Efficacy of Delayed Enhancement MRI-Guided Ablation vs Conventional Catheter Ablation of Atrial Fibrillation

BACKGROUND AND INTRODUCTION:

Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting millions of people
in the US and around the world. Treating AF continues to be a challenge. Over the last 15
years, catheter based AF ablation procedure has been widely adopted. Approximately 50% of
patients treated with catheter ablation present with a persistent type of the arrhythmia.
Unfortunately, ablation results in this population have been dismal, not only because of low
success rates in suppressing arrhythmias, but also from a healthcare cost point of view. In
fact, the long-term success of such a procedure has been reported to be as low as 20%, and
patients may need more than two ablation procedures to achieve temporary arrhythmia
suppression. The cost of AF ablation among Medicare patients followed for a year after
ablation was found to be US$16,049 ± 12,536 if ablation was successful versus US$19,997 ±
13,958 for failed ablation. A major issue contributing to the low success of catheter
ablation is the lack of a protocol to appropriately select patients that would respond to
this treatment. Currently, cardiologists base their decision to ablate persistent AF on
various comorbidities, a concept that has not been proven successful. With the introduction
of AF ablation as a first line therapy option in the recent guidelines, a better and more
accurate selection protocol is urgently needed. There is a strong association between AF and
atrial tissue fibrosis. Recently, a novel DE-MRI (Delayed-Enhancement MRI) based imaging
modality has been demonstrated to reveal the degree of fibrotic atrial tissue in patients
suffering from AF. When applied in various studies, including a multicenter study, extent of
fibrotic atrial changes was shown to be the strongest independent predictor of a successful
treatment in patients undergoing ablation of AF. Moreover, in the multicenter observational
study DE-MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial
Fibrillation (DECAAF), the strongest independent predictor of successful outcome was the
surface area of fibrosis covered by ablation lesions. In fact, the number of encircled
pulmonary veins, the most common adopted approach to ablate AF today, did not predict
catheter ablation success.

The use of non-invasive ambulatory electrocardiography (ECG) devices including 24-48 hour
Holter monitors and 30-day cardiac event monitors have been widely used for the detection of
cardiac rhythm abnormalities. The duration of time for rhythm evaluation is key to detect
arrhythmias and conduction abnormalities, as number of arrhythmia diagnoses increases with
increasing duration of monitoring. The longer duration of monitoring occurs at the expense of
patient comfort and patient compliance. Previous FDA- approved devices for standard of care
monitoring are limited in the duration of monitoring. At many institutions, it is standard of
care to wear a 60-day cardiac event monitor for the detection and evaluation of cardiac
arrhythmias in the post-ablation blanking period.

The percentage of asymptomatic recurrences of AF drastically increases after ablation. Thus,
post-procedure devices are necessary for close monitoring and detection of asymptomatic AF in
ablation patients. Compliance with the current cardiac event monitors may be low for many
reasons. Electrode intolerance due to skin rashes, irritation and/or breakdown, and the
unwillingness for continuous devices to be worn are some known areas of non-compliance.

A higher level of monitoring can be provided with use of new wireless ECG technologies,
specifically, the FDA approved ECG Check mobile heart monitor designed by Cardiac Designs.
This mobile heart monitor will enable patients to record their heart rhythm anytime and
anywhere. The device will automatically analyze the ECG for symptomatic or asymptomatic
arrhythmias for the duration of their life as long as it is compatible with their current
"smart phone" or tablet computer. This is a patient-owned monitor.

The ECG Check is the first FDA-approved over-the-counter ECG monitor that is currently
compatible with approved smart phones. This will allow patients to record, store, transfer
and analyze single-channel ECG wirelessly through the ECG Check app and the ECG Check Web
Center. The information will be uploaded to a protected server through Cardiac Designs.

DESIGN:

DECAAF II is a prospective, randomized, multicenter trial of patients with persistent AF and
presence of atrial fibrosis. After consenting to participate in the study, the subject will
undergo a DE-MRI scan to assess for extent of atrial fibrosis. Consented patients will be
randomized to one of two study groups to receive conventional PVI ablation (Group 1) or PVI +
fibrosis-guided ablation (Group 2). In Group 1, PVI ablation will be performed as recommended
by the Heart Rhythm Society (HRS) consensus statement and physicians will be blinded to the
pre-ablation MRI fibrosis results. In Group 2, physicians will receive the DE-MRI scan prior
to the ablation procedure and will complete conventional PV isolation and will target left
atrial fibrosis detected by MRI during the ablation procedure.

Once randomized, the follow-up period for each patient will extend for 18 months following
the patient's ablation procedure or until a common administrative censoring date 12 months
after the ablation procedure of the final randomized subject, whichever comes first. If a
randomized patient fails to undergo ablation, the patient will be followed for 18 months from
the patient's randomization date or until 12 months after the last patient is randomized,
whichever comes first.

This is an event-driven trial, in which patient enrollment and follow-up will continue until
approximately 517 randomized subjects experience the primary endpoint of AA recurrence. Under
the assumptions described in the analysis section, it is anticipated that 888 subjects will
be randomized, including 444 assigned to Group 1 and 444 assigned to Group 2. The actual
number enrolled and the duration of the follow-up period will be adjusted as necessary to
achieve the 517 required events.

STUDY PROCEDURES

Recruitment Clinical Center staff will approach all potentially eligible patients to
participate in the study. The de-identified characteristics of those refusing to participate
will be collected to ascertain if there is any selection bias that would limit applicability
of the results.

Consent If the patient has met the eligibility criteria, the Clinical Center investigator or
delegated study staff will approach the patient to explain the study and obtain informed
consent from the subject to participate. The investigator or designated staff will provide an
explanation of study procedures of the benefits and risks, and the costs and compensation
involved with the study. Participants will be given sufficient time to read the consent form
and the individual obtaining the informed consent will answer any questions posed by the
participant.

Imaging Protocol All patients will undergo a DE-MRI within 30 days prior to the ablation
procedure using the Marrek DE-MRI protocol (MRI sequence and Image processing software). The
purpose of the initial MRI is to quantify the degree of atrial structural remodeling or
fibrosis prior to the ablation. If a patient has a heart rate ≥ 90 beats per minute, they
will be pre-medicated with a beta blocker prior to the MRI in order to obtain optimal images.
Images will be sent to Marrek Inc., (Salt Lake City, UT) and will be reviewed for quality by
trained technicians using a standard protocol. Images that do not meet quality standards will
not be further processed. The site physician may opt to repeat the MRI scan and re-submit it
for evaluation. If the image meets quality standards and can be processed, then Marrek will
verify that the subject has some proportion of atrial fibrosis (not limited to advanced stage
fibrosis). Utah Stages 1-4 will be used to classify patients based on percent fibrosis.
Subjects for whom images are successfully evaluated and scored for fibrosis will be
randomized. Following ablation, DE-MRIs will be obtained at the 90 day follow up to detect
and quantify ablation-related scar formation.

Randomization After images have been processed and scored for fibrosis, the Data Coordinating
Center (DCC) staff will complete randomization procedures using a web-based randomization
service. Randomization will be stratified by Clinical Center and by Utah Stage (with two Utah
stage strata defined by Utah stages I - II and Utah stages III - IV). For subjects who are
randomized to the fibrosis-guided ablation arm (Group 2), DCC will make the processed images
available to the investigator at the Clinical Center for use during the ablation procedures.
Processed fibrosis images of subjects who are randomized to the PVI ablation group (Group 1)
will not be made available to clinicians or site staff. All images will be retained at the
Marrek site for storage and later analysis. Clinical investigators will schedule the ablation
procedures to occur within approximately 30 days after imaging has been completed.

The study outcome is formally defined by at least two consecutive, valid ECG tracings
indicating an atrial arrhythmia (AA) (atrial fibrillation, atrial flutter or atrial
tachycardia). Both tracings must be completed after the 90-day blanking period. The two
consecutive tracings demonstrating an atrial arrhythmia must be recorded between 6 hours and
7 days of each other. If an ECG Check tracing demonstrates a non-self-terminating bout of an
atrial arrhythmia (AA), the DCC systems will send a notification to the Clinical Center
indicating that an atrial arrhythmia has been observed. If a second, consecutive ECG Check
reading also demonstrates an atrial arrhythmia 6 hours or up to 7 days after the first
recording, the DCC system will again notify the Clinical Center. In cases where a 12-lead
ECG, obtained for clinical or other reasons, first demonstrates an atrial arrhythmia, a
subsequent, consecutive, valid ECG reading will also be confirmatory of having met the study
outcome. The 12-lead ECG data will be transmitted to the DCC for inclusion in the study
database. This ECG will not be transmitted to the central location for review; rather any
12-lead obtained in association with a study outcome will be read by an independent expert to
verify the presence of AA. This expert will be blinded to study arm. In the possible scenario
where a second ablation is performed after the 90-day blanking period, but there is no
recurrence demonstrated by either ECG measure (12 lead or ECG Check), AA recurrence will be
inferred and assigned to the date of the second ablation.

Devices utilized in this trial In this trial, 3 different U.S. Food and Drug Administration
(FDA) approved devices will be utilized. The first is a hand-held ECG application that
transmits the ECG. This device has been approved for the transmittal of ECG information. The
second is a software application for viewing and post-processing of cardiovascular MRIs to
obtain left atrial enhancement quantification and visualization on a 3D model, which has been
previously approved for this indication. Finally, ablation catheters that are used for atrial
fibrillation treatment are being used in their approved manner. Although this trial will be
the first to use all 3 devices together, this use does not necessitate a new IDE as this
composite utilization falls within current approvals for each device for their approved
indications.

Study Endpoints The primary endpoint of the study is the recurrence of atrial arrhythmia
post-ablation, defined as a non-self-terminating bout of atrial fibrillation, atrial flutter,
or atrial tachycardia demonstrated by at least two consecutive, valid ECG tracings occurring
within 6 hours up to a maximum of 7 days of each other after the 90-day post-ablation
blanking period. The primary endpoint will be determined from tracings from the ECG Check
mobile device or a clinically obtained 12-lead ECG indicating persistent atrial arrhythmia.
The clinically obtained 12-lead ECG option will be used if the subject is unwilling or unable
to continue to use the ECG check device. It is difficult to anticipate whether the subject
population will have technical difficulty or accessibility issues using the smart phone and
tablet devices on a daily basis; the 12-lead ECG option is geared to offer an option for
those unable to continue to use the device. If a subject undergoes a second ablation
procedure during the study period (after the 90-day blanking period) but does not have a
documented atrial arrhythmia by the methods described previously, the ablation will also
constitute a study endpoint. Ablations occurring within the 90 day blanking period will not
be counted as an outcome.

Project Enrollment and Follow-up Timeline: This will be a 3-year study with approximately 9
months allotted for developing materials, Institutional Review Board (IRB) approvals, startup
activities, and rolling patient enrollment, approximately 12 months for follow-up after the
last patient is randomized, and 6 months for close-out activities and manuscript preparation.
Our success with DECAAF and the basic inclusion criteria highlight the feasibility of this
project to be completed within 3 years. In addition, many of these Clinical Centers
participated in DECAAF and presented successful recruitment.

STATISTICAL ANALYSIS AND POWER

Analysis Populations Randomized Study Population The randomized study population consists of
all randomized patients, irrespective of whether the patient receives an ablation procedure
or remains in the trial at the close of the blanking period.

Safety Population. The safety population consists of all randomized patients who receive an
ablation procedure.

Modified Intent-to-Treat Population. The modified intent-to-treat population consists of all
randomized patients who remain in follow-up at the close of the 90-day blanking period
irrespective of whether or not the ablation was actually performed.

Unless indicated otherwise, all statistical analyses of efficacy outcomes will be performed
in the modified intent-to-treat population and all analyses of safety outcomes will be
carried out in the safety population.

Descriptive Analyses of Baseline Characteristics Descriptive summaries of baseline clinical
and demographic characteristics will be provided by randomized treatment assignment for a)
the randomized study population, b) the safety population, and c) the modified
intent-to-treat population. Baseline characteristics will also be summarized by randomized
group in the modified intent-to-treat population for each region (North America, Europe,
Asia) and for each clinical center. In the event that substantial imbalances in particular
factors between the randomized treatment groups are detected, sensitivity analyses will be
performed after adding these factors as covariates to the Cox regression analyses described
in the Primary Analysis section below.

Primary Analysis of Atrial Arrhythmia Recurrence The primary efficacy analysis will be
performed in the modified intent-to-treat population using a stratified log-rank test to
compare the time to the first atrial arrhythmia recurrence after the blanking period between
the randomized treatment groups. The log rank test will be stratified by Utah Stage (separate
strata for Utah stages I, II, III, and IV) and region (US/Asia/Canada and Europe). Follow-up
will be censored at loss-to-follow-up or death. The primary analysis will be performed with a
2-sided significance level (alpha) of 0.05.

An associated Cox proportional hazard regression analysis with the same stratification
factors will be performed to estimate the hazard ratio between the fibrosis guided ablation
and conventional ablation groups with its 95% confidence interval. The possibility that the
hazard ratio for treatment assignment varies over the follow-up period (non-proportional
hazards) will be investigated by smoothed Schoenfeld residual plots and by performing
time-dependent Cox regressions including interaction terms between treatment assignment and
follow-up time [S1, S2]. Cumulative incidence curves for the first atrial arrhythmia
recurrence and for death will be constructed by randomized group using a competing risk
framework [S3, S4].

Components of Atrial Arrhythmia Recurrence The frequencies and proportions of patients
experiencing each of three components of the primary atrial arrhythmia outcome - 1) atrial
fibrillation, 2) atrial flutter, and 3) atrial tachycardia - will be tabulated by treatment
group. As in the primary analysis, only events occurring after the end of the blanking period
will be counted in these analyses. Cox regression analyses in which the baseline hazard
function is stratified by Utah stage and region will be used to obtain estimates of
cause-specific hazard ratios and associated 95% confidence intervals to compare the three
components of the primary outcome between the randomized treatment groups. Cumulative
incidence curves will be constructed for each of the three components and death under a
competing risk framework [S3, S4]. The same analyses will also be performed for symptomatic
atrial arrhythmia and for symptomatic atrial arrhythmia requiring treatment. Because the
analyses of the components of the primary endpoint are explanatory, no adjustment for
multiple comparisons will be performed.

Subgroup Analyses of Atrial Arrhythmia Recurrence Stratified log-rank tests and
Cox-regressions similar to those described for the primary analysis will be used to compare
the fibrosis guided ablation and conventional interventions in subgroups defined by baseline
fibrosis ≤ or > 20%. The log-rank test and Cox regression in the fibrosis ≤ 20% subgroup will
be stratified by Utah Stages I and II, while the analyses of the fibrosis > 20% subgroup will
be stratified by Utah Stages III and IV. These analyses will be repeated for the three
components of the primary outcome.

Within-Treatment Group Analyses of Atrial Arrhythmia Recurrence Cumulative incidence curves
for the first Atrial Arrhythmia recurrence and for death will be constructed by randomized
group separately for each of the four Utah stages in order to estimate the proportions of
subjects reaching these events by 1 year and by 18 months within each Utah stage. Separate
Cox regression models using cubic splines for percent fibrosis will be used to relate the
hazard for Atrial Arrhythmia recurrence to the pre-ablation percent fibrosis within each
randomized group. Similar Cox regressions with cubic splines will be performed within each
randomized group to relate the hazard for Atrial Arrhythmia recurrence to the percentage of
fibrosis which is covered by the ablation procedure.

Main Secondary Efficacy Outcome Quality of life as measured by the Toronto Score will be
treated as the main secondary efficacy outcome. The main secondary analyses will estimate the
effect of the treatment on the mean Toronto scores at months 3, 12, and 18 under a mixed
effects model in which the baseline Toronto score, visit month (treated as a categorical
variable) and the interaction between treatment and visit month are included as fixed
effects. An unstructured covariance model will be used to account for serial correlation in
the Toronto scores across the follow-up visits. The main contrast for testing the effect of
the treatment will compare the adjusted mean Toronto scores at month12 between the guided
ablation and usual care groups. A secondary contrast will compare the adjusted mean Toronto
scores at months 3 and 12 between the guided ablation and usual care groups.

Additional Efficacy Outcomes Stratified log-rank tests and associated Cox-regressions will
also be used to compare initial occurrences of a) a composite outcome including AA recurrence
and prescription of an anti-arrhythmic medication, b) stroke, c) cardiovascular
hospitalization, d) a repeat ablation, and e) AA recurrence following repeat ablation between
the randomized treatment groups. The analysis of repeat ablations will evaluate the time from
the end of the blanking period to the first ablation performed after the close of the
blanking period. The analysis of AA recurrence following repeat ablation will evaluate the
time from the end of the blanking period to the first AA recurrence following the first
repeat ablation. If the patient has an AA recurrence after the blanking period but does not
have a repeat ablation, the outcome for this analysis will be defined as the initial AA
recurrence after the blanking period.

Mixed effects analyses similar to those described for the Toronto scores will be performed to
compare the physical and mental composite scores from the San Francisco-36 (SF-36) between
the randomized group at months 3, 12 and 18, with primary emphasis given to the month-12
comparison.

The proportions of positive responses to the 5 questions asked every other week pertaining to
chest pain, shortness of breath, heart racing, dizziness, and syncope will displayed
graphically along with associated exact binomial 95% confidence intervals by follow-up week
and treatment group. The mean proportions of positive responses over the full follow-up
period will be compared between the targeted ablation group and the usual care group using
generalized estimating equations with a working identity covariance matrix, with covariate
adjustment for the baseline responses [S5]. The Huber sandwich estimator will be used to
compute robust standard errors for statistical inferences.

AA burden will be estimated for each month of follow-up for each subject as a time-weighted
average of the proportion of ECG Check readings during that follow-up month which indicate
the presence of atrial arrhythmia. Generalized estimating equations with stabilized inverse
probability of censoring weights to account for early loss-to-follow-up will be used to
compare these proportions between the randomized treatment groups.

Safety Outcomes The primary safety composite outcome is defined by occurrence of one or more
of the following events during the 1 week period following the ablation procedure: 1) stroke,
2) peripheral vascular stenosis, 3) bleeding, 4) heart failure and 5) death. Additional
safety outcomes include each of the individual components of the primary safety composite as
well as the occurrence of 6) cardiac perforation, or 7) esophageal injury within 1 week of
the ablation procedure. The primary safety composite and the other safety outcomes will be
compared between the randomized treatment groups among patients in the safety population
using Fisher exact tests. The distributions of the duration of the ablation procedure and
fluoroscopy time will also be summarized by randomized group.

Inclusion Criteria:

1. Patients with persistent AF undergoing first AF ablation as per recent HRS consensus
document. Persistent AF is defined by 7 days or more in AF as evidenced by either 1)
rhythm strip or 2) written documentation.

2. Must have some proportion of atrial fibrosis (not limited to advanced stage fibrosis)

3. Able to understand and willing to sign the Informed Consent Form

4. Age ≥ 18 years

Exclusion Criteria:

1. Contraindication for DE-MRI with a full dose of Gadolinium-based contrast agent

2. Previous left atrial ablation or surgical procedure

3. Women currently pregnant

4. Mental or physical inability to take part in the study

5. Uncontrolled hypertension

6. Inability to be placed in MRI due to body mass