Adjunctive Renal Denervation to Modify Hypertension and Sympathetic Tone as Upstream Therapy in the Treatment of Atrial Fibrillation
Phase: NA
Conditions: Uncontrolled Hypertension, Atrial Fibrillation
Sponsor: Vivek Reddy

H-FIB: Adjunctive Renal Denervation to Modify Hypertension and Sympathetic
Tone as Upstream Therapy in the Treatment of Atrial Fibrillation 
PI: Vivek Reddy, MD 
NCT01635998 
Document Date: July 8, 2016

Vivek Reddy, M.D.  
 
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PROTOCOL 
H-FIB: 
ADJUNCTIVE RENAL DENERVATION TO MODIFY 
HYPERTENSION AND SYMPATHETIC TONE AS 
UPSTREAM THERAPY IN THE TREATMENT OF ATRIAL 
FIBRILLATION (HFIB) 
 
 
Version 5.9 
July 2016 
 
 
 
 
Principal Investigator: Vivek Reddy, M.D.
 
Data Coordinating Center: 
Electrophysiology Clinical Research Group 
Icahn School of Medicine at Mount Sinai 
New York 
 
 

Vivek Reddy, M.D. 
 
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STUDY NETWORK 
 
Data Coordinating Center  
Electrophysiology Clinical Research Group, Icahn School of Medicine at Mount Sinai 
(Vivek Reddy, MD, Betsy Ellsworth, MSN, ANP, Sam Cammack, MA, MPH) 
 
Study Chair  
Vivek Reddy, MD; Icahn School of Medicine at Mount Sinai 
 
 
Study Sponsors  
Vivek Reddy, MD 
 
Funding Agency 
Boston Scientific, Inc.  
 
Protocol Development Committee  
Vivek Reddy, MD 
Marc Miller, MD 
Emilia Bagiella, PhD 
Sam Cammack, MA, MPH 
Betsy Ellsworth, MSN, ANP 

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TABLE OF CONTENTS 
1. ABBREVIATIONS ................................................................................................................................... 8 
2. ABSTRACT ............................................................................................................................................ 10 
TABLE 1. 
SCHEDULE OF TREATMENTS AND TESTS ................................................................ 11 
3.  OBJECTIVES .......................................................................................................................................... 8 
4.  BACKGROUND ...................................................................................................................................... 9 
5.  SPECIFIC AIMS ................................................................................................................................... 12 
6.  STUDY DESIGN ................................................................................................................................... 13 
7.  RANDOMIZATION ............................................................................................................................. 13 
8.  MASKING ............................................................................................................................................. 14 
9.  STUDY POPULATION ........................................................................................................................ 20 
10. TREATMENT INTERVENTIONS .................................................................................................... 21 
11.  DEFINITIONS AND MEASUREMENT OF ENDPOINTS ............................................................ 20 
12.  CLINICAL CENTERS ....................................................................................................................... 32 
13.  SCREENING AND BASELINE DATA COLLECTION ................................................................ 33 
14.  POST-RANDOMIZATION DATA COLLECTION ........................................................................ 36 
15.  DATA MANAGEMENT ..................................................................................................................... 38 
16.  ANALYTICAL PLAN ........................................................................................................................ 40 
17.  ORGANIZATION OF THE STUDY ................................................................................................. 50 
18.  REFERENCES .................................................................................................................................... 52 
APPENDIX I:  NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) ....................... 51 
APPENDIX II:  QUALITY OF LIFE MEASURES ................................................................................ 52 
APPENDIX III: TRANSTHORACIC DOPPLER ECHOCARDIOGRAPHY .................................... 54 
APPENDIX IV: BLOOD PRESSURE TREATMENT GUIDELINES ................................................. 55 
APPENDIX V: STUDY SITES ................................................................................................................. 55 
APPENDIX VI: LIST OF APPROVED ATRIAL FIBRILLATION ABLATION DEVICES  ........... 55

Vivek Reddy, M.D.  
 
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1. ABBREVIATIONS 
 
AAD  
Anti-arrhythmic drugs 
ACC  
American College of Cardiology 
ACT  
Activated Clotting Time 
AE 
 
Adverse Event 
AF 
 
Atrial Fibrillation 
AFEQT 
Atrial Fibrillation Effect on Quality-of-Life  
AFL 
Atrial flutter 
AHA 
American Heart Association 
ALT 
Alanine transaminase 
ARBs 
Angiotensin receptor blockers 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
BNP 
Brain natriuretic peptide 
BP 
Blood Pressure 
BSA 
Body surface area 
CABG 
Coronary artery bypass grafting 
CFAE  
Complex fractionated atrial electrograms 
CHF 
 
Congestive heart failure 
CMC  
Clinical Management Committee 
CT 
 
Computerized tomography 
CTI 
 
Cardiac Troponin I 
CV 
 
Curriculum Vitae 
CVP 
 
Central Venous Pressure 
DC 
 
Direct current  
DCC  
Data Coordinating Center 
DSMB  
Data Safety Monitoring Board 
EAC  
Event Adjudication Committee 
ECG  
Electrocardiogram 
eCRFs  
Electronic Case Report Forms 
EDC  
Electronic Data Capture 
eGFR  
Estimated Glomerular Filtration Rate 
EP 
 
Electrophysiology 
FDA  
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
HRS 
 
Heart Rhythm Society 
ICU 
 
Intensive Care Unit 
INR 
 
International Normalized Ratio 
IRB 
 
Institutional Review Board 
I/O 
 
Input/Output 

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InCHOIR 
International Center for Health Outcomes & Innovation Research 
JNC-7  
Joint National Committee 7 
LA 
 
Left atrium 
LAA  
Left atrial appendage 
LBBB  
Left bundle branch block 
LMW  
Low molecular weight 
LV 
 
Left ventricle 
LVEF  
Left ventricular ejection fraction 
MACE  
Major adverse cardiac event 
MDRD 
Modification of Diet in Renal Disease 
MI 
 
Myocardial infarction 
MR 
 
Mitral regurgitation 
MRI 
 
Magnetic resonance imaging 
MV 
 
Mitral valve 
NIHSS  
National Institutes of Health Stroke Scale 
NYHA  
New York Heart Association 
PCI 
 
Percutaneous coronary intervention 
PV 
 
Pulmonary vein 
OHRP  
Office of Human Research Protections 
OR 
 
Operating Room 
QoL 
 
Quality of Life 
RBC  
Red blood cells 
RF 
 
Radiofrequency 
RVAD  
Right Ventricular Assist Device 
SAE 
 
Serious Adverse Event 
SF-12  
Short Form – 12 
SSL 
 
Secure Socket Layer  
ST-T  
ST segment/T wave 
SVC 
 
Superior vena cava 
TDI 
 
Tissue Doppler Imaging 
TEE 
 
Trans-esophageal echocardiography 
TIA 
 
Transient Ischemic Attack 
TTE 
 
Trans-thoracic echocardiography 
UADE  
Unanticipated adverse device effect 
UP  
 
Unanticipated Problem 
URL  
Upper Reference Limit

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2. ABSTRACT 
 
Objectives 
Determine the role of adjunctive blood pressure management and sympathetic modulation 
attained via renal sympathetic denervation in the prevention of AF recurrence in patients 
with hypertension scheduled for an AF ablation procedure. Patients will be randomized to 
either AF catheter ablation (usual therapy) or AF catheter ablation plus renal sympathetic 
denervation. 
Study Design 
Prospective, placebo-controlled, double-blind, randomized (1:1) clinical trial; patients 
randomized to either catheter ablation (control group) or a catheter ablation + renal 
denervation (study group). 
Target Population 
History of documented significant hypertension (defined as SBP ≥160 mm Hg and/or DBP 
≥100 mmHg) and receiving treatment with at least one anti-hypertensive medication, or a 
known history of hypertension and receiving treatment with at least two anti-hypertensive 
medications (specifically for hypertension).   
Rx arms 
AF catheter ablation alone versus AF catheter ablation plus renal sympathetic denervation  
Sample Size 
Total:  300 patients: provides 80% power to detect a 40% decrease in AF recurrence (24% 
versus 40%) (measured at 12 months)  
This study is divided into two phases: an initial PILOT phase (to include 50 patients) 
followed by the remaining 250 patients to a total of 300 patients. The PILOT phase will be 
conducted at up to 10 US sites. An interim safety analysis will be conducted when all 
patients in the PILOT phase (50 subjects) have completed the 3-month follow up visit.  The 
purpose of this analysis is only for safety.  The efficacy/outcome data for the primary 
endpoint will not be examined; this will permit pooling these 50 patients with the 
subsequent 250 patients for the final efficacy analysis. 
 
Duration 
24 months follow-up following randomization.  
1 Endpoints 
Single-procedure freedom from AF recurrence off all AADs (after the 90 day blanking 
period) at 12 months.  
2 Endpoints 
AAD-free single-procedure freedom from AF recurrence 24 months (not-including 
recurrences within the first 90 days of the initial ablation procedure); freedom from AF 
recurrence at 24 months (not-including a 90 day blanking period) despite taking AADs; 
blood pressure control between the two groups as compared to baseline at t = 6 months, 12 
months and 24 months; Major Adverse Cardiac Events (MACE); differences in measures of 
LV hypertrophy (LV wall thickness, mitral inflow parameters, LV mass index2.7) and LA 
size recorded via TTE at baseline and at 12 months for each patient; procedure adverse 
events; total number of anti-hypertensive medications at study end, compared between the 2 
treatment arms; QOL. 
Inclusion Criteria 
Age ≥ 18; history of AF and planned for a catheter ablation procedure; history of 
hypertension and on at least one anti-hypertensive medication; accessibility of renal 
vasculature (as determined by intra-procedural renal angiography); Ability to understand the 
requirements of the study; Willingness to adhere to study restrictions and comply with all 
post-procedural follow-up requirements 
Exclusion Criteria 
Inability to undergo AF catheter ablation (e.g., presence of a left atrial thrombus, 
contraindication to all anticoagulation); Prior left atrial ablation for an atrial arrhythmia 
(before this index procedure); NYHA class IV congestive heart failure; Individual has 
known secondary hypertension;  Individual has renal artery anatomy that is ineligible for 
treatment including: a) Inability to access renal vasculature, b) Main renal arteries < 3 mm 
in diameter or < 20 mm in length., c) Hemodynamically or anatomically significant renal 
artery abnormality or stenosis in either renal artery which, in the eyes of the operator, would 
interfere with safe cannulation of the renal artery or meets standards for surgical repair or 
interventional dilation, d) History of prior renal artery intervention including balloon 
angioplasty or stenting that precludes a possibility of ablation treatment; Individual has an 
estimated glomerular filtration rate (eGFR) of less than 45mL/min/1.73m2, using the MDRD 
calculation; Individual has a single functioning kidney (either congenitally or 
iatrogenically); Individual is pregnant or nursing;  Life expectancy <1 year for any medical 
condition 

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Table 1. 
Schedule of Treatments and Tests 
 
Baseline 
Procedure 
Discharge 
3, 6, 12, 18 & 
24 mos 
Event Driven 
Type of visit 
Office 
Hospital 
Office 
 
Informed Consent 
X 
 
 
 
 
Brief History & Physical 
X 
 
X 
X 
 
Office BP Measurement 
X 
 
 
 
X 
 
Medications 
X 
 
X 
X 
 
Blood chemistry 
X 
 
 
6 & 12 mo 
only 
 
Quality-of-Life Assessment 
X 
 
 
12 & 24 mo 
only 
 
TTE ф 
X 
 
 
12 mo only 
 
ECG 
X 
 
 
 
X 
Continuous ECG Monitoring 
(7 days each) 
 
 
 
3 mo, 6 mo, 
12 mo, 24 mo 
only 
 
Renal Doppler  
 
 
 
6 mo only  
 
Blinding assessment 
 
 
 
12 mo only 
 
Randomization* 
 
X 
 
 
 
Hospital Admission 
 
X 
 
 
X 
EP Mapping & AF Ablation 
 
X 
 
 
X 
Renal Angiography 
 
X 
 
 
X 
Renal Sympathetic 
Denervation § 
 
X 
 
 
 
Adverse Events 
 
 
 
 
X 
AF recurrence 
 
 
 
 
X 
Missed Visit Assessment 
 
 
 
 
X 
Mortality 
 
 
 
 
X 
Study Completion/Early 
Termination 
 
 
 
 
X 
ф Performed within 3 months of randomization (i.e., within 3 months of the planned ablation procedure). 
* Randomization will occur after renal angiogram.  
§ The blinding of the patient is maintained by the fact that the renal angiogram and renal denervation steps 
will be performed with the same sedation as used for the ablation procedure: either deep sedation or general 
anesthesia (per the usual protocol of the EP laboratory). 

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3.  OBJECTIVES  
 
Purpose of the Study 
The objective of the H-FIB trial is to determine the role of renal sympathetic denervation 
in the prevention of Atrial Fibrillation (AF) recurrence in patients with hypertension for 
whom a catheter-based AF ablation procedure is planned. Patients will be randomized to 
either AF catheter ablation (usual therapy) or AF catheter ablation plus renal sympathetic 
denervation.  
 
 
3.1 Primary Hypothesis 
In hypertension patients with atrial fibrillation, there is ample evidence of a strong 
association between the chronic hypertension and arrhythmia-inducing cardiac substrate 
modifications; the association seems related to both hypertension itself (along with 
derangements in the renin-angiotensin-aldosterone system), and elevated sympathetic 
tone.  It is hypothesized that a treatment strategy targeting both these ancillary conditions 
(hypertension and elevated sympathetic tone) and atrial fibrillation triggers themselves 
may lead to greater and more durable procedural success post-catheter ablation.  In 
hypertensive patients undergoing catheter ablation for AF, we hypothesize that there will 
be a difference through 12 months between the two treatment arms in AAD-free freedom 
from recurrent AF after a 90 day blanking period following a single AF ablation 
procedure. The null hypothesis of principal interest is that there will be no difference 
through 12 months between the two treatment arms in single-procedure freedom from AF 
off of all AADs after a 90 day blanking period in patients randomized to AF ablation with 
a single renal sympathetic denervation procedure compared to patients randomized to AF 
ablation alone.  
 
3.2 Secondary Aims  
1. Compare AAD-free single-procedure freedom from AF recurrence through 24 
months (not-including recurrences within the first 90 days of the initial ablation 
procedure) 
2. Compare freedom from AF recurrence through 24 months regardless of 
antiarrhythmic drug (AAD) use (excluding the 90 day blanking period) 
3. Examine blood pressure control between the two groups as compared to baseline 
at 6 months, 12 months and 24 months 
4. Examine differences between treatment groups in measures of LV hypertrophy 
(LV wall thickness, mitral inflow parameters) and LA size by TTE at baseline and 
at 12 months for each patient 
5. Procedure-related adverse events 
6. Major Adverse Cardiac Events (MACE) 
7. Serious Adverse Events 
8. Compare anti-hypertensive medication use in the two treatment arms at 24 
months.  
9. Compare quality of life between treatment arms and differences in quality of life 
from baseline using a disease specific scale (AFEQT) at 12 and 24 months. 

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4.  BACKGROUND 
 
There is a wealth of epidemiological, pre-clinical and clinical data that suggests that both 
hypertension and sympathetic overdrive have important effects on the cardiovascular 
system that increases the propensity for atrial fibrillation.  Furthermore, there is pre-
clinical and early clinical data that indicate that this relationship can be modulate by 
catheter-based renal sympathetic denervation (by virtue of its effects on both the renin-
angiotensin-aldosterone system and sympathetic tone).  The following details some of 
these preliminary data which provides the scientific basis for this proposed HFIB clinical 
trial. 
 
Hypertension and Atrial Fibrillation 
 
Aside from its obvious impact on renal function, chronic hypertension significantly 
increases the risk for stroke, coronary artery disease, heart failure, and vascular disease, 
and is believed to mediate the pathogenesis and progression of atrial fibrillation (AF) via 
its remodeling effects on cardiac anatomy. This inextricable link between hypertension 
and cardiovascular health has been well described, as has their combined effect on up to 
40% of the aging, obesity-battling Western world.   
 
Furthermore, from the perspective of a cardiovascular electrophysiologist, the prevalence 
of hypertension has important implications for the prognosis of patients with cardiac 
arrhythmias—particularly, drug-resistant AF.  Despite significant advances in the field of 
catheter ablation for AF, the prevailing evidence suggests that even when procedural 
success can be obtained acutely, a considerable rate of PV electrical reconnection is 
observed over time. This is further supported by a 15–50% rate of clinical AF recurrence 
during follow-up; and as demonstrated by several recent studies which have extended 
follow-up to 6 years, clinical recurrence is even more likely with increasing scrutiny and 
duration of follow-up.    
 
The situation is more complicated for patients with persistent AF—the treatment of 
which has been less effective with PV isolation alone. Although the pathogenesis is not 
completely understood, hypertension is believed to mediate the pathogenesis and 
progression of paroxysmal to persistent AF, via its remodeling effects on cardiac 
anatomy.  This includes left ventricular hypertrophy, impaired ventricular filling, left 
atrial enlargement, and alteration of atrial electrophysiology. It is therefore reasonable to 
assume that limiting or reversing such morphological changes could have a profound 
effect on the effectiveness and durability of currently available ablative therapies for AF.  
Indeed, there is a substantial (albeit at times, a conflicting) body of evidence suggesting 
that treatment with “positively” remodeling agents (such as antagonists of the renin-
angiotensin system) may decrease AF recurrence in patients after cardioversion or as 
adjunctive treatment with antiarrhythmic drugs. 
 
Renal sympathetic denervation is a therapeutic modality that has been shown to affect the 
sympathetic state in various pre-clinical and clinical disease states.  While Symplicity 
HTN-3 was overall a negative study for the control of resistant hypertension, there are 

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compelling data suggesting that one of the most important reasons for the negative 
outcome was technical: namely, the inability of point-by-point radiofrequency ablation to 
achieve circumferential denervation of the peri-renal sympathetic fibers.  To this point, as 
opposed to the initial (and somewhat crude) spot radiofrequency ablation catheter 
employed in that trial, there are now a number of other renal denervation systems 
specifically designed to safely deliver a circumferential array of ablative lesions (that in 
pre-clinical animal models, is very effective in achieving excellent renal denervation). 
 
 
Potential Role of renal sympathetic denervation as an adjunct therapy in the 
treatment of AF: Potential benefits beyond BP control.  
 
Multiple pre-clinical and clinical studies have demonstrated that the sympathetic 
nervous system (SNS) plays an important role in the initiation and maintenance of AF, 
especially in patients with any degree of structural heart disease 3,4. Increases in 
sympathetic tone frequently precede the onset of AF 5, 6, 7, and excessive sympathetic 
nervous activation (assessed by 123I-mIBG scintigraphy) can predict recurrences of AF 
after catheter ablation 8. One explanation for the ‘pro-fibrillatory’ effects of the 
sympathetic nervous system is the distribution of cardiac autonomic innervations.  The 
PV-LA junction has abundant sympathetic innervations, which become the dominant 
sites for the origin of focal atrial tachyarrhythmias in response to heightened sympathetic 
tone 9.  Low concentrations of tyramine, which activates sympathetic neurons by releasing 
norepinephrine from nerve endings, can initiate spontaneous AF by early after-
depolarization-mediate triggered activity from the LA-PV junction 11. Following catheter 
ablation, or rapid atrial pacing, the PV-LA junction can undergo further neural 
remodeling (i.e. sympathetic hyperinnervation), potentially making these sites even more 
sensitive to adrenergic stimuli 11,12. The importance of the autonomic nervous system in 
mediating AF is further strengthened by the results of interventions intended to inhibit 
sympathetic outflow to the heart. Low-level vagus nerve stimulation, which suppresses 
stellate ganglion nerve activities, significantly reduces the frequency of paroxysmal atrial 
tachyarrhythmias in ambulatory canines 13.  This excessive sympathetic nervous 
activation, which contributes to the pathogenesis of atrial fibrillation, is a potential target 
of renal sympathetic denervation, beyond just the control of blood pressure.  
 
An additional consideration is the effect of renal sympathetic denervation on 
cardiac structure and function. In patients with essential hypertension, increased left 
ventricular mass (LVM) is an independent predictor of both AF and cardiovascular 
outcomes. Furthermore, reductions in LVM are associated with prognostic benefits, 
independent of reductions in blood pressure 14,15. To this end, Brandt and colleagues 
recently demonstrated that renal sympathetic denervation significantly reduced LVM and 
improved diastolic function; two established risk factors for the development and 
maintenance of AF 16. Interestingly, even in a small group of BP ‘non-responders’, there 
was marked reductions on LVM and improvements in diastolic parameters. Regression of 
LVM during antihypertensive therapy is associated with a lower likelihood of new-onset 
AF, independent of blood pressure lowering and treatment modality in essential 
hypertension 17.  In total, these studies suggest that renal sympathetic denervation has the 

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potential to reduce the frequency of AF recurrences in patients with significant essential 
hypertension who are undergoing catheter ablation of AF.   
 
Furthermore, there is now a substantial body of pre-clinical data demonstrating that in 
animal models, renal denervation has profound effects on both atrial electrophysiology 
and atrial ultrastructure (decreasing fibrosis).  And as a consequence, renal denervation 
has favorable effects on AF initiation and duration in animal models of AF. 
 
Preliminary Data & Rationale for this Study 
 
A single-center randomized controlled trial examined the effects of adjunctive renal 
denervation in a group of patients with resistant hypertension and atrial fibrillation 18.  In 
this study, 27 patients were enrolled, 14 were randomized to AF ablation only and 13 
were randomized to AF ablation with renal artery denervation. Nine of the 13 patients 
(69%) treated with PVI with renal denervation were AF-free at the 12-month post-
ablation follow-up examination versus 4 (29%) of the 14 patients in the PVI-only group 
(p = 0.033).  While this was admittedly a small study, and included the unusual 
population of patients with both AF and resistant hypertension, it nonetheless was the 
proof-of-principle that adjunctive renal denervation can have potent antiarrhythmic 
effects. 
 
Furthermore, a more recent study examined the link between sympathetic system 
overdrive and atrial arrhythmogenesis, independent of hypertension control.19  In this 
study of patients undergoing catheter ablation of AF, the investigators tested whether 
moxonidine, a centrally-acting sympathoinhibitory agent, can similarly lead to a 
reduction in post-ablation AF recurrence.  In this prospective, double-blinded study, 291 
hypertensive patients were randomized to receive either moxonidine (0.2-0.4 mg daily) or 
placebo, along with standard antihypertensive treatment.  Despite the fact that there were 
no significant differences in blood pressure between the two groups, the 12-month AF 
recurrence rates were 36.9% in the AF ablation alone group and 20.0% in the AF ablation 
+ moxonidine group (p=0.007).  This study provides addition clinical proof-of-principle 
that modification of the sympathetic system would provide ameliorative anti-arrhythmic 
effects post-AF ablation even without significant effects on the blood pressure. 
 
Finally, we conducted a pilot H-FIB study (FDA IDE# G120025) which revealed 
interesting outcomes.  This single-blind, multicenter (10 sites) study enrolled patients 
with a history of significant hypertension (defined as a SBP ≥ 160 mmHg and/or DBP ≥ 
100 mmHg) and receiving treatment with at least one anti-hypertensive medication, and 
scheduled to undergo AF ablation.  After AF ablation, patients were randomized to no 
further therapy or renal denervation using an off-the-shelf radiofrequency ablation 
catheter (Celsius Thermocool, Biosense-Webster, Inc).  Briefly, 13 patients were 
randomized to AF ablation + renal denervation (study group) and 17 patients to AF 
ablation only (control group).  After a mean of 15 months of follow-up, freedom from AF 
was achieved in 77% (10/13) of the study group compared to 53% (9/17) of Controls.  
While not statistically significant, these data are nonetheless quite compelling.  However, 
there were significant safety events that prompted us to halt the study: 3 patients with 

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renal artery dissection, and 3 patients with significant post-ablation renal artery stenosis 
(>60%). Thus, while the off-the-shelf ablation catheter had been safe in our single-center 
experience, we were not able to replicate these favorable safety results in the multicenter 
study.  Together, these data suggest that the H-FIB study should be re-started utilizing a 
dedicated renal denervation catheter. 
 
To this point, the H-FIB trial will re-start using the Vessix renal denervation system.  
Patients meeting the inclusion / exclusion criteria will undergo a catheter ablation 
procedure for AF according to the standard practice.  During the procedure, they will 
additionally undergo a renal angiogram to assess the accessibility of the renal 
vasculature.  Assuming that the anatomy is suitable for renal denervation, the patient will 
be randomized to receive either: (1) AF ablation + catheter-based renal sympathetic 
denervation, or (2) AF ablation alone.  Both groups will be followed for two years. 
 
The primary endpoint is single-procedure survival free from AF (without taking AADs) 
through 12 months, with a 90 day blanking period.  The H-FIB trial will be conducted in 
up to 20 participating sites in the United States and Europe (10 sites for the initial 50 
patients).  The aim of H-FIB is to assess the potential therapeutic and quality-of-life 
benefit of performing hypertension-associated cardiac substrate modification, in addition 
to the standard practice of catheter ablation of atrial fibrillation.  It is believed that 
because both hypertension and sympathetic overdrive both independently (and likely 
synergistically) allow for the genesis and/or propagation of atrial fibrillation, significantly 
reversing and/or reducing the effects of such atrial remodeling by renal denervation will 
improve the durability of procedural success after an ablation.  
 
 
5.  SPECIFIC AIMS 
 
5.1 Primary Endpoint 
Efficacy 
The primary endpoint of this study is AAD-free single-procedure freedom from AF 
recurrence through 12 months (not including a 90 day blanking period). 
 
5.2 Secondary Endpoints 
AAD-free single-procedure freedom from AF recurrence through 24 months (not-
including recurrences within the first 90 days of the initial ablation procedure). 
 
Freedom from AF recurrence through 24 months (not-including the pre-defined 90 
day blanking period) despite taking AADs. 
 
Blood pressure control between the two groups as compared to baseline at 6 months, 12 
months and 24 months. 
 

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Major adverse cardiac events (MACE)  
 
- 
defined as a non-weighted composite score of:  death, stroke, CHF 
hospitalization, clinically diagnosed thromboembolic events other than stroke and 
hemorrhage requiring transfusion within 12 months of randomization 
 
Serious Adverse Events 
 
Differences in measures of LV hypertrophy (LV wall thickness, mitral inflow 
parameters) and LA size  
 
Procedure adverse events 
 
Total number of anti-hypertensive medications at study end, compared between the two 
treatment arms 
 
Quality of Life  
 
 
6.  STUDY DESIGN 
 
This is a prospective, multi-center, double-blinded, randomized trial.  The trial will be 
conducted in up to 20 clinical sites from both within and outside the United States, for a 
total of 300 randomized patients.  During the enrollment of the initial 50 patients, the 
number of sites will be 10.  Accrual is expected to take 24 months, and all patients will be 
followed for 24 months post randomization. 
 
7.  RANDOMIZATION   
 
All patients who have given informed consent for the study will undergo catheter ablation 
for AF, as this is the standard care they would receive regardless of enrollment in the 
study. During the procedure, a renal angiogram will be performed to assess the 
accessibility of the renal vasculature, and its appropriateness for catheter-based renal 
sympathetic denervation.  If the renal anatomy meets the protocol defined dimensions, 
the patient will then undergo randomization.  
 
Patients will be randomized to one of two treatment groups: 
 
Group 1:  catheter ablation of atrial fibrillation plus renal sympathetic denervation 
Group 2: catheter ablation of atrial fibrillation (control group)  
 
Patients will be randomized in a 1:1 fashion.  By this arrangement, 50% of the patients 
will undergo renal sympathetic denervation (Group 1) and 50% will not (Group 2). All 
patients will undergo AF catheter ablation. 
 

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Randomization Procedure 
A DCC representative will be available to discuss any questions regarding patient 
eligibility.  Once the site investigator has confirmed that the patient meets all eligibility 
criteria for participation in the trial, and has completed the eligibility forms in the 
Electronic Data Capture (EDC) system, randomization will be performed electronically.  
Randomization to the study assignment will be generated by the EDC system once the 
checklist of inclusion and exclusion criteria has been completed and verified. For the 
purpose of the primary analysis, patients are considered enrolled in the study once they 
have signed informed consent. 
 
 
8.  MASKING 
 
The operating physician will be aware of the randomization assignment, but the patient 
will not.  The blinding of the patient is maintained by the fact that the renal angiogram 
and renal denervation steps will be performed with the same sedation as used for the 
ablation procedure.  This is typically either deep sedation or under general anesthesia (per 
the usual protocol of the EP laboratory); this amount of anesthesia used for the AF 
ablation procedure is sufficient for the discomfort felt during the renal denervation 
procedure. This approach has been selected to minimize (1) study bias and (2) placebo 
effect. The randomization schema will be blocked by size for each site.  Core labs will 
also be blinded to treatment assignment.  Adverse events will be adjudicated by an Event 
Adjudication Committee and trial oversight will be provided by an independent DSMB.  
Those assessing the primary outcome will be blinded to patients' treatment assignment. 
 
 
9.  STUDY POPULATION 
 
Characterization of Patient Population 
The patient population for this trial consists of patients with atrial fibrillation and a 
history of hypertension.  All patients should be planned for a catheter ablation procedure 
for atrial fibrillation. All patients who meet the eligibility criteria may be included in the 
study regardless of gender, race or ethnicity. 
 
Inclusion Criteria 
1. 
Age ≥ 18 years of age 
2. 
History of AF (paroxysmal or persistent) and planned for a guideline-
supported catheter ablation procedure  
3. 
History of significant hypertension (defined as SBP ≥160 mm Hg and/or 
DBP ≥100 mmHg) and receiving treatment with at least one anti-
hypertensive medication,  
or 
Clinical History of hypertension and receiving treatment with at least two 
anti-hypertensive medications (specifically for blood pressure reduction) 
4. 
Renal vasculature is accessible as determined by intra-procedural renal 
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5. 
Ability to understand the requirements of the study 
6. 
Willingness to adhere to study restrictions, comply with all post-
procedural follow-up requirements and to sign informed consent 
 
Exclusion Criteria 
1. 
Inability to undergo AF catheter ablation (e.g., presence of a left atrial 
thrombus, contraindication to all anticoagulation)   
2. 
Prior left atrial ablation for an atrial arrhythmia (before this index 
procedure) 
3. 
Patients with NYHA class IV congestive heart failure 
4. 
Individual has known secondary hypertension 
5. 
Individual has renal artery anatomy that is ineligible for treatment 
including: 
a. Inability to access renal vasculature 
b. Main renal arteries < 3 mm in diameter or < 20 mm in length. 
c. Hemodynamically or anatomically significant renal artery abnormality 
or stenosis in either renal artery which, in the eyes of the operator, 
would interfere with safe cannulation of the renal artery or meets 
standards for surgical repair or interventional dilation. 
d. A history of prior renal artery intervention including balloon 
angioplasty or stenting that precludes a possibility of ablation 
treatment. 
6. 
Individual has an estimated glomerular filtration rate (eGFR) of less than 
45mL/min/1.73m2, using the MDRD calculation. 
7. 
Individual has a single functioning kidney (either congenitally or 
iatrogenically). 
8. 
Individual is pregnant or nursing. 
9. 
Life expectancy <1 year for any medical condition 
Recruitment Strategies 
Recruitment strategies may include: mailings to referring physicians of the study 
hospitals, symposia and health care events targeted towards this population; as well as 
telephone calls to neighboring health care facilities.  The DCC will regularly assess actual 
enrollment in relation to pre-specified goals, and additional interventions to increase 
enrollment will be implemented as needed.  The Screening Log will identify numbers of 
patients screened and reasons for non-enrollment in the trial.   
 
Roll-in phase 
Each site has the option of enrolling two patients as part of a roll-in phase. Each roll-in 
patient will have AF ablation, renal angiography and renal sympathetic denervation 
performed.  Patient data on these roll-in patients will not be used for the final analysis. 
 
• Roll-in patients will be required to sign the study ICF, but will not be randomized. 
 
• Although the data will not be used for the primary analysis, patients will asked to 
adhere to the same follow up schedule of visits as randomized patients. 
 

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• As per FDA, roll-in patients will count toward the enrollment ceiling. 
 
• The CRF must be adjusted to clearly reflect roll-in patients from randomized 
patients. 
 
10. TREATMENT INTERVENTIONS 
Catheter Ablation for Atrial Fibrillation 
• The approach to catheter ablation of AF should be performed according to the EP 
lab standards.  A few general comments (and restrictions) are noted below: 
 
• Patient anesthesia will be administered according to standard EP lab protocol. 
 
• Arterial and venous access will be achieved through cannulation of the right 
and/or left femoral arteries and veins as per the usual practice of the treating 
electrophysiologist. 
 
• Full systemic anticoagulation will be instituted as per standard hospital 
procedures to a target ACT of approximately 300 seconds or greater (or 
equivalent level depending on testing system performed).  As per the most recent 
AF consensus document 20, pre-procedural anticoagulation management should 
include performing the ablation on therapeutic oral anticoagulation – e.g.,: 
warfarin with a goal INR 2-3, or one of the newer oral anticoagulants: dabigatran, 
rivaroxaban, apixaban, or edoxaban (either continuing one of these agent to the 
time of the procedure, or discontinuing it 3 to 5 days prior to ablation, followed 
by periprocedural bridging using low-molecular-weight heparin).  These 
recommendations apply to the cardiac ablation.  Consistent with the Symplicity-1 
and -2 trials, there are no specific additional recommendations pertaining to pre-
procedural anticoagulation prior to or following renal sympathetic denervation. 
 
Patients in the study will include patients with paroxysmal AF and non-paroxysmal 
AF.  The AF ablation procedure will be performed with any catheter approved for 
that such specific indication or per clinical practice at the study site for that indication 
(i.e., for non-paroxysmal AF). 
 
For US and OUS sites, a list of recommended catheters is in Appendix V.  OUS sites 
may use catheters which have been approved in their jurisdiction for that indication. 
 
• All Patients:  Pulmonary vein isolation with an approved irrigated radiofrequency 
ablation catheter, laser ablation or cryoballoon ablation catheter (as per the usual 
practice of the treating physician).  PV isolation must be confirmed by a multi-
electrode mapping catheter after placing the last ablation of the PV-isolating 
lesion set. 
 
➢ Paroxysmal AF Patients: 
▪ Additional ablation may be performed to target non-PV triggers 
▪ SVC isolation is permitted (as per the physician’s usual practice) 

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▪ A typical flutter CT isthmus line may be placed in patients with 
either a history of ECG-determined typical flutter or induced 
typical flutter during the procedure 
▪ One should not perform additional targeting of CFAE sites or the 
placement of linear lesions 
 
➢ Non-Paroxysmal AF Patients: 
▪ This category includes all patients with AF sustained for ≥ 7 days, 
and requiring termination by pharmacological or electrical 
cardioversion 
▪ Additional ablation may be performed to target non-PV triggers, 
SVC isolation, linear lesions (e.g., CT isthmus line, Mitral Isthmus 
line, Roof line) 
▪ Additional targeting of rotor activity using approved mapping 
technology is permitted  
▪ Ablation of CFAE sites is not permitted 
 
• As per usual practice of the treating physician, an approved catheter navigation 
system (such as the robotic or magnetic navigation system) may be employed for 
AF ablation.   
 
• During radiofrequency ablation, power titration should be performed as per the 
physician’s usual practice to avoid thromboembolic complications or perforation.  
One reasonable strategy includes careful power titration to achieve an impedance 
drop not exceeding 10%.  In general, the tip temperature should not exceed 45°C, 
and preferably should stay below 42°C. 
 
• During cryoballoon ablation, ablation lesions should be placed as per usual 
practice (2-4 min lesions/PV).  During ablation of the right pulmonary veins, as 
per the center’s usual practice, a strategy should be used to minimize the 
possibility of phrenic nerve injury.  Two examples of such appropriate strategies 
include: i) pacing the phrenic nerve from the SVC during ablation and monitoring 
of diaphragmatic excursion to indicate phrenic nerve integrity, and ii) monitoring 
diaphragmatic excursion with free breathing during ablation to indicate phrenic 
nerve integrity.  
 
• During laser ablation, the CardioFocus HeartLight Catheter must be used 
according to the guidelines set in the FDA approved Instructions for Use 21.  
Phrenic nerve pacing is recommended to avoid injury to the phrenic nerve.  As 
per the IFU, one method for conducting pacing is to pace from the superior vena 
cava once the Balloon is inflated near the right superior pulmonary vein (RSPV) 
and if desired, the right inferior pulmonary vein (RIPV) to assess the location of 
the phrenic nerve by observing any “capture” at the target energy delivery site.  It 
is advised that pacing be conducted at high output to ensure capture of the phrenic 
nerve.  When pacing prior to energy delivery, the site of diaphragmatic 
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compared via fluoroscopy or ICE with the target energy delivery site.  Energy 
should not be delivered to any area where there is phrenic nerve capture.  
Alternatively, concomitant phrenic nerve pacing can be performed using a pacing 
catheter in the SVC during laser balloon energy delivery to the RSPV (or RIPV).  
When used, energy delivery must be discontinued if movement of the diaphragm 
slows or changes during energy delivery. 
 
• During the ablation, an intravenous heparin infusion will be maintained for a 
target ACT >300 seconds.  ACTs should be monitored every 30-60 minutes (per 
usual practice). 
 
Renal Angiography 
• A renal angiogram will be performed after the AF ablation procedure is complete.  
Once the renal arteries are found to be acceptable for ablation, randomization will 
occur.  Once angiography is performed, no additional atrial ablation is permitted. 
 
• Following completion of the cardiac ablation and renal angiography, if the patient 
was randomized to the control group, the heparin infusion will be discontinued. 
The arterial and venous sheaths will be removed and hemostasis achieved with 
manual pressure (protamine may be used to facilitate this) and/or percutaneous 
vascular closure devices (as per the institution’s practice). If the patient was 
randomized to the renal sympathetic denervation arm (study group), these steps 
will be performed after the renal artery ablation has been completed.  
 
Renal Sympathetic Denervation 
• After confirmation of eligibility, the radiofrequency ablation catheter will be 
introduced into each renal artery. 
• Despite some variability in renal vascular anatomy, the method for performing the 
procedure is fairly straightforward.  An aortogram is performed to visualize the 
renal vessels and deem suitability (no significant renal artery stenosis or 
atherosclerosis, etc.). 
• The renal ablation procedure will be performed using the VessixTM Renal 
Denervation System (Boston Scientific, Quincy, Massachusetts).  The operating 
physician will manipulate the ablation catheter into the renal arteries as per 
standard operating procedures.   
 

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• The Vessix catheter is available in various sizes, and can be used to treat arteries 
between 3 mm and 7 mm in diameter and more than 20 mm in length.  
Radiofrequency energy is delivered via 8 electrodes to four distinct sites within 
the artery in a bipolar fashion.  As with other renal denervation procedures, this 
catheter delivers four lesions in the artery which are separated along the length of 
the artery and are also separated orthogonally in different planes (anterior, 
inferior, posterior, and superior). 
• The Vessix generator is pre-programmed with a temperature-controlled treatment 
algorithm.  Energy is delivered to achieve a temperature of 68oC.  Treatment time 
is 30 seconds.  Average power is approximately 1 watt per electrode and is 
displayed on the generator screen during treatment.  The system is designed to 
automatically deliver the proper amount of energy to achieve the appropriate 
temperature.  The user does not need to (nor can he/she) adjust or set any of the 
biophysical parameters when using this system. The generator uses a proprietary 
algorithm (including impedance measurement) to determine appropriate 
apposition with the vessel wall.  Electrodes which do not have appropriate 
apposition (such as those extending into the aorta) are automatically disabled by 
the generator. 
• Only one catheter placement is required in most renal arteries.  If the operator 
determines that the initial placement is unsatisfactory to treat the full length of the 
artery, a second activation will be permitted in a different location. No more than 
two full catheter activations will be allowed in each renal artery; however, if a 
lesion is terminated early (i.e., in <15 sec), then an additional ablation lesion is 
permitted to compensate for this. 
• After delivery of a complete lesion (30 seconds), no further testing is required to 
ensure renal denervation.  Physiologic endpoints for renal denervation have not 
been standardized. 
 
Post-procedure Hospitalization 
• As per usual practice, post-ablation patients will be admitted overnight to a 
telemetry unit for monitoring.  ECG recordings will be obtained from all patients. 

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If intracardiac echo was not used during the procedure (and at procedure end) to 
assess for pericardial effusion, patients will undergo trans-thoracic 
echocardiography to assess for pericardial effusion.  
 
Anticoagulation 
• As per the ACC/AHA/HRS Guidelines on AF ablation, systemic anticoagulation 
should be administered to the patient for a minimum of 2 months after the 
procedure.  Options include: 
 
1. Warfarin: for a target INR 2-3.  
2. One of the novel Thrombin or Factor Xa inhibitors   
3. LMW heparin formulations (such as Fragmin/Lovenox) injected 
subcutaneously 
• As per the ACC/AHA/HRS Guidelines on AF ablation, long-term management of 
anticoagulation should be according to the baseline risk status for embolic stroke 
 
Blanking Period and Second Procedures 
• The duration of the blanking period for all patients is 90 days.   
 
• All Class I and III antiarrhythmic drugs should be stopped no later than 90 days 
after ablation of paroxysmal and non-paroxysmal AF patients.  The use of any 
Class I or III AADs after the 90 day blanking period will be considered a primary 
failure. 
 
• Any repeat AF ablation will cause the patient to be considered a primary failure. 
 
• No repeat renal denervation procedures will be allowed. 
 
Risks and Benefits  
 
Pre-clinical 22 studies using similar lesion location and lesion duration parameters 
demonstrated no evidence of clinically significant adverse renal artery damage/stenosis. 
Our protocol utilizes an average power of 1 watt per electrode.  
 
11.  DEFINITIONS AND MEASUREMENT OF ENDPOINTS 
 
11.1 Primary Endpoint 
 
Efficacy 
The primary endpoint of this study is AAD-free freedom from AF recurrence through 12 
months (not including the pre-defined 90 day blanking period).  This will be defined by 
absence of any electrocardiographically documented AF, clinically documented AF or 
AF determined by Holter monitoring. 
o Patients who die prior to the 12-month assessment will be considered as treatment 
failures (not free from AF). 

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o The use of any Class I or III AADs after the 90 day blanking period will be 
considered a primary failure. 
 
 
11.2 Secondary Endpoints 
 
AAD-free single-procedure freedom from AF recurrence through 24 months (not-
including recurrences within the first 90 days of the initial ablation procedure). 
 
Recorded at the 12 and 24 month visits for each patient. 
 
Freedom from AF recurrence through 24 months (not-including the pre-defined 90 
day blanking period) despite taking AADs. 
 
Freedom from AF recurrence will be defined by absence of any electrocardiographically 
documented AF, clinically documented AF or AF determined by Holter monitoring. 
o Patients who die prior to the 12-month assessment will be considered as treatment 
failures (not free from AF). 
 
Blood pressure control between the two groups as compared to baseline at 6 months, 12 
months and 24 months. 
 
Determined by office visit blood pressure readings. 
 
Differences in measures of LV hypertrophy (LV wall thickness, mitral inflow 
parameters) and LA size  
 
Recorded via TTE at baseline and at 12 months for each patient. 
 
Serious Adverse Events 
 
Major Adverse Cardiac Events 
 
o Major adverse cardiac events (MACE) defined as a non-weighted composite score 
of:  death, stroke, CHF hospitalization, clinically diagnosed thromboembolic 
events other than stroke and hemorrhage requiring transfusion within 12 months 
of randomization 
 
Total number of anti-hypertensive medications at study end, compared between the two 
treatment arms 
 
Recorded at the 24 month visit for each patient. 
 
Quality of Life  
  

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The change in QoL from baseline to 12 months will be measured using one quality of life 
instrument (AFEQT).  The AFEQT is a 20-item disease-specific scale developed to 
capture subjective ratings of AF disease and treatment burden.  The AFEQT 
questionnaire can be found in Appendix II. For this trial, the AFEQT is available in 
English, Spanish, French, German, and Czech.  Inability to read and complete the 
instrument in the available languages does not preclude a patient from enrollment in the 
trial.   
 
11.3 Safety 
 
Adverse Events 
The incidence of serious adverse events over the course of the trial will be compared 
between the two treatment groups.  All serious and all protocol-defined adverse events 
(AE) will be adjudicated by an Event Adjudication Committee (EAC).  The endpoints for 
safety will be reported as the frequencies of occurrence of each adverse event, the rate of 
adverse events per patient/year and time to each event. In addition, the number of patients 
with each serious adverse event type will be recorded.  Safety data will be collected 
throughout this study and the incidence of each event type will be computed along with 
the 95% confidence intervals. 
 
An adverse event (AE) is any undesirable experience (sign, symptom, 
illness, abnormal laboratory value, or other medical event) occurring to a 
subject during the course of the study.  Physical findings (including vital 
signs) observed at follow-up, or pre-existing physical findings that worsen 
compared to baseline, are adverse events if the investigator determines 
they are clinically significant. 
 
AF recurrence by itself is considered a recurrence of disease (pre-existing 
condition), and, therefore, does not meet the definition of an AE. 
Recurrence of pre-existing AFL/AT is also considered recurrence of disease, 
and does not meet the definition of an AE. 
 
The following clinical events will not be considered an adverse event for this 
clinical study: 
 
• Minor pericarditis attributable to the ablation procedure defined as 
pleuritic chest discomfort with or without pericardial rub and ECG changes. 
 

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• AF/AFL/AT recurrence requiring pharmacological or synchronized electrical 
cardioversion during the hospitalization for the index ablation procedure, or 
throughout the duration of the study. However, new onset of left atrial 
flutter occurring post-ablation is an AE. 
• Re-ablation for AF or pre-existing AFL/AT 
• Standard follow-up or exacerbation of pre-existing conditions unrelated to the 
cardiovascular system including diabetes, cancer/tumors, multiple sclerosis, allergies, 
osteoporosis, arthritis, emphysema, vision or aural problems and rectal polyps.  
• Physical trauma determined to be unrelated to the ablation or renal sympathetic 
denervation procedures including pain due to musculoskeletal injuries, muscle aches due 
to over-exertion, joint degeneration, tendonitis and bursitis and burns from external 
causes.  
• Newly developed disease or illness unrelated to AF, the ablation or renal sympathetic 
denervation procedures, a study device or the drugs used to treat cardiovascular illness 
including gastrointestinal ulcers, hemorrhoids, immune system deficiencies like HIV or 
AIDS, infectious diseases like hepatitis or herpes viruses, neurological/psychological 
disorders such as Alzheimer’s, Parkinson’s, dementia, obsessive/compulsive or eating 
disorders. 
• Other illness, if clearly isolated from the cardiovascular disease, including jaundice 
unrelated to systemic infection, infection in extremities unrelated to the procedure, 
bacterial infection or cellulitis.  
• Common ailments unrelated to the cardiovascular system, the ablation or renal 
sympathetic denervation procedures, a study device or the drugs used to treat 
cardiovascular illness including common headache, muscle pain, food poisoning, 
superficial infections, rashes, warts, shingles, constipation, eczema, hernias, upper 
respiratory infections or influenza.  
Serious Adverse Event
A serious adverse event (SAE) is any event that meets one or more of 
the following criteria: 
 Leads to a death 
 Leads to a serious deterioration in the health of a subject that resulted 
in: 
 a life-threatening illness or injury 
 a permanent impairment of a body structure or a body function 

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 in-patient hospitalization or prolongation of an existing 
hospitalization*
 medical or surgical intervention to prevent life-threatening illness 
or injury or permanent impairment to body structure or a body 
function 
 Leads to fetal distress, fetal death or a congenital abnormality or birth 
defect. 
This definition excludes hospitalization solely due to arrhythmia recurrence 
or non-medically urgent cardioversion. 
*Planned hospitalization for a condition present prior to the participant’s 
enrollment in the study will not meet the definition of an SAE. An AE 
would meet the criterion of “hospitalization” if the event necessitated an 
admission to a health care facility (e.g., an overnight stay). Emergency 
room visits that do not result in admission to the hospital should be 
evaluated for one of the other serious outcomes. 
Unanticipated Serious Adverse Event 
An unanticipated (unexpected) serious adverse event is any serious adverse event that is 
not protocol-defined or documented in the patient consent form.  Expedited reporting is 
required for serious adverse events that are unexpected.  
Unanticipated Adverse Device Effects 
An unanticipated adverse device effects (UADE) is any serious adverse effect on health 
or safety or any life-threatening problem caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan, or any other unanticipated serious problem 
associated with the device that relates to the rights, safety, or welfare of subjects. 
Unanticipated Problems  
According to the Office for Human Research Protections (OHRP), an Unanticipated 
Problem (UP) generally includes any incident, experience, or outcome that meets all of 
the following criteria: (1) Unexpected (in terms of nature, severity, or frequency) given 
(a) the research procedures that are described in the protocol-related documents, such as 
the IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; and (2) Related or possibly related 
to participation in the research (in this guidance document, possibly related means there 
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caused by the procedures involved in the research); and  (3) Suggests that the research 
places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized.  
 
Based on the definitions above and as illustrated below (per OHRP guidance), many 
adverse events are not unanticipated problems, and many unanticipated problems are not 
adverse events. However, some adverse events are also unanticipated problems. For 
example, a serious adverse event that is unexpected and at least possibly related to study 
participation is also by definition an unanticipated problem. As stated above, an 
unanticipated problem may not necessarily be an adverse event, which is the case when 
the problem does not cause actual physical harm to participants. For example, if a laptop 
computer with sensitive, identifiable study data is stolen, this theft places the participants 
at greater risk of psychological or social harm; this is an unanticipated problem that is not 
an adverse event. Another example of an unanticipated problem that is not an adverse 
event is if the FDA announces that one of the study drugs is tainted (e.g., with paint 
chips), yet no participant experiences any adverse effects. 
 
Event Recording 
The following adverse events will be captured throughout the period of trial participation: 
o Protocol-defined (as described below) 
o Serious unanticipated events (serious “Other” adverse events) 
 
Causality 
The investigator will assess the relationship of an adverse event to the intervention.  The 
investigator should distinguish the relationship between the event and (a) ablation 
procedure (i.e. AF ablation procedure or other concomitant procedures), and (b) renal 
sympathetic denervation.  Causality will be defined as follows:  
 
Probable 
Adverse events that, after careful medical evaluation, are considered with a high 
degree of certainty to be related to the intervention (AF ablation ± renal 
sympathetic denervation). The following characteristics will apply: 
o A reasonable temporal relationship exists between the event and the 
intervention, and  
o The event is a known reaction to the intervention, and cannot be explained 
by an alternative etiology commonly occurring in the 
population/individual. 
Possible 
Adverse events that, after careful medical evaluation, do not meet the criteria for a 
probable relationship to the intervention, but for which a connection cannot be 
ruled out with certainty. The following characteristics will apply: 
 
o The event occurs after intervention, and 
o The event is not a known reaction to intervention, but cannot be explained 
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Unlikely 
 
Adverse events that, after careful medical evaluation, do not meet the criteria for a 
possible or probable relationship to intervention and for which a connection is 
unlikely. The following characteristics will apply: 
o The event does not follow a reasonable temporal sequence from 
administration of the intervention, or 
o May have been produced by environmental factors, and there is no 
apparent pattern of response to the intervention. 
Reporting of Serious Adverse Events and Unanticipated Adverse Device Effects  
All investigators must report both expected (protocol-defined) and unexpected SAEs. All 
protocol defined SAEs must be reported directly to the clinical center’s IRB and the DCC 
within 10 business days of knowledge of the event, or as dictated by the specific IRB 
policy, whichever is sooner.  All deaths, UADEs, and unexpected SAEs that are possibly 
or probably related to the renal sympathetic denervation must be reported to the DCC and 
the clinical center’s IRB within 24 hours of knowledge of the event, or as dictated by the 
specific IRB policy, whichever is sooner.  All unexpected SAEs that are unlikely related 
to the study intervention must be reported to the DCC and the clinical center’s IRB within 
5 business days of knowledge of the event, or as dictated by the specific IRB policy, 
whichever is sooner.  
 
The DCC will report these events to the DSMB chair within 72 hours of notification.  All 
SAEs will be reported to the DSMB at least semi-annually, at the discretion of the DCC 
medical monitor.   
 
Reporting of Unanticipated Problems 
All UPs that are also SAEs, which are at least possibly related to the study intervention, 
must be reported to the DCC within 24 hours of knowledge of the event.  All UPs that are 
not SAEs must be reported to the DCC within 5 calendar days of knowledge of the event, 
or as dictated by the specific IRB policy, whichever is sooner.  
 
DCC Reporting to FDA  
The DCC will report unexpected SAEs that are possibly or probably related to the 
investigational device or UADEs to FDA as appropriate. The DCC will send an initial 
IDE safety report communication to the FDA within 2 business days of notification from 
the site. The DCC will submit a follow-up safety communication to the FDA, based on 
source documentation or PI Report from the site, within 10 business days from 
notification of a UADE for this IDE trial. 
 
Specific Adverse Event Definitions 
 
 
Allergic Reactions 
Allergic reactions can occur to the local anesthetic, sedatives, x-ray dye, heparin, 
protamine, or other agents administered during the procedure. 23-29 

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Arterial or Venous Injury 
Arterial or venous injury including arterial dissection, thrombosis, occlusion or 
hemorrhage at the catheter insertion sites or at other sites along the vessels (risk 
<1%). 30-31 This may result in hemorrhage, hematoma or ischemic injury to an 
extremity or major organ. 
 
Bleeding 
A bleeding event is defined by any one of the following: 
o Transfusion of > 2 units RBC within the first 24 hours following ablation 
o Death due to hemorrhage 
o Re-operation for hemorrhage or tamponade 
NOTE: Hemorrhagic stroke is considered a neurological event and not as a 
separate bleeding event. 
 
Major Infection 
 
A new clinical infection accompanied by pain, fever, drainage and/or leukocytosis 
that is treated by anti-microbial agents (non-prophylactic).  A positive culture 
from the infected site or organ should be present unless strong clinical evidence 
indicates the need for treatment despite negative cultures.  The general categories 
of infection are listed below: 
 
Sepsis 
Evidence of systemic involvement by infection, manifested by positive blood 
cultures and hypotension.  In addition, we will record systemic antibiotic use for 
presumptive sepsis.  
 
Localized Infection  
Infection localized to any organ system or region, including the mediastinum, 
pericardium, or endocardium, without evidence of systemic involvement (see 
sepsis definition), ascertained by standard clinical methods and either associated 
with evidence of bacterial, viral, fungal or protozoal infection, and/or requiring 
empirical treatment.  
 
Occlusion of Coronary Artery 
Radiofrequency current or cryoenergy may cause occlusion of a coronary artery, 
either by direct thermal damage, spasm, or thrombosis (risk <0.5%).30-31  
Coronary arterial occlusion could produce myocardial infarction, angina or death. 
Should occlusion of a coronary artery occur for any reason, the physician will 
attempt to restore coronary blood flow through pharmacological, catheter and/or 
surgical intervention as medically indicated.  
 
Damage to AV Conduction System 

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The application of radiofrequency or cryoenergy current close to the AV node or 
His bundle could damage or destroy the normal AV conduction system, producing 
complete heart block.  
 
Embolization of Thrombus 
The placement of linear lines of ablation may require a large number of RF 
lesions to be delivered to the left ventricle.  The risk of stroke due to embolization 
of thrombus is approximately 1%.  To minimize this risk, patients will be 
heparinized to an activated clotting time of greater than 300 seconds during the 
procedure.   
 
Cardiac Perforation 
Cardiac perforation may result from catheter manipulation or application of 
radiofrequency current or cryoenergy (risk is <1%).30-31  This may result in 
cardiac tamponade and may require percutaneous pericardial drainage or surgical 
repair.  Significant hemodynamic compromise can result in neurological injury or 
death.  An increased risk of cardiac perforation may be associated with the use of 
saline-irrigated electrode catheter due to its creation of a larger, deeper RF lesion. 
 
Valvular Injury 
Injury to a cardiac valve may result from catheter manipulation or the application 
of radiofrequency current or cryoenergy (risk <1%).30-31  This may produce 
valvular insufficiency and possibly require surgical valve replacement. 
 
Pulmonary Vein Stenosis 
While advances in technique and increased physician experience have made 
pulmonary vein stenosis unusual (risk 1.3%), 30-31 it may occur in patients who 
undergo catheter ablation.  
 
Radiation Exposure 
Radiation exposure during the fluoroscopic imaging of the catheters may result in 
an increase in the lifetime risk of developing a fatal malignancy (0.1%) or a 
genetic defect in offspring (0.002%).30, 31-33 
 
Pneumonia 
Rales, pulmonary edema, ARDS and asthmatic attack can be sequelae of 
aspiration pneumonia and nosocomial pneumonia.  Aspiration of gastric contents 
can occur when subjects are intubated, and nosocomial pneumonia is well 
documented as the second most common nosocomial infection.  The incidence of 
aspiration pneumonia and nosocomial pneumonia after AF ablation is rare (<1%). 
 
 
Phrenic Nerve Damage  
Phrenic nerve damage can be a sequela of pulmonary vein isolation; also rare 
(<1%) with RF catheter ablation. 
 

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Cardiac Arrhythmias 
Any documented arrhythmia (excluding atrial fibrillation and atrial flutter) that 
results in clinical compromise (e.g., hemodynamic compromise, oliguria, pre-
syncope or syncope) that requires hospitalization.  Cardiac arrhythmias are 
classified as: 
1. Sustained ventricular arrhythmia requiring defibrillation or cardioversion 
(either DC or chemical) 
2. Cardiac conduction abnormalities requiring permanent pacemaker  
 
Pericardial Fluid Collection 
Accumulation of fluid or clot in the pericardial space that requires surgical 
intervention or percutaneous catheter drainage.  This event will be subdivided into 
those with clinical signs of tamponade (e.g. increased central venous pressure and 
decreased cardiac output) and those without signs of tamponade. 
 
Pleural Effusion 
 
Accumulation of fluid or clot in the pleural space documented by chest radiogram 
 
or chest CT that requires evacuation with surgical intervention or chest tube 
 
placement.   
 
Heart Failure 
New onset of signs or symptoms of congestive heart failure or worsening of pre-
existing heart failure by ≥ 1 NYHA class. 
 
Myocardial Infarction 
Myocardial infarction (MI) should be classified when there is evidence of 
myocardial necrosis in a clinical setting consistent with myocardial ischemia.  
Under these conditions, any one of the following criteria meets the diagnosis for 
myocardial infarction.35 
 
Myocardial Infarction 
Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at 
least one value above the 99th percentile of the upper reference limit (URL) 
together with evidence of myocardial ischemia with at least one of the following: 
o Symptoms of ischemia; 
o ECG changes indicative of new ischemia (new ST-T changes or new left 
bundle branch block [LBBB]); 
o Development of pathological Q waves in the ECG; 
o Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality. 
 
Sudden unexpected cardiac death, involving cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, and accompanied by presumed new 
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angiography and/or autopsy, with death occurring before blood samples obtained, 
or at a time before the expected appearance of cardiac biomarkers in blood will be 
classified as a mortality due to MI. 
 
Atrioesophageal Fistula 
Atrioesophageal fistula is a rare (risk < 1%) but often fatal risk of RF catheter 
ablation.36-37   
 
Neurologic Dysfunction 
Any new, temporary or permanent, focal or global neurological deficit ascertained 
by a standard neurological examination (administered by a neurologist or other 
qualified physician and documented with appropriate diagnostic tests and 
consultation note).  The examining physician will distinguish between a transient 
ischemic attack (TIA), which is fully reversible within 24 hours (and without 
evidence of infarction), and a stroke, which lasts longer than 24 hours (or less 
than 24 hours if there is evidence of infarction).   
Each neurological event must be subcategorized as:  
 
Transient Ischemic Attack  
Defined as an acute event that resolves completely within 24 hours with no 
imaging evidence of infarction.  
 
Ischemic or Hemorrhagic Stroke (Cerebrovascular Accident) 
Defined as an event that persists beyond 24 hours or less than 24 hours associated 
with infarction on an imaging study.  Hemorrhagic conversion of an ischemic 
stroke should be classified as ischemic. 
 
Toxic Metabolic Encephalopathy  
Defined as a disorder of the brain function that arises from abnormal systemic 
metabolism or exogenous substances, altering awareness and/or consciousness, in 
which there is a non-focal neurological examination and a negative brain image. 
 
Other Neurologic Dysfunction 
 
Renal Events 
Two categories of renal events will be identified: 
Renal Dysfunction 
Abnormal kidney function defined as serum creatinine increase >50% or >0.3 
mg/dl rise in serum creatinine (Cr) from baseline.  
 
 
Renal Failure  
New requirement for hemodialysis related to renal dysfunction.  This definition 
excludes aquapheresis for volume removal alone. 
 

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Respiratory Failure 
Impairment of respiratory function requiring re-intubation, tracheostomy or the 
inability to discontinue ventilatory support within 48 hours post-catheter 
intervention.  This excludes intubation for re-operation or temporary intubation 
for diagnostic or therapeutic procedures. 
 
Arterial Non-CNS Thromboembolism 
An acute systemic arterial perfusion deficit in any non-cerebrovascular organ 
system due to thromboembolism confirmed by one or more of the following: 
o Standard clinical and laboratory testing 
o Operative findings 
o Autopsy findings 
 
This definition excludes neurological events. 
 
Venous Thromboembolic Event 
Evidence of venous thromboembolic event (e.g. deep vein thrombosis, pulmonary 
embolism) by standard clinical and laboratory testing. 
 
 
Other 
An event that causes clinically relevant changes in the patient’s health, or any 
event that is life-threatening, results in a fatality, results in permanent disability, 
requires hospitalization, or prolongs an existing hospital stay. 
 
As specifically related to the renal denervation procedure, additional potential adverse 
ANTICIPATED events that may occur include:  
 
Occlusion of Renal Artery 
Radiofrequency current may cause occlusion of a renal artery, either by direct 
thermal damage, spasm, or thrombosis (risk <0.5%).  Renal arterial occlusion 
could produce renal infarction, acute renal failure, possibly resulting in the need 
for hemodialysis. Should occlusion of a renal artery occur for any reason, the 
physician will attempt to restore blood flow through pharmacological, catheter 
and/or surgical intervention as medically indicated.  
 
Renal Artery Stenosis 
Renal artery stenosis (defined as ≥ 60% reduction) by renal duplex 
ultrasonography will be defined as a i) renal-aortic ratio of 3.5 or more or a ii) 
peak systolic velocity of more than 200 cm/s. 38-40  Renal artery stenosis may also 
occur insidiously over time, and may not manifest until weeks after the ablation 
procedure.  The risk of this is minimized by longitudinally staggering the ablation 
lesions such circumferential lesions are not placed in the same segment of the 
artery. 

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12.  CLINICAL CENTERS 
 
The study will be conducted in up to 20 sites both in and outside the United States.  Each 
clinical center will be required to obtain IRB approval for the protocol and consent (and 
their revisions) in a timely fashion, to recruit patients, to collect data and enter it 
accurately in the electronic data capture (EDC) system, to faithfully follow the protocol 
and adhere to the standards of Good Clinical Practice (GCP).  In addition, centers will be 
required to provide the DCC with the information necessary for interim, annual, and final 
reports, to provide source documents, data and regulatory documents for study monitors, 
provide prompt responses to DCC inquiries, and to participate in analyses and reporting 
of study results. 
 
Investigator Profile 
All surgeons, cardiologists, coordinators and other investigators in the study must 
complete the Investigator Profile form, including hospital affiliation, address, telephone, 
fax, beeper and email information.  The physicians and coordinators must email their CV, 
Conflict of Interest Statement and Financial Disclosure Certification, and Institutional 
Health Insurance Portability and Accountability Act (HIPAA) Certificates to the DCC. 
 
Qualifications and Training 
Clinical investigators will be electrophysiologists with expertise in atrial fibrillation 
ablation.  The certified operator will either perform the ablation and renal denervation on 
their own patient, or participate in the ablation and renal denervation of an enrolled 
patient. The clinical site Principal Investigator will be responsible for overseeing the 
ongoing performance of the other participating investigators at that site over the course of 
the study.   
 
All clinical site investigators and coordinators will be trained by the DCC in the specifics 
of the protocol at a site initiation visit in advance of patient enrollment.  In addition, the 
investigators and coordinators will undergo a separate training session to gain familiarity 
with the electronic data capture system. 
 
Signature Verification 
Investigators will input an electronic signature into the electronic data capture system 
(EDC). It will be updated throughout the study as new site personnel are approved. 
 
Conflict of Interest and Financial Disclosure Agreement 
This statement verifies that all investigators have no conflict of interest with any 
institution that may influence their participation in this study.  All investigators need to 
complete this statement.  Investigators will also submit a financial disclosure agreement. 
 
Site Approval 
The following documents must be collected prior to site approval: 
 

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• 
Clinical Study Agreement  
• 
Clinical site IRB roster 
• 
Clinical site IRB approval, version and date for protocol and consent 
• 
Clinical Center Laboratory Certification 
A signed agreement between the clinical site and the DCC (Icahn School of Medicine at 
Mount Sinai) is required prior to site initiation.  Prior to enrolling a patient, 
representatives from the DCC will conduct a site initiation for all investigators, 
coordinators, and any other health care professionals who may be involved in the study 
(e.g. engineers, social workers).  
 
Patient Confidentiality 
All patients’ records will be kept confidential according to HIPAA guidelines. Study 
Investigators, site Institutional Review Boards (IRBs), and the DCC may review source 
documentation as necessary, but all unique patient and hospital identifiers will be 
removed. The aggregate data from this study may be published as per publication policy 
documented in the trial agreements; however, no data with patient identifiers will be 
published. 
 
 
13.  SCREENING AND BASELINE DATA COLLECTION 
 
Pre-Screening Failure Form  
Prior to informed consent 
Prior to approaching a patient to begin the informed consent process, the study personnel 
will review data on prospective patients to determine eligibility for inclusion in the trial. 
All pre-screened patients (patients who are not consented) who are not enrolled are 
recorded in the Pre-Screening Failure form.  For these patients, reasons for failing the 
pre-screening process are documented.  The data collected is HIPAA compliant and does 
not include patient identifiers but only includes screening quarter, screening year, age, 
gender and reason for not being eligible. The reasons for screening failure for patients 
who were consented are collected on the Eligibility Evaluation Form.   
 
Consent 
Prior to screening data collection and protocol-defined procedures (initiated ≥24 hours 
prior to randomization) 
Prior to screening, a thorough explanation of the risks and benefits of the study will be 
outlined by the investigator to the patient and the patient will be asked to sign a consent 
form.  
 
Release of Medical Information 
Prior to screening data collection and protocol defined procedures 
The patient must sign the Release of Medical Information form or equivalent that 
authorizes release of medical records to the study investigators, monitors, and the FDA. 
 

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Demographics Form 
At initiation of screening 
A screened patient is defined as an individual (a consented patient) who was referred to, 
or identified at a clinical site for consideration of entry into the study, and for whom 
some preliminary (i.e. medical record) data have been collected and/or reviewed. For all 
patients screened, the first, middle, and last initial, date of birth, ethnic origin, and sex 
will be captured on the screening log and registration form.  The EDC will generate a 
unique 8-digit identification code that will identify the patient throughout the course of 
the study. 
 
Medical History 
Within 60 days prior to randomization  
This form captures the information pertaining to the medical history, including but not 
limited to previous myocardial infarction, myocardial revascularization, arrhythmias, 
automatic implantable cardioverter-defibrillator, permanent right ventricular or 
biventricular pacemaker, stroke and other comorbidities such as diabetes and peripheral 
vascular disease.  Information regarding the current medical condition is also captured, 
including but not limited to disposition at time of screening (outpatient, inpatient, ICU 
monitoring, etc.). 
 
New York Heart Association Classification  
Within 60 days prior to randomization 
Functional status will be assessed using the NYHA classification.  NYHA classification 
will be determined by investigative center personnel and documented on the “New York 
Association Classification” form.  The NYHA classification scheme is detailed in 
Appendix I. 
 
Medications 
Within 60 days prior to randomization 
This form captures all medications taken within 30 days prior to randomization. 
 
Physical Examination 
Within 60 days prior to randomization 
This form captures the comprehensive physical examination including vital signs 
cardiopulmonary examination, abdominal examination, and anthropometrics (height, 
weight and BSA).  
 
Quality of Life 
Within 30 days prior to randomization 
AFEQT (Appendix II) Questionnaire will be completed by the patient and used to assess 
QoL.  Data regarding completeness of QoL data collection and reasons for missing 
responses to questionnaires will be collected. 
 
Office Blood Pressure Measurement 
The auscultatory method of BP measurement will be used. Persons will be seated quietly 
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and arm supported at heart level. Caffeine, exercise and smoking will be avoided for at 
least 30 minutes prior to measurement. The bladder of the cuff will encircle at least 80 
percent of the arm circumference. Three readings will be taken at intervals of at least 1 
minute, and the average of those readings will be used to represent the patient’s blood 
pressure.  This approach is the standard approach recommended by JCN-7. 41-42  
 
Laboratory Assessment 
Within 30 days prior to randomization 
• 
Hematology 
• 
Coagulation 
• 
Blood chemistry 
• 
Liver function tests 
• 
Glomerular Filtration Rate 
• 
Urine or beta serum HcG (women of childbearing potential) 
 
Eligibility Criteria/Eligibility Evaluation Form 
Prior to randomization 
The inclusion and exclusion criteria will be documented by the clinical site study 
coordinator and verified with the site Principal Investigator in the Eligibility Evaluation 
Form. All screened patients (patients who are consented) who are not randomized in the 
trial will have the reasons for non-randomization documented in the Eligibility 
Evaluation Form.  The data collected is HIPAA compliant and includes reason for not 
being randomized.  
 
A representative from the DCC will be available to discuss any questions regarding 
patient eligibility. 
 
Electrocardiogram (ECG) 
Within 3 days prior to randomization 
An ECG will be done at baseline.  This tracing will be used to assess heart rhythm on all 
patients and provide part of the documentation needed to establish the diagnosis of 
longstanding persistent AF. 
 
Transthoracic Echocardiography 
Must be performed within three months prior to randomization 
Transthoracic Doppler echocardiography will be used to measure LA function (a) atrial 
filling, (b) LA ejection fraction, (c) atrial systolic mitral annular velocity (TDI). MV 
function, mitral regurgitation and LV function and LV mass. The LV mass will be 
derived from 2D TTE imaging or MR imaging.  Two-dimensionally guided M-mode 
echocardiography will be performed from a parasternal long-axis view.  Using the 
leading edge–to–leading edge technique, the left ventricular end-diastolic dimension 
(LVED), posterior wall thickness, and interventricular septal thickness will be measured 
at end-diastole at the level just below the mitral valve leaflets.  LV mass will be 
calculated using the following equation:  0.8{1.04[(LVED + left ventricular posterior 
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will be calculated from this by dividing the LV mass by the height exponentiated to the 
power of 2.7. 
 
14.  POST-RANDOMIZATION DATA COLLECTION 
 
Ablation Procedures 
Initial catheter intervention and event driven 
Includes information regarding specific primary procedure, operative variables, device 
used for ablation, lesion sets created, additional procedures performed at time of initial 
operation, intra-operative pharmacological agents.  The procedure form will also include 
a section where the investigator can depict the lesion set created by annotating a diagram; 
this form will be mailed/faxed to the DCC.  
 
Hospitalizations 
Index hospitalization and event driven  
For all patients the index (baseline) hospitalization and all subsequent hospital 
admissions (for any reason) must be reported on the Hospitalization form.  
 
Patient Pre-discharge 
Prior to discharge  
▪ Medications  
All cardiovascular medications are recorded.   
▪ Physical Examination (including vital signs and cardiopulmonary examination) 
▪ Adverse Events 
Detailed information regarding adverse events is recorded at the time an event 
occurs during hospitalization.  Investigators are asked to make a judgment as to 
the seriousness and relationship of the event to the intervention. 
 
Holter Monitoring 
3, 6, 12 and 24 months. 
Prior to each time point, patients will be given a Holter device and instructed in its use.   
 
Follow-up Visits 
3 months (±14 days); 6 and 9 months (±14days); 12, 18 and 24 months (±30 days) 
Follow-up visits will be conducted by investigative site personnel to document that the 
patient is alive and to assess the following:   
 
▪ 7-day Holter Monitoring (3, 6, 12, 24 months only) 
The Holter device provided to patients prior to each time point will be used for 
this assessment. 
 
▪ Laboratory Assessment (6, 12 months only) 
• 
Blood chemistry 
 

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▪ Medications  
All cardiovascular, inotropic, antiplatelet agents and anticoagulants will be 
recorded.  Medications (including AADs) will be recorded at each follow-up, and 
also as indicated at the time of associated adverse events.  We will also record 
response to DC cardioversions (success or failure; failure defined as the inability 
to restore sinus rhythm for ≥ 30 seconds post-electrical cardioversion20). 
▪ Adverse Events, Anti-arrhythmic Interventions, and Hospitalizations 
Patients will be asked to recall any adverse events (including stroke and bleeding) 
and the number of hospitalizations that occurred out of network since the previous 
contact.  Patients will also be asked if they had a permanent pacemaker insertion, 
cardioversion or subsequent ablation since the last contact. 
 
▪ Renal Doppler (6 months only) 
All patients will undergo follow-up renal Doppler echocardiography at the 
investigative center.  If the 6 month renal duplex ultrasonography indicates 
significant renal stenosis (≥60%) and/or image quality is inadequate to assess the 
severity of stenosis, than an MRI or CT should be performed as confirmatory 
testing.  
 
▪ Transthoracic Doppler Echocardiogram (12 months only) 
All patients will undergo follow-up transthoracic Doppler echocardiography at the 
investigative center (See Appendix III).  
 
Quality of Life 
 The AFEQT questionnaire (Appendix II) will be used to assess QoL. The patients 
themselves must complete this questionnaire and return it to the investigative 
center.   
▪ Functional Status  
The NYHA class will be documented on the “New York Heart Association 
Classification” form. 
▪ Adverse Events  
Patients will be asked to recall any adverse events (including stroke and bleeding) 
and the number of hospitalizations that occurred out of network since the last 
contact.  Patients will also be asked if they had a permanent pacemaker insertion, 
cardioversion or subsequent ablation since the last contact. 
▪ Blinding assessment (12 months only) 
Patients will be asked to determine which treatment(s) they believe they have 
received.  
▪ Follow-up Treating Physician Blinding assessment (12 months only) 
A patient’s follow-up treating physician will be asked to determine which 
treatment(s) the physician believes that the patient has received. 
 

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Event Driven Data Collection  
 
Follow-Up Surgical Procedures  
Event Driven 
All operations following the initial procedure(s) must be reported on the procedure form 
within 48 hours of the knowledge of the event. If the operation is to address a 
complication, the coordinator must also complete an adverse event report. All intra-
operative transfusion requirements must be documented. 
 
Adverse Events 
Event Driven 
Detailed information regarding adverse events will be recorded at the time an adverse 
event occurs. Investigators will be asked to make a judgment as to the seriousness and 
relationship of the event to the procedure using the guidance provided. All adverse events 
will be recorded until completion of the trial.  All serious and all protocol-defined 
adverse events will be adjudicated by an EAC. 
 
Missed Visit Assessment 
Event Driven 
If a patient is unable to attend any follow-up visit before the closure of a study visit 
window, a missed visit assessment must be completed that captures the reason for 
missing the follow-up. 
 
Mortality 
Event Driven within 24 hours of knowledge of event 
The investigator will record the date of death, immediate cause of death, primary 
underlying cause of death, notation of autopsy being performed, and clinical narrative of 
the event. 
 
Study Completion/Early Termination 
Event Driven or End of Study 
This form records the date and reason for study completion or early termination.  The 
reasons for a patient to be withdrawn from this study at the patient’s request or at the 
physician’s discretion will also be documented on this form. 
 
 
Investigator’s Statement  
End of study 
The Principal Investigator will review all of the electronic case report forms (eCRFs) and 
patient summaries at that center.  His/her electronic signature will attest to the accuracy 
and completeness of the data collected.  
 
 
15.  DATA MANAGEMENT 
 

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All study data will be entered in the web-based electronic data capture (EDC) system 
(specified in detail in the operations manual). Study personnel requiring access will have 
their own Login/Password. Access to clinical study information will be based on 
individuals' roles and responsibilities.  The application provides hierarchical user 
permission for data entry, viewing, and reporting options. For optimum security, the 
system operates Secure Socket Layer (SSL) 128-bit encryption protocol over Virtual 
Private Networks.  This application is designed to be in full compliance with 
International Conference on Harmonization and Good Clinical Practices (ICH-GCP), the 
FDA’s Code of Federal Regulations (CFR) Number 21 Part 11 Electronic Record and 
Electronic Signatures, the FDA's "Guidance For Industry:  Computerized Systems Used 
in Clinical Trials", and the Privacy Rule of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). 
 
15.1 Quality Assurance 
The data quality assurance tool has been designed as an automatic feature of the EDC 
system.  When a form is submitted the system conducts instantaneous validation and 
cross-form validation checks.  A query is generated and sent to the site coordinator 
electronically so that data may be verified and corrected. All changes made to a form are 
stored in an audit log. 
 
15.2 On-Site Monitoring 
The primary objectives of the DCC in monitoring clinical sites are to educate, support, 
identify and resolve issues related to the clinical trial.  The monitors will discuss the 
protocol in detail, and clarify any areas of uncertainty.  At initiation of the study, the 
monitors will conduct a tutorial on the EDC system.  The coordinators will practice 
entering data so that the monitors can confirm that the coordinators are proficient in all 
aspects of data entry, query response, and communication with the data management 
team. 
 
The DCC will employ a risk-based approach to monitoring for this study.  This will be 
accomplished via centralized or remote monitoring of data via the EDC with a focus on 
safety, study endpoints, data completion and data outliers.  The DCC will also centrally 
monitor study logs including the Informed Consent Log, the Protocol Violation/Deviation 
Log and the Serious Adverse Event/IND Safety Report Log periodically to ensure that 
the sites are adhering to the study protocol and procedures. The DCC will generate 
performance metrics to analyze site characteristics such as recruitment rates and 
timeliness of data entry.  This will allow the DCC to identify trends across sites and to 
address low-performing sites appropriately.  
 
The DCC will also conduct one on-site monitoring visit each year for every clinical site 
for the duration of the study.  In addition, interim monitoring will be conducted on an 
ongoing basis using the EDC system.  During the annual on-site monitoring visits, the 
monitor will collect copies of any source documents (de-identified) for all deaths and 
AEs.  Prior to each EAC meeting copies of any source documents (de-identified) 
requested by the DCC must be sent via FedEx or secure fax line to the DCC. 
 

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The monitors will review the source documents to determine whether the data reported in 
the EDC system are complete and accurate.  They will also verify that all serious and 
protocol-defined adverse events exist on the source documents, are consistent with the 
protocol and are documented in the appropriate format.  Source documents include 
medical charts, initial hospital admission reports, operative procedure records, discharge 
and re-admission reports, consult notes, radiology reports, lab reports, clinic records, and 
other study-related notes. The study monitors reserve the right to copy de-identified 
records in support of all adverse events and outcomes.  
 
The monitors will also confirm that the regulatory (administrative) binder is complete and 
that all associated documents are up to date.  The regulatory binder should include all 
revisions of the protocol and informed consent, IRB roster, IRB approvals for all of the 
above documents, IRB correspondence, investigator’s agreements, CVs of all study 
personnel, institutional HIPAA certificates, monitor site visit log, telephone contact log, a 
study device log and correspondence with the DCC. 
 
If a problem is identified during the visit (i.e., poor communication with the DCC, 
inadequate or insufficient staff to conduct the study, missing study documents, etc.), then 
the monitor will assist the site in resolving the issue.  Some issues may require input from 
the Steering Committee or the Principal Investigator, as well as the sponsor. 
 
The combination of yearly on-site monitoring and ongoing monitoring using the EDC 
system that includes instantaneous electronic validation, and visual cross-validation to 
detect complex errors, it is anticipated that the best possible quality and most complete 
data will be collected.  
 
The monitor will verify a minimum of the following variables for all patients: initials, 
date of birth, sex, signed informed consent, eligibility criteria, date of randomization, 
anticoagulation, serious and protocol-defined adverse events, mortality, NYHA 
Classifications and QoL.  These data will be 100% source data verified.  All other data 
collection will be monitored as indicated by the data completeness and accuracy at each 
clinical site. 
 
16.  ANALYTICAL PLAN    
 
16.1 Statistical Analysis Plan 
General Design Issues 
This is a prospective, multi-center, double-blinded, randomized trial.  Patients with 
hypertension and planning to undergo an AF ablation procedure will be randomized using 
a 1:1 allocation to either AF catheter ablation (usual therapy) or AF catheter ablation plus 
renal sympathetic denervation. Patients will be blinded to their group assignment (control 
vs. study group) throughout the duration of the study.  The physician responsible for 
blood pressure management in the post-operative period (who will not be the same as the 
operator who performed the procedure) will also be blinded to group assignment.  The 

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operator performing the procedure will not be blinded to the treatment.  Outcomes will be 
assessed and recorded by study personnel masked to treatment assignment.  The trial’s 
primary goal is comparing two treatment arms: an AF ablation control and AF ablation + 
renal sympathetic denervation study group.  The null hypothesis of principal interest is 
that there will be no difference through 12 months between the two treatment arms in 
single-procedure freedom from AF off of all AADs after a 90 day blanking period.  There 
are a number of secondary objectives, including 1) assessing the 24-month single 
procedure freedom from AF off of all AADs after a 90 day blanking period;  2) 
measuring the impact of arrhythmia event reduction on Quality of Life, and 3) other 
surrogate measures of potential benefit from renal denervation (such blood pressure 
differences, differences in LV mass and the number of anti-hypertensive medications at 
study end).  
 
Sample size 
 
 
16.2 Randomization Design and Procedure 
This trial will randomize a total of 300 patients in equal proportions to AF ablation with 
renal sympathetic denervation versus AF ablation alone.  The randomization will be 
stratified by clinical center and use a random permuted block design, with blocks of size 
4 or 8 chosen at random.  Randomization will be implemented as described in section 
eight.  A total of three hundred patients provides 80% power to detect a relative 40% 
decrease in the one-year incidence of atrial fibrillation (from 40% to 24%) in patients 
treated with  AF ablation with renal sympathetic denervation compared to AF ablation 
alone based on a two-tailed 0.05 level chi-squared test. The sample size accounts for two 
planned interim analyses.  
 
This study is divided into two phases: a PILOT phase (to include 50 patients) followed by 
the remaining 250 patients to a total of 300 patients. The PILOT phase will be conducted 
at up to 10 US sites: TBD.  An interim safety analysis will be conducted when all patients 
in the PILOT phase (50 subjects) have completed the 3-month follow up visit.  The 
purpose of this analysis is only for safety.  The efficacy/outcome data for the primary 
endpoint will not be examined; this will permit pooling these 50 patients with the 
subsequent 250 patients for the final efficacy analysis. 
 
 
 
16.3 Data Monitoring and Analysis  
Methods of Analysis 
The primary efficacy outcome of this randomized clinical trial is single procedure 
freedom from AF over 12 months post randomization, excluding a 90 day blanking 
period.  Patients who die within 12 months will be considered treatment failures (not free 
of AF).  The null hypothesis is that there is no difference in the proportion of patients 
meeting the primary outcome between patients randomized to AF ablation plus renal 
sympathetic denervation or AF ablation alone.  That is, we will test 
 
H0: π0 = π1 versus H1: π0 ≠ π1 
 

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where π0 and π1 represent the proportion free from AF at 12 months assessment 
(following a single AF ablation procedure and off AADs after 90 days) among patients 
randomized to receive either AF ablation plus a single renal sympathetic denervation 
procedure or AF ablation alone.  The primary null hypothesis will be tested in an intent-
to-treat analysis at the 0.05 level. To compare the proportion of patients free from AF in 
the two treatment groups, we will use a mixed model in which the type of catheter is 
considered as a random effect to account for the heterogeneity that could be brought 
about by the use of different catheters.  The benefit of AF ablation plus renal sympathetic 
denervation to AF ablation alone will be quantified by the relative risk and associated 
95% confidence interval (adjusted for two interim looks).  
 
Patients who die prior to the 12-month assessment, or who are determined by an 
independent adjudicator to be too ill to undergo AF measurement, will be considered as 
treatment failures (not free of AF).  In the primary analysis, patients in both treatment 
arms who undergo ablation therapy for AF subsequent to the index procedure will be 
considered treatment failures (not free of AF). Patients missing the 12-month assessment, 
for reasons other than death or illness, will have their primary outcome imputed using a 
multiple imputation algorithm described below.  Imputed data will be rounded to 0 (free 
of AF) or 1 (AF present). 
An implicit assumption of the proposed primary analysis is that the results for all of the 
study centers can be pooled or combined.  We will assess the validity of this assumption 
by a variety of means, recognizing that establishing poolability merits both clinical and 
statistical examination.   
We do not anticipate that pooling of results across study centers will be threatened due to 
any clinically important differences in trial conduct. Centers participating in the study 
have been selected for their experience and demonstrated success in conduct of clinical 
trials and adherence to study protocols.  Frequent site monitoring and regular contact 
including teleconferences involving site coordinators and investigators, as well as in 
person meetings, ensure that all centers strictly follow trial protocols.  
Additionally, we will conduct several statistical analyses to assess poolability of results 
across centers. These include center specific analyses of the primary endpoint to assess 
the consistency of results, and similarity of patient demographics and baseline 
characteristics across centers.  In addition to uncovering potential poolability issues that 
would require further exploration, differences may indicate the need for additional, more 
complex, statistical analysis. The effect of center will be explicitly assessed by a 
secondary analysis testing the interaction of treatment with center via a logistic regression 
model incorporating centers through a series of indicator variables. Power for detecting 
an interaction may be low, so we will use a p-value of 0.15 to assess interaction, and also 
consider the qualitative analysis of center specific results to assess the extent the 
heterogeneity of treatment by center. 
 
Interim Analysis 

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We plan to perform two interim analyses with respect to the primary outcome to give the 
option of stopping early should results strongly favor one arm or the other.  The proposed 
timing of the two analyses is at 0.33 and 0.67 on the information scale, i.e., after 33% and 
67% of patients reach the primary endpoint.  The utility of performing these analyses will 
depend on the rate of accrual of patients into the trial.   A group sequential procedure 
allows for flexibility in the number and timing of interim analyses should the DSMB 
choose to modify the proposed plan, or should accrual mitigate the usefulness of an 
interim look.  We will use the Lan-DeMets approach, implementing an O'Brien-Fleming-
type spending function that allots most of the type I error to the final look. 43   
 
In addition to the ethical concern of continuing a trial that shows a clear benefit in favor 
of one treatment, there is also a corresponding ethical concern of continuing a trial that 
has little chance of ever showing a benefit of one treatment compared to the other.  We 
propose that the trial’s conditional power, under the original alternative hypothesis, be 
computed at the interim look and that the DSMB use this as a basis to determine whether 
randomization, if not completed, be halted for futility.  We propose that consideration be 
given to halting the trial for futility if, given the data up to the point of the interim 
analysis, the probability of detecting an absolute 16% benefit for patients randomized to 
AF ablation + renal sympathetic denervation is less than 40%. 
 
In addition an initial safety review will be performed after 40 patients have been enrolled 
and ablated.  The proposed analysis after 40 patients have been ablated will only assess 
safety concerns. The results of this analysis, a summary and comparison of adverse 
events by treatment arm, will be provided to FDA for review. We propose to continue 
enrollment during this period of FDA review, up to a maximum of 80 patients. If 80 
patients have been randomized, and FDA has not concluded its review, enrollment would 
cease pending FDA approval for study continuation. No study modifications are proposed 
based on this initial review. 
 
Assessment of Balance of the Randomization 
The success of the randomization procedure in balancing important covariates between 
randomization groups will be assessed at the interim analysis and at the final analysis. 
Continuous measures will be compared using t-tests, while chi-squared tests will be used 
to compare categorical variables such as age and ethnicity.  As 300 patients will be 
randomized, no substantial imbalances are expected.  However, should any covariate 
differ significantly between treatment groups at the 0.01 level, and be substantively large, 
we will adjust for those covariates in all analyses. Additional sensitivity analysis will be 
employed to determine the effect on the trial’s primary analysis result when adjusted for 
any covariate found to differ between groups at the 0.15 level. 
 
Secondary Analyses 
A number of secondary analyses are planned to supplement the primary analysis. 
Comparisons will be based on chi-squared test for categorical variables and t-tests for 
continuous variables. Incidence rates of any serious adverse event will be compared using 
Poisson regression. These secondary analyses will be performed at a two-sided 0.01 
level.   

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• Compare AAD-free single-procedure freedom from AF recurrence at 24 
months (not-including recurrences within the first 90 days of the initial ablation 
procedure)  
 
• Compare freedom from AF recurrence at 24 months regardless of AAD use 
(excluding the 90 day blanking period) 
 
• Examine blood pressure control between the two groups as compared to 
baseline, 6 months, 12 months and 24 months 
 
 
• Compare Major adverse cardiac events (MACE)  
 
- 
defined as a non-weighted composite score of:  death, stroke, CHF 
hospitalization, clinically diagnosed thromboembolic events other than stroke and 
hemorrhage requiring transfusion within 12 months of randomization 
 
• Serious Adverse events 
 
Demographic, baseline, and outcome characteristics will be summarized numerically and 
graphically. For continuous variables numerical summaries will include the mean, 
standard deviation, median, inter-quartile range and range. Graphical summaries will 
include histograms and box plots.  Categorical variables will be summarized by observed 
frequency distributions and bar graphs. Clinical reports will provide summaries by 
clinical sites, and by region (U.S. versus Europe). Additional descriptive analyses 
include: 
 
Anti-arrhythmic Interventions 
In addition to use of AADs after 90 days post-randomization, anti-arrhythmic 
interventions include the requirement for permanent pacemaker placement, electrical 
cardioversion, and any AF ablations (surgical or percutaneous) at any point following the 
treatment intervention.  We will compare the need for anti-arrhythmic interventions 
between treatment groups.   
 
Anti-hypertensive medication use in the two treatment arms at 24 months 
 
Measures of LV hypertrophy (LV wall thickness, mitral inflow parameters) and LA size 
by TTE at baseline and at 12 months for each patient 
 
Procedure related adverse events (Safety) 
Differences in the incidence of individual protocol-defined and serious adverse events 
within 24 months of randomization will be summarized using  exact 95% confidence 
intervals (based on the Poisson distribution) for the risk ratios for individual adverse 
events for treatment with AF ablation with renal sympathetic denervation versus 
treatment with AF ablation alone will be computed. 

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Quality of Life 
Compare quality of life between treatment arms and differences in quality of life from 
baseline using a disease specific scale (AFEQT) at 12 and 24 months.   
 
Mortality 
Survival will be assessed by all-cause mortality at 24 months. The proportion of deaths 
between randomization groups will be primarily compared by a continuity-corrected chi-
squared test. Time to death will also be described by Kaplan-Meier curves and 
differences between randomization groups will be assessed via the log-rank test. 
 
Analysis of other Atrial Fibrillation Endpoints 
 
Imputation Procedure for Missing Data 
 
Randomized patients missing the primary efficacy endpoint is a potential problem in all 
clinical trials.  Adherence to the intention-to-treat principle requires that all randomized 
patients be included in the primary analysis.  We will report reasons for missing data for 
each randomization group and compare the reasons qualitatively.  The effect that any 
missing data might have on results will be assessed via sensitivity analysis of augmented 
data sets (for example, best-case or worst-case scenarios).  Patients missing the trial’s 
primary endpoint will be included in the analysis by modern imputation methods for 
missing data. 
 
Data imputation methods generally require several assumptions to support their validity 
theory.  One such assumption is that data are missing at random 45, i.e., the missing 
nature of the variable is independent of value of the variable given the observed data.  
While it is not possible to explicitly verify assumptions about the missing data 
mechanism, it may be possible to detect when data are not missing at random.  If there is 
no evidence that the data are not missing at random, the imputation method described 
below will be implemented.  If the assumption of missing at random appears untenable, 
then additional procedures including selection modeling and pattern mixture modeling 
will be considered. 
 
The main feature of the imputation approach is the creation of a set of clinically 
reasonable imputations for the respective outcome for each dropout.  This will be 
accomplished using a set of repeated imputations created by predictive models based on 
the majority of participants with complete data.  The imputation models will reflect 
uncertainty in the modeling process and inherent variability in patient outcomes, as 
reflected in the complete data.  The specific imputation model to be used will be specified 
prior to the examination of any outcome data. 
 
After the imputations are completed, all of the data (complete and imputed) will be 
combined and the analysis performed for each imputed-and-completed dataset.  Rubin’s 
method of multiple (i.e., repeated) imputation will be used to estimate treatment effect.  

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We propose to use 15 datasets (an odd number to allow use of one of the datasets to 
represent the median analytic result).  A tipping point analysis will also be performed. 
 
These methods are preferable to simple mean imputation, or simple “best-worst” or 
“worst-worst” imputation, because the categorization of patients into clinically 
meaningful subgroups, and the imputation of their missing data by appropriately different 
models, accords well with best clinical judgment concerning the likely outcomes of the 
dropouts, and therefore will enhance the trial’s results. 
 
Crossovers 
Crossovers (patients who after randomization switch from the allocated treatment to the 
non-allocated treatment) are not expected to occur in this trial, given the nature of the 
interventional therapy. 
 
17.  ORGANIZATION OF THE STUDY 
 
Event Adjudication Committee 
The charge of the Event Adjudication Committee (EAC) is to review source documents 
and adjudicate all adverse events and causes of mortality. The individuals who will serve 
on the committee are unaffiliated with the clinical sites and the DCC, and will be 
appointed by the DCC. The committee will consist, at least, of a statistician, a 
cardiologist, and a nephrologist. The EAC will meet every 6 months or as needed to 
review outcomes data for each subject enrolled. 
 
Data and Safety Monitoring Board 
To meet the study's ethical responsibility to its subjects, an independent data safety 
monitoring board (DSMB) will monitor results during the study.  The board consists of 
physicians and  a biostatistician who have no formal involvement or conflict of interest 
with the subjects, the investigators, or the DCC, and will be appointed by the Executive 
Steering Committee.  The DSMB will act in a senior advisory capacity to the DCC 
regarding data and safety matters throughout the duration of the study. In addition, the 
DSMB will review interim summary results of the accumulating data from the Event 
Adjudication Committee every 6 months.  These data include adverse events (e.g., 
infection, bleeding, right heart failure) and mortality.  They will communicate their 
findings directly with the DCC. The FDA will be provided a copy of any written 
communication from the DSMB to the study sponsor related to safety concerns, or 
changes to the study protocol, procedures or informed consent document.  The DSMB 
will be provided a copy of any letter from the FDA to the study sponsor related to safety 
concerns, or changes to the study protocol, procedures or informed consent document.  
The clinical centers will have no contact with the members of DSMB regarding this trial 
and no voting member of the committee may participate in the study as an investigator.  
Non-DSMB members will not be allowed during DSMB closed meetings. 
 

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Data Coordinating Center 
A university-based DCC bears responsibility for study design, monitoring interim data, 
and analyzing the study's results in conjunction with the investigators.  The DCC will 
coordinate and monitor the trial.  The DCC will administrate the DSMB and EAC. 
 
Electrophysiology Core Lab 
All Holter rhythms will be centrally analyzed by the Helmsley Electrophysiology Center 
Core Lab directed by Joseph Anthony Gomes, MD, located at the Icahn School of 
Medicine at Mount Sinai, New York, NY.   
 
Executive Steering Committee 
The Executive Steering Committee (with the assistance of the protocol development 
committee) will provide the overall scientific direction for the study.  The responsibilities 
of the Steering Committee are to: (a) maintain contact with study investigators to ensure 
high quality data collection; (b) approve and implement major protocol changes in 
response to advice from the DSMB; (c) collaborate in data analysis, interpretation, and 
publication; (d) establish criteria for authorship on all manuscripts, publications and 
presentations that arise from the study. 
 

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17.  Okin, PM, et al.  Regression of electrocardiographic left ventricular hypertrophy and 
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28. Capucci A, Villani GQ, Aschieri D, et al. Oral amiodarone increases the efficacy of 
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33. Nakashima H, Kumagai K, Urata H, et al. Angiotensin II antagonist prevents electrical 
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35. Joint ESC/ACCF/AHA/WHF Task for the Redefinition of Myocardial Infarction, 
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42. Pickering, TP, et al.  Recommendations for blood pressure management in humans and 
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Appendix I:  New York Heart Association Classification (NYHA) 
 
 
 
 
Class 
Patient Symptoms 
Class I (Asymptomatic) 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, discomfort 
is increased. 
 
 
References: 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 

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Appendix II:  Quality of Life Measures 
 
 
 
 
 
 
 

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References: 
Spertus J, Dorian P, Bubien R, Lewis S, Godejohn D, and Burk C. Validation of the atrial fibrillation effect on 
quality-of-life (AFEQT) questionnaire for atrial fibrillation (AF): A new disease-specific health status measure.  
Heart Rhythm, 7 (5), May Supplement 2010: S214. 

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Appendix III: Transthoracic Doppler Echocardiography 
 
Transthoracic Doppler echocardiography will be used to measure LA function (a) atrial 
filling, (b) LA ejection fraction, (c) atrial systolic mitral annular velocity (TDI). MV 
function, mitral regurgitation and LV function and LV mass. The LV mass will be 
derived from 2D TTE imaging or MR imaging.  Two-dimensionally guided M-mode 
echocardiography will be performed from a parasternal long-axis view.  Using the 
leading edge–to–leading edge technique, the left ventricular end-diastolic dimension 
(LVED), posterior wall thickness, and interventricular septal thickness will be measured 
at end-diastole at the level just below the mitral valve leaflets.  LV mass will be 
calculated using the following equation:  0.8{1.04[(LVED + left ventricular posterior 
wall thickness + interventricular septal thickness) − LVED]} + 0.6.  The LV mass index 
will be calculated from this by dividing the LV mass by the height exponentiated to the 
power of 2.7. 

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 Appendix IV: Study Sites 
 
Icahn School of Medicine at Mount Sinai 
Massachusetts General Hospital 
Na Homolce Hospital 
Medical University of South Carolina 
Others to be determined 
 
 
 
 

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Appendix V: List of Recommended Atrial Fibrillation Ablation Devices 
 
Biosense Webster Celsius Thermocool Ablation Catheter 
Biosense Webster Celsius Thermocool SF Ablation Catheter 
Biosense Webster Navistar Thermocool Ablation Catheter 
Biosense Webster Navistar Thermocool SF Ablation Catheter 
Biosense Webster Thermocool Smarttouch Ablation Catheter 
Medtronic Arctic Front Cryoballoon Ablation Catheter 
St Jude Medical Tacticath Ablation Catheter 
CardioFocus HeartLight Ablation Catheter