Prospective, Multi-center, Randomized, Evaluation Comparing the Protocol Specified Ablation Approach to the Current Standardized Ablation Approach in the Treatment of Non-paroxysmal Atrial Fibrillation.
Phase: NA
Conditions: Atrial Fibrillation - Symptomatic
Sponsor: Ohad Ziv

  
   Low Voltage-Directed Catheter Ablation for Atrial Fibrillation (LD-
CAF) 
 
 
 
 
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Clinical Study Protocol 
 
Low Voltage-Directed Catheter Ablation for Atrial Fibrillation 
(LD-CAF) 
LD-CAF Trial 
 
 
 
 
 
Devices:   
 
 
 
 
 Ablation catheters with contact force 
capability 
 Multi-electrode mapping catheter to be used 
in the left atrium 
 3-D electroanatomical mapping system 
 Implantable Loop Recorder 
 
         
 
 
 
 
Version: 
 
1.2   06 Dec 2016 
 
 
 
 
Sponsor:  
 
 
 
The MetroHealth System 
MetroHealth Medical Center 
2500 MetroHealth Dr. 
Cleveland, Ohio  44109 
 
 
 
 

  
   Low Voltage-Directed Catheter Ablation for Atrial Fibrillation (LD-
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Investigator (Please Print):  
 
 
 
 
 
 
 
Investigator Signature: 
   
 
 
                                   Date 
 
Investigator (Please Print):  
 
 
 
 
 
 
 
Investigator Signature: 
   
 
 
 
 
 
Date 
 
 
 
 
 
Institution: 
  
 
 
 
 
 
 
 
                               
 
 

  
   Low Voltage-Directed Catheter Ablation for Atrial Fibrillation (LD-
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Table of Contents 
 
1.0 
INTRODUCTION  
 
 
 
 
 
 
4 
1.1 BACKGROUND 
 
 
 
 
 
 
4 
1.2 PILOT STUDY DESIGN 
 
 
 
 
 
4 
2.0 PROTOCOL DESIGN  
 
 
 
 
 
 
8 
2.1 INFORMED CONSENT 
 
 
 
 
 
8 
2.2 INCLUSION CRITERIA 
 
 
 
 
 
8 
2.3 EXCLUSION CTITERIA 
 
 
 
 
 
9 
2.4 RANDOMIZATION 
 
 
 
 
 
 
9 
3.0  PREPROCEDURE 
 
 
 
 
 
 
 
10 
4.0 INTRAPROCEDURE  
 
 
 
 
 
 
10 
5.0 POSTPROCEDURE 
 
 
 
 
 
 
 
11 
6.0 STUDY OBJECTIVES  
 
 
 
 
 
 
13 
6.1 PRIMARY ENDPOINT 
 
 
 
 
 
12 
6.2 PRIMARY SAFETY ENDPOINT 
 
 
 
 
12 
6.3 SECONDARY ENDPOINTS 
 
 
 
 
 
12 
6.4 SUBANALYSIS ENDPOINTS  
 
 
 
 
13 
7.0 SAFETY 
 
 
 
 
 
 
 
 
13 
7.1 ADVERSE EVENTS 
 
 
 
 
 
 
13 
7.2 SERIOUS ADVERSE EVENTS  
 
 
 
 
13 
7.3 ANTICIPATED ADVERSE EVENTS 
 
 
 
 
13 
7.4 REPORTING OF ADVERSE EVENTS 
 
 
 
 
14 
8.0 STATISTICAL ANALYSIS 
 
 
 
 
 
 
14 
8.1 POWER CALCULATION 
 
 
 
 
 
14 
9.0 SCHEDULE OF EVENTS 
 
 
 
 
 
 
15 
10.0 
MONITORING  
 
 
 
 
 
 
15 
11.0 
REFERENCES 
 
 
 
 
 
 
 
15 
 

  
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Protocol Summary 
 
Title:  
Low Voltage-Directed Ablation for Atrial Fibrillation (LD-
CAF) 
 
Design:  
Prospective, multi-center, randomized, evaluation 
comparing the protocol specified ablation approach to the 
current standardized ablation approach in the treatment 
of non-paroxysmal atrial fibrillation. 
 
Purpose: 
To evaluate long term success of non-paroxysmal 
ablation when using a 1) specified low voltage-directed 
with pulmonary vein isolation (LD+PVI) approach 
compared, 2) empiric posterior wall isolation with 
pulmonary vein isolation (PW+PVI) approach compared 
to an approach of pulmonary vein isolation (PVI) alone.  
 
Enrollment: 
A minimum of 288 evaluable subjects.  96 subjects in 
each arm. 
 
Devices: 
Electro-anatomical Mapping System: 
 Mapping -  3D mapping platform 
 Diagnostic catheters – Mapping Catheter 
 Treatment catheters – Contact Force-Sensing 
Catheter 
 
 
 
 
Clinical Sites:  
A minimum of 4 centers will enroll over a period of 18 
months.  
 
Subject Population: 
Subjects with drug refractory non-paroxysmal AF.  
 
Endpoints:  
The primary endpoint is freedom from sustained (>30 
seconds) or symptomatic atrial fibrillation or atrial 
tachycardia without the continued use of an 
antiarrhythmic medication between the 3 month blanking 
period and 1 year post-ablation.  
 
 
The safety endpoint is the incident of procedure related 
adverse events.   
 
 
 The secondary endpoint is atrial arrhythmia burden and 
need for AAD for the study ablated arrhythmia or related 
arrhythmia at 1 year. 
 

  
   Low Voltage-Directed Catheter Ablation for Atrial Fibrillation (LD-
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Sponsor:  
The MetroHealth System 
MetroHealth Medical Center 
2500 MetroHealth Dr. 
Cleveland, Ohio  
44109 

  
   Low Voltage-Directed Catheter Ablation for Atrial Fibrillation (LD-
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Low Voltage-Directed Catheter Ablation for Atrial Fibrillation (LD-CAF) 
LD-CAF Trial 
 
 
1.0 Introduction 
 
1.1 Background 
 
Catheter ablation for symptomatic atrial fibrillation has emerged as successful 
therapy for patients with medically refractive atrial fibrillation.  Nearly uniform 
superior short- and long-term success rates compared with antiarrhythmic 
medications have prompted recent guideline changes that suggest ablation can be 
considered before use of pharmacologic therapies1.   
 
Patients that undergo ablation for paroxysmal atrial fibrillation benefit from high 
success rates.  However those with persistent and long-standing persistent atrial 
fibrillation or moderate-severe structural heart disease continue to experience 
suboptimal results and often require multiple ablations2.  As such, the ideal 
ablation strategy in these patients remains to be defined.  Early use of a linear 
ablation to replicate the surgical Maze procedure improved outcomes up to 1 year, 
but long-term proarrhythmia from incomplete lines and residual arrhythmic 
substrate continue to plague the approach1-3.  
 
Recent work has focused more on targeted ablation approaches in patients with 
persistent and long-standing persistent atrial fibrillation.  Additional ablation of 
complex fractionated electrograms (CFAE), ganglion plexi, and rotors/drivers 
have all improved outcomes up to 1 year after ablation.  Success rates of these 
approaches are largely dependent on operator experience, inter-operator 
variability in interpretation of target sites, prolongation of procedural times, and 
limitations with current mapping tools4-10. 
 
The anatomic correlates for these additional ablation sites are largely unknown.  
Atrial fibrosis and low voltage are felt to serve as sources of micro and macro 
reentry, anchoring of rotors, and rapid drivers.  As such, regional fibrosis and low 
voltage have been promoted as sources of atrial fibrillation arrhythmia 
maintenance in patients that progress to persistent and longstanding persistent 
atrial fibrillation11, 12.  Therefore, incorporating low voltage and homogenizing its 
boarders with ablation may isolate arrhythmia promoting regions and improve 
long-term success rates with catheter ablation. 
 
1.2 Pilot Study Design 
 
This hypothesis was investigated in a recent retrospective randomized pilot trial.  
In this study, low voltage-directed ablation of posterior wall in addition to 
pulmonary vein isolation was compared to an ablation strategy of pulmonary vein 

  
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isolation with additional ablation along the posterior wall based upon operator 
discretion without low voltage quantification (Figure 1). 
 
SINGLE-CENTER NON-RANDOMIZED ANALYSIS OF TWO ABLATION 
STRATEGIES (2010 – 2013) FOR PERSISTENT ATRIAL FIBRILLATION.
Atrial Fibrillation
(Persistent)
Standard 
Ablation
Pulmonary Vein
Isolation
+
Operator Discretion
Low Voltage-
Directed
Ablation
Posterior Wall
Voltage Mapping
In Sinus Rhythm
(Low Voltage ≤ 0.5 
mV)
No Low Voltage
Pulmonary Vein 
Isolation Only
Low Voltage 
PRESENT
Pulmonary Vein
Isolation
+ 
Posterior Wall
Group 1 Operators – Standard Ablation Only
Group 2 Operators – Both Ablation Strategies
Methods
 
Figure 1 
 
Low voltage mapping was performed with point-by-point mapping of the 
posterior left atrium and rendering to the anatomic shell of the left atrium and 
pulmonary veins.  Low voltage diagnosis was made if the bipolar voltage was < 
0.5 mV in the setting of adequate catheter tip-tissue contact and stability.  Finding 
showed that in those patients randomized to the low voltage-directed cohort, 42% 
had posterior wall low voltage (Figure 2). 
 

  
   Low Voltage-Directed Catheter Ablation for Atrial Fibrillation (LD-
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Patients were then followed for 1-year after their ablation with the primary 
endpoint of survival free of both atrial fibrillation and atrial tachycardia without 
the need for additional antiarrhythmic drugs.  To this endpoint, the low voltage-
directed approach improved 1-year arrhythmia free survival from 57% to 80% 
(p=0.005) (Figure 3).   
 

  
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In subsequent multivariate analysis looking at all baseline and procedural 
characteristics, only a low voltage-directed ablation approach (HR 0.30, p=0.002) 
was associated with improved arrhythmia-free outcomes (Table 1). 
 
 
Hazard Ratio 
95% CI 
p value 
Low Voltage-Directed 
0.30 
0.14–0.64 
0.002 
Posterior Wall Ablated 
0.74 
0.30–1.85 
0.53 
Posterior Wall Ablation 
using Box Technique 
1.71 
0.29–9.99 
0.55 
Demonstrated Posterior 
Exit Block 
0.48 
0.10–2.41 
0.37 
Time (performed Late vs. 
Early) 
0.92 
0.49–1.74 
0.81 

  
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Group 2 Operator 
1.37 
0.57–3.28 
0.48 
LA Diameter 
1.40 
0.83–2.35 
0.21 
LVEF 
0.41 
0.04–3.78 
0.43 
Table 1 
 
Several important insights were revealed from this pilot study that may help 
define ablation strategies, particularly in patients with more advanced subtypes of 
atrial fibrillation.  First, the low voltage-directed approach improved 1-year 
arrhythmia free survival from 57% to 80%.  The sustained improvement in 
outcomes after low voltage-directed posterior wall ablation confirms the 
feasibility of this approach and suggests the need for further study.  Next, only the 
low voltage-directed approach was predictive of improved arrhythmia free 
survival.  This finding highlights the need for understanding the atrial substrate as 
an independent variable to guide ablation.  Finally, ablation of the posterior wall 
without regard to presence of absence of low voltage on the posterior wall was not 
a predictor of arrhythmia free survival.  This latter insight highlights the need for 
upfront substrate mapping for low voltage to help define ablation approach rather 
than using a defined ablation paradigm based upon anatomy only. 
 
After this pilot study there remain several questions.  First, is point-by-point 
mapping adequate for in-vivo low voltage quantification?  Second, although this 
study highlighted the importance of low voltage treatment along the posterior 
walls, it has been well documented that low voltage formation may involve all of 
the left atrium, particularly in those patients with fibrotic atrial cardiomyopathy.  
As such, is it possible to further improve outcomes by in-vivo low voltage 
mapping of the entire left atrium and using these obtained data to guide the 
ablation approach?  Finally, what are the long-term impacts of low voltage-
mediated ablation on left atrial function, stroke and heart failure risk, and quality-
of-life?  
 
However, the pilot study results support the hypothesis that using the presence or 
absence of low voltage as determined by electro-anatomical mapping to guide 
catheter ablation beyond pulmonary vein isolation (PVI) will improve atrial 
arrhythmia free survival in patients with persistent atrial fibrillation.  
 
 
2.0 PROTOCOL DESIGN 
 
2.1 Informed Consent: 
 
The patient or legal representative must sign the most current Investigational 
Review Board approved informed consent form prior to enrollment. 

  
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2.2 Inclusion Criteria:  
 
Subjects must meet all of the following criteria:  
1. Non-Paroxysmal Atrial Fibrillation. 
2. Failed or intolerable to at least 1 one antiarrhythmic drug (AAD).  
3. 18-85 year of age at time of consent.  
4. Able and willing to comply with all protocol visit requirements. 
5. Signed Patient Informed Consent (ICF).  
 
2.3 Exclusion Criteria: 
 
Subjects will be excluded if any of the follow criteria are present: 
1. History of prior left-sided catheter or surgical ablation for AF or atypical 
atrial flutter, including MAZE or mini MAZE. 
-Prior ablation for typical atrial flutter or left-sided ablation for WPW, AV 
node reentry tachycardia or focal ectopic atrial tachycardia may be included.                               
2. Uncontrolled heart Failure or NYHA Class IIIb or IV heart failure.   
3. Ejection Fraction < 0.20    
4. Left atrial size >60 mm diameter on echocardiogram  
5. “Long standing” persistent AF defined as > or = to 1 year of continuous atrial   
      fibrillation at the time of enrollment  
6. Severe Pulmonary Hypertension (pp>70%)   
7. AF secondary to electrolyte imbalance, thyroid disease, or reversible or non-
cardiac cause.   
8. Poor candidate for general anesthesia  
9. Anticipated survival <1 year  
10. MI or CABG within 3 months  
11. Left atrial thrombus in pre-procedure imaging within 4 weeks of the 
procedure 
12. Any documented thromboembolic event within 6 months.  
13. Contraindication to anticoagulation. 
14. Significant congenital anomaly or medical condition that may affect the 
integrity of study data.  
15. Women who are pregnant (pregnancy test required if pre-menopausal or non-
sterile)  
16. Active enrollment in another investigational study involving a drug or 
device. 
 
2.4 Randomization: 
 
Patients that meet both inclusion and exclusion criteria will be randomized by the 
study clinical center.  Patients will be randomized 1:1:1 into one of the following 
arms: 
 

  
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 PVI with additional total left atrial low voltage-directed ablation. 
 PVI with posterior wall low voltage quantification and isolation 
 
 PVI alone without low voltage quantification.  
 
 
3.0 Pre-procedure 
 
All patients will receive the best conventional medical therapy and anticoagulation 
use based upon HRS consensus recommendations taking into account their baseline 
risk factors for stroke.  The need for interruption of anticoagulation and 
antiarrhythmic drug therapy for the procedure will be determined by the operator 
and their center guidelines.  
 
The trial requires continuous monitoring for atrial arrhythmias. We will 
mandate the use of implantable loop recorders (ILR). The device will be under 
sterile conditions at the manufacture’s recommended site on the precordium 
for arrhythmia monitoring. Implantation will occur between 1 month prior 
and 3 months post ablation since there will be a 3 month post ablation 
blanking period. If a dual chamber device is already present, implantation will 
not be required. 
 
 
4.0 Intra-procedure 
 
Prior to transseptal access, all patients will receive heparin with a goal ACT of 350-
400 s. Double transeptal puncture is performed as usual per protocol of each site.  
 
Arm 1: (LD+PVI) PVI & Total Left Atrial Low voltage-Directed Ablation.  If 
the patient presents in atrial fibrillation, cardioversion will be performed to sinus 
rhythm.   If the patient is still in atrial fibrillation, a synchronized cardioversion will 
be performed to allow low voltage mapping in sinus rhythm.  Using an 
electroanatmical mapping system patients will undergo an initial voltage map of the 
entire left atrium with a multipolar recording catheter or circular mapping catheter 
during sinus rhythm.  Any low voltage areas are then further assessed with detailed 
point by point voltage mapping with the ablation catheter. Low voltage will be 
defined as a location of >0.5x0.5cm that is reproducible with the contact force 
sensing catheter performed with documented contact force of >5g and <50g. Low 
voltage <0.5cm from a lesion will be considered a result of the actual lesion and 
will not be considered a low voltage region. An operator may choose to use the 
ablation catheter alone for mapping as long as the entire LA is adequately mapped 
(usually >50 points) evenly distributed along the septum, roof, posterior wall, and 
lateral wall of the left atrium.  Adequate contact force should be achieved with each 
mapping point (minimum of 5g) with a contact force sensing catheter.  Further 
ablation will be guided by the presence of left atrial low voltage and the relationship 

  
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to the pulmonary veins.   Complete isolation of LA low voltage region will be 
performed and guided by electrical pacing parameters (Non-capture at 10mA or exit 
block demonstrated and documented). Wide area antral pulmonary vein isolation 
will also be performed with the endpoint of both entrance and exit block in the 
pulmonary veins.  Isolation of the low voltage region will be left to the operator’s 
discretion and may include widening the lesion set isolating the pulmonary veins to 
include the low voltage region or linear ablation to isolate the region.  The presence 
of bidirectional block of the low voltage region will be tested.  If bidirectional block 
is not achieved, additional ablation to achieve bidirectional block is at the direction 
of the operator and must be documented either way.  However, if an isthmus is 
created by the low voltage isolation (1.5cm or less of viable atrial tissue) then 
further radiofrequency ablation will be performed to eliminate the isthmus.  Patients 
who have atrial fibrillation recur before voltage mapping is completed will have 
ablation performed based on voltage data obtained and cardioversion repeated if 
needed with completion of voltage mapping of the entire LA. All low voltage 
regions are targeted for ablation in this manner.   A 20 minute waiting period is 
required following isolation in each vein, following which each vein must be re-
tested for isolation.  If it has been found that the vein has reconnected, additional 
ablation must be performed to achieve isolation in that vein, followed by another 20 
minute waiting period until isolation is seen.  If isolation is not achieved, this must 
be documented and patients will be treated in the analysis in an intention-to-treat 
manner.  High dose isuprel will be given up to 20 mcg/min for up to 10 minutes (at 
least an increase of ventricular rate >50% of baseline for 5 minutes is required).  
Additional triggers for atrial fibrillation will be pursued if the trigger causes 
sustained AF (AF for at least 30 seconds).  In addition, if pulmonary vein 
reconnection is seen, then additional ablation to achieve pulmonary vein isolation 
will be pursued.  A 20 minute waiting period is required before retesting with 
isuprel.  If isuprel is not given,  then this must be documented.  Further ablation in 
this arm beyond the pulmonary veins, low voltage, and trigger ablation are to be 
avoided. Locations of frequent premature atrial complexes that due not induce 
sustained atrial arrhythmias under isuprel infusion should be avoided. Patients who 
receive further ablation not based on low voltage, pulmonary vein reconnection, or 
trigger ablation for sustained atrial arrhythmias will be treated in the analysis in an 
intention-to-treat manner.  All additional ablation must be documented. Patients 
who do not receive isuprel or patients who did receive isuprel and pulmonary vein 
reconnection and/or AF triggers were not pursued will also be treated in an 
intention-to-treat manner.  Testing for dormant pulmonary vein conduction with 
adenosine is discouraged.  Patients will be will be treated in an intention-to-treat 
manner if additional ablation is pursued for patients on the basis of dormant 
conduction  
 
Arm 2 (PW+PVI) PVI & Posterior Wall Ablation (not voltage directed):   If the 
patient presents in atrial fibrillation, cardioversion will be performed to sinus 
rhythm.  Voltage mapping will be performed in sinus rhythm. A voltage map will 
be performed of the entire left atrium, using the same voltage criteria, confirmation 
criteria, and mapping points as in arm 1.  However ablation will not be guided by 

  
   Low Voltage-Directed Catheter Ablation for Atrial Fibrillation (LD-
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low voltage quantification in the entire atrium or posterior wall.  Instead, empiric 
isolation of the posterior wall will be performed in combination with wide antral 
pulmonary vein isolation.  This may be performed as part of a “box” lesion set 
encompassing the posterior wall and both the left and right pulmonary vein antrums, 
or separate isolation performed at the operators’ discretion. Waiting periods of at 
least 20 minutes following isolation are required for both pulmonary veins and 
posterior wall, including testing for bidirectional block in the posterior wall.  
Additional waiting periods of 20 minutes are required before re-testing the 
pulmonary veins or the posterior wall for bidirectional block following additional 
ablation to achieve isolation.  Isuprel to test for triggers and reconnection will be 
given in the same manner as arm 1.  Patients who receive further ablation not based 
on low voltage, pulmonary vein reconnection, or trigger ablation, or if isuprel was 
not given or given and triggers/reconnections were not pursued, will be treated in 
the analysis in an intention-to-treat manner.  
    
Arm 3 (PVI alone-controls): If the patient remains in AF, cardioversion is 
performed into sinus rhythm as the other two arms.  A voltage map of the entire left 
atrium is performed as in arms 1 & 2.  However, ablation will not be guided by low 
voltage. Instead, wide area antral pulmonary vein isolation is initially performed 
with an electro-anatomical mapping system in the same manner as arms 1&2.  
Isoproterenol will be given and additional ablation performed as per the previous 
arms.  
 
In all arms, additional ablation, including atrial flutter spontaneously occurring or 
induced during the procedure is discouraged but if done must be documented by the 
operator.  Additional right atrial ablation, such as creation of a cavo-tricuspid 
isthmus line for atrial flutter or superior vena cava isolation, is also discouraged and 
if pursued, these patients will be treated in an intention-to-treat manner. 
 
 
5.0 Post Procedure 
 
One year follow-up is planned. Post procedure care is per standard of care with 
follow-up at 1 month, 3 months, 6 months, 9 months and 12 months.  ECG at every 
follow-up is performed. Download of arrhythmia data will occur at each of these 
visits as well. We will use the typical post ablation blanking period for recurrence 
of atrial fibrillation of 3 months. Antiarrhythmic medications can be used during the 
typical “blanking period” of 3 months post procedure. But per protocol are stopped 
at 3 months post procedure (2 months post procedure in case of amiodarone).  Re-
initiation of an antiarrhythmic drug after 3 months will be considered a failure of 
primary endpoint of arrhythmia free survival.  However, Anti-arrhythmic 
medication use after the blanking period for ventricular arrhythmias will not be 
included as an event. Anticoagulation is continued and monitored based on previous 
guidelines with use stratified by baseline stroke risk.  A recording (CD) of the 
mapping during the procedure is to be obtained and retained for possible future 
analysis. 

  
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6.0 Objectives/Study Endpoints 
 
The primary objective of this study is to demonstrate that low voltage mapping of 
the left atrium to guide additional ablation after wide area antral isolation of the 
pulmonary veins or posterior isolation in addition to pulmonary isolation will 
improve long-term outcomes with catheter-based radiofrequency ablation of the 
left atrium in patients with non-paroxysmal atrial fibrillation. All endpoints will be 
reviewed by a blinded adjudication committee. 
 
6.1 Primary Endpoint 
 
The primary endpoint is freedom from sustained or symptomatic atrial fibrillation, 
atrial flutter or atrial tachycardia (AF/AT) at 12 months.  Recurrence of AF/AT 
excludes the 3 month blanking period.  Sustained AF/AT is defined as >30 seconds 
as recorded on a monitoring device.   
 
6.2 Primary Safety Endpoint 
 
Safety as defined by the incidence of clinically significant Anticipated Adverse 
Events (AAEs) associated with the procedure.  Clinical significance will be 
determined by a blinded adjudication committee.    
 
6.3 Secondary Endpoints 
 
1) Arrhythmia burden determined by the composite percent of atrial arrhythmia 
during the total time recorded on implantable monitoring devices. 
2) Freedom from sustained AF/AT is defined as >30 seconds as recorded on a 
monitoring device.   
 
 
7.0 Safety 
 
Adverse events will be further defined as adverse events (AEs), serious adverse 
events (SAEs) and Anticipated Adverse Events (AAEs) as outlined below.  
 
7.1 Adverse Events (AE) 
 
An adverse event is defined as any untoward medical occurrence in a subject 
receiving treatment. Any adverse event will be recorded on the respective patient’s 
source/medical record. 
 
All AE must be recorded in the source documentation and evaluated by the 
investigator to determine if clinically significant regardless of classification, 
seriousness, intensity, outcome or causality. If clinically significant, adverse events 
will be recorded on the case report forms by the investigator or study coordinator. 

  
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7.2   Serious Adverse Events (SAE) 
 
A serious adverse event is an adverse event that: 
• Led to a death. 
• Led to a serious deterioration in the health of the subject that: 
a. Resulted in life threatening illness or injury. 
b. Resulted in a permanent impairment of a body structure or a body 
function. 
c. Required in-patient hospitalization or prolongation of existing 
hospitalization. 
• Resulted in medical or surgical intervention to prevent permanent impairment to a 
body structure or a body function. 
• Led to fetal distress, fetal death or a congenital abnormality or birth defect 
 
7.3 Anticipated Adverse Events (AAEs) 
 
Anticipated Adverse Events have been reported in association with ablation procedures.  
All anticipated adverse events occurring within 30 day of the study ablation are to be 
recorded for comparison between the 2 study arms.  Atrio-esophogeal fistulas and PV 
stenosis are to be to be recorded through the 12 month follow-up visit.  AAEs include: 
 
a. 
All-cause mortality 
b.  
Atrio-esophogeal fistula (through 12 mo) 
c.  
Atrial perforation 
d.  
Cardiac Tamponade 
e.  
Pericardial Effusion 
f.  
Pericarditis 
g. 
Heart Block 
h.  
Myocardial infarction 
i.  
Cerebrovascular Accident (CVA)  
j.  
Transient ischemic Attack  
k.  
Thromboembolism 
l.  
PV stenosis >70% from baseline (through 12 mo)  
m.  
Diaphragm Paralysis 
n.  
Pulmonary Edema 
o.  
Pneumothorax 
p.  
Limb Paralysis 
q.  
Procedural blood loss ≥ 1000cc 
r.  
Respiratory failure 
 
 
7.4 Reporting of Adverse Events 
 
The investigators at each of the participating sites are ultimately responsible for 
recording all adverse events in the source documentation.   All adverse events are to be 
evaluated by the investigator to determine whether the events are clinically significant.  
The investigator should also determine whether the adverse event is related to the 

  
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device or procedure.   All clinically significant adverse events are to be entered on the 
eCRFs at each visit and in a timely fashion so that the sponsor can review them in the 
EDC.  The eCRFs for a given visit must report all reportable adverse events that occurred 
since the last documented visit.  
8.0 Statistical Analysis 
 
8.1 Power Calculation / Study Size: 
 
In our pilot study, a Low voltage-Directed (LD) + PVI approach demonstrated a 1 
year success rate of 80%, posterior wall isolation with pulmonary vein isolation 
showed a success rate of 64% and pulmonary vein isolation alone showed a 48% 
success rate.  Based on this data, we assume the Low voltage-Directed approach 
and posterior wall isolation (PW)+ PVI to each have a 70% success rate and PVI 
alone arm to have a 50% success rate. We therefore made the following power 
calculation: 
 
For each comparison of LD+PVI vs. PVI and PW+PVI vs. PVI 
Probability of Type I Error (α) = 0.05  
Power (1 - β) = 0.8 
Survival Rate grp 1 = 0.7 
Survival Rate grp 2 = 0.5 
ratio (ssiz1 / ssiz2) = 1 
Total sample size (both groups together, two tail model) required = 192 for 
comparisons 
96 subjects in each of the 3 groups 
288 subjects in total 
 
 
We will use 4 sites, enrolling 4 patients/per site/month over 18 months. 
 
8.2 Data Analysis Plan: 
 
Primary and secondary outcomes will be analyzed using Kaplan Meier test. Cox 
proportional Hazards will be used to analyze primary outcome if baseline 
differences occur between the two arms in the study. The continuous variables 
will be reported as mean ± standard deviation (SD). The categorical variables will 
be reported as number of cases (n) and percentage. Comparison of characteristics 
across the groups will be performed using ANOVA for continuous variables and 
chi-square test for categorical variables. A two-tailed p value of <0.05 is 
considered statistically significant. 
 
 
9.0 Schedule of Events 
 

  
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Required Testing 
Screening 
Baseline - 
Procedure 
1 Month 
± 2 weeks 
3 Month3 
± 2 weeks 
6 Month 
± 4 weeks 
9 Month4 
± 4 weeks 
12 Month
± 4 weeks 
Arrhythmia History 
X 
  
  
  
  
  
  
Medical History 
X 
  
X 
X 
X 
X 
X 
Demographics 
X 
  
  
  
  
  
  
Randomization 
  
X 
  
  
  
  
  
Pregnancy Exam1 
X 
  
  
  
  
  
  
Left Atrial Thrombus 
Detection2 
  
X 
  
  
  
  
  
Recording of procedure (CD) 
 
X 
 
 
 
 
 
Physical Exam 
  
X 
X 
X 
X 
X 
X 
Review of Cardiac Medications 
X 
X 
X 
X 
X 
X 
X 
Review of Adverse Events 
  
X 
X 
X 
X 
X 
X 
ECG+ Arrhythmia download 
X 
X 
X 
X 
X 
X 
X 
ILR implantation  
X 
X 
X 
X 
 
 
 
1. required if of child bearing potential. 2. Required and according to institution standards.3. Discontinuation of AAD's required if 
clinically allowable. 4. If clinically indicated. 
 
 
10.0 Monitoring: 
 
 
Periodic monitoring will occur in order to verify data integrity.  Monitoring visit 
will provide direct access to all source documentation necessary to verify the 
study data.  All regulatory documentation will be maintained by each 
investigative site and made available to the monitoring team. 
 
11.0 References: 
 
1. January CT, Wann LS, Alpert JS, Calkins H, Cleveland JC, Jr., Cigarroa JE, 
Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson 
WG, Tchou PJ, Tracy CM, Yancy CW. 2014 aha/acc/hrs guideline for the 
management of patients with atrial fibrillation: A report of the american college of 
cardiology/american heart association task force on practice guidelines and the heart 
rhythm society. J Am Coll Cardiol. 2014 
 
2. Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns HJ, 
Damiano RJ, Jr., Davies DW, DiMarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, 
Haines DE, Haissaguerre M, Hindricks G, Iesaka Y, Jackman W, Jalife J, Jais P, 
Kalman J, Keane D, Kim YH, Kirchhof P, Klein G, Kottkamp H, Kumagai K, 
Lindsay BD, Mansour M, Marchlinski FE, McCarthy PM, Mont JL, Morady F, 
Nademanee K, Nakagawa H, Natale A, Nattel S, Packer DL, Pappone C, Prystowsky 
E, Raviele A, Reddy V, Ruskin JN, Shemin RJ, Tsao HM, Wilber D. 2012 
hrs/ehra/ecas expert consensus statement on catheter and surgical ablation of atrial 

  
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CAF) 
 
 
 
 
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fibrillation: Recommendations for patient selection, procedural techniques, patient 
management and follow-up, definitions, endpoints, and research trial design. Journal 
of interventional cardiac electrophysiology : an international journal of arrhythmias 
and pacing. 2012;33:171-257 
 
3. Themistoclakis S, Raviele A, China P, Pappone C, Ponti RD, Revishvili A, Aliot 
E, Kuck KH, Hoff PI, Shah D, Almendral J, Manolis AS, Chierchia GB, Oto A, 
Vatasescu RG, Sinkovec M, Cappato R. Prospective european survey on atrial 
fibrillation ablation: Clinical characteristics of patients and ablation strategies used 
in different countries. J Cardiovasc Electrophysiol. 2014 
 
4. Lin YJ, Chang SL, Lo LW, Hu YF, Chong E, Chao TF, Chung FP, Liao J, Li CH, 
Tsao HM, Kao T, Chen YY, Huang JL, Chen SA. A prospective and randomized 
comparison of limited versus extensive atrial substrate modification after 
circumferential pulmonary vein isolation in nonparoxysmal atrial fibrillation. J 
Cardiovasc Electrophysiol. 2014;25:803-812 
 
5. Nademanee K, McKenzie J, Kosar E, Schwab M, Sunsaneewitayakul B, 
Vasavakul T, Khunnawat C, Ngarmukos T. A new approach for catheter ablation of 
atrial fibrillation: Mapping of the electrophysiologic substrate. J Am Coll Cardiol. 
2004;43:2044-2053 
 
6. Hwang C, Chen PS. Ligament of marshall: Why it is important for atrial 
fibrillation ablation. Heart Rhythm. 2009;6:S35-40 
 
7. Pokushalov E, Romanov A, Artyomenko S, Turov A, Shugayev P, Shirokova N, 
Katritsis DG. Ganglionated plexi ablation for longstanding persistent atrial 
fibrillation. Europace. 2010;12:342-346 
 
8. Knecht S, Hocini M, Wright M, Lellouche N, O'Neill MD, Matsuo S, Nault I, 
Chauhan VS, Makati KJ, Bevilacqua M, Lim KT, Sacher F, Deplagne A, Derval N, 
Bordachar P, Jais P, Clementy J, Haissaguerre M. Left atrial linear lesions are 
required for successful treatment of persistent atrial fibrillation. Eur Heart J. 
2008;29:2359-2366 
 
9. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. 
Treatment of atrial fibrillation by the ablation of localized sources: Confirm 
(conventional ablation for atrial fibrillation with or without focal impulse and rotor 
modulation) trial. J Am Coll Cardiol. 2012;60:628-636 
 
10.  Kumagai K, Sakamoto T, Nakamura K, Nishiuchi S, Hayano M, Hayashi T, 
Sasaki T, Aonuma K, Oshima S. Combined dominant frequency and complex 
fractionated atrial electrogram ablation after circumferential pulmonary vein 
isolation of atrial fibrillation. J Cardiovasc Electrophysiol. 2013;24:975-983 
 

  
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11.  Burstein B, Nattel S. Atrial fibrosis: Mechanisms and clinical relevance in atrial 
fibrillation. J Am Coll Cardiol. 2008;51:802-809 
 
12.  Yamabe H, Morihisa K, Tanaka Y, Uemura T, Enomoto K, Kawano H, Ogawa 
H. Mechanisms of the maintenance of atrial fibrillation: Role of the complex 
fractionated atrial electrogram assessed by noncontact mapping. Heart Rhythm. 
2009;6:1120-1128