Clinical trial NCT00911508
Conditions: Atrial Fibrillation Arrhythmia
Keywords: Atrial Fibrillation Left Atrial Ablation Pulmonary Vein Isolation Catheter Ablation Antiarrhythmic Drug Therapy
Sponsor: Mayo Clinic
Start date: 2009-11-13; Completion date: 2017-12-31
Enrollment: 2204 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The (Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial) CABANA Trial has the overall goal of establishing the appropriate roles for medical and ablative intervention for atrial fibrillation (AF). The CABANA Trial is designed to test the hypothesis that the treatment strategy of left atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) will be superior to current state-of-the-art therapy with either rate control or rhythm control drugs for decreasing the incidence of the composite endpoint of total mortality, disabling stroke, serious bleeding, or cardiac arrest in patients with untreated or incompletely treated AF.

Detailed description:
The need for this trial arises out of 1) the rapidly increasing number of pts \> 60 years of age with AF accompanied by symptoms and morbidity, 2) the failure of anti-arrhythmic drug therapy to maintain sinus rhythm and reduce mortality, 3) the rapidly increasing application of radio-frequency catheter ablation without appropriate evidence-based validation, and 4) the expanding impact of AF on health care costs.

This study will randomize up to 2200 patients to a strategy of catheter ablation versus pharmacologic therapy with rate or rhythm control drugs. Each pt will have 1) characteristics similar to AFFIRM pts (≥65 yo or \<65 with \>1 risk factor for stroke, 2) Documented AF warranting treatment, and 3) Eligibility for both catheter ablation and ≥2 anti-arrhythmic or ≥2 rate control drugs. Pts will be followed every 6 months for an average of approximately 5 years and will undergo repeat trans-telephonic monitor, Holter monitor, and CT/MR studies to assess the impact of treatment.

The CABANA trial will disclose the role of medical and non-pharmacologic therapies for AF, establish the cost and impact of therapy on quality of life and will help determine if AF is a modifiable risk factor for increased mortality.

Arms: arm 1: Pulmonary vein isolation using a circumferential ablative approach in the left atrium. Ablation may be performed using circular mapping catheter-guided ablation, antral isolation using a circular guided approach, or wide area circumferential ablation. arm 2: Current state-of-the-art drug therapy for atrial fibrillation (rate control or rhythm control). Treating physicians will be encouraged to follow the American College of Cardiology / American Heart Association / European Society of Cardiology Atrial Fibrillation Guidelines with regard to drug therapy for atrial fibrillation. The specific choice of rate control versus rhythm control drug therapy and the specific drugs to be used will ultimately be left to the discretion of the treating physician.
Interventions: intervention 1: Left atrial ablation intervention 2: Rate or Rhythm Control Therapy
Intervention descriptions: intervention 1: St. Jude: Livewire TC™ , Therapy™ Dual / Thermocouple, Safire,Therapy Cool Path

Biosense Webster: NAVI-STAR, NAVI-STAR/NAVI-STAR DS, Celsius Braided/Long Tip, NAVI-STAR™ and Celsius™ ThermoCool, NAVI-STAR® RMT, Celsius® RMT, ThermoCool® SF

Medtronic CryoCath LP: Freezor®/Freezor MAX®, Artic Front®, Cardiac Ablation System

Bard: Stinger

Boston Scientific: Blazer II RF/XP, Blazer RPM, Chilli II Cooled, SteeroCath intervention 2: Rate control: Metoprolol 50-100mg, Atenolol 50-100mg, Propranolol 40-80mg, Acebutolol 200-300mg, Carvedilol 6.25-25mg, Diltiazem 180-240mg, Verapamil 180-240mg, Digoxin 0.125-0.25mg

Rhythm control: Propafenone 450-625mg, Flecainide 200-300mg, Sotalol 240-320mg, Dofetilide 500-1000mcg, Amiodarone 200-400mg, Quinidine 600-900mg, Dronedarone 800mg

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for 
Atrial Fibrillation Trial 
NCT: 00911508 
 
Date: 22 November, 2013 
 


 
CABANA Confidential 22 November, 2013                                                                    Page 1 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
 
Catheter Ablation Versus Antiarrhythmic Drug 
Therapy for Atrial Fibrillation Trial 
Grant Number: HL089709  
Grant Number: HL089786  
Grant Number: HL089907 
Grant Number: HL089645 
 
 
 
CABANA TRIAL 
 
 
 
 
 
Version: 3.5  
Date: 22 November, 2013 
IDE: G050233 
NCT: 00911508 
EudraCT-Number:  2011-002532-12 
 
 
 
Principal Investigator: 
 
 
 
Douglas L. Packer, MD   
 
Mayo Clinic 
St. Marys Hospital  
Alfred  2-416 
1216 2nd St. SW 
Rochester, MN 55902 
 
 
  
 
 
 
 
 
This document contains information that is privileged or confidential and may not be 
disclosed unless such disclosure is required by applicable laws and regulations.  The 
information in this document is the property of Mayo Clinic and may not be reproduced, 
published, or disclosed to others without written authorization from Mayo Clinic. 
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CABANA Confidential 22 November, 2013                                                                    Page 2 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Contact Information 
 
CABANA Clinical and Administrative Center 
 
Mayo Clinic/St. Marys Hospital Al 2-416 
1216 2nd St. SW 
Rochester, MN 55902 
 
Principal Investigator: Douglas L. Packer, MD 
Phone: 507-255-6263 
Fax: 507-255-3292 
packer.douglas@mayo.edu 
 
Project Director: Kristi H. Monahan, RN 
Phone: 507-255-7456 
Fax: 507-255-9608 
monahan.kristi@mayo.edu 
 
National Heart Lung and Blood Institute 
 
 
 
NHLBI 
 
 
Two Rockledge Centre 
 
 
Suite 8170, MSC 7940 
 
 
6701 Rockledge Dr., Rm. 8146  
Bethesda, MD 20892-7956 
 
 
(Fed-Ex Zip code 20817) 
 
 
 
 
 
 
 
 
 
 
 
Project Officer: Yves D. Rosenberg, MD, MPH  
Phone: 301-435-1292  
Fax: 301-480-3667  
rosenbey@nih.gov 
 
Statistics, Data and Trial Operations Coordinating Center 
 
Duke Clinical Research Institute 
2400 Pratt Street 
Durham, NC 27705 
 
Principal Investigator: Kerry L. Lee, PhD 
Phone: 919-668-8725 
Fax: 919-668-7055 
kerry.lee@duke.edu 
 
Project Leader: Kathleen L. Moretz, RN 
Phone: 919-668-8277 
Cell: 919-818-9461 
Fax: 919-668-7105 
kathleen.moretz@duke.edu 
 
 
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CABANA Confidential 22 November, 2013                                                                    Page 3 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Economic and Quality of Life Coordinating Center 
 
Duke Clinical Research Institute 
2400 Pratt Street 
Durham, NC 27705 
 
Principal Investigator: Daniel B. Mark, MD, MPH 
Phone: 919-668-8775 
Fax:  919-668-7060 
daniel.mark@duke.edu 
 
Project Leader: Tina Harding, BSN, CCRA 
Phone: 919-668-8431 
Fax:  919-668-9817 
tina.harding@duke.edu 
 
Mayo Biomedical Imaging Resource Center 
 
Mayo Clinic 
200 1st St. SW 
Medical Science 1 
Rochester, MN 55905 
 
Principal Investigator: Richard Robb, PhD  
Phone: 507-284-2997 
Fax: 507-284-1632 
robb.richard@mayo.edu 
 
Co-Investigator: David Holmes, III PhD 
Phone: 507-284-2997 
Fax: 507-284-1632 
holmes.david3@mayo.edu 
 
Co-Investigator: Maryam Rettmann, PhD  
Phone: 507-284-2997 
Fax: 507-284-1632 
rettmann.maryam@mayo.edu 
 
 
 
 
 
 
 
 
 
 
 
 
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CABANA Confidential 22 November, 2013                                                                    Page 4 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
CABANA Core Labs 
 
University of Washington 
Division of Cardiology 
1959 NE Pacific Street 
Box 356422 
Seattle, WA  98195 
 
Director ECG/EGM: Jeanne Poole, MD 
Phone: 206-685-4176 
Fax: 206 616 1022jpoole@u.washington.edu 
 
Seattle Institute Cardiac Research 
2710 California Ave. SW, #3410 
Seattle, WA 98116 
 
 
 
 
206-529-8333 
 
Director-Clinical Affairs: Jill Anderson, RN, BSN 
Phone: 206-529-1114 
jander@sicr.org 
 
 
Medicomp, Inc 
7845 Ellis Road 
Melbourne, FL  32904 
1-800-234-3278 or 1-321-676-0010 
 
President and COO: Dan Balda, MD 
Phone: 321-676-0010 x111 
dbalda@medicomp.com 
 
Clinical Director: Mauri Wilson, RN 
Phone: 321-676-0010 x105 
mwilson@medicomp.com 
 
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CABANA Confidential 22 November, 2013                                                                    Page 5 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Protocol Synopsis 
SPONSOR  
National Heart Lung and Blood Institute 
PROTOCOL TITLE 
Catheter Ablation Versus Antiarrhythmic Drug 
Therapy for Atrial Fibrillation Trial (CABANA) 
PROTOCOL TYPE 
Investigator Initiated 
IDE: G050233  
NCT: 00911508 
EudraCT-Number:  2011-002532-12 
 
DIAGNOSIS AND MAIN 
CRITERIA FOR INCLUSION 
Subjects who have new onset or under-treated 
paroxysmal, persistent, or longstanding persistent 
AF who warrant therapy for their arrhythmia, that 
(1) Over the preceding 6 months have:  
a) ≥2 paroxysmal episodes (electrocardiographic 
documentation of at least 1 episode)  lasting ≥1 
hour in duration: (that terminate spontaneously 
within 7 days or cardioversion is performed within 
48h of AF onset)  
b) electrocardiographic documentation of 1 
persistent AF episode: (sustained for ≥7 days or 
cardioversion is performed more than 48h after AF 
onset); 
c) electrocardiographic documentation of 1 
longstanding persistent AF episode:  (continuous 
AF of duration >1 year). (2) are eligible for catheter 
ablation, (3) are eligible for >2 membrane active 
drugs and/or >2 rate control drugs, and (4) are >65 
yrs of age or <65 yrs with one or more risk factors 
for stroke (hypertension, diabetes, heart failure, 
prior 
stroke 
or 
TIA 
or 
systemic 
emboli, 
Atherosclerotic vascular disease (previous MI, 
peripheral arterial disease or aortic plaque), or left 
atrial diameter ≥ 5.0 cm or left atrial volume ≥ 40 
cc/m2). Eligible subjects with persistent or long-
standing persistent AF will require at least 1 
documented episode. See main protocol for 
complete inclusion/exclusion criteria. 
STUDY HYPOTHESIS 
The treatment strategy of percutaneous left atrial 
catheter ablation for the purpose of eliminating atrial 
fibrillation (AF) is superior to current state-of-the-art 
therapy with either rate control or rhythm control 
drugs for reducing a) the composite endpoint of 
total mortality, disabling stroke, serious bleeding, or 
cardiac arrest (primary endpoint; previously the key 
secondary endpoint) and decreasing total mortality 
(secondary 
endpoint; 
previously 
the 
primary 
endpoint) in subjects with untreated or incompletely 
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CABANA Confidential 22 November, 2013                                                                    Page 6 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
SPONSOR  
National Heart Lung and Blood Institute 
treated AF warranting therapy.  
STUDY DESIGN 
Multicenter, prospective, randomized, open-label 
clinical trial. 
TREATMENT REGIMEN(S) 
One-half of the subjects will be randomly allocated 
to treatment with catheter ablation and one-half will 
be allocated to drug therapy for either rate control or 
rhythm control. 
DURATION OF STUDY 
PARTICIPATION 
Enrollment will occur over approximately 4 years, 
and subjects will be followed for an average of 
approximately 5 years.   
NUMBER OF SUBJECTS 
2000-2200 with a 1:1 randomization ratio  
NUMBER OF SITES 
Total number: approximately 180 
North American Sites: approximately 120 
Non-North American Sites: approximately 60 
PRIMARY ENDPOINT 
Composite of: 1) total mortality, 2) disabling stroke, 
3) serious bleeding, or 4) cardiac arrest. 
 
  
 
 
SECONDARY OUTCOMES 
Total mortality, 
Total mortality or cardiovascular hospitalization, 
Total mortality or stroke or cardiovascular 
hospitalization,  
Cardiovascular death,  
Cardiovascular death or disabling stroke, 
Arrhythmic death or cardiac arrest,  
Heart failure death,  
Freedom from recurrent AF,  
Cardiovascular hospitalization,  
Medical costs and resource use and cost 
effectiveness,  
Quality of life,  
Composite adverse events,  
LA size, morphology and function. 
INTERIM ANALYSES 
An interim examination of key safety and endpoint 
data will be performed at regular intervals during the 
course of the trial.  The primary objective of these 
analyses will be to evaluate the accumulating data 
for a high frequency of negative clinical outcomes.  
The interim monitoring will also involve a review of 
the control arm event rates, patient recruitment, 
compliance with the study protocol, status of data 
collection, and other factors which reflect the overall 
progress and integrity of the study.   
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Investigator Statement 
 
I have read the protocol, including all appendices and agree that it contains all necessary details 
for me and my staff to conduct this study as described.  I will personally oversee the conduct of 
this study as outlined herein and will make a reasonable effort to complete the study within the 
time designated. 
I will provide all study personnel under my supervision with copies of the protocol and access to 
all information provided by the Sponsor and or designee.   I will discuss this material with them 
to ensure that they are fully informed about the conduct of the study in general.  I am aware 
that, prior to the commencement of this study, the Institutional Review Board responsible for 
such matters must approve this protocol in the clinical facility where it will be conducted.  I agree 
to make all reasonable efforts to adhere to the attached protocol. 
I agree to provide all subjects with informed consent forms, as required by government and 
International Conference of Harmonization regulations.  I further agree to report any adverse 
experiences in accordance with the terms of this protocol and FDA regulation 21 CFR 812 
(Subpart E). 
 
 
              ________________________________________           ________________ 
                (Signature of Principal Investigator)                                   (Date) 
 
 
               ____________________________________ 
                (Please Print:  Principal Investigator)                        
 
 
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CABANA Confidential 22 November, 2013                                                                    Page 8 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Table of Contents 
Contact Information ......................................................................................................... 2 
 
Protocol Synopsis ........................................................................................................... 5 
 
Investigator Statement .................................................................................................... 7 
 
Table of Contents ............................................................................................................ 8 
 
1.0 
Introduction ........................................................................................................ 12 
1.1 
Background ....................................................................................................... 13 
1.1.1 
Increasing Incidence and Prevalence ..................................................... 13 
1.1.2 
Progression of AF .................................................................................. 13 
1.1.3 
Health Care Costs of AF ........................................................................ 13 
1.2       Clinical Experience with Drug Therapy .............................................................. 14 
1.2.1    
Anti-Thrombotic Therapy ....................................................................... 14 
1.2.2 
Drug Therapy for Rate Control ............................................................... 14 
1.2.3 
Drug Therapy for Maintaining Sinus Rhythm .......................................... 14 
1.2.4 
Mortality Benefit of Drug Therapy in Randomized Trials ......................... 14 
1.3       Clinical Experience with Catheter Ablation ........................................................ 16 
1.3.1 
Single Center Ablation Success Rates ................................................... 16 
1.3.2 
CABANA Pilot Study .............................................................................. 17 
1.4       Rationale for Maintaining Sinus Rhythm ............................................................ 18 
1.5 
Rationale for Rhythm Monitoring ........................................................................ 18 
1.6 
Rationale for Cost and Quality of Life Investigators............................................ 18 
1.7 
Rationale for Cardiac Imaging Studies ............................................................... 18 
1.8 
Significance of Trial ........................................................................................... 19 
 
2.0 
Objectives  ......................................................................................................... 19 
 
Changes to the Protocol from the Original Study Design ................................... 19 
2.1.      Primary Objective and Hypothesis ..................................................................... 20 
2.2       Secondary Endpoints/Objectives ....................................................................... 20 
2.2.1 
Total Mortality ........................................................................................ 20 
2.2.2 
Composite Mortality / Cardiovascular Hospitalization ............................. 20 
2.2.3 
Freedom from Heart Failure Mortality ..................................................... 20 
2.2.4 
Freedom from Recurrent Atrial Fibrillation .............................................. 20 
2.2.5 
Cost/Economic Impact ........................................................................... 21 
2.2.6 
Quality of Life ......................................................................................... 21 
2.2.7 
Adverse Events ...................................................................................... 21 
2.2.8 
LA Size and Function ............................................................................. 21 
 
3.0       Subject Selection .............................................................................................  21 
3.1       Inclusion Criteria ................................................................................................ 21 
3.2       Exclusion Criteria ............................................................................................   23 
 
4.0       Overview of Study ............................................................................................. 24 
4.1       Trial Design and Time Line  ............................................................................... 23 
4.2       Screening and Pre-randomization Process  ....................................................... 23 
4.3       Enrollment and Randomization .......................................................................... 23 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
4.4       Post Randomization Procedures ....................................................................... 24 
4.4.1 
Baseline Testing  .................................................................................... 24 
4.4.2 
Patient Follow Up  .................................................................................. 25 
4.4.3 
Schedule of Assessment ........................................................................ 26 
 
5.0       Treatment Arms ................................................................................................. 26 
5.1       Description of Treatment Arms  ......................................................................... 26 
5.1.1 
Treatment Strategies  ............................................................................. 26 
5.2 
Pharmacologic Approach to AF (Drug Therapy)  ............................................... 27 
5.2.1  
Drugs Approved for Rate Control ........................................................... 27 
5.2.2  
Drugs Approved for Maintenance of Sinus Rhythm ................................ 27 
5.2.3 
Drugs for Future Consideration  ............................................................. 28 
5.2.4 
AV Nodal Ablation  ................................................................................. 28 
5.2.5 
Changing Drug Therapy  ....................................................................... 28 
5.2.6 
Cross-Over Ablative Therapy  ................................................................ 28 
5.2.7 
Compliance with Treatment Protocols/Site Performance   ...................... 28 
5.3 
Primary Catheter Ablation for AF (Ablation Therapy)  ........................................ 29 
5.3.1 
Pre-ablation Assessment  ...................................................................... 29 
5.3.2 
Ablation Therapies  ................................................................................ 29 
5.3.3 
Approved Ablation Devices  ................................................................... 29 
5.3.4 
Approaches for Futures Consideration  .................................................. 30 
5.3.5 
Cross-over to Drug Therapy  .................................................................. 30 
5.3.6 
Compliance with Treatment Protocols/Site Performance  ....................... 30 
5.4 
Guidelines for Anti-thrombotic Therapy  ............................................................. 30 
5.4.1 
Guidelines for Anticoagulation in Drug Treated Patients  ........................ 30 
5.4.2 
Guidelines for Anti-thrombotic Therapy in Ablation Patients  .................. 31 
5.4.3 
Newer Antithrombotic Therapies  ........................................................... 31 
5.4.4 
Items Left to the Discretion of the Physician  .......................................... 31 
5.5 
Management of Arrhythmia Recurrences During Follow-Up  ............................. 31 
 
6.0 
Definitions & Adjudication for Study Endpoints  ................................................. 32 
6.1 
Primary Endpoints  ............................................................................................ 32 
6.2 
Secondary Endpoints & Safety Endpoints  ......................................................... 32 
 
7.0 
Adverse Events  ................................................................................................ 32 
7.1 
Adverse Event Classification  ............................................................................ 33 
7.1.1  
Anticipated Adverse Events  .................................................................. 33 
7.1.2 
Serious Adverse Event .......................................................................... 33 
7.1.3 
Adverse Event Intensity or Severity Classification  ................................. 34 
7.1.4 
Casual Relationship to Medical or Ablative Therapy  .............................. 34 
7.1.5 
Device Related Adverse Events  ............................................................ 34 
7.2 
Adverse Event Reporting  .................................................................................. 35 
7.3 
Serious Adverse Event Reporting  ..................................................................... 35 
7.4 
Expedited Event Reporting  ............................................................................... 35 
7.4.1 
Expedited events include:  ..................................................................... 35 
7.5 
Adverse Event Documentation .......................................................................... 36 
7.6 
Reporting to Regulatory Authorities  .................................................................. 36 
7.6.1 
Drug Therapy  ........................................................................................ 36 
7.6.2 
Device Therapy  ..................................................................................... 36 
7.6.3 
Criteria for Withdrawal of Subjects from Study  ...................................... 37 
 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
8.0 
Statistical Considerations ................................................................................... 37 
8.1  
Sample Size and Power Considerations  .......................................................... 37 
8.2 
Statistical Analysis  ............................................................................................ 39  
8.2.1 
Analysis of the Primary Endpoint  .......................................................... 39 
8.2.2 
Analysis of Secondary Endpoints  ......................................................... 40 
8.2.3 
Analysis of Morbidity (Adverse Events)  ................................................. 40 
8.2.4 
Analysis of Core Lab Measures of LA Size, Morphology and Function ... 40 
8.2.5 
"On-Treatment" Analysis ........................................................................ 41 
8.2.6   
Interim Analyses  .................................................................................... 41 
8.2.7 
Multiple Comparisons  ............................................................................ 42 
8.2.8 
Health Economics Analyses  .................................................................. 42 
8.2.9 
Quality of Life (QOL) Analyses ............................................................... 43 
 
9.0 
Data Management and Quality Control ............................................................. 43 
9.1 
Study Data Collection - All Patients ................................................................... 43 
9.2 
Electronic Case Report Form (eCRF) ................................................................ 43 
9.3 
Data Management and Quality ......................................................................... 44 
9.4  
Economic and Quality of Life (EQOL) Data ........................................................ 44 
 
10.0 
Investigator Responsibility/Performance ........................................................... 44 
 
11.0 
Study Data Reporting and Processing ............................................................... 45 
11.1 
Site Selection and Monitoring ............................................................................ 45 
11.1.1  
Initiating/Training Sites ........................................................................... 46 
11.1.2  
Terminating a Site ................................................................................. 46 
11.1.3  
Conflicts of Interest  ............................................................................... 46 
 
12.0 
Study Documentation ........................................................................................ 46 
 
13.0 
Source Documentation  .................................................................................... 47 
 
14.0 
Protocol Deviations ............................................................................................ 47 
 
15.0 
Data Transmittal and Record Retention ............................................................. 48 
 
16.0 
Study Closeout  ................................................................................................. 48 
 
17.0 
Audit/Inspections  .............................................................................................. 48 
 
18.0 
Informed Consent .............................................................................................. 48 
 
19.0 
Confidentiality of Subjects  ................................................................................. 49 
 
20.0     Authorization for Use and Disclosure of Protected Health Information (HIPAA)  49 
 
21.0 
Human Subject Protections  .............................................................................. 50 
 
21.1 
Research Subject Selection and Justification of Exclusions  .............................. 50 
 
22.0 
Institutional Review Board/Ethics Committee Review  ......................................  50 
 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
23.0 
Publications Policies .......................................................................................... 50 
 
24.0  Sub-Studies ....................................................................................................... 51 
24.1  CABANAgene .................................................................................................... 51 
 
25.0     References  ....................................................................................................... 52 
 
Appendix A 
Anticipated Adverse Events  .................................................................  59 
 
Appendix B 
Approved Ablation Devices .................................................................... 61 
 
Appendix C 
CABANAgene Sub-study ....................................................................... 62 
 
 
  
 
 
 
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CABANA Confidential 22 November, 2013                                                                    Page 12 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
1.0 Introduction 
 
This protocol describes The Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial 
Fibrillation (CABANA) Trial which has the overall goal of establishing the appropriate roles for 
medical and ablative intervention for atrial fibrillation (AF) in patients who require AF treatment 
and are at an increased risk for mortality, stroke and other health-related complications 
associated with AF.  The trial aims to enroll a sufficiently broad spectrum of patients to allow far-
reaching applicability of the results to the dramatically increasing numbers of patients with this 
arrhythmia.  AF specifically affects patients of advancing age, and is an escalating burden to the 
health care system. This trial arises out of the AFFIRM, RACE, STAF, and AF CHF 
investigations of rate vs. rhythm control therapy and the International AF Ablation Registry. An 
ablation trial evaluating overall mortality and major AF related events, conducted within a 
population at increased risk, will provide the most compelling evidence for guiding the therapy of 
this malady. The completion of the 60 patient CABANA Pilot Study provides solid evidence of 
the feasibility of this landmark study. The primary aim of the CABANA Trial is to test the 
hypothesis that the treatment strategy of percutaneous left atrial catheter ablation for the 
purpose of eliminating atrial fibrillation (AF) is superior to current state-of-the-art therapy with 
either rate control or rhythm control drugs for reducing: 1) total mortality, disabling stroke, 
serious bleeding, or  cardiac arrest as the primary endpoint and 2) total mortality as the 
secondary endpoint in patients with untreated or incompletely treated AF. 
 
This project is a collaborative effort sponsored by the National Heart, Lung, and Blood 
Institute and involving the following organizational units: 
 
• Mayo Clinic, Rochester, MN, Douglas L. Packer MD, [Clinical/Admin Coordinating Center] 
• Duke Clinical Research Institute (DCRI), Durham, NC, Kerry L. Lee PhD,  [Statistics and 
Data Coordinating Center] 
• Duke Clinical Research Institute (DCRI), Durham, NC, Daniel B. Mark MD, [Economics and 
Quality of Life Coordinating Center] 
• Mayo Biomedical Imaging Resource Center, Rochester, MN, Richard Robb PhD, [CT/MR 
Image Analysis] 
• University of Washington/Seattle Institute Cardiac Research (SICR), Seattle WA, Jeanne 
Poole MD, [ECG/EGM Core Lab]  
• International CABANA Investigators involving approximately 180 enrolling centers. 
 
 
 
 
 
 
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CABANA Confidential 22 November, 2013                                                                    Page 13 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Statistics/Data 
Coordinating
Center
Kerry Lee (PI), PhD
Data/Safety
Monitoring
Committee
Events
Committee
CABANA Trial Organization and Process Flow
Clinical/Admin
Coordinating
Center
Doug Packer (PI), MD
Publications
FDA/CMS
HRS/AHA/ACC
Guidelines
PI/Executive Committee
NHLBI
CT/MR Image
Analysis Core
Richard Robb (PI), PhD
Economics & QOL
Daniel Mark (PI), MD
Data Collection
Web Based Entry
CABANA
Enrolling
Centers
ECG/EGM Rhythm
Analysis Core
Jeanne Poole, MD
[ECG/EGM Core]
Trial
Results
 
Figure 1 
 
1.1 Background 
Atrial Fibrillation: The Problem 
1.1.1 Increasing Incidence and Prevalence 
In the past 15 years, AF has emerged as the leading arrhythmic malady in terms of both 
numbers and sequelae.  Several studies have documented a 1% incidence of AF in 60 year 
olds, with an increase to 8-12% in octogenarians [1].  This translates into a prevalence of 2.3 
million patients, with a projected increase to 5.6 million by the year 2050 [1-3]. The prevalence 
of AF in the setting of heart failure is even higher, with up to 45% of patients with class IV heart 
failure suffering from this arrhythmia [4-6].   
 
1.1.2  Progression of AF 
While many patients with paroxysmal AF show little propensity for arrhythmia progression, the 
majority of studies have document a transition to more persistent AF in a substantial proportion 
of patients.  The Canadian Registry of AF (CARAF) showed that 63% of 757 patients with 
paroxysmal AF had recurrent arrhythmia over a 5 year period, with progression to permanent 
AF seen in 25% [7]. Similar numbers have been documented by others [8, 9]. Although 
progression to chronic AF in patients with little underlying heart disease may be as low as 31% 
over 3 decades [10], other reports document progression to chronic AF in 48-77% of patients 
over 8-14 years[11,12]. These differences are due, in part, to the extent of underlying disease 
[13, 14]. 
 
There is also reason to anticipate an increasing impact of this arrhythmia on mortality, stroke, 
bleeding and cardiac arrest.  In the Framingham study [15], both men and women between 55 
and 75 years of age with AF showed a near doubling of mortality over the course of 10 years. 
Within that time frame, the overall death rate was approximately 15% in patients without and 
55% in those with AF.  This rate is further incremented in those individuals between the ages of 
75 and 94 years, in whom the mortality rate increased from 30% to nearly 70% in the presence 
of AF [15]. Up to 50% of individuals with a new stroke in both population-based and cohort 
studies have underlying, potentially related, AF [16-18].  This risk increases from an attributable 
risk of 1.5% in the 6th decade of life to 23.5% in 80-89 year olds [18].  The problem of AF 
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associated stroke is corroborated by another population-based study from Olmsted County 
demonstrating an increasing prevalence of stroke related to AF over the past 3 decades, 
perhaps due to increasing AF occurrence [19]. 
 
1.1.3 Health Care Costs of AF 
AF related illness is a rapidly increasing burden on the global health care system. Data from the 
2003 National Discharge Survey in the US, used to estimate the annual number and prevalence 
of hospitalizations, showed an increase from 154,086 to 376,487 admissions for AF as the first 
listed diagnosis and from 787,750 to 2,283,673 for any AF diagnosis [20]. Other studies 
document an increase in hospitalizations and nursing home need because of this arrhythmia 
[20, 21]. A recent study suggested that the excess annual health care cost in the US is also 5 
times greater in patients with, than without AF [22]. An additional four-fold increase in expense 
has also been reported in patients with multiple yearly AF recurrences [23]. Similarly, the cost of 
AF-related care in the UK rose from 244,000,000 Pounds in 1995 to 459,000,000 Pounds in 
2000[24]. The cost of AF hospitalization, the foremost driver of AF-related expense, is likewise 
increasing [24-25], presaging even greater increases in health care costs in the future.    
 
1.2 Clinical Experience with Drug Therapy 
The medical approach to patients with AF by definition requires poly-pharmacy.  Many patients 
with recurrent AF require rate control therapy.  Others, in whom sinus rhythm is desirable, 
require treatment with an anti-arrhythmic drug, while patients with risk factors for stroke or 
peripheral thromboembolic events require anti-thrombotic therapy. Many health care providers 
also remain unenthusiastic about the limited efficacy and increased proarrhythmic risks of 
membrane-active agents for AF control.   
 
1.2.1 Anti-Thrombotic Therapy 
The importance of anti-thrombotic therapy in the management of patients with AF has been 
established by the AFASAK, SPAF, BAATAF, EAFT, CAFA and other trials demonstrating a 
reduction in stroke risk with warfarin [26].  The response to aspirin or clopidogrel and aspirin has 
been disappointing, as shown in these and the recent ACTIVE Trial [27].  Both the AFFIRM and 
RACE trials also clearly demonstrated excess stroke morbidity in patients discontinuing 
anticoagulation and in those with inappropriate INRs [28, 29]. This finding may be related to the 
occurrence of asymptomatic AF seen in 40-60% of patients [30-33]. Perhaps the most crucial 
contribution of these trials is the clarion call to maintain anticoagulation, even if sinus rhythm 
has been restored. It remains unclear whether these data apply to post-ablation patients. 
 
1.2.2 Drug Therapy for Rate Control 
In many patients with new onset AF, therapy with single or combination rate control agents can 
be valuable [34].  Agents such as beta- or calcium channel blockers, or even digitalis may 
control heart rate in the many patients treated aggressively.  The AFFIRM trial demonstrated 
that 65% of patients so treated had appropriate rate control at 1 year, with 70% at 2 years, and 
75% at 3 years [28].  Comparable findings were seen in the RACE trial [29]. Nevertheless, these 
patients may have a variety of other drug-related side effects.  
 
1.2.3 Drug Therapy for Maintaining Sinus Rhythm 
Multiple small observational studies demonstrate a 40-50% chance of maintaining sinus rhythm 
with membrane active anti-arrhythmic drugs over the course of one year.  These data have 
been validated by recent larger comparative clinical trials. In AFFIRM, 82.4% of patients treated 
with rhythm control drugs were in sinus rhythm at the end of 1 year, 73.3% at 3 years, and 
62.6% at 5 years [28].  This is in comparison with the 43% prevalence of sinus rhythm at 1 year, 
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which decremented to 34.6% at 5 years in those receiving AV Nodal blocking agents alone. 
Many of these patients in sinus rhythm at the time of follow-up had recurrent arrhythmia during 
the time between these evaluations.  In the AFFIRM First Drug Study, 33% of patients taking 
amiodarone had an AF recurrence by 1 year, with 50% by 3 years. This was significantly better 
than the 52% AF recurrence in sotalol-treated patients at 1 year, and 71% recurrence at 3 years 
[35].  The findings were similar in RACE, with only 39% remaining in sinus rhythm at the end of 
the trial [29] and only 38% of patients at 2 years in the STAF Trial [36].  Overall improvements in 
quality of life (QO) were comparable in rate and rhythm control patients in AFFIRM [28, 37]. 
Rate control therapy was also more cost effective in these comparative studies [37, 38, 39, 40, 
41]. In addition to an increase in morbidity and mortality risk with rhythm control therapy 
attributable to pro-arrhythmia, AFFIRM rhythm control patients also had excess non-cardiac 
mortality compared to their rate control counterparts.  
 
1.2.4 Mortality Benefit of Drug Therapy in Randomized Trials 
The morbidity and mortality response to drug therapy for AF seen in these studies has been 
disappointing [28, 29, 36, 38, 42]. In the AFFIRM Trial, conducted in patients at increased risk 
because of age or the presence of risk factors for stroke, there was no statistically significant 
difference in mortality outcomes with rate (21.3%) and rhythm (23.8%) control strategies at 5 yrs 
[hazard ratio 1.15 (0.99-1.34) for rhythm control therapy; p=0.08] [28]. Patients treated with 
rhythm control were more likely to require rehospitalization (80.1%) than rate control patients 
(73.0%) [p<0.001] and rhythm control therapy was more expensive [43]. The outcome of the 
secondary endpoint of death, disabling stroke or anoxic encephalopathy, major bleed, or cardiac 
arrest was also similar in the two arms.  Importantly, similar trends of mortality and composite 
endpoints were seen in RACE [29], PIAF [38], and STAF [36]. As suggested by accompanying 
editorial opinion, only 40 to 50% of eligible patients were enrolled in these trials, in part because 
of bias toward rhythm control in highly symptomatic patients. These data may not be directly 
applicable to younger patients without heart disease. 
 
The outcomes of rate vs. rhythm control management strategies were also recently examined in 
patients with underlying heart failure.  The AF CHF Trial [42] enrolled 1376 patients with one AF 
episode in 6 months and either Class II-IV CHF and an EF ≤35%, or Class I CHF with a CHF 
hospitalization, or an EF ≤25%.  682 patients were randomized to rhythm control (Amiodarone 
in 82%) versus 694 to rate control (beta blockers in 88% and Digoxin in 75%) [42]. Thirty-one 
percent had paroxysmal while 69% had persistent AF, and 31% had Class III or IV CHF. There 
was no difference in the primary endpoint of CV death in rhythm (26.7%) vs. rate control 
patients (25.2%)  [HR=1.06, CI=0.86-1.30, p= 0.59] over 37 months of follow-up. There was no 
difference in total mortality (31.8% vs. 32.9%, p=0.73), stroke risk (2.6% vs. 3.6%, p=0.32), 
worsening CHF (27.6% vs. 38.8%, p=0.17) or the composite of CV death, stroke, or worsening 
CHF (42.7% vs. 45.8%, p=0.20). Bradycardia was more common in those treated to maintain 
sinus rhythm (8.5% vs. 4.9%, p=0.007) and 21% of patients crossed over from rhythm to rate 
control therapy. 
   
The findings of this trial, along with AFFIRM, RACE and STAF raise important questions 
regarding the quest for maintaining sinus rhythm in patients with AF.  These studies can be 
interpreted as supporting the thesis that the restoration and maintenance of sinus rhythm does 
not alter over-all outcome.  If true, this would indicate that 1) other factors are responsible for 
morbidity and mortality in AF patients, 2) AF is not a risk factor for either total or CV mortality, or 
3) this arrhythmia is simply a marker of CV risk related to underlying disease. Alternatively, 
there may be significant benefit to sinus rhythm, which is offset in these trials by the pro-
arrhythmia, heart failure, or organ toxicity attending anti-arrhythmic drug therapy. Disappointing 
efficacy of drugs in maintaining sinus rhythm would further diminish their appeal. 
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Any recommendation for rhythm control must be tempered by a consideration of pro-arrhythmic 
risk and occurrence of intolerable side effects.  In AFFIRM, 5% of patients had a pro-arrhythmic 
event [44], with drug discontinuation because of side effects in 10% of rate control and 30% of 
rhythm control patients [28, 29]. In addition to poor efficacy, there also may be an inadequate 
AF gradient between groups of patients due to appreciable undetected AF and accompanying 
risk in rhythm control patients or unexpectedly common sinus rhythm in rate control patients, 
both limiting discernible differences between groups.  Of note, 31% of patients in AFFIRM had 
paroxysmal AF and many of the rate control patients had sinus rhythm.  
 
Despite the pessimism potentially generated by these issues, the results of the recent ATHENA 
trial have provided incentive for the reconsideration of drug therapy for AF [45].  In comparing 
the class III antiarrhythmic agent dronedarone in 2327 patients against placebo given to 2301 
individuals, this study showed a 24% reduction in cardiovascular hospitalization or mortality 
(p,0.0001), a 29% decreased in cardiovascular mortality (p= 0.03), and a 26% decrease in 
cardiovascular hospitalization(p ≤0.0001) with active therapy at 22±5 months of follow-up. There 
were also significantly lower ACS and stroke rates with dronedarone therapy, in the setting of 
low proarrhythmia and heart failure rates. These data support the potential for cancelation of 
benefit from drug therapy by untoward toxicities of drug interventions. 
 
1.3 Clinical Experience with Catheter Ablation  
1.3.1 Single Center Ablation Success Rates 
While these trials have established the benefit/risk ratios of pharmacologic rate and rhythm 
control therapies, in the absence of longer-term studies, the comparative long-term outcomes of 
ablative intervention remain unclear. This is particularly true in patients with advancing age or 
underlying disease. Still, the outcome of the AF CHF trial, viewed within the context of AFFIRM, 
RACE, and STAF, argues strongly for alternative catheter-based or surgical intervention for AF 
elimination. The efficacy and safety outcomes of catheter ablation for AF are available in the 
form of observational studies from individual centers [46-51]. These issues have been reviewed 
in detail in the recent AF Ablation Consensus Statement [50] and the Venice Chart International 
Consensus Document on AF Ablation [51]. These clinical studies document AF elimination rates 
of 55-80% with lasso-guided ablation of paroxysmal AF [46], with a 70-90% success rate using 
more aggressive wide area circumferential or high frequency, complex electrogram-guided 
ablative approaches [47,48].  The mechanism of beneficial effect is not completely established 
but likely includes the isolation of AF-initiating triggers arising within pulmonary veins (PVs), the 
alteration of parasympathetic and sympathetic nerve ganglia in the posterior LA, and the 
disruption of candidate initiation and substrate-mediated maintenance mechanisms of AF [47]. 
These studies have several limitations including absence of randomized enrollment, variability in 
techniques, differences in end points, the inconsistent use of blanking periods, and an uncertain 
number of redo procedures. Moreover, the 60-70% ablation success rate seen in the recent 
International AF Ablation Registry detailing outcome, suggests that the efficacy rate of ablation 
may be less than seen in earlier observational studies [49].  Furthermore, recent data have 
suggested an increased recurrence rate 2-3 years after ablation [52]. 
 
The complication rates of ablative intervention have been inadequately documented.  While 
recent studies demonstrate a 1% stroke rate and a reduced PV stenosis rate down to 1-2% with 
ablative intervention, the same International AF Ablation Registry suggested that serious 
ablation events occur in up to 6% of patients [49]. The occurrence of stroke, PV stenosis, 
tamponade, and the recently reported lethal atrial-esophageal fistulae [53] indicate that the true 
complication rates of AF ablation have yet to be established.  
 
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Smaller, randomized ablation vs. drug studies include the CACAF [54], RAAFT [55], APAF [56], 
and A4 [57] Trials. These trials randomized 67-198 patients to rhythm control therapy vs. 
primary AF ablation. Over a 12-month follow-up period, a 76% average recurrence rate was 
seen in drug treated patients, which was greater than the 24% recurrence rate in ablated 
patients [54-57]. These studies also provide additional preliminary information. In the CACAF 
Trial [54], 1 of the ablation patients (1.5%) and one patient in the control group (1.5%) sustained 
a stroke, and 2 patients (3%) in the drug control group died over the course of follow-up. In the 
RAAFT Trial [55], re-hospitalization was required in 19 (54%) of anti-arrhythmic drug-treated 
patients compared with only 3 (9%) of those ablated (p<0.001). No mortality was seen in either 
treatment group. In these studies, 20-73% of drug treated patients crossed over to ablative 
therapy. Since patients over the age of 75 years were largely excluded, these early trial results 
may not apply to the increasing elderly population of patients at risk for untoward AF-related 
morbidity and mortality. Nevertheless, these data show similar rates of AF elimination, all 
favoring ablative intervention.   
 
At least 4 studies have assessed the outcome of catheter ablation for AF occurring in the setting 
of ventricular dysfunction [58-61]. In contrast to the AF CHF Trial, these studies show a 
substantial improvement in EF/CHF class in patients in whom sinus rhythm was restored and 
maintained by intervention. Accompanying data suggest that this is more likely in patients with 
non-ischemic than ischemic cardiomyopathy. Short follow-up periods in these studies make it 
impossible to draw conclusions regarding mortality and/or morbidity benefit, however. 
 
1.3.2 CABANA Pilot Study 
Sixty patients were enrolled in 10 centers and randomized to AF ablation versus drug therapy, 
indicating the feasibility of randomizing patients with CABANA characteristics [62]. Of the 
patients enrolled, 77% were men and 23% women. The average age was 59 years (37% >65 
yrs). Among the 60 patients, 80% had hypertension, 71% had 2 or more co-morbidities, 28% 
had sleep apnea and 25% had a family history of AF. Thirty two percent of patients had 
paroxysmal, 37% persistent, and 32% longstanding persistent AF. This pilot experience 
suggests that the Pivotal study will provide relevant information for a broad spectrum of AF 
patients. Only 7% of the pilot study patients had Canadian class 0 (asymptomatic) AF, 12% 
class I, 19% class II, 51% class III, and 11% had class IV symptoms [63]. Twelve percent had 
class I CHF symptoms, 31% were class II, and 5% had class III CHF. Twenty five percent had 
been on a single rhythm control drug, and 97% on rate control. Of these patients, 47% had 
required prior hospitalization for AF and 47% had been previously cardioverted. These patient 
characteristics are similar to AFFIRM patients and are very different from the typical catheter 
company PMA patients with paroxysmal AF and no other heart disease. 
 
Twenty-nine patients (48%) were randomized to ablation and 28 of them underwent ablation. All 
31 patients (52%) randomized to drug therapy were treated with rate or rhythm control agents. 
13% of patients have been treated with rate-control only, 16% with rhythm control agents only, 
and both in 71%. The overall enrollment rate in this start-up pilot study exceeded the 0.7 
patients/center/month needed to complete the pivotal study. In addition, following the change in 
focus from ablation expert-driven enrollment to non-ablationist co-PI recruitment, enrollment 
increased to 1.1 patients/site/month. The pilot study demonstrated the feasibility of recruiting 
and enrolling patients, identified the expected demographics of Pivotal Trial subjects, and has 
been very helpful in optimizing the study design of the Pivotal Trial.  
 
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1.4 Rationale For Maintaining Sinus Rhythm 
None of the trials to date address the far-reaching question of the merit of maintaining sinus 
rhythm for reducing morbidity and mortality. Recent data from the AFFIRM trial provide a 
glimpse into this issue.  In a post-hoc, time-dependent covariate assessment of the relationship 
between cardiac rhythm and survival, warfarin and sinus rhythm were associated with a lower 
risk of death [HR=0.53 CI=0.39-0.72 (p< 0.0001)] [64]. Similarly, 18 of 19 primary endpoint 
events in the STAF trial occurred in those patients remaining in AF [36]. Nearly identical findings 
were seen in patients in the DIAMOND studies, which reviewed the effect of dofetilide on total 
mortality in the setting of a prior MI or CHF [65].  The probability of survival in patients treated 
with dofetilide, who remained in sinus rhythm, was 60% at 36 months as compared to 30% in 
those remaining in AF, an effect also seen in the placebo group. Pappone et al [48] in his 
comparative report noted that 72% of all adverse events were observed in patients remaining in 
AF. In contrast, patients maintaining sinus rhythm in the RACE trial did not show improved 
survival [66]. It remains unknown whether the ability to maintain sinus rhythm is a marker of 
improved outcome, or whether sinus rhythm per se confers a mortality benefit. The post-hoc 
nature of the analyses limit the value of these results for guiding clinical practice.  
 
The data from Nademanee and coworkers [67] also bear directly on the feasibility of the 
CABANA trial. Their study examined mortality and stroke outcomes in 540 patients with 
AFFIRM characteristics (age >65 or the presence of hypertension, diabetes, atrial enlargement 
or ventricular dysfunction in patients <65yrs). Their mean age was 69 years, with 165 patients 
>75 years of age, and 124 with an EF<40%.  Fourty% had paroxysmal, 26% had persistent, and 
34% had permanent AF. Each patient underwent ablation (once in 374, while 121 underwent 2 
sessions, 43 underwent 3 sessions and 2 patients 4 sessions). 492 were followed for 4.2+1.1 
years. The 2.7% long term mortality rate in 431 (86%) patients remaining in sinus rhythm was 
substantially better than the 16% death rate in the 63 (14%) who remained in AF (p<0.0001). 
Sinus rhythm was the most important independent predictor of survival (p=0.002), whereas EF 
and warfarin had little prognostic value in these patients. These studies taken together, along 
with data from population-based studies, provide the rationale for a large, multi-center trial to 
prospectively examine the impact of sinus rhythm on total mortality, disabling stroke, serious 
bleeding and cardiac arrest in patients with AF. Information from a well-designed randomized 
mortality trial is critically needed to provide a reasoned basis for the continued application of 
advanced ablation technology, justifying its concomitant cost, or its earlier application as first 
line therapy [68]. 
 
1.5 
Rationale for Rhythm Monitoring  
Most studies examining outcomes of drug and ablative therapy use symptomatic episodes of AF 
for establishing endpoints.  While this allows assessment of AF burden and quality of life, it is an 
inadequate basis for making critical decisions regarding ongoing anticoagulation. Presumably, 
AFFIRM patients demonstrating excess morbidity after discontinuation of warfarin were felt to 
have complete control of their AF by anti-arrhythmic drug therapy [28].  Their subsequent events 
may have been due to undetected silent AF or some other underlying factor.  Other studies 
have documented a moderate prevalence of asymptomatic or “silent” AF in other settings [30-
33, 70-72]. Additionally, 10-40% of successfully ablated, asymptomatic patients may have silent 
AF [71, 72], which raises the possibility of continuing stroke risk or other morbidity, even though 
symptoms are eliminated [73]. Of note, others have reported far lower asymptomatic AF rates 
[48, 74, 75]. In addition, patients with asymptomatic AF may be at equivalent risk as their 
symptomatic counterparts. These issues, and the need to establish simple treatment efficacy, 
provide a clear rationale for careful monitoring to establish treatment efficacy.  
 
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1.6  Rationale for Cost and Quality of Life Investigations 
AF is responsible for almost 500,000 in-patient hospitalizations in the US every year [20-21]. 
The direct medical costs associated with AF account for several billion dollars of excess health 
care spending per year in this country. At the individual level, AF increases medical spending 
from 9 to 22 times that for similar patients without AF. The cost effectiveness of ablation has 
been evaluated in preliminary studies only [76, 77]. Although case control studies have 
suggested that AF-related impairment of QoL is between that of having an MI and heart failure, 
improvement is expected with treatment [28, 29, 26, 38, 78-80]. Preliminary data suggest that 
AF ablation can restore QoL to levels comparable to age/sex matched general populations [81, 
82]. Given the epidemic growth of this arrhythmia in the aging US population, more effective 
therapy offers the potential of relieving suffering in a growing number of citizens.  As part of the 
CABANA research program, we plan to examine economic and QoL outcomes comprehensively 
using state-of-the-art tools and techniques used in recent or ongoing trials (OAT, STICH and 
SCD-HeFT).   
 
1.7 
Rationale for Cardiac Imaging Studies 
Atrial remodeling, occurring with AF has been well documented, although it is difficult to know 
whether changes in atrial structure precede or follow this arrhythmia or are simply triggered by 
underlying disease. It also remains uncertain whether a reversal of atrial dysfunction occurs 
following ablation. In theory, elimination of AF should produce both electrical and anatomic 
remodeling, regardless of the therapy employed. At present, LA size and function outcomes 
following ablation are contradictory [83-88]. These data suggest an improvement in LA size and 
function following more limited PV isolation, although this might be offset by the scarring 
produced by more aggressive intervention. We also have preliminary data suggesting that LA 
dysfunction remains beyond the typical 1-2 month time frame used in deciding to stop anti-
coagulation after restoring sinus rhythm [89].  CT / MR Image Analysis will be required to 
document the occurrence of LA remodeling following AF elimination with ablation or drug 
therapy and establish its impact on overall outcome, stroke risk, and the need for post-ablation 
anti-coagulation. The real-life prevalence of catastrophic atrial-esophageal fistula formation and 
PV stenosis will also be established. While some of this desired information could be obtained 
echocardiographically, this approach is problematic given difficulties in standardizing image 
acquisition and interpretation. Furthermore, the echo approach cannot be used to assess 
pulmonary vein or esophageal status. CT or MR imaging can be standardized both in terms of 
acquisition and interpretation. 
 
1.8 
Significance of the Trial  
This trial is of substantial importance at multiple levels. Clinically, the trial will establish whether 
the emerging role of aggressive catheter ablation in the treatment of AF is justified by patient 
outcomes. This is an expensive approach, potentially complicated by life threatening events, 
which is now performed in thousands of patients without clear evidence of long-term benefit. 
The issues raised above have not been settled for “curative ablation”. The impact of age, AF 
type, and underlying disease on the outcome of ablation and drug therapy remain unclear. This 
study will answer these questions, will document the effect of ablation on AF recurrence and 
specifically examine health care costs, cost effectiveness, and quality of life outcomes. This 
study will also assess the role of earlier therapy for AF and the related utility of ablation as first 
line therapy in patients warranting treatment. 
 
Scientifically, the trial will determine whether the attainment of normal sinus rhythm is a mortality 
and stroke advantage. No trial to date has prospectively addressed this issue, nor will any 
currently envisioned 1-2 yr study be sufficiently powered for this purpose.   The trial should also 
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provide outcomes-based support for the role of AF as a modifiable risk factor of increased 
morbidity and mortality. The trial will also establish the determinants of ablation outcome. The 
CT/MR Imaging will also elucidate the structural abnormalities contributing to the occurrence of 
AF in a diverse population of patients and the modulation of those factors by drug or ablative 
intervention. 
 
From a health care policy standpoint, this trial will help establish the place for medical and non-
pharmacologic therapies for this escalating national healthcare dilemma. Aggressive 
intervention in an increasing number of patients and resulting mushrooming financial burden to 
society is already taking place at a time of increasingly constrained funding for health care.  The 
Quality of Life and cost components of the trial will firmly establish whether AF ablation 
represents good value for the money and is an efficient way of improving health in the affected 
population relative to alternative health care expenditures. It will also allow much better 
estimation of the impact of the diffusion of ablation technology into the overall health care 
system. A critical window of opportunity for a randomized trial is now present, and the outcome 
of this landmark trial will likely shape therapy decisions and health care policy for years to come. 
 
 
2.0  Objectives 
   
Changes to the Protocol from the Original Study Design 
Although CABANA was originally mandated to be a mortality trial, a careful assessment of the 
progress of the trial was undertaken by the study leadership in early 2013. Completely blinded 
to any treatment-specific outcome data, the two major issues addressed by the leadership 
group were (1) a lower than expected aggregated mortality rate, and (2) accrual of patients at a 
slower rate than projected.  Careful consideration of these issues led to a decision to (a) change 
the primary endpoint of the trial from total mortality to the original key secondary endpoint 
consisting of the composite of death, disabling stroke, serious bleeding, or cardiac arrest, and 
(b) reduce the sample size to a number that was consistent with the new primary endpoint and 
more realistically achievable. There may still be a mortality difference between treatment 
groups. This was not revealed in the interim review. These changes will be highlighted in the 
sections of the protocol that follow. 
 
2.1 
Primary Objective and Hypothesis 
The primary hypothesis of the CABANA trial is that the treatment strategy of percutaneous left 
atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) is superior to current 
state-of-the-art medical therapy with either rate control or rhythm control drugs for decreasing 
the incidence of the composite endpoint of total mortality, disabling stroke, serious bleeding, or 
cardiac arrest (primary endpoint) and reducing total mortality (key secondary endpoint) in 
patients with untreated or incompletely treated AF warranting therapy.  The study is powered to 
detect treatment with percutaneous left atrial catheter ablation will reduce the incidence of this 
endpoint by >30% compared to drug therapy. To properly interpret this composite endpoint, the 
incidence of each of the individual components will also be descriptively examined to assess its 
relative contribution to the overall composite outcome. The primary endpoint and all secondary 
endpoints will be carefully assessed and analyzed on an intention to treat basis. 
 
2.2 
Secondary Endpoints/Objectives 
1. Total mortality 
2. Total mortality or cardiovascular hospitalization 
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3. Total mortality, stroke, or CV hospitalization (for heart failure or acute ischemic events) 
4. Cardiovascular death  
5. Cardiovascular death or disabling stroke  
6. Arrhythmic death or cardiac arrest  
7. Heart failure death  
8. Freedom from recurrent AF 
9. Cardiovascular hospitalization  
10. Medical costs, resource utilization, and cost effectiveness  
11. Quality of Life  
12. Composite adverse events 
13. LA size, morphology and function 
 
2.2.1  Total Mortality  
Because of the vital importance of assessing the impact of left atrial catheter ablation on total 
mortality, this endpoint (which is a component of the primary endpoint) will be a specific 
secondary endpoint in the trial. 
Hypothesis:  Catheter ablation for AF will reduce total mortality by >30% compared to state-of-
the-art pharmacologic therapy. 
 
2.2.2 Composite Mortality / Cardiovascular Hospitalization  
By reducing the recurrence of AF, the proposed therapies should also reduce cardiovascular 
hospitalization. Additional secondary endpoints, including cardiovascular hospitalization and the 
composite of total mortality and cardiovascular hospitalization, will therefore be examined. The 
composite of total mortality, stroke or cardiovascular hospitalization will also be assessed. 
Hypothesis:  Catheter ablation for AF will be significantly (≥25%) more effective than 
pharmacologic therapy, in reducing cardiovascular hospitalization, the composite of total 
mortality or cardiovascular hospitalization, and the composite of total mortality, stroke or 
cardiovascular hospitalization. 
 
2.2.3 Freedom from Heart Failure Mortality  
AF may be seen in 40-50% of heart failure patients.  Furthermore, heart failure may occur 
because of uncontrolled ventricular response rates or as an adverse consequence of drug 
therapy.  Heart failure related mortality may be affected differently by the ablative elimination of 
AF than by ongoing pharmacologic treatment.  
 
2.2.4 Freedom from Recurrent Atrial Fibrillation  
The purpose of therapy is to eliminate accompanying symptoms in affected individuals. An 
additional secondary endpoint will be the elimination of AF, comparing complete freedom from 
and time to recurrent AF outcomes of ablation and drug therapy. Time to second AF recurrence 
and AF burden will also be established. Freedom from AF after each ablation performed in an 
individual subject will be separately tracked.  
 
2.2.5 Cost / Economic Impact  
AF is responsible for almost 500,000 in-patient hospitalizations in the US every year and several 
billion dollars of excess health care expenditures. For patients, AF increases medical spending 
from 9-22 times that of comparable patients without AF, and this effect is likely to have even 
greater impact on health care spending in the future given the growth in number of AF patients 
expected and the increasingly complicated therapies used for these patients. As part of 
CABANA, we will examine the economic impact of AF ablation using state-of-the-art techniques. 
 
 
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2.2.6 Quality of Life  
AF also causes significant impairment of quality of life, at a level between that of an MI and 
heart failure.  Preliminary case control data further suggest that ablative therapy for AF can 
restore QOL to levels comparable to age and sex matched general populations. Given the 
epidemic growth of this arrhythmia in an aging population, a more effective therapy offers the 
potential to relieve suffering in a growing number of US citizens. Therefore, QOL assessment 
must be included in this trial. 
 
2.2.7 Adverse Events  
This trial must provide a clear delineation of the “down side” of therapy and track serious 
untoward events unique to each approach. Although strict comparisons will be difficult because 
of therapy-specific adverse events, additional analyses will look at each event type descriptively. 
With drug therapy, unanticipated heart failure hospitalization, pro-arrhythmic events, 
amiodarone pulmonary toxicity, and disabling stroke remain most concerning. For AF ablation 
the adverse events of greatest concern include pulmonary vein (PV) stenosis, atrial-esophageal 
fistula formation, and disabling stroke occurrence with ablative therapy. Of note, we will also 
track descriptively other complications and adverse events of both therapies and these will be 
recorded. We anticipate that the rate of serious adverse events will be similar in both treatment 
arms, although the specific complications will vary in type and extent. 
 
2.2.8 LA Size and Function  
The impact of long-term drug or ablative therapy on LA size and function is unknown [83-89]. 
Further, the relationship between structure and function measures and morbidity and mortality 
have not been examined.  In addition to screening for PV stenosis, the CT / MR studies will 
examine these questions in both drug and ablation patients and provide mechanistic information 
above and beyond descriptive long-term outcomes data.  
 
3.0 Subject Selection 
 
The intent of the CABANA trial is to enroll patients who have new onset or under-treated 
paroxysmal, persistent, or longstanding persistent AF who warrant therapy for their arrhythmia. 
The vast majority of patients will be sufficiently symptomatic to cross the “therapy threshold” to 
active rate or rhythm control. Asymptomatic patients will be less common, but may be enrolled, 
if their AF is jeopardizing ventricular function, felt to be aggravating underlying disease, or 
requiring therapy to prevent sequelae of AF. Each patient will be screened for the 
inclusion/exclusion criteria listed below, which are similar to those of the AFFIRM trial [64].  
 
3.1 
Inclusion Criteria 
To be eligible for the trial, subjects must meet all of the following criteria: 
1. Over the preceding 6 months have:  
a) ≥2 paroxysmal (electrocardiographic documentation of at least 1) AF episodes 
lasting ≥1 hour in duration: (that terminate spontaneously within 7 days or cardioversion 
is performed within 48h of AF onset): or 
b) electrocardiographic documentation of 1 persistent AF episode: (sustained for ≥7 
days or cardioversion is performed more than 48h after AF onset): or  
c) electrocardiographic documentation of 1 longstanding persistent AF episode:  
(continuous AF of duration >1 year). 
2. Warrant active therapy (within the past 3 months) beyond simple ongoing observation  
3. Be eligible for catheter ablation and ≥2 sequential rhythm control and/or ≥2 rate control 
drugs.  
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4. Be ≥65 yrs of age, or <65 yrs with one or more of the following risk factors for stroke: 
Hypertension (treated and/or defined as a BP >140/90 mmHg) [90], Diabetes (treated 
and/or defined as a fasting glucose ≥126 mg/dl) [91], Congestive heart failure (including 
systolic or diastolic heart failure), Prior stroke, TIA or systemic emboli, Atherosclerotic 
vascular disease (previous MI, peripheral arterial disease or aortic plaque), LA size >5.0 
cm (or volume index ≥40 cc/m2), or EF ≤35. Subjects <65 yrs of age whose only risk 
factor is hypertension must have a second risk factor or LV hypertrophy to qualify. 
5. Have the capacity to understand and sign an informed consent form. 
6. Be ≥18 years of age. 
 
NOTE: Subjects may have recent onset AF (in the past 4-6 months), AF present for a longer 
time period, or may have been treated with a single anti-arrhythmic drug, providing they remain 
realistically eligible for ≥2 membrane active drugs and/or ≥2 rate control agents. Patients 
receiving new drug therapy initiated within the previous 3 months may continue that therapy if 
randomized to the drug therapy arm. Reasonable expectation of a response to therapy must be 
present. Subjects will not be excluded because of advancing age or underlying heart disease. 
Subjects with a history of a single episode of paroxysmal AF do not meet the “crossing the 
threshold/warranting therapy” litmus test. Subjects with persistent or long-standing persistent AF 
will require at least 1 documented episode, if it is of sufficient clinical importance that drug or 
ablative therapy is warranted. Subjects can be randomized before cardioversion, even if 
restoration of sinus rhythm is a desired endpoint of therapy. Patients may have documented 
atrial flutter in addition to atrial fibrillation and remain eligible for enrollment.  
 
3.2 
Exclusion Criteria 
If a subject has any of the following criteria, he or she may not be enrolled in the study: 
1. Lone AF in the absence of risk factors for stroke in patients <65 years of age  
2. Patients who in the opinion of the managing clinician should not yet receive any therapy 
for AF 
3. Patients who have failed >2 membrane active anti-arrhythmic drugs at a therapeutic dose 
due to inefficacy or side effects (Table 5.2.2) 
4. An efficacy failure of full dose amiodarone treatment >8 weeks duration at any time 
5. Reversible causes of AF including thyroid disorders, acute alcohol intoxication, recent 
major surgical procedures, or trauma  
6. Recent cardiac events including MI, PCI, or valve or bypass surgery in the preceding 3 
months 
7. Hypertrophic obstructive cardiomyopathy (outflow track) 
8. Class IV angina or Class IV CHF (including past or planned heart transplantation) 
9. Other arrhythmias mandating anti-arrhythmic drug therapy (i.e. VT, VF) 
10. Heritable arrhythmias or increased risk for torsade de pointes with class I or III drugs 
11. Prior LA catheter ablation with the intention of treating AF 
12. Prior surgical interventions for AF such as the MAZE procedure 
13. Prior AV nodal ablation 
14. Patients with other arrhythmias requiring ablative therapy  
15. Contraindication to appropriate anti-coagulation therapy 
16. Renal failure requiring dialysis 
17. Medical conditions limiting expected survival to <1 year 
18. Women of childbearing potential (unless post-menopausal or surgically sterile) 
19. Participation in any other clinical mortality trial (Participation in other non-mortality trials 
should be reviewed with the clinical trial management center)   
20. Unable to give informed consent 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
 
NOTE: Exclusion Criterion #3 includes failed membrane active antiarrhythmic drugs started 
within 3 months prior to enrollment. Prior ablation of the cavo-tricuspid isthmus alone is not an 
exclusion if the patient develops subsequent recurrent AF. Planned atrial flutter ablation in 
combination with the left atrial ablation is not an exclusion.  
 
4.0 Overview of Study 
 
4.1 
Trial Design and Time Line 
This multi-center study will randomize 2000-2200 patients in a 1:1 fashion to a strategy of 
catheter ablation vs. state-of-the-art drug therapy with either rate or rhythm control, as outlined 
in Figure 2.  Each patient will have untreated or incompletely treated AF, which in the opinion of 
the investigator warrants therapy. CABANA enrollment will occur over approximately 4 years.. 
All CABANA patients will be followed an average of approximately 5 years. Assuming criteria for 
early termination are not reached, the major trial results are expected to be reported in early 
2018.  
 
This study will be conducted in accordance with 
current 
United 
States 
Food 
and 
Drug 
Administration (FDA) Regulations and guidelines, 
the European Clinical Trials Directive and 
associated guidelines, International Conference 
on Harmonization guidelines on Good Clinical 
Practice, the principles of the Declaration of 
Helsinki, as well as all other applicable national 
and local laws and regulations.                                        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2 
 
4.2 
Screening and Pre-randomization Procedures 
Study personnel will assess each subject against each inclusion and each exclusion criterion 
and the Investigator will determine the subject’s eligibility for study participation. The principal 
investigator or documented members of the research team approved by local Institutional 
Review Board (IRB) or Ethics Committee (EC) will discuss the underlying rationale for the study, 
the procedures to be followed, the potential benefits and risks, and other issues mandated by 
the consent process. The informed consent process and all assessments will be documented in 
the subject’s medical record or comparable source document. Baseline functional status, 
economic data (including two EQ-5D forms that rate the patient’s health by using a 0-100 
“thermometer” and asking 5 brief questions), and quality of life data (including a Baseline 
Questionnaire of validated scales, ie, SF-36, DASI, Toronto Atrial Fibrillation Severity Scale, AF 
Effects on QOL (AFEQT), Work Productivity and Activity Impairment Instrument (WPAI), 
Stanford Presenteeism scale and Mayo AF Symptom Index (MAFSI)) will be collected by the 
Site Coordinator via structured interview prior to randomization.  
 
4.3 
Enrollment and Randomization 
Eligible patients, who have given written, informed consent and meet all inclusion with no 
exclusion criterion will undergo 1:1 randomization in an unblinded, parallel arm treatment format 
to a strategy of drug therapy for rate or rhythm control vs. catheter ablation.  Randomization will 
be accomplished by telephone or internet using a centralized, interactive voice and web 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
randomization system (IXRS). The enrollment scheme is based on permuted block 
randomization with stratification by clinical site. 
 
4.4 
Post Randomization Procedures 
For morbidity and mortality end points, intention-to-treat analysis will begin at randomization. All 
therapies will be established and optimized in a 3-month treatment initiation period, during which 
patients may receive alternative drugs or undergo repeat ablation if AF recurs. The duration of 
this “blanking period” is derived from standard clinical practice and the AF Ablation Consensus 
Document [50, 51]. Thereafter, therapy will be administered and patients followed for an 
average of approximately 5 years. Efficacy, (i.e. absence of AF recurrence) will be established 
by long-term follow-up beginning after the 3-month therapy initiation phase. Any AF occurring 
after the 3-month blanking period will be considered a treatment failure for the AF recurrence 
secondary endpoint. Patients will be followed at 6 and 12-month intervals from randomization 
throughout the trial.  
 
4.4.1 Baseline Testing 
  
Defining the eligibility of patients for the CABANA Trial will require information generated during 
the course of routine clinical care as dictated by their attending physician.  This information 
should be, consistent with established guidelines, consensus documents, and good clinical 
practice. Selected baseline testing data will be collected in order to characterize the type, cause 
and severity of the patient’s AF and the treatments received prior to enrollment. The baseline 
data will include information from the following clinical evaluations: 
 
1. Relevant medical history including prior and current drug treatment of AF  
2. Relevant physical examination  
3. 12 lead ECG prior to treatment 
4. Blood Tests (INR, creatinine, hemoglobin / hematocrit) (pre-treatment) 
5. Trans-thoracic 2-D echocardiography 
 
The trans-thoracic echocardiographic (TTE) data will be used to characterize the substrate 
underlying the patient’s AF, establishing the presence of LV dysfunction (LVEF), hypertrophy, 
diastolic dysfunction, or other structural abnormalities.  The TTE will also assess LA size and 
volume, and provide measures of atrial function. 
 
Following a recommended approach consistent with established guidelines, consensus 
documents, and good clinical practice, a trans-esophageal echocardiographic (TEE) study will 
be performed within 24 hours prior to ablation in patients with persistent or longstanding 
persistent AF. The TEE may be performed up to 48 hours before the procedure in patients on 
continuous anticoagulation therapy, such as warfarin at a therapeutic INR or in those 
appropriately bridged with intravenous un-fractionated or low molecular weight heparin.  
 
The performance of a pre-treatment TEE in patients with paroxysmal AF is left to the discretion 
of the investigator (5.4.4), but is not required in CABANA. Data on the performance and results 
of all TEEs performed as part of routine care will be collected in the eCRF, however. TEE data 
may also be used to confirm atrial size and morphology. The approach to cardioversion in drug 
treated patients should follow the recommendations of AF Treatment Guidelines [92]. 
 
In those centers where routine clinical practice includes the performance of pre-ablation and 
post-ablation CT/MR studies, relevant data from these studies will be collected to serve as a 
baseline for comparative quantitative LA size, morphology, and function studies, as well as 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
subsequent follow-up PV and esophageal investigations. In addition at those centers, up to 150 
patients randomized to drug therapy will be asked to undergo one research CT/MR scan prior to 
initiating therapy. This will allow the CABANA study to evaluate and compare atrial structure and 
function in response to drug or ablative therapy.  These drug-treated patients will be recruited 
from selected centers that are committed to CT/MR assessment of all enrolled patients (both 
study arms).  Since randomization is performed (stratified) within each site, this component of 
the study will still benefit from the overall study randomization. Optimally, the pre-therapy scans 
performed in all patients should be within 4 months prior to treatment.  
 
In addition to these clinically dictated studies, baseline economic and QOL data will be obtained 
after informed consent is obtained, but before randomization occurs. 
 
4.4.2 Patient Follow Up   
Follow-up in all patients will occur at 3, 6, and 12 months following randomization during the first 
year and every 6 months thereafter, with clinic visits, phone follow-up, and other testing as 
described below. Economic and QOL data, including a full follow-up questionnaire of validated 
scales, ie, SF-36, DASI, Toronto Atrial Fibrillation Severity Scale, AF Effects on QOL (AFEQT), 
Work Productivity and Activity Impairment Instrument (WPAI), Stanford Presenteeism scale, will 
be repeated by trained telephone interviewer staff from the EQOL Coordinating Center (EQOL 
CC) for patients enrolled in North America and by the Site Coordinator in sites outside North 
America.   
 
Follow-up visits/calls at 3 and 6 months should be completed within 30 days +/- of the due date 
(Ex: 3 month visit: completed between 60 days and 120 days of randomization).  
 
Follow-up visits/calls at 12 months and every 6 months thereafter should be completed within 60 
days +/- of the due date (Ex: 12 month visit: completed between 300 days and 420 days of 
randomization). 
  
Medical bills for patients enrolled at US sites will be collected throughout the trial by the EQOL 
Coordinating Center economic team. The Site Coordinators will complete a one page Rapid 
Report Form (RRF) at each CABANA study visit documenting any interim hospitalizations 
and/or ER visits since last contact. These forms will be forwarded to the EQOL Coordinating 
Center for processing.  As part of the economic and QOL data in CABANA, two EQ-5D forms 
that rate the patient’s health by using a 0-100 “thermometer”, asking 5 brief questions and Mayo 
Atrial Fibrillation Symptom Index (MAFSI) will be collected by the Site Coordinator at 3 and 12 
months following randomization during the first year and yearly thereafter throughout the trial 
and entered into the e-CRF.   
 
After enrollment, subjects will either receive a single ‘CABANA Box’ recording system to be 
used throughout the entire study, or will be followed using ambulatory event and Holter ECG 
monitoring as generated during the course of routine clinical care as dictated by their attending 
physician.  
 
At sites where the ‘CABANA Box’ has received appropriate approval, all patients enrolled will 
receive a single ‘CABANA Box’ recording system to be used for both patient activated event 
monitoring (throughout the trial), 24 hour autodetect/autocapture (AD:AC) event monitoring and 
96 hour full disclosure Holter monitoring throughout the study. During year one, subjects will be 
asked to record their heart rhythm each month. After the first year, they will be asked for a 24 
hour recording twice a year and a 96 hour recording twice a year. Fingertip recordings as well 
as AD:AC recordings can be transferred via telephone download from the patient’s home to the 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
CABANA monitoring center. Holter recordings will require downloading of information at the 
enrolling site for data transfer to the CABANA monitoring center. All recordings will be made 
available to the enrolling center for use in clinical practice. 
 
Follow up monitoring with an alternative system will be required in centers unable to use the 
“CABANA Box”. 
 
CT/MR imaging studies will be performed where clinically indicated or otherwise part of routine 
clinical care on ablation subjects after ablation therapy (between 90 days post ablation and the 
6 month follow-up) and as indicated for PV stenosis management throughout the trial. The 150 
drug therapy patients that received the CT/MR scan prior to initiating drug therapy,  will also 
undergo one  research CT/MR scan after therapy is fully established (between 90 days post 
drug treatment initiation and the 6 month follow-up).  CT/MR data will be electronically 
transferred to a server at the Mayo Biomedical Imaging Resource, the CABANA Trial Image 
Analysis Lab.  Scans will be anonymized at the site using a software tool provided by the 
Imaging Center.  Each clinical center will also perform standard site radiology evaluation and 
assessment of the CT/MR images according to the sites’ standard clinical practice.  
 
After completion of the 60 month follow-up, subjects will be asked to extend their participation. If 
agreed upon, subjects will be asked about their current state of health and any clinical events 
every 6 months by telephone until the last subject enrolled reaches approximately 36 months 
follow-up.  
 
Follow-up data will also be obtained at the time of treatment discontinuation, with a crossover in 
treatment strategy, and at the emergence of any primary or secondary endpoints. 
 
4.4.3 Schedule of Assessment  
 
Assessments 
Baseline 
Post 
Therapy 
Mo 3 
Mo 6 
Mo 12 
Mo 18 
Mo 24 
Mo 30 
Mo 36 
Mo 42 
Mo 48 
Mo 54 
Mo 60 
Extended 
every 6 
months 
 
 
 
(+/-) 30 days 
(+/-) 60 days 
(+/-) 60 days 
Medical history 
Office visit 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Medical history 
Office visit OR phone follow-
up 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Review Past/Current 
Medications 
X 
X(5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Blood Tests 
(INR, creatinine, hemoglobin, 
hematocrit) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 Lead Electrocardiogram 
(ECG) 
X 
X(5) 
 
 
 
 
 
 
 
 
 
 
 
 
Transthoracic 2-D 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trans-esophageal 
Echocardiogram (1) (2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Assessments 
Baseline 
Post 
Therapy 
Mo 3 
Mo 6 
Mo 12 
Mo 18 
Mo 24 
Mo 30 
Mo 36 
Mo 42 
Mo 48 
Mo 54 
Mo 60 
Extended 
every 6 
months 
 
 
 
(+/-) 30 days 
(+/-) 60 days 
(+/-) 60 days 
CT/MR Evaluation (1) (3) 
X 
 
X(4) 
 
 
 
 
 
 
 
 
 
 
 
CABANA Box/Ambulatory 
Monitor 
Symptom Event Recording 
 
Throughout the 60 month follow-up periods when Atrial 
Fibrillation symptoms are present 
 
CABANA Box/Ambulatory 
Monitor 
24-Hour Holter / AC;FD  
(monthly during Year 1) 
X 
Monthly / 
1,2,3,4,5,7,8,9,10,11 
 
Every 6 months /  
15,21,27,33,39,45,51,57 
 
CABANA Box/Ambulatory 
Monitor 
96-Hour Holter 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Economic and QOL Survey 
SF36, DASI,  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Economic and QOL Survey 
Toronto AF Severity Scale 
AFEQT, WPAI, 
 Stanford Presenteeism 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
AF Severity/Symptom Check 
List 
MAFSI, EQ5D 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Review Adverse Events 
X 
X(5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(1) Ablation therapy subjects; 
(2) Or as warranted throughout trial; 
(3) 150 subjects randomized to Drug Therapy; 
(4) 3 months following therapy initiation = end of blanking period. Or as indicated for PV stenosis 
(5) Hospital discharge or following Drug Therapy initiation 
 
All procedures and laboratory tests during follow-up should be performed whether or not a 
subject receives treatment according to the protocol. 
 
5.0 Treatment Arms 
 
5.1 
Description of Treatment Arms 
5.1.1 Treatment Strategies 
Rather than comparing a specific drug therapy against any specific ablative intervention, 
CABANA compares two treatment strategies.  The first is that of medical therapy with the 
intention of controlling AF rhythm or rate.  The second strategy is that of ablative intervention 
designed to eliminate AF. The following guidelines will shape therapy selection and 
implementation. 
 
5.2 
Pharmacologic Approach to AF (Drug Therapy) 
It is recommended that drug treatment patients first receive rate control medication and the 
effect on ventricular response during the blanking period documented. Medication use must 
conform to the Guidelines for Management of Subjects with AF published in 2006 by the 
ACC/AHA/ESC [92]. Approved drugs and minimum dosing guidelines are as specified below.  
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
5.2.1 Drugs Approved for Rate Control 
 
Drug 
Administration 
Minimum recommended daily dosage 
   Digoxin (Lanoxin) 
Oral 
0.125-0.25 mg 
Beta Blockers  
 
 
   Metoprolol (Toprol) 
Oral 
50-100 mg 
   Atenolol (Tenormin) 
Oral 
50-100 mg 
   Propranolol (Inderal) 
Oral 
40-80 mg 
   Acebutolol (Sectral) 
Oral 
200-300 mg 
   Carvedilol (Coreg) 
Oral 
6.25-25 mg 
   Nebivolol (Bystolic) 
Oral 
5-40 mg 
   Bisoprolol (Monocor) 
Oral 
2.5-20 mg 
Ca Channel Blockers 
 
 
   Diltiazem (Cardizem) 
Oral 
180-240 mg 
   Verapamil (Calan) 
Oral 
180-240 mg 
 
Patients without other heart disease receive beta or calcium channel blockers as first line rate 
control therapy [95]. Patients with coronary artery disease or heart failure will receive beta-
blockers. Patients with ventricular hypertrophy not warranting exclusion would receive either 
beta- or calcium channel blockers, while patients with heart failure will receive carvedilol, 
bisoprolol, or metoprolol. Rate control medications may be used in combination and doses 
adjusted to achieve resting heart rates <80 bpm and exercise heart rates on 6 minute walk or 
Holter monitoring <110 bpm [28, 92]. These criteria will also be insured by clinical activity 
assessment in patients capable of exercise, as monitored by the patient’s clinical cardiologist.  
 
5.2.2 Drugs Approved for Maintenance of Sinus Rhythm 
 
Drug 
Administration 
Minimum recommended      
daily dosage 
Type/Level 
Propafenone (Rhythmol) 
Oral 
450-625 mg 
1C/B 
Flecainide (Tambocor) 
Oral 
200-300 mg 
1C/B 
Sotalol (Betapace) 
Oral 
240-320 mg 
Class III/ A 
Dofetilide (Tikosyn) 
Oral 
500-1000 mcg 
Class III/A 
Amiodarone (Cordarone) 
Oral 
200-400 mg 
Class III/B 
Quinidine (Quinaglute/ dex) 
Oral 
600-900 mcg 
Class I, III/B 
Dronedarone (Multaq) 
Oral 
800 mg 
Class III 
 
At the documentation of failure of rate control using AFFIRM [28] and AF CHF [43] criteria, or if 
the patient has previously failed rate control by these criteria or remains symptomatic despite 
AV nodal blockers, rhythm control may be started using a membrane active drug in an approach 
consistent with the recommended Guidelines for Management of Subjects with AF [92].  Each 
patient will be placed on an anti-arrhythmic drug for an appropriate period and cardioverted to 
sinus rhythm if necessary.  During the 3 month therapy initiation period, dosage adjustments 
can be made or the drug replaced with a different rhythm control drug. In general, patients with 
no other heart disease may be treated with propafenone, flecainide, sotalol or dofetilide. 
Patients with underlying ischemic heart disease or isolated diastolic dysfunction may/can be 
treated with sotalol, dofetilide, or amiodarone.  Patients with underlying heart failure can be 
treated with dofetilide or amiodarone. Multaq (dronedarone) should not be used in patients with 
NYHA IV heart failure, or NYHA Class II-III heart failure with a recent decompensation requiring 
hospitalization or referral to a specialized heart failure clinic. Background therapy with upstream 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
ACE-I / ARBs, statins, fish oil, and aldosterone antagonists will also be encouraged and tracked 
at each follow-up.  
 
5.2.3 Drugs for Future Consideration 
It is anticipated that other rate control agents and membrane-active anti-arrhythmic drugs may 
become available over the course of the trial. Since a chief aim of the trial is to provide relevant, 
up-to-date information for guiding drug and ablative therapy for AF, these new treatment 
strategies will be incorporated in CABANA once approved by the CABANA Innovative Drug 
Therapy and Executive Committees. Drugs which have been approved by appropriate 
regulatory agencies outside of the United States may be used within that jurisdiction. 
 
5.2.4 AV Nodal Ablation 
Ablation of the AV conduction system may be considered as an alternate measure in patients 
with inadequate rate control refractory to at least 3 rate control agents or 2 membrane-active 
anti-arrhythmic drugs. 
  
5.2.5 Changing Drug Therapy 
During follow-up, patients may have recurrent AF, which constitutes an endpoint for the AF 
Recurrence secondary endpoint. Nevertheless, these patients will continue to be followed 
throughout the study to establish the occurrence of the primary and the secondary composite 
endpoints. These patients may require other drug therapy, which can be instituted during follow-
up, without patient withdrawal from the trial.  
 
5.2.6 Cross-Over to Ablative Therapy 
During follow-up, drug arm patients with recurrences may be treated with additional anti-
arrhythmic drugs or alternative rate control agents. Of note, most patients included to date in 
single center trials were treated for over one year before undergoing ablation. Thus, it is 
anticipated that most patients will be treated for at least 12 months in the drug therapy arm and 
that patients will be fully informed of this at the time of the consent process. Cross over ablative 
intervention is strongly discouraged. Crossovers must be approved by the CABANA Trial 
Administrative Center. Before approval is granted for a patient randomized to drug 
therapy to be crossed over to ablation, sites will be required to provide rationale and 
documentation that drug therapy options have been exhausted. 
 
5.2.7 Compliance with Treatment Protocols /Site Performance 
The success of the trial will be enhanced by careful consideration of 1) participating Site 
Qualification, 2) Procedure Standardization, 3) Site performance, and 4) Follow-up tracking. 
High standards in each of these areas will provide the greatest assurance that optimal, protocol-
dictated therapy is being delivered and that patients have the best opportunity of responding to 
it. Each site will be required to provide documentation of expertise in the medical management 
of AF, including at least 2 of the following: 1) successful participation in AFFIRM, RACE, STAF, 
PIAF or other multi-center clinical trials; 2) medical management of at least 30 patients with AF; 
3) site expertise in clinical practice, research, or quality assurance registries or databases; 4) an 
active AF clinic; or 5) treatment of >20 patients with sotalol, dofetilide or amiodarone. Patient 
compliance with medical therapy in rate control patients will be judged from achievement and 
maintenance of rate control targets noted in Section 5.2. Rates of sinus rhythm among rhythm 
control patients in the medical arm will be monitored and benchmarked against recent clinical 
trials including AFFIRM, AF CHF and ATHENA.  Frequent phone contacts and newsletters will 
encourage compliance during the therapy initiation phase.  These communications will then be 
continued regularly during the follow-up phase. Since we desire participation by a true cross 
section of individuals with AF, enrollment will not be based on availability of health insurance. 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
The IDE: G050233 approval establishes the approach of this trial as a CMS B2 therapy. As has 
been seen in the Pilot Study, the therapies in this trial can be billed to Medicare/3rd party payers.   
 
5.3 
Primary Catheter Ablation for AF (Ablation Therapy) 
5.3.1 Pre-ablation Assessment 
Pre-ablation assessment using standard practice patterns as outlined in the AF Ablation 
Consensus and Venice Chart Documents [50,51], will provide baseline data for safety and 
efficacy outcomes analyses. All patients who are randomized to ablative intervention will also 
undergo baseline CT or MR scanning. These studies will form the basis for comparisons of 
change in LA function with ablative or drug therapy.  
  
5.3.2 Ablation Therapies 
A potential limitation of any trial examining ablative intervention for AF is the number of different 
methodologies used for the primary curative ablation. The NHLBI Work Group on AF Ablation, 
the AF Ablation Consensus [50] and the Venice Chart [50] documents all agreed that pulmonary 
vein (PV) isolation is the starting point for AF ablation. PV isolation is therefore the minimum 
required ablation procedure for every patient in the trial. This may be a variation of: 1) Circular 
mapping catheter-guided ablation as described by Haissaguerre et al. [50, 93, 94], 2) Antral 
Isolation using a circular-guided approach as described by Natale et al. [95, 96], or 3) Wide area 
circumferential ablation [48, 97, 98]. As described in the AF Ablation Consensus Documents 
[50, 51], the approach in most expert ablation centers has evolved toward larger circumferential 
ablation outside the PVs. The selection of ablation guidance systems (circular mapping 
catheters, fluoroscopy, mapping systems and intracardiac ultrasound) is left to the discretion of 
the site PI, providing that site has performed at least 100 AF ablation cases with that approach. 
The acute endpoint of ablation is the isolation of all PVs. 
 
Adjunctive procedures such as enlarging the field of ablation for the targeting of complex 
fractionated atrial electrograms [47], sites of apparent ganglia [99], or the use of additional linear 
lesions is allowed, but only after wider area or antral PV isolation. The methods for each of 
these are as outlined in the AF Ablation Consensus Document [50]. Each ablative approach and 
adjunctive measures will be carefully tracked to establish overall contribution to outcomes. 
Additional factors such as 1) termination of AF with ablation, 2) non-inducibility with atrial 
stimulation, and 3) absence of immediately recurrent AF with 10-20 mcg/min of isoproterenol, 
although controversial, will be tracked. Of note: ablation of the AV conduction system is not 
considered an alternative for primary ablative intervention. 
 
5.3.3 Approved Ablation Devices 
The specific choice of ablation catheters is left to the investigator, but must be one or more of 
the catheters listed below (see also Appendix B). Catheters which have been approved by 
appropriate regulatory agencies outside of the United States may be used within that 
jurisdiction. 
 
Manufacturer 
Catheter 
Reference# 
St. Jude Medical 
Livewire TC™ XLS™ 
P960016 
St. Jude Medical 
Therapy™ Dual / Thermocouple 
P040014 
St. Jude Medical 
Therapy Cool Path 
P060019 
Biosense Webster 
NAVI-STAR / NAVI-STAR DS 
P990025 / P010068 
Biosense Webster 
Celsius Braided Tip / Long Reach 
P950005 
Biosense Webster 
NAVI-STAR Thermo-Cool 
P030031 
CryoCath 
Freezor® / FreezorMax 
P020045 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
 
5.3.4 Approaches for Future Consideration 
Undoubtedly, primary ablative intervention for AF will evolve over the course of this trial.  In 
order to maximize the potential for the generalizability of CABANA findings to the broader area 
of AF ablation, newly evolving methods or devices will be permitted, as approved by the 
Innovative Ablation Therapies / Executive Committees. 
 
5.3.5 Cross-over to Drug Therapy 
Patients with recurrent AF during the blanking period can be maintained on anti-arrhythmic drug 
therapy, although this should be discontinued by the end of the 90-day monitoring period.  
Subsequent AF recurrence will be considered an endpoint for the AF freedom endpoint.  Those 
who are highly symptomatic may subsequently receive anti-arrhythmic drug therapy, but will be 
followed on an intention-to-treat basis as part of the ablation treatment group for primary and 
secondary endpoint assessments.  
 
5.3.6 Compliance with Treatment Protocols /Site Performance 
CABANA ablation sites must be pre-qualified for participation by 1) demonstration that each site 
has performed >100 primary AF ablations and 2) satisfactory completion of review of 
performance-confirming site data by the CABANA Ablation Therapies Committee including: 1) 5 
prior ablation reports; 2) demonstration of an adequate prior ablation database to establish the 
CABANA patient’s position in the site’s overall series; 3) evidence of acceptable standard 
follow-up practices and data collection methods; 4) 5 pre and post lasso electrograms 
establishing acute PV isolation success; and 5) 5 prior Carto/NavX maps showing mapping 
proficiency. Taken together, these will provide validation of AF ablation expertise.  
 
Site ablation performance will be tracked throughout the trial. Ablation data including ongoing 
acute success rates in achieving PV isolation, ablation time, fluoroscopy time, and ablation 
methods captured by ablation eCRFs will be tabulated by the Data Coordinating center. Outliers 
will be identified for special review. Exact ablation methods, complications, and compliance with 
the protocol will be reviewed by the DCRI monitors and a member of the Ablation Therapy 
Committee. Timeliness and accuracy of eCRF data entry will also be monitored. 
 
5.4 
Guidelines for Anti-thrombotic Therapy 
5.4.1 Guidelines for Anticoagulation in Drug Treated Patients  
Patients with risk factors for CVA or peripheral thromboembolic events at the time of enrollment, 
treated with rate control agents alone, will remain on active anticoagulation therapy (warfarin, 
dabigatran, rivaroxiban or apixaban) throughout the duration of the trial [92]. Unlike the AFFIRM 
trial, patients receiving rhythm control therapy will also be required to receive adequate 
anticoagulation (warfarin, dabigatran, rivaroxiban or apixaban) for the duration of the trial.  In the 
use of warfarin therapy, target INRs of 2 to 3 will be required, unless higher INRs are mandated 
because of underlying disease.   
 
5.4.2 Guidelines for Anticoagulation Therapy in Ablation Patients 
Anticoagulation before, during, and after the ablative intervention will follow the guidelines of the 
AF Ablation Consensus Document [50].  Prior to the ablative intervention, patients with 
persistent and long-standing persistent AF should receive adequate anticoagulation (i.e. at least 
Manufacturer 
Catheter 
Reference# 
Bard 
Stinger 
P000020 
Boston Scientific 
Blazer II RF / RPM / SteeroCath /XP 
P920047 / P020025 
Boston Scientific 
Chilli Cooled 
P980003 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
one month of warfarin anticoagulation (INRs: 2-3)), or have a TEE excluding intra-atrial 
thrombus at the time of the intervention. During the ablative intervention, maintaining an ACT 
between 300 and 400 seconds is strongly recommended. Following the ablative intervention, 
patients will be started on IV heparin or subcutaneous injections of low molecular weight heparin 
beginning 4 to 6 hours after all sheaths are removed, and appropriate anticoagulation 
reinstituted the evening of the intervention.  Thereafter, low molecular weight heparin is to be 
maintained until anticoagulated appropriately or standard dose warfarin achieves a target INR of 
2 to 3, unless the ablation was performed at a therapeutic INR in patients maintained on 
warfarin through the ablation. One month following the ablation, dabigatran, rivaroxiban or 
apixaban may be substituted for warfarin, following recently written guidelines. Three to six 
months after ablation, warfarin may be replaced by full dose aspirin in patients with a CHADs 
score <1.  This would include patients with hypertension without hypertrophy, or those <65 
years of age, providing 1) atrial size and function are normal and 2) there is no symptomatic or 
asymptomatic AF by standard or full-disclosure monitoring.  In those patients with a CHADs 
score >2, adequate anticoagulation is to be continued throughout the trial.  Randomization of 
warfarin discontinuation is precluded by the low post-ablation stroke rates that would require at 
least 10,000 patients for detecting differences in stroke prevalence.  Nevertheless, the 
characteristics, follow-up monitoring results, and long-term anticoagulation status of ablation 
patients will be compared to descriptively identify predictors of events and profiles of patients at 
high risk for warfarin discontinuation. The utility of trans-telephonic, auto-detection / full 
disclosure, and Holter monitoring, as a future aid in the decision to discontinue anticoagulation 
will also be critically examined. 
 
5.4.3 Newer Antithrombotic Therapies 
It is likely during the course of the trial that newer antithrombotic therapies non-inferior to 
warfarin or dabigatran will be approved. These agents may be used as replacement therapy for 
warfarin on approval of local regulatory agencies and the Innovative Antithrombotic 
Therapies/Executive Committees. 
 
5.4.4 Items Left to the Discretion of the Physician  
Specific items left to the investigators discretion include:  1) specific choice of rate control vs. 
rhythm control drug therapy and specific drugs to be used; 2) hospitalization to initiate anti-
arrhythmic drug therapy; 3) choice of TEE guided direct current cardioversion (DCCV) vs. 
DCCV after 4 weeks of appropriate anticoagulation therapy, such as warfarin to an INR of 2-3; 
4) pre-ablation TEE assessment in patients with simple paroxysmal AF and hypertension 
without hypertrophy; 5) continuation of warfarin to maintain a therapeutic INR at the time of 
catheter ablation; 6) selection of warfarin versus dabigatran, rivaroxiban or apixaban. 
 
5.5 Management of Arrhythmia Recurrences During Follow-Up 
During the 3 months of “therapy initiation”, patients randomized to drug therapy may receive 
alternative drugs. Patients in the ablation arm may undergo repeat ablation in those cases 
where the recurrent arrhythmia is not felt to be due to the irritation and inflammation of the 
ablative intervention. These patients may also be treated with rhythm control drug therapy, 
providing it is discontinued by the end of the blanking or “therapy initiation phase”. Any event 
occurring during this period will be tracked as an “Early Event”.  Long-term follow-up with 
respect to efficacy will begin 3 months after the initiation of drug therapy or ablation therapy. 
These events will be used for the determination of overall freedom from recurrent AF, but will 
not be of sufficient importance to remove the patient from the trial. Patients achieving a 
secondary endpoint through non-fatal events will be followed throughout the remaining follow-up 
period. 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
6.0 Definitions & Adjudication for Study Endpoints 
 
6.1 
Primary Endpoints 
The primary endpoint is the composite of total mortality, disabling stroke, serious bleeding or 
cardiac arrest.  All components will be adjudicated by an independent Clinical Events 
Committee (CEC) and the most proximate cause of the event established.  A Disabling Stroke 
will be considered present using a modification of a Rankin Stroke score [100], and will be 
adjudicated by a Neurologic Events Committee. Serious (or Life-threatening) bleeding will be 
considered present using a modification of the GUSTO bleeding Scale adapted for use in 
catheter ablation [101]. These events will be tracked regardless of treatment randomization. The 
definition for each of these events is listed in the CEC Charter. When there is disagreement 
between the CEC and the principal investigator, the CEC’s decision will be considered final. 
Procedures for adjudicating events are described in the CEC Charter, which is available upon 
request. The CEC will also confirm whether a death is cardiac/vascular/non-cardiovascular in 
origin; as well as witnessed/un-witnessed; or sudden/non-sudden. Cardiac mortality will be 
further categorized as tachyarrhythmic, bradyarrhythmic, heart failure, or due to other cardiac 
causes using the events adjudication form. Hospitalization will also be tracked with specific 
reason for admission (heart failure, acute ischemic event, etc.) determined by the site principal 
investigator as reported in the eCRF. 
 
6.2 
Secondary Endpoints & Safety Endpoints 
Secondary endpoint events, including  total mortality and a composite of total mortality or 
cardiovascular hospitalization will be confirmed. 
While hospitalization for any atrial fibrillation, atrial flutter or atrial tachycardia in both treatment 
arms will be carefully tracked and compared, it will be considered as an “AF recurrence” and 
counted against efficacy, not safety.  Therefore, AF recurrence and/or worsening of AF need 
not be reported as an adverse event. 
 
7.0 Adverse Events  
 
Adverse events, defined as any undesirable medical occurrence in a clinical study patient which 
occurs during the course of the study and can be attributed to a device, procedure, or 
medications required by a procedure, protocol, or trial will be tracked throughout the study.  
 
An adverse event (AE) will be considered present if 1) there are untoward signs, symptoms, 
illnesses, or other medical events that develop or worsen in severity during the course of the 
study, 2) they are clinically relevant and if they are clinically related to the study. Note: Disease, 
signs symptoms, and or laboratory abnormalities already existing at randomization are not 
considered adverse events unless they represent an intensity or frequency exacerbation. An 
adverse event designation should reflect the reason for a diagnosis or abnormal measurement.  
Procedures planned prior to randomization and the conditions leading to these measures are 
not adverse events. 
 
An event inherent to an intervention/medication that is expected to occur for a projected 
duration in some or all subjects is considered unavoidable.  Unavoidable adverse events will not 
be tracked during the trial (examples: pain at catheter insertion sites during and after a 
procedure; pain at injection sites; palpitations; nausea due to anesthesia, etc.).  
 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
The DCRI will evaluate any safety information that is spontaneously reported in the time frame 
specified in the protocol.  For each subject, adverse events occurring after randomization must 
be recorded on the applicable Adverse Events page(s) in the electronic Case Report Form 
(eCRF).  Recording should be done in a concise manner using standard, acceptable medical 
terms.  The adverse event recorded should not be a procedure or a clinical measurement (i.e., a 
laboratory value or vital sign) but should reflect the reason for the procedure or the diagnosis 
based on the abnormal measurement.  It is the responsibility of the Principal Investigator to 
oversee the safety of the patients enrolled in the study at his/her site. This responsibility 
includes careful assessment and appropriate reporting of adverse events. The primary 
mechanism for reporting adverse events in CABANA is for study personnel at the clinical sites 
to enter the relevant information and the details and description of each event using the adverse 
event forms that are part of the InForm electronic data capture (EDC) system being used in the 
trial.  
 
Again, AF recurrence and/or worsening of AF need not be reported as an adverse event. 
 
7.1 
Adverse Event Classification 
The investigator will evaluate all AEs with respect to seriousness, severity (intensity), and 
causality (relationship to study therapy or device) according to the following definitions and 
guidelines: 
 
7.1.1 Anticipated Adverse Events  
An anticipated event is one that has been identified in previous studies, published literature, or 
product labeling to be related to the disease state or therapies. A listing of commonly occurring 
‘anticipated/expected’ events in the population being studied can be found in Appendix A.  An 
unanticipated/unexpected adverse event is any adverse event that has not been reported in 
previous studies, published literature, product labeling, or which is not anticipated in the 
population being studied (see appendix A). 
 
7.1.2 Serious Adverse Event 
An adverse event that warrants additional action, includes any untoward event that: 
1. Is fatal 
2. Is life-threatening 
3. Requires inpatient hospitalization or prolongation of existing hospitalization >48 hours. 
Exceptions- therefore not reportable: 
a. Preplanned (prior to the study) hospital admissions unless the hospitalization is 
prolonged >48 hours beyond the anticipated length of stay. 
b. Planned admissions (as part of a study – e.g. admission for drug change or 
titration for treatment of atrial fibrillation) 
c. 23 hour hospitalizations OR observation. 
d. Hospitalization for elective procedure (e.g. cardioversion). 
e. Emergency room visits that do not result in hospitalization. 
f. Hospitalization to titrate or optimize medical therapy to treat recurrence of atrial 
fibrillation. 
4. Results in persistent or significant disability or incapacity. 
5. Results in a congenital anomaly or birth defect. 
6. Important medical events that may not result in death, be life-threatening, or require 
inpatient hospitalization may be considered an SAE when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
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7.1.3 Adverse Event Intensity or Severity Classification 
The intensity or severity of each AE will be classified according to the following guidelines: 
1. Mild: Any event that results in minimal transient impairment of a body function and does 
not threaten damage to a body structure, and/or does not require intervention other than 
monitoring (easily tolerated). 
2. Moderate: Any event which results in moderate transient impairment of a body function 
or damage to a body structure, or which requires intervention. 
3. Severe: Any event which is life threatening, results or could result in significant 
permanent impairment of a body function or damage to a body structure, requires 
significant and timely intervention to prevent permanent impairment of a body function or 
damage to a body structure, or which is intolerable or places the subject at immediate 
risk of harm. 
 
7.1.4 Causal Relationship to Medical or Ablative Therapy 
The International Council of Harmonization (ICH) Guidelines (1995) indicate that 
“reasonable causal relationship” means that “there are facts [evidence] or arguments to 
suggest a causal relationship.” The causality assessment must be made by the 
investigator based on information available at the time that the adverse event eCRF is 
completed. The initial causality assessment may be revised as new information 
becomes available. 
 
1. Definitely related: there is a reasonable temporal relationship to study therapy or device 
a. follows a known response pattern (e.g., study drug, treatment or device is known 
to cause this AE) 
b. there is no alternative etiology or explanation for the event 
2. Probably related: there is a reasonable temporal relationship which 
a. follows a suspected response pattern  
b. no evidence for a more likely alternative etiology though could be unrelated 
3. Possibly related: there is a reasonable temporal relationship but 
a. equivocal evidence that the event is study related as opposed to an alternative 
etiology  
4. Probably not related: there is not a reasonable temporal relationship OR 
a. good evidence for a more likely alternative etiology  
5. Not related: there is not a temporal relationship OR 
a. clear and compelling evidence that the event is due to an alternative etiology  
 
7.1.5 Device Related Adverse Events 
1. Device-related: any adverse event for which a causal relationship between the device 
and the event is a reasonable possibility. The likelihood that the event is device related 
will also be sub-classified using the approach in 7.1.4 above. The event will be further 
classified as whether it is a device failure or malfunction (7.1.5.2) and whether it is 
unanticipated (7.1.5.3), as described in these sections.  
2. Device Failure or Malfunction: a device has failed if it is used in accordance with the 
Instructions for Use, but does not perform or function according to Instructions for Use 
and negatively impacts the treatment by preventing treatment as intended. Such a failure 
does not necessarily result in significant adverse outcome. 
3. Unanticipated Adverse Device Effect (UADE): any serious adverse effect on health or 
safety or any life-threatening problem or death 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 application (including a supplementary plan or 
application) or prior medical literature, or any other unanticipated serious problem 
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associated with a device that relates to the rights, safety, or welfare of subjects. This 
event needs to be entered into the eCRF SAE pages within 24 hours of the site’s 
knowledge. 
 
7.2 
Adverse Event Reporting  
The goal is to have an adverse event reporting process that is (a) clear and simple for site 
investigators and study coordinators to understand and implement, (b) satisfies all regulatory 
reporting requirements, (c) eliminates any duplication in data collection and reporting, and (d) 
has a balanced focus on both the drug and ablation arms of the trial.  
 
All related adverse events, serious and non-serious, that occur between the time of 
randomization and the last study-related procedure/visit will be followed until resolution, 
stabilization, or to trial completion.  Adverse events for subjects who discontinue study 
participation at any time during the study should be collected/reported through at least the time 
of discontinuation. In addition, the required Institutional reporting structure will be followed 
and/or as described in this protocol.  
   
7.3 
Serious Adverse Event Reporting 
Regardless of causality, the investigator will record all serious adverse events occurring 
between randomization and the last study-related procedure/visit or completion of the trial into 
the electronic database within 24 hours of knowledge of the event. DCRI will report all 
unanticipated/unexpected study related serious adverse events to Mayo Clinic, NHLBI and the 
DSMB chair within 2 business days of receipt. 
 
The investigator must update the eCRF SAE when important follow-up information (final 
diagnosis, outcome, results of specific investigations, etc.) becomes available after submission 
of the initial entry.  Follow-up information should be entered within forty eight (48) hours of 
knowledge.  All reportable events will be followed until resolution, stabilization, or to trial 
completion, whichever occurs first.  In addition, the required Institutional reporting structure will 
be followed and/or as described in this protocol. 
 
7.4 
Expedited Event Reporting  
Specified events as listed below that meet serious criteria (see section 7.1.2 of the protocol), 
are related (possibly/probably/definitely) to either study drug or the ablation device or 
procedure, and are unanticipated/unexpected if occurring between randomization through 
completion of follow-up (end of trial) require expedited reporting to the DCRI and in turn to the 
appropriate regulatory agencies. 
 
7.4.1 Expedited events include:  
 
 
1. Unexpected, SAE related to study drug  
2. Unanticipated ablation procedure related events  
3. Unanticipated  Adverse Device Effect (UADEs)   
4. Device failures or malfunctions 
5. Events of Interest (EOI): Drug or ablation therapy or ablation procedure related events 
(index and/or follow-up): The related events that resulted in death, and the following events if 
they are life-threatening or severe in nature; pro-arrhythmic events, myocardial perforation / 
tamponade requiring intervention, esophageal atrial fistula, and/or severe pulmonary vein 
stenosis that were life threatening or classified as severe in nature.  
 
 
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7.5 
Adverse Event Documentation 
All AEs and SAEs must be documented on the appropriate eCRF. The outcome of each AE and 
SAEs will be tracked through the major endpoints of the trial, if present. Otherwise these events 
will be tabulated and addressed descriptively, as gleaned from the eCRF. 
 
Expedited Events must be entered on the appropriate eCRF pages or if the electronic database 
is unavailable for more than 24 hours, the event would be reported on an Expedited Event Form 
and faxed/emailed to DCRI Safety Surveillance within 24 hours of knowledge of the event. 
When available, the event must be entered into the electronic data base. 
 
DCRI Safety Surveillance 
Telephone: 1-919-668-8624 
Toll Free: 1-866-668-7799 
Email: Safetysurveillance@mc.duke.edu 
Fax: 1-919-668-7138 
Toll Free Fax: 1-866-668-7138 
 
It is understood that complete information about the event may not be known at the time the 
initial report is submitted. The investigator must assess the relationship of the event to the study 
device or study therapy and should make every attempt to obtain as much information as 
possible concerning the event. Additional information pertaining to an expedited event should be 
submitted to DCRI Safety Surveillance as it becomes available. All reported events will be 
followed until resolution, stabilization, or until the trial completion whichever occurs first. 
  
7.6 
Reporting to Regulatory Authorities 
7.6.1 Physician Reporting of Drug or Device Adverse Events 
Physician reporting of drug or device-related unexpected/unanticipated serious adverse events 
(as mandated by regulatory authorities) using MedWatch or Council for International 
Organizations of Medical Sciences (CIOMS) forms, should continue independently of any 
CABANA reporting.  
 
It is anticipated that pphysicians and/or the appropriate healthcare professional will complete 
this reporting by, 1) MedWatch- submit form 3500 for drug or device via the FDA's MedWatch 
Adverse Event Reporting program online at www.fda.gov/MedWatch/report.htm, by phone 1-00-
FDA-1088, or by returning the postage-paid FDA form 3500 downloaded from 
ww.fda.gov/MedWatch/getforms.htm by mail to MedWatch, 5600 Fishers Lane, Rockville, MD 
20852-9787 or fax 1-800-FDA-0178, 2) CIOMS- using http://www.cioms.ch/index.htm, postal 
address: c/- World Health Organization, Avenue Appia, 20 CH - 1211 Geneve, 27 Switzerland, 
telephone: +41 (0) 22 791 34 13 or fax: +41 (0) 22 791 42 86.  
 
7.6.2 CABANA Reporting of Drug or Device Adverse Events  
For CABANA trial purposes, adverse events will be reported through the eCRF submission 
process designed to facilitate notification to DCRI Safety Surveillance and/or their designee.  
DCRI Safety Surveillance will review and code all SAEs. 
 
The Safety Surveillance Medical Monitor (a physician trained and experienced in safety 
reporting) will review Events of Interest, and unexpected/unanticipated SAEs related to ablation 
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therapy or CABANA approved rate or rhythm control drugs. The decision regarding ultimate 
classification will be made by individuals within CABANA Leadership with expertise in 
antiarrhythmia and ablation therapies and clinical trial experience.  
 
DCRI Safety Surveillance will notify the NHLBI and Mayo within 1-2 business days of an 
unexpectedness/unanticipated event determined to be related to the drug, device, and/or 
therapy.  The final report will be submitted to the Regulatory Authorities and all participating 
investigators 
per 
regulations. 
Investigators 
are 
responsible 
for 
reporting 
trial 
unexpectedness/unanticipated events to their reviewing IRB within 10 working days of first 
learning of the event.  
 
DCRI Safety Surveillance will notify the NHLBI within 5 business days of all reported Events of 
Interest (as identified above).  
 
7.6.3 Criteria for Withdrawal of Subjects from Study 
No subjects will be removed from the study, and attempts will be made to collect follow-up 
information for all subjects except those who specifically withdraw consent for release of such 
information. 
 
8.0 Statistical Considerations 
     
8.1 
Sample Size and Power Considerations 
In initially planning the CABANA trial, several design factors and research objectives were 
considered in developing an appropriate sample size for the study.  First, the number of patients 
was determined so there would be a sufficient number of endpoints to provide a high degree of 
confidence (power > 90%) for testing the primary hypothesis.  Second, important secondary 
endpoints were considered. Third, it was considered important for the overall sample to be large 
enough to permit a prudent examination of treatment effects in selected subgroups of patients 
where AF ablation might be particularly advantageous, or where the question of a treatment 
benefit from this invasive procedure is particularly relevant.  Important pre-specified subgroups 
of interest in this study include those defined by age, gender, race, AF type (paroxysmal, 
persistent, or long-standing persistent), AF duration, heart failure class, presence/absence of 
underlying structural heart disease, presence/absence of hypertension, and ejection fraction.  
Finally, the sample size was determined to provide a reasonable level of confidence of detecting 
clinically important therapeutic effects even if current projections of event rates and treatment 
differences prove to be optimistic. 
 
As described in Section 2.0, the study was originally designed with total mortality as the primary 
endpoint. However, in early 2013 a careful assessment of the progress of the trial was 
undertaken by the study leadership. Completely blinded to any treatment-specific outcome data, 
the two major issues addressed by the leadership group were (1) a lower than expected 
aggregated mortality rate, and (2) accrual of patients at a rate much slower than projected.  
Careful consideration of these issues led to a decision to (a) change the primary endpoint of the 
trial from total mortality to the key secondary endpoint consisting of the composite of death, 
disabling stroke, serious bleeding, or cardiac arrest, and (b) reduce the sample size to a number 
that was consistent with the new primary endpoint. The following paragraphs, which outlined the 
key considerations in determining the original sample size, are also relevant for the revised 
sample size. 
 
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A combination of data from recent AF trials that reflect patient outcomes when treated with drug 
therapy (rate control or rhythm control) provide useful information on the range of outcomes that 
would be expected among the patients enrolled in the drug arm of CABANA. These studies 
include AFFIRM, RACE, STAF, PIAF and AF CHF. Since the study population in CABANA will 
be most like patients enrolled in the AFFIRM trial, the most reliable estimates of mortality and 
other endpoint events applicable to the drug arm of CABANA can be obtained from the AFFIRM 
data.  The five-year mortality in AFFIRM was 23.8% in patients assigned to receive rhythm 
control drugs and 21.3% in patients assigned to rate control drugs.  The crude death rate based 
on a mean follow-up of 3.5 years was 16.4%.  However, the Kaplan-Meier curves in the primary 
AFFIRM publication reflect mortality rates at 3 years of 13% in the rhythm control arm and 11% 
in the rate control arm.  At 3.5 years, mortality was approximately 16% in the rhythm control arm 
and 14% in the rate control arm.  Based on this information, the mortality rate in the drug-treated 
arm of CABANA was projected to be approximately 12% after 3 years of follow-up and 15% 
after 3.5 years of follow-up (3.5 years is the average duration of follow-up originally projected for 
CABANA).  With the original secondary endpoint elevated to become the primary endpoint, the 
incidence of the new primary endpoint is expected to be higher than the mortality rates. 
 
In addition to the control (drug) arm event rate, a key driver of the sample size is the magnitude 
of the treatment effect (i.e., the reduction in the primary endpoint expected in the ablation arm).    
A synthesis of information from multiple published sources [48, 58-61, 67] suggests that the 
event rate in ablation-treated patients has been relatively low (less than 3% per year), which 
translates to a projected 3-year event rate of 8-9 % or a 3.5 year rate of 10% or less in the 
ablation arm of the trial (i.e., a reduction by one-third compared to the drug arm). 
 
Another important factor that must be considered in sample size calculations is the extent to 
which patients randomized to the drug arm may cross over to receive an ablation during the 
course of their follow-up (if the AF and its symptoms are not adequately controlled by drugs).  
Although there are strict guidelines regarding changes to a patient’s assigned therapy, in certain 
instances a downstream change may be clinically indicated.  All crossovers and reasons for 
them must be carefully documented.  However, crossovers of drug-arm patients to receive 
ablation will have the impact of reducing the event rate of patients randomized to drug therapy 
(assuming ablation is effective), and diminishing the magnitude of the treatment effect.  
Allowance for these crossovers is essential in determining the appropriate sample size.  It is 
possible that up to 25-30% of patients randomized to the drug arm will cross over to ablation at 
some point during follow-up.  Although the length of follow-up in the CABANA Pilot study was 
only 1 year, the rate of crossover to ablation of patients randomized to drug therapy was only 
9.7%. 
 
In addition to drug-arm patients crossing over to ablation, there may also be patients 
randomized to the ablation arm who require drug therapy.  The number of patients randomized 
to ablation, that following randomization decline the procedure and are treated with drugs, is 
expected to be small and inconsequential in the sample size calculations.  However, there will 
be patients randomized to ablation that during the course of their follow-up after the ablation are 
treated with drugs, including in some cases membrane-active antiarrhythmic drugs. For 
purposes of sample size calculations, these patients are assumed to receive the full benefit of 
ablation in reducing clinical outcomes, although one might argue that antiarrhythmic drugs, with 
their possible proarrhythmic effects, might attenuate the clinical benefits of the ablation.      
 
Since the primary treatment comparisons in this study will be based on time-to-event 
methodology using the log-rank test [102] or equivalently, the Cox proportional hazards model 
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[103], the approach used for calculating sample size requirements for CABANA was based on 
the method of Schoenfeld [104] developed for the proportional hazards model.   
 
To provide an adequate number of patients in the trial that will be relatively robust under various 
assumptions regarding the control-arm event rates and the magnitude of the treatment benefit, 
2,000-2,200 patients will be enrolled.  With a minimum follow-up of 3 years (amounting to an 
average follow-up of approximately 5 years), 2,200 patients will provide 90% power for detecting 
a 30% reduction in the new primary endpoint, and 2,000 patients will provide 88% power, 
assuming a 3-year event rate in the drug arm of 12% and allowing for a 2% loss to follow-up.  
Thus, the study will have high power for detecting an important benefit if the control arm event 
rate is consistent with the rate expected based on previous studies.  A sample size in this range 
will also provide acceptable power (86% with 2200 patients and 82% with 2000 patients) for 
detecting a 25% reduction with ablation in the primary endpoint if the 3-year drug arm event rate 
is 15%.  Thus we will have good power for detecting a more conservative estimate of the benefit 
in the composite endpoint if the control arm event rate is higher, but still consistent with previous 
studies. A 25-30% reduction in primary events will be highly important from a clinical and public 
health standpoint, given the large population of patients in this country and throughout the world 
who suffer from AF. 
 
This number of patients (2,000-2,200) will also provide adequate power for detecting a 25% 
reduction in other important secondary composite endpoints listed in section 2.2 such as the 
endpoints that involve cardiovascular hospitalization where the incidence is expected to be 
higher than for the primary endpoint. 
 
8.2 
Statistical Analysis 
Statistical analyses will be performed by the Coordinating Center. All major treatment 
comparisons will be performed by intention to treat, and endpoints will be attributed to the 
treatment arm to which the patients were randomized, regardless of treatment crossover or 
post-randomization medical care.  Statistical comparisons will be performed using two-sided 
significance tests.   
 
8.2.1 Analysis of the Primary Endpoint 
The log-rank test will be the primary analytic tool for comparing outcome differences between 
the two therapies. Kaplan-Meier estimates of cumulative event rates as a function of follow-up 
time will be calculated and displayed.  Relative risks will be expressed as hazard ratios with 
95% confidence intervals generated using the Cox proportional hazards model.  
 
Supplementary analysis involving covariate adjustment will be performed with the Cox model.  
Such adjustment will be limited to a relatively small, prospectively defined set of patient 
characteristics that are known a priori to have a strong prognostic relationship with the primary 
endpoint.  The covariate-adjusted analysis will serve as a prelude to supplementary analyses 
examining differential treatment effects.  The covariates will include age, sex, race, heart failure 
class, presence/absence of structural heart disease, whether the patients’ AF is paroxysmal, 
persistent or long-standing persistent, duration of AF, presence/absence of hypertension, and 
ejection fraction.  Cox model analyses may also be performed using appropriate groupings of 
sites as a stratification factor.   
 
If the data provide evidence of an overall difference in outcome between treatment groups, an 
assessment will be made of whether the therapeutic effect is similar for all patients, or whether it 
varies according to specific patient characteristics.  This analysis will focus on whether the 
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relative therapeutic benefit differs according to patient age, sex, race, type of AF, duration of AF, 
heart failure class, presence/absence of structural heart disease, presence/absence of 
hypertension, and ejection fraction.  These analyses will utilize the Cox model by testing for 
interactions between treatment and these specific baseline variables. In addition to the formal 
assessment of treatment interactions, treatment effects characterized by a hazard ratio (with 
95% confidence interval) will be calculated and displayed for prospectively-defined subgroups of 
patients defined by the variables listed above.  These descriptive hazard ratios will be carefully 
interpreted in conjunction with the formal interaction tests. 
 
8.2.2 Analysis of Secondary Endpoints 
Secondary endpoints, including total mortality and secondary endpoints 2 through 9 listed in 
Section 2.2, will all involve time-to-event analyses and thus will be analyzed similar to the 
primary endpoint using the log-rank test, Cox model, and Kaplan-Meier event-rate estimates.  
 
8.2.3 Analysis of Morbidity (Adverse Events)  
Statistical comparisons of major adverse events are challenging in this trial because of therapy-
specific differences in the nature of the adverse events.  For drug therapy, the major events 
include unanticipated hospitalizations for heart failure, drug-related proarrhythmic events, and 
pulmonary toxicity from amiodarone.  For the ablation arm, the major events include myocardial 
perforation with tamponade requiring resuscitation, symptomatic pulmonary vein stenosis 
requiring intervention, and atrial-esophageal fistula formation. The frequency with which these 
events (and other serious adverse events) occur will be descriptively tabulated.  Treatment 
comparisons with respect to these serious adverse events will of necessity be more informal 
rather than statistically rigorous (since different adverse events are expected in the two arms), 
bringing to bear clinical judgment as to the relative seriousness of these various adverse events.   
Adverse complications or adverse events of either therapy will be carefully tabulated and 
descriptively summarized, using statistical comparisons of the treatment groups where 
appropriate, and interpreting such comparisons in the context of treatment differences in the 
primary and major secondary clinical endpoints. 
 
8.2.4 Analysis of Core Lab Measures of LA Size, Morphology, and Function  
Patients enrolled at a subset of the clinical sites will undergo baseline and follow-up CT/MR 
imaging studies, and core lab measures of left atrial size, morphology, and function will be 
examined.  Of interest will be the change in atrial size (volume) and function (i.e., atrial ejection 
fraction) from the baseline to the follow-up study within each treatment arm, and then 
importantly, a comparison of whether the change in size and function in the patients randomized 
to ablation therapy differs from the change in size and function of the patients randomized to 
drug therapy.  
 
The distribution of these measures from the baseline and follow-up studies in each treatment 
arm will be descriptively characterized using univariate descriptive statistics and graphical tools 
such as box and whisker plots. The statistical significance of the changes in left atrial size and 
function from baseline to follow-up within each treatment arm will be assessed using a paired-
sample test such as the paired-t test.  A two-sample comparison of the two groups with respect 
to changes in size and function will be performed using general linear models, including the 
baseline value as a covariate, and assessing treatment group differences.  This comparison will 
be performed for the changes in atrial size (left atrial volume) and also for atrial function (atrial 
ejection fraction).  
 
In dealing with this type of data, the completeness of which is dependent on obtaining both the 
baseline and follow-up studies, there will inherently be missing data resulting from patients in 
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whom it is not possible to obtain both studies (because they die or fail to return for other 
reasons to enable the follow-up measurements to be made).  Every effort will be made to 
minimize the amount of missing data.  However, because some data are expected to be 
missing, several missing data strategies will be employed in order to assess the sensitivity of 
the conclusions to the approach used.  The approaches that will be considered include (1) 
analyzing only patients with complete data; (2) assigning “worst case” scores to missing 
observations; (3) carry forward previously observed data to the observation period missed; and 
(4) use of likelihood-based methods to impute missing data.  By synthesizing the results from 
these different but complementary approaches, it will be possible to provide a comprehensive 
assessment with respect to these key mechanistic data.  
 
8.2.5 “On-Treatment” Analysis 
Although the intention to treat analyses will serve as the standard for interpreting treatment 
differences in the key clinical outcomes and constitute the primary analyses in the trial, because 
a number of patients from the drug arm may cross over to receive ablation during the trial, we 
will supplement the intent to treat comparisons with “on-treatment” comparisons. The “on-
treatment” analysis will involve a comparison of patients who received ablation (even if originally 
assigned to the drug arm) versus those who did not.  Statistically, this will be accomplished 
using the Cox proportional hazards model with ablation included in the analysis as a time-
dependent covariate.  Thus, event-free follow-up time for a patient in the drug arm who later 
crosses over to ablation would be credited to the drug arm until the time of crossover, and at 
that point, the patient would be shifted to the ablation group.  Because treatment assignment is 
no longer random, results can be biased by an association between the likelihood of treatment 
change and the risk of a clinical event (i.e., factors that make a patient more likely to cross over 
may also make them more likely to have an event).  Thus such analyses should be cautiously 
interpreted.  The “on-treatment” analyses will also include an assessment of freedom from AF in 
ablation patients after each ablation performed, including those undertaken after the end of the 
blanking period.   
 
An analysis using a time-dependent covariate with the Cox model will also be conducted to 
examine the prognostic relationships of sinus rhythm with clinical outcomes.  The analyses 
described in this section will be covariate adjusted for baseline prognostic factors that are 
related to the clinical outcomes of interest.  These analyses will be strictly exploratory and 
supplementary to the primary intent to treat analyses. 
   
8.2.6 Interim Analyses 
For ethical reasons, an interim examination of key safety and endpoint data will be performed at 
regular intervals during the course of the trial.  The primary objective of these analyses will be to 
evaluate the accumulating data for an unacceptably high frequency of negative clinical 
outcomes in any of the treatment arms.  In addition, the interim monitoring will also involve a 
review of the control arm event rates, patient recruitment, compliance with the study protocol, 
status of data collection, and other factors which reflect the overall progress and integrity of the 
study.  The results of the interim analyses and status reports will be carefully and confidentially 
reviewed by an NHLBI-appointed Data and Safety Monitoring Board (DSMB). 
 
The DSMB will meet at approximately 6-month intervals to review the accumulating data. Prior 
to each meeting, the Statistical and Data Coordinating Center will conduct the desired statistical 
analyses and prepare a summary report that will be carefully reviewed by the DSMB.  The 
extracted data files and analysis programs for each DSMB report will be archived and 
maintained at the Data Coordinating Center for the life of the study.  Reports will be presented 
describing the progress of patient enrollment, the rates of compliance with therapy, and the 
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frequency of protocol violations.  The Data Coordinating Center will also report on the number 
(status) of data forms completion, the number of outstanding queries, the number of queries 
completed, and the number of forms reviewed through on-site monitoring. 
 
These interim safety and efficacy reports introduce well-recognized statistical problems related 
to the multiplicity of statistical tests performed on an accumulating set of data.  To properly 
account for the repeated interim testing in CABANA, a group sequential method similar to that 
proposed by O'Brien and Fleming [105] as a guide in interpreting interim analyses will be used.  
This procedure requires large critical values early in the study, but relaxes (i.e., decreases) the 
critical value as the trial progresses.  Because of the conservatism early in the trial, the critical 
value at the final analysis is near the "nominal" critical value.  Hence the sample size 
requirements with this group sequential procedure remain essentially the same as the 
conventional fixed sample size estimate.  The actual method for this interim monitoring that will 
be employed in CABANA is the “spending function” approach to group sequential testing 
developed by Lan and DeMets [106].  The Lan-DeMets approach only requires specification of 
the rate at which the Type I error (which in this trial will be α=0.05 for the primary endpoint) will 
be "spent".  This procedure allows "spending" a portion of α at each interim analysis in such a 
way that at the end of the study, the total Type I error does not exceed 0.05.  One such 
spending function generates boundaries that are nearly identical to the O'Brien-Fleming 
boundaries.  It is this approach that will be used in CABANA, namely two-sided, symmetric 
O'Brien-Fleming type boundaries generated using the flexible Lan-DeMets approach to group 
sequential testing.  Since the number of looks and the increments between looks need not be 
predetermined, it allows flexibility in the monitoring process for accommodating additional 
comparative examinations of the data in response to concerns of the DSMB that may arise 
during the course of the trial.   
 
The analytic approach that will be used at the interim analyses for assessing treatment 
differences will be the time-to-event analysis methods described previously, except that 
interpretation of statistical significance associated with treatment comparisons will be guided 
using the group sequential monitoring boundaries outlined above.   
 
Judgment concerning the continuation or termination of the study will involve not only the 
degree of statistical significance observed at the interim analysis, but also the likelihood of 
achieving significance should enrollment continue to the originally projected sample size.  As an 
aid in this latter assessment, the Coordinating Center will supplement the group sequential 
analyses outlined above with calculations of conditional power, namely the conditional 
probability that the treatment comparison will be significant at the end of the trial at the α level 
used in the design, given the hypothesized treatment difference and the data observed to date.  
After approximately 50% of the total events have occurred, conditional power for the primary 
treatment comparison will be computed and provided to the DSMB as part of the interim study 
reports. 
 
8.2.7 Multiple Comparisons 
With the primary hypothesis and the various secondary endpoints that have been outlined, there 
is a multiplicity of analyses to be performed, which leads to an increased probability that at least 
one of the comparisons could be "significant" by chance.  Although adjustments (e.g., based on 
the Bonferroni inequality) could be used to preserve the overall type I error level, to adjust for 
the effects of the repeated significance testing that will occur as part of the interim monitoring 
(discussed above), plus adjust for the multiplicity of secondary endpoints, would require that 
very small significance levels be used for every comparison.  Although the overall level of 
significance for the assessment of the primary composite endpoint will be 0.05, to account in 
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part for the multiplicity of comparisons involving secondary endpoints, a conservative approach 
will be taken while interpreting those results, taking into account the degree of significance, and 
looking for consistency across endpoints.  The actual p-value for each comparison will be 
reported to aid in the overall interpretation.        
 
8.2.8 Health Economics Analyses 
The health economic analyses for CABANA will consist of two major parts, an empirical 
intention to treat cost comparison and a cost effectiveness analysis. Primary statistical 
comparisons between the two treatment arms of empirical costs will be performed by intention-
to-treat.  The patients enrolled outside the United States will be excluded from the primary cost 
intention-to-treat analyses. Confidence limits around the observed cost differences will be 
constructed using bootstrap methods. 
  
The cost-effectiveness analyses will estimate the incremental cost required to add an extra life 
year with the investigational ablation arm relative to control medical therapy. In secondary 
analyses, we will incorporate utility weights to estimate the incremental cost per quality adjusted 
life year gained with ablation, relative to medical therapy. These analyses will be conducted 
from a societal perspective and will use a lifetime time horizon so that the estimated incremental 
cost-effectiveness and cost-utility ratios can be compared with societal benchmarks. We will 
also calculate within-trial cost-effectiveness/cost-utility ratios, although these ratios are limited in 
their value due to their failure to account for long-term benefits and costs and the absence of 
comparative benchmarks. Costs will be adjusted for inflation and both costs and life expectancy 
will be discounted to present value at a 3% annual discount rate. Adjustments for censored data 
due to staggered entry will be made following the approach of Bang and Tsiatis [107]. Extensive 
sensitivity analyses will be performed. 
 
8.2.9 Quality of Life (QOL) Analyses 
For each of the QOL measures examined in this study, data analysis will proceed in two stages. 
First, we will provide simple descriptive and comparative analyses by intention-to-treat. Second, 
we will examine changes over time from baseline and identify the major determinants of those 
changes using regression analysis. Since there is currently no consensus in the statistical 
literature about the best way to deal with the multiple comparisons problem arising from testing 
each individual scale separately, we propose two complementary approaches. First, we will pre-
specify functional status (Duke Activity Status Index), AF symptom burden, and patient utilities 
(EuroQOL-5-D) as the primary QOL comparisons of interest and assign all other comparisons to 
a secondary (exploratory) status. Second, we will use the average of post-baseline values in the 
primary analyses of these 3 endpoints to reduce the problem of comparisons at multiple time 
points. Statistical power estimates for this part of our analysis show that we should have in 
excess of 90% power to detect ¼ SD differences in our 3 principal QOL endpoints. 
 
9.0 Data Management and Quality Control 
 
9.1 Study Data Collection -- All Patients 
The full study dataset will be collected for subjects who enter the randomized/ treatment phase 
of the study. The primary data collection system for CABANA is based on the electronic data 
capture (EDC) system, InForm™. All data collected at any point in the trial, except the economic 
and quality of life information and core lab data are entered into this system. Data from the 
CT/MR Imaging Lab, the ECG Core Lab, and the Medicomp Monitoring Core Lab are 
transferred electronically to the Data Coordinating Center on a regular basis.  
 
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9.2 Electronic Case Report Form (eCRF) 
This study will use web-based electronic CRFs (e-CRFs) developed through a validated, 
Electronic Record, Electronic Signatures (ERES) compliant platform (21 CFR Part 11).  Prior to 
initiation of the trial, each site will be contacted as to computer availability, hardware 
specifications, and internet connectivity, to evaluate the capacity of the site to use this type of 
data collection system.  Data will be entered into the InForm™ eCRF by personnel at the clinical 
sites.  The Investigator's site staff who will be entering data will receive training on the system, 
after which, each person will be issued a unique user identification and password. For security 
reasons, and in compliance with regulatory guidelines, it is imperative that only the person who 
owns the user identification and password access the system using their own unique access 
codes.  Access codes are non-transferable. Site personnel who have not undergone training 
may not use the system and will not be issued user identification and password until appropriate 
training is completed. 
 
During monitoring visits, the site will make their computer and/or high speed Internet access 
available to the CRA, so that he/she may verify the data entries with the source documentation.  
At the conclusion of the study, each enrolling site will be provided with a compact disc (CD) 
containing PDF files of both the individual subject's data and the audit trail (changes made to 
the database).  This will be maintained at the site according to the requirements for records 
retention. 
 
Components of the eCRF in CABANA include enrollment and demographics form; a form for 
recording relevant history, symptoms, physical exam, ECG data and other baseline presenting 
characteristics; forms to document the details of the drug therapy and ablation procedure; 
follow-up forms for use at the regular follow-up visits and tracking the patient’s clinical course 
over time; and event forms for recording the circumstances and details surrounding the 
occurrence of a death, stroke, cardiac arrest, or bleeding event as well as other adverse events.  
In addition to the eCRF, there are specialized additional forms for collecting various components 
of the quality of life and health status information.  Detailed instructions for completing the 
various data forms, along with a detailed Manual of Operations will be provided to each of the 
clinical sites  
 
9.3 Data Management and Quality  
Any out-of-range values and missing or inconsistent key variables are flagged and 
addressed/answered at the site in real time during the data entry process.  When a query is 
generated on a particular variable, a flag is set in a field in the database enabling the system to 
track the queries and produce reports of outstanding queries.  Queries can also be generated 
from manual review of the data forms.  These queries will be entered into the database and 
tracked in the same manner as the computer-generated queries.  At regular intervals, all data 
will be transferred from InFormTM to SAS for statistical summarization, data description, and data 
analysis.  Further cross-checking of the data is performed in SAS, and discrepant observations 
flagged and appropriately resolved through a data query system. 
 
The Data Coordinating Center will perform internal database quality-control checks, and data 
audits throughout the course of the trial.  All clinical site patient-related payments are prompted 
by completion of data forms with appropriate responses to all data elements.  
 
9.4 Economic and Quality of Life (EQOL) Data 
For the CABANA study the economic and quality of life studies will be fully integrated into the 
clinical trial, including their inclusion in the main trial Informed Consent Form.  The EQOL data 
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will be quality controlled and entered into the study data base at the EQOL Coordinating Center. 
Measurements of utilities by the EQ-5D and 0-100 Thermometer (EuroQoL) will be obtained 
throughout the trial in the CABANA EDC system. Statistical analysis of the EQOL data by 
intention-to-treat will be performed by the EQOL Coordinating Center. 
 
10.0 Investigator Responsibility/Performance 
 
By signing this protocol, the clinical site investigators agree to be responsible for implementing 
and maintaining quality control and quality assurance systems to ensure that all work incidental 
to this protocol is conducted and data are generated, documented, and reported in compliance 
with the protocol, accepted standards of Good Clinical Practice, and all applicable federal, state, 
and local laws, rules and regulations relating to the conduct of the clinical study. 
 
The Investigator will provide current copies of the study protocol to all Sub-Investigators or other 
site personnel responsible for study conduct. The investigator must ensure that all site staff 
involved in the conduct of the trial are familiar with and have appropriate knowledge of the 
protocol and all study-specific procedures.  
 
The Investigator will provide DCRI and/or their designee with copies of all IRB or EC actions 
regarding the study. 
 
11.0 Study Data Reporting and Processing 
 
The principal investigator is required to sign the eCRF on the appropriate pages to verify that 
he/she has accepted responsibility for the recorded data.  This review and sign-off may be 
delegated to a qualified physician appointed as a sub-investigator by the principal investigator.  
The transfer of duties to a sub-investigator will be recorded on the Delegation list (kept on file at 
the site).  
 
11.1 Site Selection and Monitoring 
To qualify as an investigative site, each group must be committed to enrollment and 
randomization without bias or inclination toward early cross-over from drug to ablative therapy.  
Each site must also demonstrate the skill and expertise for participating in clinical trials as 
judged from their past trial performance. A Co-PI approach to the enrollment and treatment of 
patients will be required. A cardiac electrophysiologist skilled in the art of AF ablation will work 
closely with a non-interventional clinical cardiologist or internist.  This will also help counter 
potential bias in favor of ablation.  The focus of recruitment will be in Primary and Secondary 
Care clinics, Hospital ERs, and first referrals to ablation centers.  Each site will be strongly 
encouraged to minimize the time between randomization and ablation to <2 weeks, by “holding” 
ablation slots.  
 
As part of a concerted effort to follow the study in a detailed and orderly manner in accordance 
with established principles of Good Clinical Practice and applicable regulations, the Monitoring 
Plan is being revised with Executive Committee approval. A DCRI study monitor or their 
designee will no longer perform on-site visits to Active study sites regularly and throughout the 
study. Rather they will maintain frequent telephone and written communication, as well as 
perform on-site visits to a subset of sites to ensure data integrity. 
 
The on-site monitoring visits will be made to assure that the Investigator obligations are fulfilled 
and all applicable regulations and guidelines are being followed. These visits will assure that the 
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facilities are still acceptable; the protocol and investigational plan are being followed, the 
IRB/EC has been notified of approved protocol changes as required, complete records are 
being maintained, appropriate and timely reports have been made to DCRI and/or their 
designee and the IRB/EC, study drug and study drug inventory are controlled and the 
Investigator is carrying out all agreed activities. 
 
During on-site monitoring visits, the Monitor will perform a review of all Inclusion/Exclusion 
criteria of selected randomized subjects. Review of informed consent forms, HIPAA 
Authorization, all events meeting criteria for expedited event reporting as well as selected SAE’s 
and Events of Interest (EOI)’s will be performed. Additional review will be performed on a site-
by-site basis, as warranted.  Key variables (inclusion/exclusion criteria, adherence to treatment 
assignment and safety) on the eCRF will be compared with each subject’s source documents. 
Any discrepancies will be noted and resolved. 
 
During monitoring visits, the site will make their computer and/or high speed Internet access 
available to the CRA, so that he/she may verify the data entries with the source documentation. 
 
11.1.1 Initiating / Training Sites 
Over the first year of the trial, sites will come on-line for active participation once all local 
regulatory requirements have been met.  Unconditional IRB/EC approval will be required at 
each site. Training for data collection and reporting must be completed. Individual sites will also 
be trained at the time of the first general investigator meeting held at the beginning of the trial.  
The specific site’s ablation and clinical investigators and the clinical study coordinator will be 
required to attend these meetings.  
 
 
11.1.2 Terminating a Site 
Any activated site may be terminated from the trial for failure to enroll any subjects, within a 
reasonable period of time.  Also, any site may be suspended from active enrollment, if it fails to 
meet reasonable enrollment goals or comply with study procedures.  Specifically, any site 
consistently failing to provide timely reports or adequate data quality will be withdrawn from 
active enrollment.  A cross-over rate >10% over any 6 month period will result in a warning to 
that site.  A crossover rate >15% will prompt suspension of enrollment.  A 3-month period for 
resolving any operational difficulties will be required prior to reinstating or permanently 
terminating a specific site to further enrollment. All subjects randomized must be followed until 
death or the end of the trial, even if the site has been inactivated due to enrollment or study 
compliance. 
  
11.1.3 Conflicts of Interest: The two principal investigators from each site, along with 
additional study staff will be required to disclose any present or potential conflicts of interest 
following guidelines established by the American College of Cardiology. 
 
12.0 Study Documentation  
 
Study documentation includes all electronic data collection forms, source documents, 
monitoring logs and appointment schedules, sponsor-investigator correspondence and 
regulatory documents, etc.  
 
The investigator will prepare and maintain complete and accurate study documentation in 
compliance with Good Clinical Practice standards and applicable federal, state, and local laws, 
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rules and regulations; and, for each subject participating in the study, promptly complete all 
original case report forms and such other reports as required by this protocol. 
 
 By signing the protocol, the investigator acknowledges that, within legal and regulatory 
restrictions and institutional and ethical considerations, study documentation will be promptly 
and fully disclosed and shall be made available at the investigator’s site upon request for 
inspection, copying, review and audit at reasonable times by representatives of DCRI and/or 
their designee or responsible government agencies as required by law.  
 
The investigator agrees to promptly take any reasonable steps that are requested by DCRI 
and/or their designee as a result of an audit to cure deficiencies in the study documentation and 
case report forms. 
 
13.0 Source Documentation  
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical study.   
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document. 
 
Regulations require that Investigators maintain information in the study subject’s medical 
records which corroborate data collected on the CRF (eCRF). In order to comply with these 
regulatory requirements, the following information will be maintained and made available as 
required by DCRI and/or their designee monitors and/or regulatory inspectors: 
1. Medical history/physical condition of the study subject prior to involvement in the study 
sufficient to verify protocol entry criteria. 
2. Medical record documenting that informed consent was obtained for the subject’s 
participation in the study 
3. Notes for each subject visit including results of examinations. 
4. Lab results  
5. Dated printouts or reports of special assessments, (e.g., ECG reports). 
6. Description of adverse events and follow-up of the adverse events (minimally event 
description, severity, onset date, duration, relation to study drug or device, outcome and 
treatment for adverse event). 
7. Notes regarding concomitant medications taken during the study (including start and 
stop dates). 
8. Subject’s condition upon completion of or withdrawal from the study. 
 
 
14.0 Protocol Deviations 
 
A protocol deviation is defined as an event where the Investigator or site personnel did not 
conduct the study according to the Investigational Plan or the Investigator Agreement. 
 
Investigators are required to obtain prior approval from CABANA Administration before initiating 
deviations from the investigational plan or protocol, except where necessary to protect the life or 
physical well-being of a subject in an emergency. Such approval will be documented in writing 
and maintained in study files.  Unless CABANA Administration has consented to any such 
deviations in writing, CABANA Administration will not assume any resulting responsibility or 
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liability.  Prior approval is generally not expected in situations where unforeseen circumstances 
are beyond the Investigator’s control, (e.g., subject did not attend scheduled follow-up visit, 
blood sample lost by laboratory, etc.); however, the event is still considered a deviation. 
 
Deviations will be reported to DCRI and/or their designee regardless of whether medically 
justifiable, preapproved by CABANA Administration, or taken to protect the subject in an 
emergency.  Subject specific deviations will be reported on the [study specific, e.g., Report of 
Non-Compliance] Form.   
 
Investigators will maintain documentation of the dates and reasons for each deviation from the 
protocol, in compliance with the ICH-GCP guidelines, Code of Federal Regulations (CFR) 
812.140 and national legislation. 
  
15.0  Data Transmittal and Record Retention 
 
Required data will be recorded on the appropriate eCRF at the time of or as soon as possible 
after the subject visit or the availability of test results.  
 
As forms are completed or updated, data will be transmitted via the Internet from investigational 
sites to a central site utilizing state-of-the-art encryption mechanisms to ensure security and 
confidentiality. 
 
The investigator takes responsibility for retaining adequate and accurate hard copy source 
documents of all observations and data generated during this study.  Such documentation is 
subject to inspection by DCRI and/or their designee as well as the FDA and other regulatory 
agencies, as provided by law. DCRI and/or their designee will be contacted if the investigator 
plans to leave the institution so that arrangements can be made for transfer of responsibilities. 
  
16.0 Study Closeout 
 
The end of the trial is defined as the day of the official end of patient follow-up in the trial.  
 
For clinical trial sites located in the EU, a declaration of the end of the clinical trial will be made 
according to the procedures outlined in Directive 2001/20/EC. For sites located in countries 
outside the EU, local regulations will be followed. 
 
Upon completion of the study DCRI and/or their designee will notify the site of closeout and a 
study closeout visit will be performed.  The DCRI monitor and/or their designee will ensure that 
the Investigator’s regulatory files are up to date and complete, and that any outstanding issues 
from previous correspondences have been resolved.  Other issues to be reviewed at the 
closeout visit include: discussing retention of study files, possibility of site audits, publication 
policy, and notifying the IRB of study closure. 
 
 
17.0 Audit/Inspections 
 
DCRI Quality Assurance personnel and/or their designee may conduct audits at the study 
site(s).  Audits will include, but not be limited to: audit trail of data handling and processes, 
SOPs, drug supply, presence of required documents, the informed consent process, and 
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comparison of case report forms/database with source documents.  The investigator agrees to 
accommodate and participate in audits conducted at a reasonable time in a reasonable manner, 
as needed. 
 
Regulatory authorities worldwide may also audit the investigator during or after the study.  The 
investigator should contact the Sponsor immediately if this occurs, and must fully cooperate with 
governmental (e.g. FDA) audits conducted at a reasonable time in a reasonable manner. 
 
18.0 Informed Consent 
 
The investigator has both ethical and legal responsibility to ensure that each subject being 
considered for inclusion in this study is given a full explanation of the study.  Written informed 
consent will be obtained from all subjects before any study-related procedures are performed or 
given.  
 
The principal investigator or IRB-documented members of the research team will approach the 
patient to obtain written informed consent on an informed consent form (ICF) approved by the 
same IRB/EC responsible for approval of this protocol. The informed consent document will 
conform to FDA regulations in 21 CFR Part 50, and/or to the national requirements for informed 
consent. It must include all elements required by law, local regulations, GCP and International 
Conference on Harmonization guidelines and study specific procedures.  The underlying 
rationale for the study, the procedures to be followed, the potential benefits, risks, alternatives, 
and other issues mandated by the consent process will be fully disclosed. If new information 
becomes available during the course of the trial that may be relevant to the subject’s consent, 
the Informed Consent Form will be revised and the revised version will be submitted for EC/IRB 
approval before use.  
 
The investigator agrees to obtain approval from DCRI and/or their designee of any ICF intended 
for use in the study, prior to submission for IRB approval. 
 
19.0 Confidentiality of Subjects 
 
Subject confidentiality will be maintained throughout the clinical study in a way that ensures the 
information can always be tracked back to the source data.  For this purpose, a unique subject 
identification code (ID number and subject name code) will be used that allows identification of 
all data reported for each subject. 
 
Subject information collected in this study and all records will be kept confidential and the 
subject’s name will not be released by study staff at any time.   
 
When requested patient medical records may be examined by authorized monitors (DCRI 
and/or their designee) or Clinical Quality Assurance auditors appointed by the sponsor, by 
appropriate IRB / IEC members and by domestic and foreign regulatory authorities.  In all cases, 
caution will be exercised to assure the data are treated confidentially and that the subject’s 
privacy is protected. 
 
Furthermore; for clinical trial sites located in the US, the NHLBI has issued CABANA a 
Certificate of Confidentiality to protect the privacy of research subjects by withholding their 
identifiable information from all persons not connected with this research.  
 
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20.0 Authorization for Use and Disclosure of Protected 
Health Information (HIPAA) 
 
For clinical trial sites located in the US, an Authorization for use and disclosure of protected 
health information (PHI) under the HIPAA Privacy Rule [45 CFR § 164.102 et seq] will be 
obtained from every trial subject prior to, or at the time of, enrollment.  It will be presented to, 
and signed by, the subject at the same time as the Informed Consent Form (ICF). The 
investigator is responsible for obtaining subjects’ authorizations and signatures, and for 
explaining the elements of the HIPAA Authorization form if necessary. 
 
HIPAA Authorization may either be a separate form or included in the study ICF, dependent 
upon local requirements.  If a separate HIPAA document is signed, the investigator will append 
one signed original of each executed HIPAA Authorization to the trial subject’s signed ICF, and 
file it in the site’s regulatory file.  If a second copy of the signed ICF is filed in the subject’s 
medical records, an additional copy of the signed HIPAA Authorization form will be appended.  
Subjects will be given the other signed duplicate for their personal records. 
The HIPAA Authorization form will contain all elements required under the HIPAA Privacy Rule.  
By law, site IRB approval of the Sponsor-provided Authorization form for use in this study is not 
required, and no such approval will be sought or requested.  However, DCRI or their designee, 
upon request, will provide advance copies of its HIPAA Authorization form to the investigator or 
the site’s privacy board or privacy official, and will work with the site to eliminate any concerns. 
The investigator or the site will promptly inform DCRI or their designee of any restrictions on the 
use or disclosure of PHI of any subject to which the site or the investigator have agreed under 
the Privacy Rule.  The investigator or the site will also promptly inform DCRI or their designee of 
any written revocation of any subject’s HIPAA Authorization. 
 
21.0   Human Subject Protections 
. 
21.1 
Research Subject Selection and Justification of Exclusions 
There will be no exclusion from participation in the study on the basis of ethnicity or race.  
Subjects will undergo a screening process, during which they will have multiple opportunities to 
ask questions.  The Principal Investigator or authorized designee will provide a detailed 
discussion of the protocol, and answer any questions.  The subject will be given time to consider 
study participation. No coercion or undue influence on this decision will be used.  Only those 
subjects who give written, informed consent and complete enrollment testing will be considered 
for participation in the study.   
 
22.0 Institutional Review Board/Ethics Committee Review 
 
This study will be initiated only after all required documentation has been reviewed and 
approved by the respective IRB/EC and competent authority (CA) according to national and 
international regulations.   
The investigator will provide DCRI or their designee with the study approval documentation 
before the study may begin.  The same is applicable for the implementation of changes 
introduced by amendments. 
Where applicable, the investigator must also provide to DCRI and/or their designee the following 
documentation:  
1. 
A copy of IRB annual re-approval of the protocol per current Title 21 CFR 312.66 
regulations and 1997 International Conference on Harmonization guidelines. 
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2. 
IRB approval of revisions to the informed consent documents.  Administrative changes 
(such as a change in address or phone number) must be sent to IRBs/Ethics 
Committees but do not require their approval.   
3. 
The investigator must submit periodic status reports to their EC as required, as well as 
notification of completion of the study and a final report where applicable. 
4. 
The investigator will provide DCRI or their designee with documentation of all approvals. 
 
23.0 Publication Policies 
 
Trial results will be released in several manuscripts providing outcomes of the trial as a whole.  
No details will be released prior to the scheduled presentation of the main trial results.  Data 
summaries will be provided to the DSMB and NHLBI as appropriate for trial regulation.  Release 
of other results, including those generated in any sub-study must be done in a manner so as to 
protect the integrity of the trial as a whole.  Portions of the database will not be released to 
single or groups of enrolling centers for analysis. 
 
The Publication Committee will receive and review applications and potential authors for sub-
studies beyond those comprising main trial results, and make recommendations to the 
Executive Committee for approval. A detailed list of the sub-studies, the requesting 
investigators, and the timing of applications will be maintained in anticipation of other 
publications. 
 
All manuscripts, abstracts and presentations will be reviewed by the Publication Committee for 
scientific merit, appropriateness of the presentation or manuscript, and for authorship. All 
presentations or publications of any type are expected to maintain the integrity of the main 
objectives of the overall project.  By agreement of the principal investigators, endpoint data will 
not be presented prior to the release of main study results. Authorship on ancillary studies will 
depend on contribution to the trial effort. 
 
24.0 Sub-Studies 
All activated sites will be given the opportunity to participate or not participate. All proposed sub-
studies will be first submitted for review and approval to the respective IRB/EC and competent 
authority (CA) based on national and international regulations. It is further acknowledged that 
subjects enrolled in CABANA will have the choice to participate or to not participate in sub-
studies. 
 
24.1  CABANAgene 
CABANAgene: a resource that will accumulate DNA samples from CABANA subjects to enable 
subsequent genotype-phenotype studies.   
 
Appendix C, page 62, the CABANAgene protocol, provides the rationale for studies and 
approaches that are anticipated.  The major goal of CABANAgene is to create the resource. 
Specific projects to use the samples would require approval of the CABANA study group, and 
phenotypes to be studied would be those collected by and adjudicated by the CABANA study 
group.  The CABANAgene project is included in the Pharmacogenetics Research Network 
(PGRN) arrhythmia site renewal.  Participation under the PGRN umbrella also provides access 
to advanced genotyping and genetic statistical methods to investigators accessing the 
CABANAgene resource.  
 
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Examples of issues that CABANAgene could address include: 1) predictors of response to 
antiarrhythmic or rate control drug therapies; 2) predictors of response to warfarin therapy; 3) 
predictors of response to ablation therapy and; 4) clinical and genetic approaches to defining AF 
subtypes.  
  
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66. Rienstra M, Van Gelder IC, Hagens VE, Veeger NJ, Van  Veldhuisen DJ, Crijns HJ. 
Mending the rhythm does not improve prognosis in patients with persistent atrial fibrillation: 
a subanalysis of the RACE study. Euro Hrt J. 2006; 27(3):357–64. 
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68. Van Gelder I, Hemels M. The progressive nature of atrial fibrillation: a rationale for early 
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70. Vasamreddy CR, Dalal D, Dong J, Cheng A, Spragg D, Lamiy SZ, Meininger G, Henrikson 
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71. Hindricks G, Piorkowski C, Tanner H, Kobza R, Gerds-Li JH, Carbucicchio C, Kottkamp H. 
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72. Piorkowski C, Kottkamp H, Tanner H, Kobza R, Nielsen JC, Arya A, Hindricks G. Value of 
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73. Flaker GC, Belew K, Beckman K, Vidaillet H, Kron J, Safford R, Mickel M, Barrell P, AFFIRM 
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74. Oral H, Veerareddy S, Good E, Hall B, Cheung P, Tamirisa K, Han J, Fortino J, Chugh A, 
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75. Verma A, Minor S, Kilicaslan F, Patel D, Hao S, Beheiry S, Lakkireddy D. Elayi SC, 
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Incidence of atrial arrhythmias detected by permanent pacemakers (PPM) post-pulmonary 
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recurrence. J Cardiovasc Electrophysiol. 2007; 18(6):601–6. 
76. Chan P, Vijan S, Morady F, Oral H. Cost-effectiveness of radiofrequency catheter ablation 
for atrial fibrillation. J Am Coll Cardiol 2006; 47(12): 2513-20. 
77. Khaykin Y. Cost-effectiveness of catheter ablation for atrial fibrillation. Current Opinion in 
Cardiology. 2007; 22(1):11-17.  
78. Reynolds M, Lavelle T, Essebag V, Cohen D, Zimetbaum P. Influence of age, sex, and atrial 
fibrillation recurrence on quality of life outcomes in a population of patients with new-onset 
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79. Falk R. Atrial fibrillation or sinus rhythm? Controversy and contradiction in quality of life 
outcomes. J Am Coll Cardiol. 2006; 48(4):731-733. 
80. Schron E, Jenkins L. Quality of life in older patients with atrial fibrillation. Am J Geriatric 
Cardiol. 2005; 14(2):87-90. 
81. Weerasooriya R, Jais P, Hocini M, Scavee C, MacLe L, Hsu F, Sandars P, Garrigue S, 
Clementy J, Haissaguerre M. Effect of catheter ablation on quality of life of patients with 
paroxysmal atrial fibrillation. Heart Rhythm 2005; 2(6): 619-23. 
82. Wokhlu A, Hodge DO, Haroldson J, Wock K, Monahan KH, Friedman PA, Asviratham S, 
Munger TM, Packer DL. Long-term quality of life after ablation for atrial fibrillation: symptom 
relief or placebo effect? Heart Rhythm. 2008: Abstract in press. 
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83. Pappone C, Oreto G, Rosanio S, Vicedomini G, Tocchi M, Gugliotta F, Salvati A, Dicandia 
C, Calabro M, Mazzone P, Ficarra E, DiGioia D, Gulletta S, Nardi S, Santinelli V, Benussi S 
and Alfieri O. Atrial electroanatomic remodeling after circumferential radiofrequency 
pulmonary vein ablation. Efficacy of an anatomic approach in a large cohort of patients with 
atrial fibrillation. Circulation. 2001; 104: 2539 - 44. 
84. Beukema WP, Elvan A, Sie HT, Misier AR, Wellens HJ. Successful radiofrequency ablation 
in patients with previous atrial fibrillation results in a significant decrease in left atrial size. 
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85. Tops LF, Bax JJ, Zeppenfeld K, Jongbloed MR, van der Wall EE, Schalij M. Effect of 
radiofrequency catheter ablation for atrial fibrillation on left atrial cavity size. Am J Cardiol. 
2006; 97(8): 1220-2. 
86. Reant P, Lafitte S, Jais P, Serri K, Weerasooriya R, Hocini M, Pillois X, Clementy J, 
Haissaguerre M, Roudaut R.  Reverse remodeling of the left cardiac chambers after catheter 
ablation after 1 year in a series of patients with isolated atrial fibrillation. Circulation 2005; 
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87. Verma, A, Marrouche N, Yamada H, Grimm R, Cummings J, Burkhardt J, Kilicaslan F, 
Fhargava M, Karim A, Thomas J, Natale A. Usefulness of intracardiac Doppler assessment 
of left atrial function immediately post-pulmonary vein antrum isolation to predict short-term 
recurrence of atrial fibrillation. Am J Cardiol. 2004; 94(7): 951-4. 
88. Lemola K, Desjardins B, Sneider M, Case I, Chugh A, Good E, Han J, Tamirisa K, Tsemo A, 
Reich S, Tschopp D, Igic P, Elmouchi D, Bogun F, Pelosi F Jr., Kazerooni E, Morady F, Oral 
H. Effect of left atrial circumferential ablation for atrial fibrillation on left atrial transport 
function. Heart Rhythm 2005; 2(9): 923-8. 
89. Chandrasekaran K, Asirvatham S, Packer D. Wide area circumferential ablation impairs the 
left atrial function significantly compared to Lasso-guided pulmonary vein ablation in chronic 
atrial fibrillation. Mayo Clinic Data 2006. 
90. Rosendorff C, Black HR, Cannon DP, Gersh BJ, Gore J, Izzo JL Jr., Kaplan NM, O’Connor 
CM, O’Gara PT, Oparil S.  Treatment of hypertension in the prevention and management of 
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Epidemiology and Prevention. Hypertension 2007; 50:e28-55. 
91. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes 
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92. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le 
Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC 
Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, 
Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers 
JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, 
Tamargo JL, Zamorano JL, American College of Cardiology/American Heart Association 
Task Force on Practice Guidelines. European Society of Cardiology Committee for Practice 
Guidelines. European Heart Rhythm Association. Heart Rhythm Society. ACC/AHA/ESC 
2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the 
American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines and the European Society of Cardiology Committee for Practice Guidelines 
(Writing Committee to Revise the 2001 Guidelines for the Management of Patients With 
Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association 
and the Heart Rhythm Society. Circulation. 114(7):e257-354, 2006 Aug 15.  
93. Haissaguerre M, Jais P, Shah D, Takahashi A, Hocini M, Quiniou G, Garrigue S, LeMouroux 
A, LeMetayer P, Clementy J.  Spontaneous initiation of AF by ectopic beats originating in 
the pulmonary veins. New England Journal of Medicine. 1998; 339:659-66. 
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CABANA Confidential 22 November, 2013                                                                    Page 61 of 78 
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94. Haissaguerre M, Jais P, Shah D, Lavergne T, Hocini M, Peng J, Roundaut R, Clementy J.  
Electrophysiological endpoint for catheter ablation of AF initiated from multiple pulmonary 
venous foci. Circulation. 2000; 101:1409-17. 
95. Marrouche N, Martin D, Wazni O, Gillinov A, Klein A, Bhargava M, Saad E, Bash D, Yamada 
H, Jaber W, Schweikert R, Tchou P, Abul-Karim A, Saliba W, Natale A. Phased-array 
intracardiac echocardiography monitoring during pulmonary vein isolation in patients with 
AF: Impact on outcome and complications.  Circulation. 2003; 107:2710–16. 
96. Verma A, Marrouche NF, Natale A. Pulmonary vein antrum isolation: intracardiac 
echocardiography-guided technique.  J Cardiovasc Electrophysiol. 2004; 15(11):1335-40. 
97. Pappone C, Rosanio S, Vicedomini G, Tocchi M, Gugliotta F, Salvati A, Dicandia C, Calabro 
MP, Mazzone P, Ficarra E, DiGioia C, Gulletta S, Nardi S, Santinelli V, Benussi S, Alfieri O. 
Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein 
ablation.  Efficacy of an anatomic approach in a large cohort of patients with AF. Circulation. 
2001; 104:2539-44. 
98. Packer DL, Bluhm CM, Monahan KH, Asirvatham S, Friedman A, Shen WK, and Haroldson 
JM. Outcome of AF Ablation Using a Wide Area Circumferential Ablative Approach: A 
Comparison With Lasso-Guided Ablation. Heart Rhythm. 2004; 1(1S):S11. 
99. Nakagawa H, Scherlag BJ, Lockwood D, Wolf RK, Peyton M, Wu R, Yokoyama K, Po SS, 
Herring L, Lazzara R, Jackman WM, Armour JA.  Localization of left atrial autonomic 
ganglionated plexuses using endocardial and epicardial high frequency stimulation in 
patients with AF. Heart Rhythm. 2005; 2(1S):S10. Abstract. 
100. Uyttenboogaart M, Stewart RE, Vroomen PCAJ, De Keyser J, Luijckx GJ. Optimizing cutoff 
scores for the Barthel Index and the Modified Rankin Scale for defining outcome in acute 
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101. Rao SV, O’Grady K, Pieper KS, Granger CB, Newby LK, Mahaffey  KW, Moliterno DJ, 
Lincoff AM, Armstrong PW, Van de Werf F, Califf RM, Harrington RA. A Comparison of the 
Clinical Impact of Bleeding Measured by Two Different Classifications Among Patients with 
Acute Coronary Syndromes. J Am Coll Cardiol. 2006; 47:809-16. 
102. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data (Second Edition). . 
New York, NY: John Wiley & Sons, Inc, 2002. 
103. Cox DR. Regression models and life-tables (with discussion). J Royal Statist Soc B 1972; 
34:187-220. 
104. Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. 
Biometrics 1983; 39(2):499-503.  PMID:6354290 
105. O'Brien PC, Fleming TR.  A multiple testing procedure for clinical trials.  Biometrics 1979; 
35(3):549-556.56.  PMID:497341 
106. Lan KKG, DeMets DL.  Discrete sequential boundaries for clinical trials.  Biometrika 1983; 
70:659-663. 
107. Bang H, Tsiatis AA.  Estimating medical costs with censored data.  Biometrika 2000; 87: 
329-343. 
 
 
 
 
 
 
 
 
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CABANA Confidential 22 November, 2013                                                                    Page 62 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Appendix A Adverse Events 
The following events have been identified as “Anticipated Events” for subjects randomized 
to drug or ablation therapy for this study.   
CATEGORY
ANTICIPATED EVENT
CARDIOVASCULAR
1
Air embolism
17 Intraventricular conduction delay
2
Bradycardia
18 Ischemia 
3
Cardiac arrest
19 Left ventricular dysfunction
4
Cardiac thromboembolic event
20 Myocardial infarction
5
Chest pain during energy delivery
21 Myocardial perforation
6
Clinically relevant AV node dysfunction
22 Pacemaker damage
7
Clinically relevant sinus node block
23 Pericardial effusion
8
Complete/permanent AV block
24 Pericarditis
9
Coronary artery dissection
25 Proarrhythmia; new or worsened arrhythmia
10 Coronary artery occlusion
26 Persistant PFO / iatrogenic ASD
11 Coronary artery spasm
27 Prolonged QT
12 Nonsustained VT
28 Sustained VT
13 Elevated creatinine phosphokinase (CPK)
29 Tamponade
14 Heart failure (Class I, II, III, IV)
30 Torsade des pointes
15 Heart valve damage
31 Transient AV block
16 Hypotension
32 Ventricular fibrillation 
ENDOCRINE
32 Hyperthyroidism
33 Hypothyroidism
GENERAL 
34 Allergic reaction (skin rash, SOB)
39 Radiation skin burn
35 Bluish / gray skin tone
40 Skin rashes
36 Fatigue
41 Temperature elevation
37 Photosensitivity
42 Volume overload
38 Radiation related cancers
GASTROINTESTINAL
43 Constipation
48 Stomach disorder
44 Diarrhea
49 Nausea
45 Esophageal atrial fistula
50 Poor appetite
46 Esophageal disorder
51 Unusual taste (metallic or other)
47 Gastroesophageal reflux
52 Vomiting 
53 Abnormal liver functions
GENITOURINARY
54 Impotence
56 Renal failure
55 Kidney damage
57 Urinary tract infection
INFECTIOUS 
58 Infection
59 Sepsis
NEUROLOGIC
60 Alteration of color vision
68 Phrenic nerve damage
61 Blindness
69 Seizure
62 Blurred / double vision
70 Stroke
63 Depression
71 Syncope
64 Deteriorating vision
72 TIA
65 Dizziness / light headedness
73 Unsteady gait / imbalance
66 Headache 
74 Vasovagal reaction
67 Pain
75 Visual migraine
 
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CABANA Confidential 22 November, 2013                                                                    Page 63 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Appendix A Adverse Events (continued) 
The following events have been identified as “Anticipated Events” for subjects randomized 
to drug or ablation therapy for this study.  
 
CATEGORY
ANTICIPATED EVENT
PULMONARY
76
Asthma exacerbation
84
Pulmonary hypertension
77
Hemothorax
85
Pulmonary vein damage/dissection
78
Lung toxicity
86
Pulmonary vein stenosis
79
Pleural effusion
87
Pulmonary vein thrombus
80
Pneumonia
88
Respiratory depression
81
Pneumothorax
89
Shortness of breath/dyspnea
82
Pulmonary edema
90
Wheezing
83
Pulmonary embolism
91
Pleuritic chest pain
PERIPHERAL VASCULAR 
92
A-V fistula
97
Peripheral edema
93
Bleeding
98
Peripheral thromboembolic event
94
Bruising / ecchymosis
99
Pseudoaneurysm
95
DVT
100 Thromboembolic event
96
Hematoma
101 Vessel trauma 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CABANA Confidential 22 November, 2013                                                                    Page 64 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Appendix B  
Approved Ablation Devices for CABANA 
IDE: G050233 
CATHETER
DESCRIPTION
SIZE
PMA#
Biosense Webster
NAVI-STAR
7F/4mm
P990025
Biosense Webster
NAVI-STAR DS
7F/8mm
P010068
Biosense Webster
CELSIUS Braided Tip
7F/4-5mm
P950005
Biosense Webster
CELSIUS Braided Tip
8F/4-5mm
P950005
Biosense Webster
CELCIUS Long Reach
7F/4-5mm
P950005
Biosense Webster
CELCIUS Long Reach
8F/4-5mm
P950005
Biosense Webster
NAVI-STAR™ and CELSIUS™ Thermo-Cool 7.5F/3.5mm
P030031
Biosense Webster
Navistar® RMT
7F/4mm
P990025
Biosense Webster
Navistar® RMT
7F/8mm
P010068
Biosense Webster
Celsius® RMT
7F/4mm
P950005
Biosense Webster
ThermoCool® SF
8F/3.5mm
P990071
Medtronic Cryocath LP Freezor®
7F/4mm
P020045
Medtronic Cryocath LP Freezor® Xtra
7F/6mm
P020045
Medtronic Cryocath LP Freezor® MAX
9F/8mm
P020045
Medtronic Cryocath LP Arctic Front®
23mm  28mm P100010
Medtronic
Cardiac Ablation System
P100008
St. Jude Medical
Livewire TC™ XLS™ Medium Sweep
7F/4mm
P960016
St. Jude Medical
Livewire TC™ XLS™ Large Sweep
7F/4mm
P960016
St. Jude Medical
Livewire TC™ XLS™ Medium Curl
7F/4mm
P960016
St. Jude Medical
Livewire TC™ XLS™ Large Curl
7F/4mm
P960016
St. Jude Medical
Livewire TC™ XLS™ Medium Sweep
7F/5mm
P960016/S006
St. Jude Medical
Livewire TC™ XLS™ Large Sweep
7F/5mm
P960016/S006
St. Jude Medical
Livewire TC™ XLS™ Medium Curl
7F/5mm
P960016/S006
St. Jude Medical
Livewire TC™ XLS™ Large Curl
7F/5mm
P960016/S006
St. Jude Medical
Therapy™ Dual8- small
7F/8mm
P040042
St. Jude Medical
Therapy™ Dual 8- medium
7F/8mm
P040042
St. Jude Medical
Therapy™ Dual 8- large
7F/8mm
P040042
St. Jude Medical
Therapy™ Dual 8- X-large
7F/8mm
P040042
St. Jude Medical
Therapy™ Dual -8 extended
7F/8mm
P040042
St. Jude Medical
Therapy™ Dual -8 far reach
7F/8mm
P040042
St. Jude Medical
Therapy™ Thermocouple small
7F/4mm
P040014
St. Jude Medical
Therapy™ Thermocouple medium
7F/4mm
P040014
St. Jude Medical
Therapy™ Thermocouple large
7F/4mm
P040014
St. Jude Medical
Therapy™ Thermocouple X-large
7F/4mm
P040014
St. Jude Medical
Therapy™ Thermocouple extended
7F/4mm
P040014
St. Jude Medical
Therapy™ Thermocouple far reach
7F/4mm
P040014
St. Jude Medical
Safire™ Sm/Med/Lg Sweep
7F/4mm
P960016/S014
St. Jude Medical
Safire™ Sm/Med/Lg Curl
7F/4mm
P960016/S014
St. Jude Medical
Safire™ Sm/Med/Lg Sweep
7F/5mm
P960016/S014
St. Jude Medical
Safire™ Sm/Med/Lg Curl
7F/5mm
P960016/S014
St. Jude Medical
Therapy Cool Path Med Curve
7F/5mm
P060019
St. Jude Medical
Therapy Cool Path Large Curve
7F/5mm
P060019
St. Jude Medical
Therapy Cool Path X-Large Med Curve
7F/5mm
P060019
St. Jude Medical
Therapy Cool Path Flutter Curve
7F/5mm
P060019
Bard
Stinger
4&5mm
P000020
Boston Scientific
Blazer II RF
7F/4mm
P920047
Boston Scientific
Blazer II XP
8F/8mm
P020025
Boston Scientific
Blazer RPM
8F/5mm
P020047
Boston Scientific
Chilli II Cooled
7F4mm
P980003
Boston Scientific
SteeroCath
7F/4mm
P920047
 
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CABANA Confidential 22 November, 2013                                                                    Page 65 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Appendix C  
 
 
 
 
 
 
 
 
 
 
 
 
CABANAgene 
 
A Resource to Evaluate Genetic Predictors of Efficacy and Adverse Reactions During the 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
(CABANA sub-study protocol) 
 
 
 
Dawood Darbar,1 M.D., and Dan M. Roden,2 M.D. 
1Associate Professor of Medicine,  
Chief, Arrhythmia Service 
 
2Professor of Medicine and Pharmacology 
Director, Oates Institute for Experimental Therapeutics 
Assistant Vice-Chancellor for Personalized Medicine 
 
Vanderbilt University Medical Center 
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CABANA Confidential 22 November, 2013                                                                    Page 66 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Table of Contents: 
 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 
Statistical Considerations 
11.0 
Privacy/Confidentiality Issues 
12.0 
Follow-up and Record Retention 
 
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CABANA Confidential 22 November, 2013                                                                    Page 67 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
1.0 
Background and Significance 
CABANA is comparing two major approaches for management of atrial fibrillation (AF): drugs to 
maintain sinus rhythm and ablation.  As in all other large clinical trials, responses to therapy will be 
variable in both treatment arms. Abundant evidence points to genetic factors as a contributor to 
such variability in important human phenotypes such as response to treatment,1 and the goal of 
CABANAgene is the creation of a large resource linking to test hypotheses that relate genetic 
variation to disease susceptibility and treatment responses.  Collecting DNA from patients in 
CABANA will address questions such as which patients are most likely to respond to ablation or 
drug therapy and which patients are most likely to develop complications with ablation or drug 
therapy.  
 
Approaches to identifying associations between genotypes and phenotypes:  Three general 
approaches have been used in studies addressing the relationship between genotype and 
phenotype:  
1. Family studies: Initial genotype-phenotype relations were identified by studying kindreds 
with manifest phenotypes like sickle cell disease, long QT syndrome or hypertrophic 
cardiomyopathy. Indeed, similar approaches have now been used to identify rare but 
clinically important genetic variants that cause familial AF.2-7 
2. Candidate gene studies: Here, the biologic basis for the phenotype in question is first 
intensively studied, and then the role of genes modulating that biology was explored.  This 
approach has been used to identify genetic variants contributing to AF susceptibility in 
families with more than one affected member.  In addition, candidate gene approaches have 
been remarkably effective in identifying genetic variants that modulate drug action 
(pharmacogenomics).1  These can be in the genes involved in drug transport or metabolism 
(e.g. members of the CYP superfamily), in genes encoding drug targets (e.g. ion channels 
genes for antiarrhythmics; adrenergic receptor gene variants for beta-blockers; VKORC1 for 
warfarin), or in other genes that modulate the biologic context in which drugs interact with 
their target molecules.  The traditional approach interrogates a small number of well-
characterized variants in a candidate gene, and relates these to the phenotype of interest; in 
CABANA, such phenotypes may include beneficial drug effect, failure of drug or ablation, or 
adverse drug effect. Newer “next-generation” sequencing technologies can interrogate 
whole candidate genes or pathways, and analytical approaches to identifying true positive 
signals in this work are in development.  
3. “Unbiased” approaches: Human genomes contain millions of common polymorphisms, such 
as single nucleotide polymorphisms (SNPs) or copy number variations (CNVs). The 
genome-wide association study (GWAS) paradigm8,9 compares hundreds of thousands of 
such variants in cases and controls (or across a continuous trait) to identify, in an unbiased 
fashion, loci modulating the trait. Because GWAS searches for common variants that confer 
modest odds ratios, large cohorts are required,10,11 and there is a high risk of false positive 
associations; thus, the accrual of a very large well-ascertained cohorts (as in this proposal) 
represents an important enabling tool for these studies.  A compromise approach has been 
to focus not on high priority single genes or single variants, but to cast a somewhat wider 
net and focus on variation in genes within a “pathway”, e.g. a cholesterol12 or thrombosis 
“pathway”. Indeed, this approach has been adopted to interrogate >1500 SNPs in 18 
candidate genes in an “arrhythmia drug response pathway” to study determinants of drug-
induced arrhythmias, among others.13  
 
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CABANA Confidential 22 November, 2013                                                                    Page 68 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
2.0 
Rationale and Specific Aims 
The primary goal of the Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation 
(CABANA) trial is to establish appropriate roles for medical and ablative intervention by randomizing 
2,000 – 2,200 patients. This protocol will create CABANAgene: a resource that will 
accumulate DNA samples from CABANA subjects to enable subsequent genotype-
phenotype studies, based on the rationales described above.   
Examples of issues that CABANAgene could address include:  
• 
predictors of response to antiarrhythmic or rate control drug therapies 
• 
predictors of response to ablation therapy 
• 
predictors of response to anticoagulation therapy 
• 
genetic factors defining AF subtypes  
• 
predictors of LA morphology size and function 
o Is it primary AF or AF secondary to underlying heart disease  
o Is it early recurrent atrial fibrillation (ERAF) 
o Does it increase the non pulmonary vein foci. 
o Left Atria and Stroke 
o Anticoagulant issues  
 
All projects will require approval of the CABANAgene Principal Investigators and CABANA 
Executive Committee. The CABANAgene project is included in the Pharmacogenetics of Arrhythmia 
Therapy (PAT) node of the Pharmacogenomics Research Network (PGRN).  CABANAgene’s 
participation under the PGRN umbrella will also provide access to advanced genotyping and 
genetic statistical methods via this resource.   
3.0 
Previous Human Studies 
PAT investigators, in collaboration with other arrhythmia groups around the country and 
internationally, have used family studies, candidate gene studies, and unbiased approaches to 
identify genetic predictors of variability in AF susceptibility and in response to drugs used to treat 
AF.  Examples of these findings are presented here in brief to illustrate the value of a resource such 
as CABANAgene with well-phenotyped patients and outcomes in advancing AF-related genome 
science. One important conclusion to draw from the studies presented is that large datasets, such 
as Framingham, the Vanderbilt AF registry, the German AF network, or CABANAgene are enabling 
for contemporary unbiased genomic studies.14-17 In addition, large datasets permit the accrual of 
subjects with specific intermediate phenotypes that may relate to AF risk.  Examples of such 
phenotypes include prolonged P wave duration,4 atrial fibrillatory rate derived from frequency-
domain analysis of surface ECGs during AF,18 and right precordial J point elevation, that is reported 
to be common in lone AF19 and that we have observed with AF-associated mutations in sodium 
channel genes.20 A resource such as CABANAgene will allow much more rigorous exploration of 
the relationships among these endophenotypes, genetic variants that underlie them, and clinical 
course in AF.   
Family studies 
With the support of the NHLBI’s Resequencing and Genotyping (RS&G) resource, PAT 
investigators screened subjects in the Vanderbilt AF Registry for variants in genes encoding ion 
candidate channel subunits (KCNQ1, KCNE1-5, KCNJ2, KCNA5, sodium channel [α- and β-
subunits], L-type Ca2+) and non-ion channel protein candidates (connexin40, PITX2, ANP).  Non-
synonymous variants in sodium channel α-subunits, β-subunits, and potassium channels have been 
identified in ~10% of subjects.  These cosegregate in extended kindreds (where they are available), 
and those studied to date show abnormal electrophysiology in vitro.5,20,21  One common feature in 
these kindreds is that penetrance is variable; that is, each kindred includes multiple mutation 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
carriers with early onset AF as well as other mutation carriers with no AF by age 50.  As described 
below, GWAS has identified common variants at chromosome 4q25 as risk factors for atrial 
fibrillation. We studied 12 families in which AF was present in ≥2 individuals who also shared a rare 
genetic variant in ion channel or related genes thought to cause familial AF. There were a total of 
33 subjects with AF before age 40 and 17 mutation carriers who had reached age 50 without AF. 
We found a very highly statistically significant association between the presence of common 4q25 
variants and clinical AF in these families (P<10-9): that is, those family members with AF carried 
both rare mutation as well the common susceptibility allele, while those with only the rare mutation 
(without the 4q25 susceptibility allele) did not display AF.22  These data support the overall concept 
that AF risk includes multiple genomic components; identifying these components requires large 
datasets.  In addition, the rare ion channel and other variants that we and others have identified in 
patients with AF have obvious (but as yet untested) therapeutic implications.  A gain of function 
potassium channel mutation would be predicted to respond to a potassium blocking drug, while 
sodium channel blockers would be predicted to be ineffective (and possibly proarrhythmic) in 
subjects with AF arising from slow conduction or decreased sodium current. 
Candidate gene studies 
Candidate gene approaches have been especially useful in pharmacogenomics, where single 
variants in genes responsible for drug disposition or for the interaction of drugs with their 
pharmacologic targets may produce large and clinically important variability in drug action.1  This is 
especially the case for drugs with narrow therapeutic indexes such as antiarrhythmic and 
anticoagulant agents. We and many others (including the International Warfarin Pharmacogenomic 
Consortium)23-27 have shown that ~50% of the variability in warfarin steady state dose is determined 
by variants in CYP2C9 (responsible for the drug’s metabolism) and VKORC1 (encoding the warfarin 
target).  In addition, PAT investigators have shown that the time to initial anticoagulation is 
determined by VKOC1 variants. The extent to which warfarin use will be supplanted by newer 
agents in CABANA is uncertain, but the collection of a large set of patients with well-characterized 
warfarin responses will be of considerable interest to the IWPC and other investigators in the 
warfarin and anticoagulant areas.   
Proarrhythmia is one well-recognized risk during drug therapy for AF.  We have used both 
candidate and unbiased approaches to address risk for drug-induced torsades de pointes (diTdP) in 
large cohorts generated by collaborations among multiple sites. Screening coding and flanking 
regions of these has identified potential contributory rare DNA variants, i.e. sub-clinical congenital 
long QT syndrome, in <10-20% of patients with diTdP.  We used a candidate pathway approach to 
interrogate 1536 common SNPs in 18 candidate genes and identify rs1805128, resulting in KCNE1 
D85N, as a risk allele: the allelic odds ratio for 176 cases versus 530 drug-exposed controls was 
9.0 (95% confidence interval: 3.5-22.9), and the variant allele was present in 8.6% of cases, 2.9% 
of drug-exposed controls, and 1.8% of population controls. Other drug hypothesis: Do drugs create 
problems due to genetics? Is there a ‘hopeless’ patient population? 
Unbiased approaches 
The GWAS paradigm has been successfully applied to identify risk loci for AF at Chromosomes 
4q25, 1q21 and 16q22.14,15,28 Interestingly, these loci not only represent risk factors for the 
development of AF, but also appear to predict development of AF after cardiac surgery,29 stroke,30  
and (in smaller studies) the success of ablation therapy31 and of antiarrhythmic or rate control 
therapy in AF.32,33  The biologic underpinnings of this increased risk are now being explored in 
mouse models and for the 4q25 locus (the one with the largest signal), evidence points to variable 
expression of a cardiac isoform of the transcription factor PITX2c.34,35  Consistent with this 
observation is the finding that multiple SNPs at the 4q25 locus act independently to modulate AF 
risk;36 this finding allows the identification of small sets of subjects drawn from larger databases 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
(such as CABANA) in whom response to ablative or medical therapies may differ on a genetic 
basis.  GWAS has also been applied to study warfarin steady state dose, and has identified variants 
in CYP2C9, VKORC1, and CYP4F2 (which plays a role in vitamin K metabolism) with major effects, 
but no other common variants.25,26   
4.0 
Inclusion/Exclusion Criteria 
Inclusion/exclusion in this study is dependent only on inclusion/exclusion in the primary study. The 
CABANA specific criteria can be found in Appendix A.  
5.0 
Enrollment/Randomization 
All enrollment will be performed at CABANA participating centers and subjects enrolled in CABANA 
are eligible to participate in this ancillary study. There will be no randomization specific to 
CABANAgene. No subjects will be enrolled at the CABANAgene Coordinating Center.  
6.0 
Study Procedures 
Consent: PGRN has developed standard suggested language for consent to perform genomic 
analyses of the type proposed here, subject to local IRB revision. We have created a model 
consent form in which this language was incorporated and this form is provided to each site for local 
modification if necessary and IRB submission. IRBs at PGRN affiliated centers have adopted this or 
very similar language in most instances.  
 
Current NIH guidelines require that the results of large genotyping efforts accomplished with NIH 
funds be deposited in public databases such as the database for Genotypes and Phenotypes 
(dbGaP).  dbGaP submissions include deidentified phenotypic data; thus, current consent forms 
include consent for such deposits.   
 
Once consent is obtained, a 30 mL blood sample for subsequent DNA extraction will be obtained at 
any time during the CABANA trial, preferably at the time of a scheduled venipuncture.  Each study 
site will be provided with kits for mailing the samples to the Vanderbilt DNA Resources Core, where 
DNA extraction and archiving will be performed. Contents of each subject kit and instructions are 
listed in Appendix B.  If it is determined that a sample is damaged/unusable upon arrival, 
communication with the sender will be made and a replacement sample will be requested. 
 
The Vanderbilt DNA Resources Core has extensive experience in storing and extracting DNA from 
over 100,000 individuals. 2D bar-coding of samples and aliquots eliminates repetitive paper work, 
thereby reducing recording errors. All DNA is currently extracted using the automated Autopure 
system (Gentra systems, Minneapolis). Samples are logged into the system using a study specific 
code number to match with the assigned DNA Resources Core sample number, and only the 
sample number is used thereafter.  Each sample must be associated with an IRB-approved consent 
form. The Autopure system generates very high quality, high yield (routinely 20-30 μg/ml), and 
substantial consistency across samples.  All samples are quantitated and stored at 4oC in a locked 
cold room.  An aliquot is also frozen at -20oC to serve as a back-up in case a sample is accidentally 
contaminated, lost, or depleted.  DNA samples for approved CABANA projects can be provided to 
investigators in a range of formats, most commonly 96-well plates.   
 
Results of the tests run on specific samples will not be shared with or reported to subjects, care 
providers, or the general public. 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Genotyping 
CABANA currently anticipates enrolling in 2009-2015, with an average of approximately 5 years  
follow-up.  Thus initial analyses of end-points will not be available until interim analysis  early 2018. 
We anticipate that investigators will develop hypotheses that require accrual of specific genotypes 
(e.g. CYP2D6 and beta-blocker response; 4q25 variants and response to ablation therapy).  
Further, we anticipate that the size and scope of the CABANA dataset will provide an opportunity 
for directed resequencing to test other hypotheses (e.g. do patients with a specific AF 
endophenotype have coding region variants in specific candidate genes?).  Finally, we anticipate 
that unbiased approaches will be proposed to address other questions (e.g. are there genomic 
regions that predict response to ablation therapy?); we anticipate that genome-wide analysis will 
still be the standard for addressing these questions, although whole genome resequencing may be 
a competing method by 2014.  
 
Funds to support accrual of DNA at participating centers, mailing costs, and DNA extraction at 
Vanderbilt have been incorporated into the CABANAgene proposal.  We anticipate that the process 
to access CABANAgene samples by CABANA (or other) Investigators will require submission of a 
specific study plan, including appropriate quality control and statistical analysis, access to clinical 
variables in the central CABANA dataset, and approval by the CABANA steering committee.  
 
The current PAT budget includes support for genome-wide genotyping and analysis of genotype-
drug response phenotype relations and these will be used to develop a separate PAT proposal to 
access CABANA samples. The specific questions to be addressed and platform to be used will be 
selected at the time of projected analysis, at the termination of the trial (~3-5 years after study 
initiation). Technologies available at the Vanderbilt, and at multiple other sites in PGRN, include 
Affymetrix and Illumina high-throughput systems, as well as robust lower throughput systems for 
targeted genotyping, such as the Illumina Bead-station, Sequenom, or Taqman. Genotyping 
laboratories in PGRN adhere to standard practice, including appropriate negative and positive 
controls, to ensure that the genotyping results are robust.  Genotypic and phenotypic data will be 
combined in an Oracle database to allow biostatistical and genetic epidemiologic analysis. The PAT 
center has developed expertise in robust quality control and statistical analyses of these large 
datasets.   
 
7.0 
Risks 
Minor soreness and/or bruising when blood is taken, feeling lightheaded, or although rare, 
continued bleeding or infection at the site of the needle stick are risks involved at the participating 
centers. 
 
The risk of released PHI exists, but this is minimized by the use of code numbers in the DNA 
Resources Core. 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
Any adverse events or unanticipated problems occurring at participating centers will be reported to 
the IRB of record. Any release of information that occurs will be immediately reported to the PI and 
the Vanderbilt IRB. 
 
9.0 
Study Withdrawal/Discontinuation 
Participation in this study is voluntary. A patient who has agreed to participate in this study may 
leave at any time. This will not affect their regular care or cause them to lose any benefits they 
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CABANA Confidential 22 November, 2013                                                                    Page 72 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
would normally have. If a patient wants to withdraw, they must contact the primary study physician. 
Samples in storage at the Vanderbilt University DNA Resources Core will be destroyed upon 
notification from the participating centers. Research data that have already been gathered using the 
withdrawn subject’s sample will not be withdrawn. 
 
The investigator or research sponsor (NHLBI) may decide to withdraw a subject if the study is 
stopped. The sponsor may stop the study at any time. 
 
10.0 
Statistical Considerations 
Study power will depend on the number of genotypes and other variables being assessed (the 
problem of multiple comparisons), the effect size, the sample size, and variance of the phenotype 
under study. For genome-wide experiments, even in a set of this magnitude, any analysis is likely to 
be underpowered and to require replication by analysis in other populations or by other approaches 
(e.g. studies of biologic function).  We anticipate that use of the CABANAgene resource will be 
conditioned on a statistical plan appropriate for the study size proposed.  
 
11.0 
Privacy/Confidential Issues 
Samples will only be labeled with a study identification (ID) number. No other data will be included 
that would identify a person. Any health information which might identify the patient will not be 
available to any person or group other than the investigators of this study. The files with the ID 
numbers that link the sample to the patient will be kept in a locked, secure area accessible only to 
the study team. The results of any study using the resource may be published for all the subjects as 
a group but will not identify the patient individually. 
 
12.0 
Follow-up and Retention 
Samples for DNA extraction will be collected and genotyping will be performed the 4th year of the 
study. Following completion of the primary study, data analyses will be performed once genotyping 
is complete. Genotype data may be archived indefinitely for subsequent analyses. The DNA sample 
will be kept for an unknown length of time (maybe years) for future research.  The sample will be 
destroyed when it is no longer needed. Samples will be used for research only and will not be sold 
or used to make products that could be sold for money. 
 
 
 
 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
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Kostulas K, Ng MC, Baum L, So WY, Wong KS, Chan JC, Furie KL, Greenberg SM, Sale M, 
Kelly P, Macrae CA, Smith EE, Rosand J, Hillert J, Ma RC, Ellinor PT, Thorgeirsson G, 
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Vasan RS, Nothen MM, Macrae CA, Stricker BH, Hofman A, Uitterlinden AG, Levy D, 
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Kaab S. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 
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Lunetta KL, Larson MG, Levy D, Macrae CA, Ruskin JN, Wacker A, Schomig A, Wichmann 
HE, Steinbeck G, Meitinger T, Uitterlinden AG, Witteman JC, Roden DM, Benjamin EJ, 
Ellinor PT. Large scale replication and meta-analysis of variants on chromosome 4q25 
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Intermediate ECG Phenotype in Patients with Persistent Lone Atrial Fibrillation. Circ 
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Roden DM. Mutations in Sodium Channel Beta-1 and Beta-2 Subunits associated with Atrial 
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Jr., Roden DM. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. 
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Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated 
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DM, Stein CM. Genetic Determinants of Response to Warfarin during Initial Anticoagulation. 
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KE, Veenstra DL, Rettie AE. Effect of VKORC1 haplotypes on transcriptional regulation and 
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P. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal 
genetic determinants of warfarin dose. PLoS Genet 2009;5:e1000433. 
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Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl 
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 28.  Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, Chung MK, Sinner MF, deBakker P, 
Mueller M, Lubitz SA, Fox E, Darbar D, Smith NL, Smith JD, Schnabel R, Soliman EZ, Rice 
KM, Van Wagoner DR, Beckmann BM, van Noord C, Wang K, Ehret GB, Rotter JI, Hazen S, 
Steinbeck G, Makino S, Boerwinkle E, Milan DJ, Perz S, Kottgen A, Mobus S, Newton-Cheh 
C, Mohlenkamp S, Wang TJ, Ramachandran V, Nothen M, Macrae CA, Levy D, Nelis M, 
Metapalu A, Topol EJ, Psaty BM, Roden DM, Meitinger T, Wichmann HE, Witteman JC, 
Barnard J, Arking DE, Benjamin EJ, Heckbert SR, Kääb S. Common Variants in the Calcium 
Activated Potassium Channel, KCNN3, are Associated with Lone Atrial Fibrillation. 
submitted 2009. 
 29.  Body SC, Collard CD, Shernan SK, Fox AA, Liu KY, Ritchie MD, Perry TE, Muehlschlegel 
JD, Aranki S, Donahue BS, Pretorius M, Estrada JC, Ellinor PT, Newton-Cheh C, Seidman 
CE, Seidman JG, Herman DS, Lichtner P, Meitinger T, Pfeufer A, Kaab S, Brown NJ, Roden 
DM, Darbar D. Variation in the 4q25 chromosomal locus predicts atrial fibrillation after 
coronary artery bypass graft surgery. Circ Cardiovasc Genet 2009;2:499-506. 
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A, Kostulas K, Kuhlenbaumer G, Bevan S, Jonsdottir T, Bjarnason H, Saemundsdottir J, 
Palsson S, Arnar DO, Holm H, Thorgeirsson G, Valdimarsson EM, Sveinbjornsdottir S, 
Gieger C, Berger K, Wichmann HE, Hillert J, Markus H, Gulcher JR, Ringelstein EB, Kong 
A, Dichgans M, Gudbjartsson DF, Thorsteinsdottir U, Stefansson K. Risk variants for atrial 
fibrillation on chromosome 4q25 associate with ischemic stroke. Ann Neurol 2008;64:402-
409. 
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and atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2010;55:747-753. 
 32.  Vaglio JC, Rowan SB, Stubblefield T, Carter S, Roden DM, Darbar D. Genetic and clinical 
predictors of response to rate control therapy in patients with atrial fibrillation. Circulation 
2008;118:S828. 
 33.  Rowan SB, Estrada JC, Stubblefield T, Kucera G, Carter S, Roden DM, Darbar D. A single 
nucleotide polymorphism at 4q25 associated with atrial fibrillation modulates symptomatic 
response to antiarrhythmic drug therapy. Heart Rhythm 2009;6:PO04-7. 
 34.  Mommersteeg MTM, Brown NA, Prall OWJ, de Gier-de Vries C, Harvey RP, Moorman AFM, 
Christoffels VM. Pitx2c and Nkx2-5 Are Required for the Formation and Identity of the 
Pulmonary Myocardium. Circ Res 2007;101:902-909. 
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susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification. Proc Natl 
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 36.  Lubitz SA, Sinner MF, Lunetta KL, Makino S, Pfeufer A, Rahman R, Veltman CE, Barnard J, 
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SM, Furie KL, van Noord C, Boerwinkle E, Stricker BHC, Witteman J, Smith JD, Chung MK, 
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Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
Appendix A:  CABANA Inclusion / Exclusion Criteria 
 
Inclusion Criteria 
To be eligible for the trial, subjects must meet all of the following criteria: 
1. Over the preceding 6 months have:  
a) ≥2 paroxysmal (electrocardiographic documentation of at least 1) AF episodes lasting 
≥1 hour in duration: (that terminate spontaneously within 7 days or cardioversion is 
performed within 48h of AF onset): or 
b) electrocardiographic documentation of 1 persistent AF episode: (sustained for ≥7 days 
or cardioversion is performed more than 48h after AF onset): or  
c) electrocardiographic documentation of 1 longstanding persistent AF episode:  
(continuous AF of duration >1 year). 
2. Warrant active therapy (within the past 3 months) beyond simple ongoing observation  
3. Be eligible for catheter ablation and ≥2 sequential rhythm control and/or ≥2 rate control 
drugs.  
4. Be ≥65 yrs of age, or <65 yrs with one or more of the following risk factors for stroke: 
Hypertension (treated and/or defined as a BP >140/90 mmHg) [90], Diabetes (treated and/or 
defined as a fasting glucose ≥126 mg/dl) [91], Congestive heart failure (including systolic or 
diastolic heart failure), Prior stroke, TIA or systemic emboli, Atherosclerotic vascular disease 
(previous MI, peripheral arterial disease or aortic plaque), LA size >5.0 cm (or volume index 
≥40 cc/m2), or EF ≤35. Subjects <65 yrs of age whose only risk factor is hypertension must 
have a second risk factor or LV hypertrophy to qualify. 
5. Have the capacity to understand and sign an informed consent form. 
6. Be ≥18 years of age. 
 
NOTE: Subjects may have recent onset AF (in the past 4-6 months), AF present for a longer time 
period, or may have been treated with a single anti-arrhythmic drug, providing they remain 
realistically eligible for ≥2 membrane active drugs and/or ≥2 rate control agents. Patients receiving 
new drug therapy initiated within the previous 3 months may continue that therapy if randomized to 
the drug therapy arm. Reasonable expectation of a response to therapy must be present. Subjects 
will not be excluded because of advancing age or underlying heart disease. Subjects with a history 
of a single episode of paroxysmal AF do not meet the “crossing the threshold/warranting therapy” 
litmus test. Subjects with persistent or long-standing persistent AF will require at least 1 
documented episode, if it is of sufficient clinical importance that drug or ablative therapy is 
warranted. Subjects can be randomized before cardioversion, even if restoration of sinus rhythm is 
a desired endpoint of therapy. Patients may have documented atrial flutter in addition to atrial 
fibrillation and remain eligible for enrollment.  
 
3.2 
Exclusion Criteria 
If a subject has any of the following criteria, he or she may not be enrolled in the study: 
1. Lone AF in the absence of risk factors for stroke in patients <65 years of age  
2. Patients who in the opinion of the managing clinician should not yet receive any therapy for 
AF 
3. Patients who have failed >2 membrane active anti-arrhythmic drugs at a therapeutic dose 
due to inefficacy or side effects (Table 5.2.2) 
4. An efficacy failure of full dose amiodarone treatment >8 weeks duration at any time 
5. Reversible causes of AF including thyroid disorders, acute alcohol intoxication, recent major 
surgical procedures, or trauma  
6. Recent cardiac events including MI, PCI, or valve or bypass surgery in the preceding 3 
months 
Confidential


 
CABANA Confidential 22 November, 2013                                                                    Page 77 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
7. Hypertrophic obstructive cardiomyopathy (outflow track) 
8. Class IV angina or Class IV CHF (including past or planned heart transplantation) 
9. Other arrhythmias mandating anti-arrhythmic drug therapy (i.e. VT, VF) 
10. Heritable arrhythmias or increased risk for torsade de pointes with class I or III drugs 
11. Prior LA catheter ablation with the intention of treating AF 
12. Prior surgical interventions for AF such as the MAZE procedure 
13. Prior AV nodal ablation 
14. Patients with other arrhythmias requiring ablative therapy  
15. Contraindication to appropriate anti-coagulation therapy 
16. Renal failure requiring dialysis 
17. Medical conditions limiting expected survival to <1 year 
18. Women of childbearing potential (unless post-menopausal or surgically sterile) 
19. Participation in any other clinical mortality trial (Participation in other non-mortality trials 
should be reviewed with the clinical trial management center)   
20. Unable to give informed consent 
 
NOTE: Exclusion Criterion #3 includes failed membrane active antiarrhythmic drugs started within 3 
months prior to enrollment. Prior ablation of the cavo-tricuspid isthmus alone is not an 
exclusion if the patient develops subsequent recurrent AF. Planned atrial flutter ablation in 
combination with the left atrial ablation is not an exclusion.  
 
Appendix B: CABANAgene Kit Contents and Instructions 
 
Patient Kit Contents 
I. Blood Draw supplies 
one pair (1 pair) disposable gloves 
one (1) tourniquet 
two (2) alcohol Swabs 
one (1) #23 or 21 G  Butterfly with tube holder 
three (3) 5cc EDTA purple top Vacutainer tubes 
one (1) gauze ball 
one (1) band-aid 
 
II. 3-Tube Mailing System 
one (1) absorbent square 
one (1) styrofoam container 
one (1) strip of red sealing tape 
one (1) biohazard bag 
one (1) cardboard outer shipping container 
one (1) UN 3373 Diagnostic Specimen label 
one (1) FedEx ClinicalPak 
one (1) FedEx Airbill with completed ship to information 
 
III. Instructions with contact information 
Instructions for Blood Draw and Shipping 
Blood draw and shipping supplies included in the patient kit are listed above.  Please draw blood 
Monday-Thursday and ship overnight via FedEx (or UPS) for arrival at Vanderbilt Tuesday-Friday 
am.  Notify receiving lab by submitting subject sample(s) at website address 
I. Blood Draw 
Confidential


 
CABANA Confidential 22 November, 2013                                                                    Page 78 of 78 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) 
 
1. Draw 3 purple top Vacutainer tubes (5cc each).  
 
2. Mix the blood well with the anticoagulant by gently inverting the tube several times.   
 
3. Label the tubes with the Sample ID.  Please keep the samples at room temperature. 
 
II. Shipping 
 
1. Package samples by securely placing the blood tubes in the styrofoam container slots.   
 
2. Place the absorbent pad on top of the blood tubes and close the container.   
 
3. Peel off the protective strip from the red tape and seal the styrofoam container with the 
tape.   
 
4. Place the sealed styrofoam container inside the biohazards bag and seal the bag.   
 
5. Place the sealed biohazards bag inside the cardboard outer shipping container.   
 
6. Affix the UN 3373 Diagnostic Specimen label to the outside of the cardboard shipping 
container.   
 
7. Place the shipping container inside the FedEx Clinical Pak and seal the pack   
 
8. Complete the FedEx Airbill, including date and sender information.   
 
9. Ship overnight at room temperature via FedEx. 
 
10. Notify receiving lab of shipment:   
 
 Login to the member page at website address and Submit Subject Sample(s)  
 
III. Ancillary Study Contact: 
Kris Norris, RN 
 
 
 
 
Phone: 615-936-1131 
Fax: 
615-936-2222 
E-mail: kris.norris@vanderbilt.edu 
 
      IV. Shipping Address:  Vanderbilt University Medical Center  
                                               1266 MRB IV 
                                                Nashville, TN  37232-0575 
 
 
 
Confidential

SAP_001.pdf: 
 
 
 
 
 
 
 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for 
Atrial Fibrillation Trial – Statistical Analysis Plan 
NCT: 00911508 
 
Date: 26 February, 2018 
 


1 
 
Statistical Analysis Plan for CABANA 
 
Analysis Plan dated February 26, 2018 
Duke Clinical Research Institute 
 
              Protocol Date:  November 22, 2013 (Version 3.5) 
              Sponsor:            National Heart, Lung, and Blood Institute 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
Table of Contents 
1.  Study Title ................................................................................................................................................................ 3 
2.  Study Overview ........................................................................................................................................................ 3 
3.  Objectives ................................................................................................................................................................. 3 
3.1   Primary Objective .............................................................................................................................................. 3 
3.2   Secondary Objectives ........................................................................................................................................ 4 
4.  Subject Randomization ............................................................................................................................................. 4 
5.  Primary Analysis Population .................................................................................................................................... 4 
6.  Data Sources ............................................................................................................................................................. 5 
7.  General Analysis Methodology ................................................................................................................................ 5 
7.1   Demographic and Baseline Analyses................................................................................................................. 6 
7.2   Disposition of Subjects ...................................................................................................................................... 6 
7.3   Missing Data ...................................................................................................................................................... 6 
8.  Primary Endpoint Analysis ....................................................................................................................................... 7 
8.1   Other Analyses of Primary Endpoint Data (as randomized): ............................................................................. 8 
9.  Analysis of Secondary Endpoints ............................................................................................................................. 9 
9.1   All-cause mortality (key secondary endpoint) ................................................................................................... 9 
9.2   All-cause Mortality or Cardiovascular Hospitalization ................................................................................... 10 
9.3   All-cause Mortality, Stroke, or Hospitalization for Heart Failure or Acute Ischemic Events ......................... 11 
9.4   Cardiovascular Death....................................................................................................................................... 11 
9.5   Cardiovascular Death or Disabling Stroke ...................................................................................................... 12 
9.6   Arrhythmic Death or Cardiac Arrest ............................................................................................................... 13 
9.7   Heart Failure Death.......................................................................................................................................... 13 
9.8   Recurrent Atrial Fibrillation ............................................................................................................................ 14 
9.9   Cardiovascular Hospitalization ........................................................................................................................ 15 
9.10 Medical Costs, Resource Use and Cost Effectiveness. .................................................................................... 17 
9.11 Quality of Life. ................................................................................................................................................ 17 
9.12 Major Non-Endpoint Adverse Events. ............................................................................................................. 17 
9.13 LA Size, Morphology and Function. ............................................................................................................... 17 
10. “On-Treatment” Analysis ...................................................................................................................................... 18 
11. Per-Protocol Analysis ............................................................................................................................................ 19 
12. Multiple Comparisons ........................................................................................................................................... 19 
13. Interim Analyses .................................................................................................................................................... 20 
References ................................................................................................................................................................... 22 
 
 
 


3 
 
 
1. Study Title 
 
Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) 
 
 
2. Study Overview 
 
CABANA is a multi-center randomized clinical trial to assess the safety and efficacy of 
percutaneous left atrial catheter ablation versus antiarrhythmic drug therapy in subjects who are 
at least 18 years of age and have new onset or under-treated paroxysmal, persistent, or long-
standing persistent atrial fibrillation (AF) and warrant therapy for their arrhythmia.  The study 
population consists of 2,204 subjects enrolled at 126 clinical sites over a period of approximately 
six years. Subjects were randomized in equal proportions (1:1) to receive either catheter ablation 
or drug therapy and followed at regular intervals for the duration of the study.  The minimum 
length of follow-up will be slightly less than 2 years, and the median duration of follow-up will 
be approximately 4 years.  At study entry and during the follow-up period, extensive clinical, 
quality-of-life, and economic data are collected.  
 
 
3. Objectives 
 
3.1 Primary Objective 
 
The primary objective of CABANA is to determine whether the treatment strategy of 
percutaneous left atrial catheter ablation for the purpose of eliminating atrial fibrillation will 
improve clinical outcomes compared to treating the arrhythmia with current state-of-the-art drug 
therapy consisting of either rate control or rhythm control drugs. 
 
The primary endpoint is the time to the first event among a composite of major clinical 
outcomes consisting of  
• Death (all-cause) 
• Disabling stroke 
• Serious bleeding 
• Cardiac arrest 
 
The primary hypothesis of the study is that the treatment strategy of percutaneous left atrial 
catheter ablation will reduce the incidence of this composite endpoint in patients with untreated 
or under-treated AF warranting therapy, compared to current state-of-the-art drug therapy.   
 


4 
 
3.2 Secondary Objectives 
 
The secondary objectives are to compare the following clinical, economic, and quality-of-life 
outcomes in subjects randomized to catheter ablation versus state-of-the-art drug therapy: 
 
1. All-cause mortality (key secondary endpoint) 
2. All-cause mortality or cardiovascular hospitalization 
3. All-cause mortality, stroke, or hospitalization for heart failure or for an acute ischemic 
event 
4. Cardiovascular death 
5. Cardiovascular death or disabling stroke 
6. Arrhythmic death or cardiac arrest 
7. Heart failure death 
8. Recurrent atrial fibrillation 
9. Cardiovascular hospitalization 
10. Medical costs, resource utilization, and cost effectiveness 
11. Health-related quality-of-life 
12. Composite adverse events 
13. Left atrial size, morphology, and function  
 
To aid in the interpretation of the primary and several of the secondary endpoint comparisons, 
the individual components of the primary endpoint (in addition to death) will also be summarized 
between the randomized arms of the trial.  
  
 
4.  Subject Randomization 
 
The treatment modalities being studied in CABANA are clinically-established treatment 
strategies that are used routinely across the U.S. and around the world.  No experimental drug or 
treatment is involved. The trial intervention is simply the random assignment of the subjects to 
one or the other of the two treatment strategies.  
 
Eligible subjects who provided written informed consent and met all inclusion and no exclusion 
criteria were randomly assigned in equal proportions (1:1) to either the catheter ablation arm or 
the drug arm using permuted blocks, stratified by clinical site.  Subject randomization was 
accomplished by telephone through a centralized toll-free Interactive Voice Response System 
(IVRS). 
 
 
5. Primary Analysis Population 
 
Except where otherwise noted, all randomized subjects will be included in the analysis 
population for assessing the primary and secondary endpoints.  All major treatment comparisons 
between the randomized groups in the trial will be performed according to the principle of 
"intention-to-treat" (ITT); that is, subjects will be analyzed and endpoints attributed according to 
the treatment arm to which the patients were randomized, regardless of subsequent crossover or 


5 
 
post-randomization medical care.  As explained later in this document (section 10), some 
additional analyses will be conducted using “on-treatment” data.   
 
 
6. Data Sources 
 
The enrolling clinical sites complete a series of electronic Case Report Forms (eCRF) for each 
subject randomized, including demographic, clinical, and quality of life forms at enrollment and 
at specified follow-up intervals (the follow-up intervals are detailed in the study protocol), event 
forms for death, neurological events, bleeding, cardiac arrest, and other ancillary forms as 
required. 
 
Clinical data are collected using the InForm electronic data capture (EDC) system.  Except as 
noted below in section 9.8, rhythm data are collected using the “CABANA Box,” a rhythm 
monitoring system provided for each patient by Medicomp.  The rhythm monitoring data are sent 
from Medicomp to the Duke Clinical Research Institute (DCRI), where a determination is made 
as to which rhythms should be sent to the ECG core lab in Seattle for review and adjudication.  
The core lab sends adjudicated results back to the DCRI.  Sites with any subjects not using the 
“CABANA Box” submit rhythm data on those subjects through a secure portal using the 
CABANA sharepoint website, which is then processed and submitted to the ECG core lab for 
adjudication.  CT/MRI data are received and processed by Mayo Clinic’s Imaging Analysis 
Laboratory, and the information is then transferred to the DCRI.   
 
All data collected in the study are managed and analyzed at the CABANA Statistical and Data 
Coordinating Center at the DCRI.  The InForm eCRF data are carefully reviewed, queried as 
needed, and then downloaded as raw SAS data files, and further review and checking of the data 
occur.  The raw SAS data, analysis datasets, and analysis programs are stored on the secure 
DCRI statistical server.  Final analyses will be performed at the DCRI using SAS version 9.4 or 
higher (SAS Institute Inc., Cary, NC).  All programs written to create analysis datasets and 
perform analyses will be validated according to SOPs established by the DCRI Statistical 
Programming group. 
 
 
 
7. General Analysis Methodology 
 
As stated previously and except where otherwise noted, all major treatment comparisons will be 
performed according to the principle of "intention-to-treat.”  Subjects will be analyzed and 
endpoints attributed according to the treatment arm to which patients were randomized, 
regardless of subsequent crossover or post-randomization medical care.       
 
Appropriate statistical models and tests will be used to examine the effect of the treatment 
strategies on the primary and secondary endpoints.  For time-to-first-event endpoints, the log-
rank test1 and Cox proportional hazards model2 will be used for statistically comparing the 
treatment groups unless otherwise specified.  Additional perspective regarding the interpretation 
of the data will be provided through extensive use of confidence intervals and graphical displays, 
including plots of Kaplan-Meier3 event-rate estimates.  All statistical comparisons will be 


6 
 
performed using two-sided significance tests and a nominal level of significance of α=0.05 
unless otherwise specified.    
 
7.1. Demographic and Baseline Analyses 
 
Descriptive summaries of the distribution of continuous baseline variables will be presented in 
terms of percentiles (median, 25th and 75th percentiles), while discrete variables will be 
summarized in terms of frequencies and percentages.  Statistical comparisons of treatment 
groups with respect to baseline characteristics will be limited to selected variables and disease 
factors known to influence prognosis.  These variables will include: age, sex, race, descriptors of 
comorbidity, heart failure class, type of AF (paroxysmal, persistent or permanent), years since 
onset of AF, days from most recent qualifying episode of atrial fibrillation to enrollment, 
presence/absence of structural heart disease, and CHA2DS2-VASc score.  For comparisons of 
treatment groups with respect to continuous or ordinal baseline variables, the nonparametric 
Wilcoxon rank-sum test will be used.  Group comparisons with respect to discrete baseline 
variables will use the Pearson’s chi-square test or Fisher’s exact test as appropriate. 
 
7.2   Disposition of Subjects 
 
The disposition of subjects (number randomized, number who received the randomly assigned 
treatment, number of treatment crossovers, number of patients who withdrew consent, and 
number lost to follow-up) will be summarized overall and by treatment arm.  The summary of 
treatment crossovers will distinguish the patients randomized to the drug arm who subsequently 
underwent catheter ablation (crossed over to ablation) during the course of their follow-up and 
the patients randomized to the ablation arm who never received an ablation.  The distribution of 
the length of follow-up for the overall study population and for each randomized arm will be 
characterized in terms of percentiles (median, 25th, and 75th percentiles).  The number and 
percentage of patients who had at least 3 years of follow-up, and at least 5 years of follow-up 
will also be tabulated and reported.  Among patients in the drug arm who crossed over to 
ablation, the distribution of length of follow-up prior to the crossover will be described in terms 
of percentiles.  Also the distribution of follow-up among patients who withdrew consent (i.e., 
patients who withdrew prior to the protocol-specified 3 years of follow-up) will be summarized 
in terms of percentiles.  Additionally, the number and percentage of patients who withdrew 
consent before 3 years, after 3 to <5 years, and after 5 years will be tabulated.      
 
7.3   Missing Data 
 
Missing data will be handled differently for covariates and endpoints. Data for covariates (see 
Section 8.1) are expected to be complete or near complete for all patients. Where missing data do 
occur, using single-imputation methods, continuous variables will be imputed using the median 
value and categorical variables will be imputed using the mode.   
 
Most primary and secondary endpoints are time-to-event analyses which rely on the ability to 
calculate the time from randomization (or in some cases time from the end of the 90-day 
blanking period) to when the event occurred or the date of last contact for censored individuals.  
Here, missing data may occur when: 1) a visit form or question that indicates if an event 
occurred (or not) is not completed, and 2) a form or question indicates that an event occurred, but 


7 
 
the event date is missing.  The first category prevents the assignment of whether an event 
occurred or not, while the second category prevents calculation of time to the event.  In all 
analyses, we consider only non-missing data in the determination of whether or not an event 
occurred (i.e., cases in category 1 will not be considered).  Time-to-event for known events when 
the event date is missing (category 2), will be assigned based on the visit with which the event is 
recorded.  For example, if the event is reported on the month 3 visit, then the time to event would 
be set to 91.26 days (365/12 * 3). If the event is reported on the month 6 visit, then the time to 
event would be set to 182.52 days (365/12 * 6), and so on for all visits up to month 96. If patients 
do not experience an event, and have an event-free status associated with a visit but no visit date 
on their last known visit, they will be assigned a censor date in the same manner. For patients 
with multiple events including a death, any imputed non-death event dates (e.g., cardiovascular 
(CV) hospitalization) will be forced to occur before the date of death. 
 
If an event or censored status is reported, but both the visit number and event/censored date are 
missing, then the date of event/censor will be imputed using relevant data and considered on a 
case-by-case basis.   
 
       
8.  Primary Endpoint Analysis 
 
Primary Endpoint:  Time from randomization to the first event among a composite of major 
clinical outcomes consisting of  
• Death (all-cause) 
• Disabling stroke 
• Serious bleeding 
• Cardiac arrest 
 
All possible events are carefully reviewed and adjudicated by a Clinical Events Committee 
(CEC) completely blinded to the randomized treatment assignment.   
 
Endpoint Definitions:  Detailed definitions for each of the events are outlined in the CEC 
charter.  We note that a disabling stroke during follow-up must be documented by a neurologic 
evaluation or brain CT / MR studies and result in a disabling, irreversible physical limitation defined 
by a Rankin Stroke Scale > 2.  Serious (or life-threatening) bleeding is considered to have occurred if 
intracranial bleeding or other bleeding occurs at any time during follow-up accompanied by 
hemodynamic compromise that requires surgical intervention or a transfusion of > 3 units of blood.  
The serious bleeding definition does not include bleeding occurring with cardiac perforation or 
tamponade.  
 
The time from randomization to the first event among the components of the primary composite 
endpoint will be measured (in days) for those who experienced an event and calculated as the 
date of the first event minus the date of randomization.  For patients who do not experience any 
of the component events or who withdraw consent or drop out of the study before experiencing 
an event, time from randomization to the date of last contact will be used in the analysis, and 
those patients will be considered as censored observations in the time-to-event analysis.    For 


8 
 
interim analyses, the best available endpoint data will be used (i.e., adjudicated data when 
available; otherwise site-reported event data). 
 
Statistical Methods:  The log-rank test1 will be the primary analytic tool for statistically 
assessing outcome differences between the two randomized treatment strategies with respect to 
the primary composite endpoint. This analysis will be conducted using PROC LIFETEST in 
SAS.  A hazard ratio (HR) and 95% confidence interval (CI) summarizing the difference in 
outcome between the two randomized arms will be computed using the Cox proportional hazards 
model2  (PROC PHREG in SAS), using treatment as the only predictor in the model.   
 
In addition to the statistical hypothesis testing, cumulative event rates will be calculated 
according to the method of Kaplan and Meier3 for each randomized arm as a function of time 
from randomization, and the estimated event probabilities will be displayed graphically.   
 
The methods described above will constitute the primary analysis of this endpoint. The primary 
hypothesis is defined as: 
H0:     Sa(t) = Sd(t), vs. 
Ha:     Sa(t) ≠ Sd(t), 
where Sa(t) is the event-free survivor function for the ablation arm of the trial, and Sd(t) is the 
event-free survivor function for the drug arm, both of which are a function of follow-up time t.  
In other words, we are testing whether the event-free survival experience of the two arms of the 
trial is the same vs. whether it is different.  The above hypothesis will be tested at a 2-sided 
significance level of 0.049 in the ITT population to account for a single interim analysis (see 
Section 13).  
Because the Cox model will be used for calculating a hazard ratio and confidence interval to 
summarize the difference in outcome between the two randomized arms, the proportionality 
assumption in the Cox model (i.e., constant hazard ratio over time) will be checked and tested 
through adding an interaction term (treatment*log(t)) to the Cox model, and by examining a plot 
of Schoenfeld residuals. 
The hypothesis as expressed above will also be used for the time-to-event analyses of secondary 
endpoints described below using a 2-sided significance level of 0.05. 
 
8.1 Other Analyses of Primary Endpoint Data (as randomized): 
 
Treatment comparison with covariate adjustment.  Using the Cox model, the effect of treatment 
strategy will be tested, adjusting for the following prospectively defined set of baseline patient 
characteristics that are expected to have a prognostic relationship with the primary endpoint: age 
(as a continuous variable), sex, minority status, baseline AF type, years since onset of AF, 
coronary artery disease, history of congestive heart failure, structural heart disease, hypertension, 
and CHA2DS2-VASc score.  These characteristics will serve as a prelude to analyses for 
examining differential treatment effects.  Structural heart disease will be defined as: history of 
valve disease with either surgical correction or percutaneous intervention, history of 


9 
 
cardiomyopathy, mitral valve regurgitation of moderate or greater severity, or mitral valve 
stenosis of moderate or greater severity. 
 
Differential treatment effects.  If there is an overall difference in outcome between treatment 
groups, supplementary analyses will be performed to assess whether the therapeutic effect is 
consistent across all patients, or whether it varies according to specific patient characteristics.  In 
particular, these analyses will focus on whether the relative therapeutic effect of ablation 
compared to drug therapy differs according to the following baseline variables: 
• Age (<65 , 65 to 74, and  >75 years) 
• Sex (male vs. female) 
• Race (white vs. racial minorities) 
• AF type (paroxysmal vs. persistent, or long-standing persistent) 
• Years since onset of AF (>1 vs ≤1) 
• Days from most recent qualifying episode of atrial fibrillation to enrollment (>12 vs ≤12 
days) 
• NYHA Heart Failure Class at enrollment (no heart failure or Class I vs. > Class II ) 
• History of congestive heart failure (yes vs. no) 
• Structural heart disease (present vs. absent) 
• Hypertension (present vs. absent) 
• Hypertension with LVH (present vs. absent) 
• CHADS2 (0 or 1 vs >1) 
• CHA2DS2-VASc score (0 or 1 vs >1) 
• Sleep Apnea (present vs. absent) 
• Family history of atrial fibrillation (yes vs. no) 
• Obesity (BMI >30 vs. < 30) 
• Left ventricular ejection fraction (LVEF) (≤35 vs >35) 
• North American vs. other international sites 
 
These analyses will utilize the Cox model and will be accomplished by testing for interactions 
between the randomized treatment strategy and the specific baseline variables listed above.  In 
addition to the formal assessment of treatment by covariate interactions, the effect of the 
treatment strategy characterized by a hazard ratio and 95% confidence interval will be calculated 
and displayed using a forest plot for the subgroups of subjects defined by the variables listed 
above.  These descriptive hazard ratios will be carefully interpreted in conjunction with the 
formal interaction tests.   
 
The effect of the treatment strategy may also be examined in other subgroups of clinical interest 
in addition to those listed above.   
 
9.  Analysis of Secondary Endpoints 
 
9.1 All-cause mortality (key secondary endpoint) 
 
Endpoint Definition:  Time from randomization until death.   
 


10 
 
For subjects who have not met this endpoint (and thus are censored observations), time from 
randomization until the subject’s last follow-up contact will be used in the analysis. 
 
Great effort will be made to gather mortality information on every randomized subject.  For 
patients who withdraw consent or are lost to follow-up during the course of the trial, mortality 
databases such as the National Death Index, the Social Security Death Index, Ancestry.com, as 
well as any other sources of information or national registries, will be consulted in an effort to 
determine whether the subjects have died.  Any subject found through one of these sources to 
have died will be considered to have met this key secondary endpoint even if not enough 
information is available for the CEC to classify the mode of death.  Subjects for whom no vital 
status information can be found in these database searches will be censored at the time of their 
last follow-up contact. 
 
Statistical Methods:  The analysis of this key secondary endpoint will use the same methods as 
described for the primary endpoint in Section 8.  Specifically, the log-rank test will be the 
primary analytic tool for statistically assessing mortality differences between the two randomized 
treatment strategies.  A hazard ratio and 95% confidence interval summarizing the difference in 
outcome between the two randomized arms will be computed using the Cox model.  The level of 
significance for the assessment of this endpoint will be α=0.05.  Also, Kaplan-Meier cumulative 
event rates will be calculated for each randomized arm as a function of time from randomization, 
and the estimated event probabilities will be displayed graphically.  
 
Supplementary analyses of this secondary endpoint will be performed using the same methods 
described for the primary endpoint in Section 8.1.   
 
9.2 All-cause Mortality or Cardiovascular Hospitalization  
 
Endpoint definition: Time from randomization to the first event in this composite endpoint (i.e., 
time from randomization to either death or the subject’s first cardiovascular hospitalization).  
 
For subjects who have not experienced either component of this endpoint (i.e., who are censored 
observations), time from randomization until the subject’s last follow-up contact will be used in 
the analysis. 
 
The cause of hospitalization will be based on the site-reported data in the CABANA electronic 
data capture (EDC) system.  For this endpoint, cardiovascular hospitalization will not include a 
hospitalization to initiate therapy.  For example, among patients randomized to the ablation arm, 
the hospitalization to perform the ablation will not be counted for this secondary endpoint.  
Similarly, if a patient randomized to the drug arm is hospitalized to monitor the patient while 
loading the initial drug therapy, that hospitalization will not be counted.  All other 
hospitalizations designated by the clinical site as cardiovascular will be counted, including the 
hospitalization of a patient randomized to the drug arm who is hospitalized for a therapy change 
(either a change to a different drug therapy or for crossing over to ablation). Hospitalization to 
perform second or subsequent ablation procedures will be counted as a CV hospitalization event.     
 


11 
 
Statistical Methods:  The analysis of this secondary endpoint will use the same methods as 
described for the primary endpoint and key secondary endpoint in sections 8 and 9.1, including 
statistical testing using the log-rank test, calculation of a hazard ratio and 95% confidence 
interval using the Cox model, and Kaplan-Meier cumulative event rate calculations. The level of 
significance for the assessment of this endpoint will be α=0.05.  
 
9.3   All-cause Mortality, Stroke, or Hospitalization for Heart Failure or an Acute Ischemic 
Event 
 
Endpoint definition: Time from randomization to the first event in this composite endpoint.  
 
For subjects who have not experienced any component of this endpoint (i.e., censored 
observations), time from randomization until the subject’s last follow-up contact will be used in 
the analysis.  The stroke component of this endpoint is defined the same as the stroke component 
of the primary endpoint, namely as a disabling stroke characterized by a Rankin Scale > 2.  The 
cause of hospitalization will be based on the site-reported data in the CABANA electronic data 
capture (EDC) system. 
 
Statistical Methods:  The analysis of this secondary endpoint will use the same methods as 
described for the primary endpoint and secondary endpoints in the sections above, including use 
of the log-rank test, hazard ratio and 95% confidence interval calculated using the Cox model, 
and Kaplan-Meier cumulative event rate calculations. The level of significance for the 
assessment of this endpoint will also be α=0.05.  
 
This endpoint is similar to the first co-primary endpoint of the Early treatment of Atrial 
fibrillation for Stroke prevention Trial (EAST)4 with the exception that EAST is using 
cardiovascular mortality rather than all-cause mortality as the death component of the endpoint 
and also a different definition of stroke (any stroke rather than a disabling stroke).  Therefore, to 
provide results that can be compared to those of EAST, supplemental comparative analyses will 
be performed using cardiovascular mortality in this endpoint rather than all-cause mortality, and 
a definition of stroke that corresponds to the EAST definition.  The statistical methods for these 
analyses will employ the competing risk methodology described in the next section for analyzing 
cardiovascular death, as well as the approach described in the preceding paragraph where all-
cause mortality is a component of the endpoint. 
 
9.4  Cardiovascular Death 
 
Endpoint definition: Time from randomization to the occurrence of a cardiovascular (CV) death.  
 
Patient deaths will be classified by the Clinical Events Committee (CEC) as to whether the mode 
of death was due to a cardiovascular (CV) cause.  If insufficient source documents are obtained 
to allow CEC adjudication of the cause of death, and the CEC classifies the cause of death as 
“unknown,” then the site-reported cause of death (if available) will be used.  If neither the site 
nor the CEC can provide a classification of the cause of death, the death will not be considered 
as a cardiovascular death.  As supplemental analyses, however, this endpoint will also be 
examined using (a) only the deaths classified by the CEC as cardiovascular, and (b) using deaths 


12 
 
classified by the CEC as cardiovascular, but also including any deaths in the cardiovascular 
category that are classified as unknown by the CEC.     
 
Statistical Methods:  The analysis of this endpoint will be performed using the competing risks 
methodology of Fine and Gray5, where death due to a non-cardiovascular cause is considered as 
a competing risk.  This methodology, rather than treating non-cardiovascular death as a 
censoring event, makes use of the cumulative incidence function, and is performed within the 
proportional hazards framework using the marginal failure sub-distribution associated with the 
event of interest (cardiovascular death).  The features of the Fine-Gray approach for handling 
competing risks data are available as part of the PHREG procedure in SAS.  The cumulative 
incidence function for the two arms will be estimated, statistically compared, and graphically 
presented using the PHREG software features in SAS.  For subjects who have not died, time 
from randomization until the subject’s last follow-up contact will be used in the analysis.  The 
level of significance for the assessment of this endpoint will be α=0.05.  
      
Additional analysis of this secondary endpoint will be performed using the same methods as 
described for the primary endpoint and secondary endpoints in the sections above, including use 
of the log-rank test, hazard ratio and 95% confidence interval generated using the Cox model, 
and Kaplan-Meier cumulative event rate calculations. Patients who have died but whose cause of 
death is classified by the CEC as non-cardiovascular will be censored at the time of their non-CV 
death.  The number of such patients is expected to be relatively small in this study.  The results 
of these two different approaches will be carefully examined and synthesized into an overall 
interpretation of treatment differences with respect to CV death.     
 
9.5 Cardiovascular Death or Disabling Stroke 
 
Endpoint definition:  Time from randomization to the occurrence of either a cardiovascular 
death or disabling stroke.  
 
All potential strokes will be carefully reviewed and classified as disabling by the neurological 
events committee using the Rankin Stroke Scale as described in Section 8.  The neurological 
committee that reviews and adjudicates the strokes is an important part of the overall clinical 
events adjudication process.  A disabling stroke will be defined as a stroke whose severity on the 
Rankin Scale is > 2.  Cardiovascular deaths will be classified as described in Section 9.4 above. 
 
Statistical Methods:  The analysis of this secondary endpoint will also use the competing risks 
methodology of Fine and Gray5 described in Section 9.4 for the secondary endpoint of CV death 
where death due to a non-cardiovascular cause is considered as a competing risk rather than a 
censoring event.  The analysis will make use of the cumulative incidence function, and (as 
described in Section 9.4) will be performed within the proportional hazards framework using the 
marginal failure sub-distribution associated with the event of interest.  The cumulative incidence 
function for the two arms will be estimated, statistically compared, and graphically presented 
using the PHREG procedure in SAS.  For subjects who have not died, time from randomization 
until the subject’s last follow-up contact will be used in the analysis.  The level of significance 
for the assessment of this endpoint will be α=0.05.  
      


13 
 
As in the case of the cardiovascular death endpoint, additional analysis of this secondary 
endpoint will be performed using the log-rank test, hazard ratio and 95% confidence interval 
generated using the Cox model, and Kaplan-Meier cumulative event rate calculations. Patients 
who have died but whose cause of death is classified by the CEC as non-cardiovascular will be 
censored at the time of their non-CV death.  Results of these two different approaches will be 
carefully compared and synthesized into an overall interpretation of treatment differences with 
respect to the endpoint of CV death or disabling stroke.     
 
9.6  Arrhythmic Death or Cardiac Arrest 
 
Endpoint definition:  Time from randomization to the occurrence of either an arrhythmic death 
or cardiac arrest.  
 
Since cardiac arrest is a component of the primary endpoint, all potential cardiac arrests will be 
reviewed and adjudicated by the Clinical Endpoints Committee.  As described earlier, the mode 
of death is also classified by the Clinical Endpoints Committee.  
 
Statistical Methods:  The analysis of this secondary endpoint will proceed in much the same way 
as described above for the endpoint of CV death or disabling stroke and use the competing risks 
methodology of Fine and Gray5 described in previous sections.  In this analysis, death due to a 
cause other than arrhythmic is considered as a competing risk rather than a censoring event.  The 
analysis will make use of the cumulative incidence function, and will be performed within the 
proportional hazards framework using the marginal failure sub-distribution associated with the 
event of interest.  The cumulative incidence function for the two arms will be estimated, 
statistically compared, and graphically presented using the features available in the PHREG 
procedure in SAS.  For subjects who have not died, time from randomization until the subject’s 
last follow-up contact will be used in the analysis.  The level of significance for the assessment 
of this endpoint will be α=0.05.  
      
For this endpoint, we will also perform additional analysis using the log-rank test, hazard ratio 
and 95% confidence interval generated using the Cox model, and Kaplan-Meier cumulative 
event rate calculations. Patients who have died but whose cause of death is classified by the CEC 
as other than arrhythmic will be censored at the time of the non-arrhythmic death.  The results of 
these two different approaches will be compared and synthesized into an overall interpretation of 
treatment differences with respect to the endpoint of arrhythmic death or cardiac arrest.  
    
9.7  Heart Failure Death 
 
Endpoint definition:  Time from randomization to the occurrence of a heart failure death.   
 
Classification of deaths as being due to heart failure will be performed by the blinded Clinical 
Endpoints Committee.    
 
Statistical Methods:  The analysis of this endpoint will make use of the competing risks 
methodology of Fine and Gray5 described in previous sections for other secondary endpoints.  In 
this case, death due to a cause other than heart failure will considered as a competing risk.  The 


14 
 
features of the Fine-Gray approach for handling competing risks data available as part of the 
PHREG procedure in SAS will be employed to estimate the cumulative incidence function for 
each of the two arms, to statistically compare these functions, and graphically present them using 
the software features in SAS.  The level of significance for the assessment of this endpoint will 
also be α=0.05. 
 
Additional analysis of this secondary endpoint will also be performed using the log-rank test, 
hazard ratio and 95% confidence interval (CI) generated using the Cox model, and Kaplan-Meier 
cumulative event rate calculations.  For this analysis, patients who have died, but their death is 
classified by the CEC as due to a cause other than heart failure, will be censored at the time of 
their non-heart failure death. The results of the competing risk analysis and of this traditional 
analysis will be compared to synthesize an overall interpretation of the treatment differences.  
 
9.8  Recurrent Atrial Fibrillation  
 
Endpoint definition: This particular outcome will be analyzed with different endpoint 
definitions in order to provide an overall perspective of the extent of the AF burden experienced 
by the study subjects. The first analysis will consider the first episode of recurrent AF as the 
endpoint, defined as an episode >30 seconds following the end of the 90-day blanking period, 
where the 90-day blanking period begins at the time of receiving the randomly assigned 
treatment (either ablation or drug therapy). The endpoint will be defined as the time until the first 
recurrence of AF according to this definition.  Similar analyses will be performed where the 
endpoint is defined as: (a) an episode of symptomatic recurrent AF, (b) an episode of atrial 
fibrillation or atrial flutter or atrial tachycardia, and (c) an episode of symptomatic atrial 
fibrillation, atrial flutter, or atrial tachycardia.   
 
Analysis Population: Because recurrent atrial fibrillation is defined with respect to the end of the 
blanking period, which begins after receipt of the assigned treatment, all analyses for recurrent 
atrial fibrillation will include only patients who have received their randomly assigned treatment 
and live to the end of the blanking period.  
 
In addition, separate analyses will be performed according to the method used for monitoring AF 
recurrence.  As indicated in Section 6 (Data Sources), rhythm data for many of the patients 
enrolled in CABANA (approximately 2/3 of the randomized patients) are collected using the 
“CABANA Box,” a robust rhythm monitoring system provided by Medicomp.  The rhythm 
monitoring data are sent from Medicomp to the Duke Clinical Research Institute (DCRI), where 
a set of programmed rules are run to determine which rhythms should be submitted to the ECG 
core lab for review and adjudication.  Following core lab review, the adjudicated results are 
electronically transmitted back to the DCRI.  Sites that are not using the “CABANA Box” 
(generally these are international sites where use of the CABANA Box was not approved) submit 
rhythm data through a secure portal using the CABANA website, which is then processed and 
submitted to the core lab for adjudication.   Because the CABANA Box data are more 
comprehensive and more routinely and rigorously collected, separate analyses of recurrent atrial 
arrhythmias will be performed using (a) patients whose rhythms were monitored using the 
CABANA Box, (b) all remaining patients (i.e., non-CABANA Box patients), and (c) the pooled 
group of all patients (with use of CABANA Box as a covariate if justified).  In the case of 


15 
 
patients who initially used the CABANA Box and later ceased to provide information via 
CABANA Box, the analysis will censor that data at the time of last CABANA Box recording.  
The primary analysis of this endpoint will be the analysis of patients with CABANA Box data 
because of the more comprehensive collection of that rhythm monitoring information.  Analysis 
which includes non-CABANA Box patients (“b” and “c” above) will be considered 
supplementary analysis.             
 
Statistical Analysis:  First, descriptive summaries of baseline characteristics of subjects 
receiving their assigned treatment and living to the end of the blanking period in both treatment 
arms will be presented to determine how comparable the patients in the two arms are for this 
analysis. Continuous variables will be presented in terms of percentiles (median, 25th and 75th 
percentiles), while discrete variables will be summarized in terms of frequencies and 
percentages. 
  
The treatment arms will be compared using statistical methods described in the sections above 
for other secondary endpoints, including the competing risk method of Fine and Gray4, as well as 
use of the log-rank test, hazard ratio and 95% confidence interval generated using the Cox 
model, and Kaplan-Meier cumulative event rate calculations.  In this case, all-cause mortality 
will be a competing risk and zero-time (i.e., when the clock starts) for this analysis will be the 
end of the 90-day blanking period. Analyses will be repeated with adjustment for the baseline 
covariates described in section 8.1. 
 
Of key interest will be whether the effect of ablation on recurrent atrial arrhythmias is similar or 
different according to the type of AF the patients experienced prior to enrolling in the trial (i.e., 
whether the effect varies according to whether patients’ baseline AF was paroxysmal, persistent 
or long-standing persistent).  This analysis will utilize the Cox model to test for an interaction 
between the randomized treatment strategy and the baseline type of AF classified as (a) 
paroxysmal or (b) persistent or longstanding persistent.  In addition to the interaction test, the 
effect of the treatment strategy characterized by a hazard ratio and 95% confidence interval and 
Kaplan-Meier event rate calculations will be calculated and displayed for the subgroups of 
patients whose baseline AF history was (a) paroxysmal and (b) persistent or longstanding 
persistent.   Similar comparative analyses will be performed in subgroups defined by age (<65, 
65-74, and >75) and by CHA2DS2-VASc Score (0 or 1 vs >1).  
 
9.9  Cardiovascular Hospitalization 
 
A key part of the analysis and interpretation of the results of this endpoint will be the analysis 
performed in connection with secondary endpoint #2 (the composite of death or cardiovascular 
hospitalization).  Analysis of cardiovascular hospitalization as an endpoint by itself must be 
analyzed and interpreted cautiously, particularly if there is a mortality difference between the 
two arms of the trial.  If patients in one arm have lower mortality, that arm may have more 
hospitalizations simply because more patients are alive and at risk for needing to be hospitalized.  
Another important aspect of the analysis of this endpoint is that patients may have multiple 
hospitalizations, and so a comprehensive analysis of hospitalizations must take into account the 
recurrent hospitalization events rather than simply the first one.  Consequently, there will be 


16 
 
several parts to the analysis of this endpoint in addition to a careful examination of the results of 
the composite endpoint consisting of death or cardiovascular hospitalization (see Section 9.2). 
 
Statistical Methods:   
a. The first analysis will consider time until the first cardiovascular hospitalization in each 
arm and use the competing risks methodology of Fine and Gray5 where death from any 
cause is considered as a competing risk.  The analysis will make use of the cumulative 
incidence function, and will be performed within the proportional hazards framework 
using the approach described in Section 9.4.  The cumulative incidence function for each 
of the two arms will be estimated, statistically compared, and graphically presented using 
the PHREG procedure in SAS.  For subjects who have not experienced a CV 
hospitalization, time from randomization until the subject’s last follow-up contact will be 
used in the analysis.  The level of significance for the assessment of this endpoint will be 
α=0.05. 
b.   An additional analysis of this endpoint will be performed using the log-rank test, hazard 
ratio and 95% confidence interval generated using the Cox model, and Kaplan-Meier 
cumulative event rate calculations. Patients who have died will be censored at the time of 
their death.  This analysis and the approach in (a) above will be compared and 
summarized into an overall interpretation of treatment differences with respect to the 
endpoint of time to the first CV hospitalization.  
c.  The analyses described above will be extended to a multiple events analysis, designed to 
take into account multiple hospitalization events that may occur during the course of a 
patient’s follow-up.  When considering one event per patient as in (a) or (b) above (i.e., 
the time until the first event), those events are independent because they occur in 
different patients.  When considering multiple events for a patient, the events are no 
longer all independent because some of them are occurring within the same patient.   This 
correlation (covariance) must be taken into account in deriving inferences.  The multiple- 
event methods that will be used represent different extensions of Cox model 
methodology, and take into account the timing of the events and the correlation among 
multiple events occurring within an individual patient. 
   
The main statistical approach will use a generalization of the Cox model developed by 
Andersen & Gill6,7, with robust standard errors to account for heterogeneity and for the 
correlation between recurrent events within a patient.   
 
Similar to time-to-1st event methods, a terminal event (death) could introduce bias in the 
recurrent events analysis, especially if there is a differential mortality between the study 
arms.  Thus, the Ghosh and Lin8 nonparametric method can be utilized in calculating the 
cumulative rate of CV hospitalizations, while accounting for mortality as a competing 
risk.  In addition, the average number of CV hospitalizations per 100-person years 
utilizing the Ghosh-Lin method can  be calculated for each treatment group. 
   
The Andersen-Gill recurrent events method will be performed using PROC PHREG in 
SAS software.  However,  the Ghosh-Lin method requires implementation of a validated 
package in R software.   
 


17 
 
9.10 Medical Costs, Resource Use and Cost Effectiveness. 
 
Cost data will be analyzed by the CABANA EQOL Coordinating Center in close collaboration 
with the Data Coordinating Center, and the analysis approach will be detailed in a separate 
analytic plan. 
  
9.11 Quality of Life.  
 
Quality of life data will also be analyzed by the CABANA EQOL Coordinating Center in close 
collaboration with the Data Coordinating Center.  Again, the analysis approach will be detailed 
in a separate analytic plan. 
 
9.12 Major Non-Endpoint Adverse Events.   
 
Major adverse events (AE) will be monitored and reported during the trial.  For drug therapy, the 
major serious or life-threatening events include unanticipated hospitalizations for heart failure, 
drug-related pro-arrhythmic events, and pulmonary toxicity from amiodarone.  For the ablation 
arm, the major events include symptomatic pulmonary vein stenosis requiring intervention, 
myocardial perforation/tamponade requiring intervention, and atrial-esophageal fistula formation. 
The frequency of each of these events (and other serious adverse events such as peripheral 
thromboembolic events) will be descriptively tabulated using MedDRA System Organ Class.  
Treatment comparisons with respect to these serious adverse events will be more descriptive 
rather than statistically rigorous (since different adverse events are expected in the two arms), 
bringing to bear clinical judgment as to the relative seriousness of these various adverse events.   
Other adverse complications or adverse events of either therapy will be tabulated and 
descriptively summarized, using statistical comparisons of the treatment groups based on chi-
square tests where appropriate, and interpreting such comparisons in the context of treatment 
differences in the primary and major secondary clinical endpoints. 
 
9.13  LA Size, Morphology and Function.   
 
For the subjects participating in the CT/MR imaging sub-study, left atrial size, morphology, and 
function will be examined. Of interest will be the change in atrial size (volume) and function 
(i.e., atrial ejection fraction) from the pre-treatment to the post-treatment study within each 
treatment arm, and then importantly, a comparison of whether the change in size and function in 
the patients randomized to ablation therapy differs from the change in size and function of the 
patients randomized to drug therapy. 
 
The distribution of these measures from the pre- and post-treatment studies in each treatment arm 
will be descriptively characterized using summary descriptive statistics and graphical tools 
including box and whisker plots. The statistical significance of the changes in left atrial volume 
and atrial ejection fraction from pre- to post-treatment studies within each treatment arm will be 
assessed using general linear models (GLM), including the baseline value as a covariate, and 
assessing treatment group differences. If there appears to be differences in other baseline 


18 
 
covariates between groups, adjustment for covariates will be considered. Secondary analyses will 
use a paired-sample t-test instead of GLM.     
 
In dealing with this type of data, the completeness of which is dependent on obtaining both the 
pre- and post-treatment studies, there will inherently be missing data resulting from patients in 
whom it was not possible to obtain both studies (because they died or failed to return for other 
reasons to enable the follow-up measurements to be made).  The completeness of the data will be 
fully described, and the statistical comparisons will be based on patients for whom both the 
baseline and follow-up studies are available.  
   
   
10. “On-Treatment” Analysis 
 
The intention-to-treat analyses in this trial will constitute the primary analyses and will serve as 
the standard for interpreting treatment differences in the key clinical outcomes.  However, 
because a number of patients in the drug arm may cross over to receive ablation during the trial, 
and some patients randomized to ablation may not undergo the procedure, we will supplement 
the intent-to-treat comparisons of the primary endpoint and selected secondary endpoints with 
“on-treatment” comparisons. The “on-treatment” analysis will involve a comparison of patients 
who received ablation (even if originally assigned to the drug arm) versus those who did not.  
Statistically, this will be accomplished using the Cox proportional hazards model with ablation 
included in the analysis as a time-dependent covariate. This analysis will be repeated for the 
primary endpoint, all-cause mortality, all-cause mortality or cardiovascular hospitalization, all-
cause mortality, stroke, or hospitalization for heart failure or acute ischemic events, 
cardiovascular death, cardiovascular death or disabling stroke, arrhythmic death or cardiac arrest, 
heart failure death, and cardiovascular hospitalization with and without adjustment for covariates 
listed in section 8.1.  No analyses will include competing risks, and on-treatment analysis will 
not be conducted for multiple events analyses (section 9.9). For recurrent atrial fibrillation, we 
will only conduct this on-treatment analysis for the first episode of recurrent AF without 
competing risks in the 3 patient populations (Cabana box, non-cabana box, and pooled).  
Secondary analyses may consider other measures of recurrent atrial fibrillation (e.g., 
symptomatic recurrent AF, atrial fibrillation or atrial flutter or atrial tachycardia, and 
symptomatic atrial fibrillation, atrial flutter, or atrial tachycardia).   
 
The time-dependent ablation variable to be included in the analysis will be created using 3 
different methods: For method 1, the ablation variable starts as 0 (no ablation) for all patients.  
For patients who received ablation, the ablation variable is set to 1 at the time of ablation.  In 
method 2, the ablation variable starts as 1 for all patients who were randomized to ablation and 
actually received ablation.  For all other patients, the ablation variable is started as 0 and set to 1 
at the time of ablation if they received ablation during the trial.  Method 3 has the ablation 
variable started as 1 for patients who were randomized to ablation.  For all other patients (i.e., 
randomized to drug), the ablation variable is started as 0 and set to 1 at time of ablation.  
 
Among the 3 methods described above, method 2 will be considered the main statistical method 
in handling cross-overs via a time-dependent variable in Cox model.  The other 2 methods are 
considered as sensitivity analyses. 


19 
 
 
Differential treatment effects for the primary endpoint and major secondary endpoints of interest 
using on-treatment analyses will also be conducted. Subgroups of interest will include those 
listed in section 8.1. 
 
Because treatment assignment is no longer random, results can be biased by an association 
between the likelihood of treatment change and the risk of a clinical event (i.e., factors that make 
a patient more likely to cross over may also make them more likely to have an event).  Thus, 
such analyses will be cautiously interpreted.  Each of the analyses described in this section will 
be covariate adjusted using the covariates described in section 8.1 for the primary endpoint.  
 
 
11.  Per-Protocol Analysis 
 
Using the methods described for the primary endpoint in Section 8, an analysis will also be 
performed to compare the primary endpoint and the key secondary clinical outcomes of the two 
treatment strategies among the subset of patients who fully satisfied the inclusion/exclusion 
criteria and received the treatment to which they were randomly allocated.  This analysis will 
include patients randomized to the drug arm who were treated with drug therapy, and patients 
randomized to the ablation arm who underwent the ablation within 6 months following 
enrollment in the trial. The follow-up of drug-arm patients who crossed over to ablation will be 
censored at the time of the ablation.  Patients randomized to the ablation arm who were not 
ablated within 6 months will be excluded from this analysis.  Additional sensitivity analyses will 
be performed in which the window for ablation is varied to include a shorter interval (3 months) 
and a longer window (1 year).  
 
The analyses outlined in Sections 10 and 11 will be strictly supplementary to the intent-to-treat 
analyses described earlier.          
 
 
12. Multiple Comparisons 
  
 
With the primary hypothesis and the various secondary endpoints that have been outlined, there 
is a multiplicity of analyses to be performed, which leads to an increased probability that at least 
one of the comparisons could be "significant" by chance.  There are adjustments (e.g., based on 
the Bonferroni inequality) that could be used to preserve the overall type I error level. To attempt 
to adjust for the effects of the repeated significance testing that will occur as part of the interim 
monitoring (discussed below), plus adjust for the multiplicity of secondary endpoints, would 
require that very small significance levels be used for every comparison.  The overall level of 
significance will be 0.049 for the assessment of the primary endpoint (see Section 13) and 0.05 
for all secondary endpoints.  However, to account in part for the multiplicity of comparisons 
involving secondary endpoints, we will be conservative in the interpretation of the analyses, 
taking into account the degree of significance, and looking for consistency across endpoints.  The 
actual p-value for each comparison will be reported to aid in the overall interpretation. We have 


20 
 
also pre-specified the primary and secondary outcome variables to avoid over-interpretation of 
strictly exploratory comparisons.   
 
 
13. Interim Analyses 
 
For ethical reasons, an interim examination of key safety and endpoint data has been performed 
at regular intervals during the course of the trial.  The primary objective of these analyses was to 
evaluate the accumulating data for an unacceptably high frequency of negative clinical outcomes 
in either of the treatment arms.  In addition, the interim monitoring involved a review of the  
aggregated event rates, patient recruitment, compliance with the study protocol, status of data 
collection, and other factors which reflected the overall progress and integrity of the study.  The 
results of the interim analyses and status reports were carefully and confidentially reviewed by 
an NHLBI-appointed Data and Safety Monitoring Board (DSMB). 
 
The DSMB met at approximately 6-month intervals to review the accumulating data. Prior to 
each meeting, the Statistical and Data Coordinating Center (SDCC) at the DCRI conducted the 
desired statistical analyses and prepared a summary report for review by the DSMB.  The 
extracted data files and analysis programs for each DSMB report were archived and maintained 
at the DCRI.  Reports were presented describing the progress of patient enrollment, the rates of 
compliance with therapy, and the frequency of protocol violations.  The SDCC also reported on 
the number (status) of data forms completed and the overall quality and completeness of the 
information. 
 
In CABANA, a group sequential method similar to that proposed by O'Brien and Fleming9 was 
used as a guide in interpreting interim analyses.  This procedure required large critical values 
early in the study, but relaxed (i.e., decreased) the critical value as the trial progressed.  Because 
of the conservatism early in the trial, the critical value at the final analysis is near the "nominal" 
critical value.  The actual method used for the interim monitoring was the Lan and DeMets10 
group sequential method with monitoring boundaries based on a two-sided, symmetric O'Brien-
Fleming type spending function.  The Lan-DeMets approach only required specification of the 
rate at which the Type I error (which in this trial is α= 0.05 for the primary endpoint) was 
"spent".  The procedure allowed "spending" a portion of α at each interim analysis in such a way 
that at the end of the study, the total Type I error did not exceed 0.05.  The specific formulation 
of the spending function is described in Chapter 5 of Proschan et al (formula 5.4)11.  Since the 
number of looks and the increments between looks did not need to be predetermined, it allowed 
considerable flexibility in the monitoring process for accommodating comparative examinations 
of the data in response to concerns of the DSMB that may arise during the course of the trial.   
 
The analytic approach used at the interim analyses for assessing treatment differences consisted 
of the time-to-event analysis methods described previously, except that interpretation of 
statistical significance associated with treatment comparisons of key study endpoints was guided 
using the group sequential monitoring boundaries.  The critical value of the test statistic and the 


21 
 
corresponding p-value required for significance was presented so that significance could be 
assessed precisely.    
 
Although the CABANA DSMB has met approximately twice each year, the board has seen 
interim treatment-specific primary endpoint data only one time during the course of the trial.   
At all other meetings, only overall (aggregated) event data have been presented to them. As a 
result of the single treatment-specific DSMB presentation, the overall level of significance for 
the final analysis of the primary endpoint has been calculated to be .049 (using the O’Brien-
Fleming boundary). 
 
 


22 
 
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