dekker L, Yap SC,
Bhagwandien R, Albrecht EM, Cielen N, Richards E, et al. Novel
cryoballoon to isolate pulmonary veins in patients with paroxysmal
atrial fibrillation: long-term outcomes in a multicentre clinical
study.\emph{J Interv Card Electrophysiol} . 2022;65:609-616. doi:
10.1007/s10840-022-01200-5

21. Heeger CH, Pott A, Sohns C, Riesinger L, Sommer P, Gasperetti A,
Tondo C, Fassini G, Moser F, Lucas P, et al. Novel cryoballoon ablation
system for pulmonary vein isolation: multicenter assessment of efficacy
and safety-ANTARCTICA study. \emph{Europace} . 2022;24:1917-1925. doi:
10.1093/europace/euac148

22. Razzack AA, Lak HM, Pothuru S, Rahman S, Hassan SA, Hussain N,
Najeeb H, Reddy KT, Syeda H, Yasmin F, et al. Efficacy and Safety of
Catheter Ablation vs Antiarrhythmic Drugs as Initial Therapy for
Management of Symptomatic Paroxysmal Atrial Fibrillation: A
Meta-Analysis. \emph{Rev Cardiovasc Med} . 2022;23:112. doi:
10.31083/j.rcm2303112

23. Kuck KH, Furnkranz A, Chun KR, Metzner A, Ouyang F, Schluter M,
Elvan A, Lim HW, Kueffer FJ, Arentz T, et al. Cryoballoon or
radiofrequency ablation for symptomatic paroxysmal atrial fibrillation:
reintervention, rehospitalization, and quality-of-life outcomes in the
FIRE AND ICE trial. \emph{Eur Heart J} . 2016;37:2858-2865. doi:
10.1093/eurheartj/ehw285

24. Kuniss M, Pavlovic N, Velagic V, Hermida JS, Healey S, Arena G,
Badenco N, Meyer C, Chen J, Iacopino S, et al. Cryoballoon ablation vs.
antiarrhythmic drugs: first-line therapy for patients with paroxysmal
atrial fibrillation. \emph{Europace} . 2021;23:1033-1041. doi:
10.1093/europace/euab029

25. Verma A, Haines DE, Boersma LV, Sood N, Natale A, Marchlinski FE,
Calkins H, Sanders P, Packer DL, Kuck KH, et al. Pulsed Field Ablation
for the Treatment of Atrial Fibrillation: PULSED AF Pivotal
Trial.\emph{Circulation} . 2023;147:1422-1432. doi:
10.1161/CIRCULATIONAHA.123.063988

26. Reddy VY, Gerstenfeld EP, Natale A, Whang W, Cuoco FA, Patel C,
Mountantonakis SE, Gibson DN, Harding JD, Ellis CR, et al. Pulsed Field
or Conventional Thermal Ablation for Paroxysmal Atrial
Fibrillation.\emph{N Engl J Med} . 2023. doi: 10.1056/NEJMoa2307291

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/753280/articles/723620-one-year-outcomes-of-pulmonary-vein-isolation-with-a-novel-cryoballoon-primary-results-of-the-frozen-af-trial}

\textbf{Hosted file}

\verb`image2.emf`  available at \url{https://authorea.com/users/753280/articles/723620-one-year-outcomes-of-pulmonary-vein-isolation-with-a-novel-cryoballoon-primary-results-of-the-frozen-af-trial}

\textbf{Figures:}

\textbf{Figure 1. Balloon Size and Freeze Profile Characterization}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 1.} Aggregate freeze curve profiles of console export
data from all available (A.) FROZEN AF (28mm), and available (B.) 31mm
FIT Extension ablations. Plots generated as mean of all second-by-second
console exported freeze curve data. Upper and lower lines reflect 2
standard deviations from the mean of data at each one second time point.



\textbf{Figure 2: Safety}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Figure 2.} Safety endpoint data. This primary arm of the study
had a KM event free rate of 96\%, which met the 89\% performance goal.

\textbf{Figure 3: Effectiveness}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Figure 3.} A) This study had an effectiveness freedom form event
rat of 59.9\%, which met the performance goal of 50\%. Notably,
examination of components of the composite efficacy endpoint (B)
revealed differential contributions over time of the distinct
components. Examination of Anti-arrhythmic drug usage in study patients
over time (C) showed that usage of Class I/III drugs dropped
dramatically over the course of the study.

\textbf{Figure 4. FIT Safety and Effectiveness}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Figure 4.} Examination of the FIT extension arm revealed a
safety event free rate of 100\% (A), which met the overall study safety
goal of 89\%. KM analysis of performance data in the FIT extension arm
showed an overall effectiveness rate of 78\% (B). Component based KM
analysis of the performance data showed that the largest cause of
treatment failure was documented recurrence (C), where freedom from
recurrence was 82\%.

\textbf{Figure 5. Representative Lesion Characterization}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image7/image7}

\end{center}
\end{figure}

Figure 5. Representative images of pre- and post-isolation
electroanatomic maps collected with an ultra-high definition mapping
system and 64 electrode basket mapping catheter. Maps were collected by
a single operator during a 28mm FROZEN AF case and a FIT Extension arm
case where the 31mm configuration was used for all PVs. Fractional
antral was calculated based on
(PV\textsuperscript{pre}-PV\textsuperscript{post})/PV\textsuperscript{pre},
Voltage Bracket 0.1mV-0.5mV, scar defined as \textless{}0.1mV.

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-Freeze-Profiles/Figure-1-Freeze-Profiles}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-Safety/Figure-2-Safety}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-Effectiveness/Figure-3-Effectiveness}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4-FIT/Figure-4-FIT}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5-EAMS/Figure-5-EAMS}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

