Clinical trial NCT02608099
Conditions: Atrial Fibrillation
Keywords: Atrial fibrillation Non-valvular atrial fibrillation Catheter ablation Apixaban Warfarin Harvard Clinical Research Institute
Sponsor: Baim Institute for Clinical Research
Start date: 2015-11-01; Completion date: 2017-04-01
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the prospective, randomized cohort in this study is to assess the safety and efficacy of 2 apixaban treatment strategies (uninterrupted versus interrupted) in subjects planned to undergo catheter ablation for the treatment of non-valvular atrial fibrillation (NVAF).

Simultaneously, a retrospective cohort of 300 warfarin-treated individuals, identified by chart review, who are matched to the prospective randomized subjects, will be identified. The purpose of the retrospective warfarin cohort is to compare the efficacy and safety of warfarin(the current clinical practice) to that of apixaban (uninterrupted, interrupted, combined uninterrupted and interrupted).

Detailed description:
Prospective, Randomized Cohort

Subjects undergoing ablation for NVAF who meet all eligibility criteria and sign informed consent will be enrolled into the study. Subjects will be treated with apixaban for ≥21 days prior to the ablation procedure (for subjects already on apixaban for ≥21 days, it is not necessary to wait 21 days before the ablation procedure. Apixaban dose will be 5 mg b.i.d. per product label, or 2.5 mg b.i.d. in subjects with 2 or more of the following: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.

Eligible subjects will then be randomized in a 1:1 ratio to 2 peri-procedural treatment strategies:

* Uninterrupted treatment: administer the evening apixaban dose on the day prior to the procedure; administer the morning apixaban dose on the day of the procedure; administer heparin bolus before transseptal puncture to maintain a target activated clotting time \[ACT\] \> 300 seconds; administer the evening apixaban dose after the procedure if there were no peri-procedural complications that necessitate withholding anticoagulation for longer duration.
* Interrupted treatment: administer the evening apixaban dose on the day prior to the procedure; do not administer the morning apixaban dose on the day of the procedure; administer heparin bolus before transseptal puncture to maintain a target ACT \> 300 seconds; administer the evening apixaban dose after the procedure if there were no peri-procedural complications that necessitate withholding anticoagulation for longer duration.

Randomization will take place prior to the procedure (on the day of the procedure or up to 3 days prior to the procedure) and will be stratified by site.

It is anticipated that up to 360 subjects may be enrolled in order to evaluate a total of 300 randomized subjects (150 subjects per treatment arm):

Randomized subjects will continue treatment with apixaban for 1 month post procedure.

Retrospective, Warfarin Cohort In addition, a chart review of 300 warfarin-treated patients who underwent catheter ablation for NVAF on or after September 1, 2013 in the enrolling centers and who have documented follow-up in the medical record for ≥ 30 days post-ablation procedure will be performed. Patient records for warfarin-treated individuals who meet the applicable inclusion/exclusion criteria and who are matched 1:1 to a subject in the prospective, randomized cohort for age (+/- 5 years), gender and atrial fibrillation (AF) type (paroxysmal vs. persistent), will be identified. Sites will document key demographic and outcome variables. This review will be performed in a blinded manner such that site personnel are blinded to the outcome of each retrospective subject during the subject selection process. Only pre-existing data will be collected for the analysis of this cohort.

Arms: arm 1: Apixaban dose is administered on the evening prior to the procedure; apixaban dose is held on the morning of the procedure; apixaban dose is administered on the evening after the procedure if there were no peri-procedural complications that necessitated withholding anticoagulation for longer duration. arm 2: Apixaban dose is administered on the evening prior to the procedure; apixaban dose is administered on the morning of the procedure; apixaban dose is administered on the evening after the procedure if there were no peri-procedural complications that necessitated withholding anticoagulation for longer duration.
Interventions: intervention 1: Interrupted apixaban intervention 2: Uninterrupted apixaban
Intervention descriptions: intervention 1: Apixaban dose is administered on the evening prior to the procedure; apixaban dose is held on the morning of the procedure; apixaban dose is administered on the evening after the procedure if there were no peri-procedural complications that necessitated withholding anticoagulation for longer duration. intervention 2: Intervention description: Apixaban dose is administered on the evening prior to the procedure; apixaban dose is administered on the morning of the procedure; apixaban dose is administered on the evening after the procedure if there were no peri-procedural complications that necessitated withholding anticoagulation for longer duration.

Protocol documents:
Prot_001.pdf: 
 
The AEIOU Trial: Apixaban Evaluation of Interrupted Or 
Uninterrupted Anticoagulation for Ablation of Atrial 
Fibrillation  
 
CV185-373 
 
Protocol 
 
Version 1.1 
 
September 2, 2015 
 
Matthew Reynolds, MD, MSc, Principal Investigator 
Harvard Clinical Research Institute  
Director, Economics and Quality of Life Research  
930-W Commonwealth Ave. 
Boston, MA 02215 
T (617) 307-5489, F (617) 307-5600 
matthew.reynolds@hcri.harvard.edu 
Lahey Hospital & Medical Center 
Director of Electrophysiology Research, Division of 
Cardiology 
41 Mall Road, Burlington, MA 01805 
T (781) 744-8863, F (781) 744-5577 
 
Christopher P. Cannon, MD, Co-Principal 
Investigator 
Harvard Clinical Research Institute  
Executive Director, Cardiometabolic Trials 
930-W Commonwealth Ave 
Boston, MA 02215 
T (617) 307-5431, F (617) 307-5605 
christopher.cannon@hcri.harvard.edu 
Cardiovascular Division Brigham and Women’s Hospital 
Professor of Medicine, Harvard Medical School 
 
 
 
NCT02608099


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Document History 
 
 
 
 
Revision Author 
Date 
reviewed/ 
revised 
Changes 
Reason for Changes 
1.0 
 
 
Joanna 
Suomi 
April 2, 2015 
New document 
N/A 
1.1 
Priscilla 
Driscoll 
Shempp 
September 2, 2015 
Minor edits to language 
describing retrospective 
cohort, 
enrollment 
window for prospective 
cohort  and addition of 
study schema 
Clarification 


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STUDY PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
The undersigned have reviewed and approved the following protocol: 
 
  
 
 
 
9/4/2015 
_______________________________________ 
 
______________________ 
Matthew Reynolds, MD, MSc 
 
 
 
Date 
Principal Investigator 
 
Harvard Clinical Research Institute  
Director, Economics and Quality of Life Research  
930-W Commonwealth Ave. 
Boston, MA 02215 
T (617) 307-5489, F (617) 307-5600 
matthew.reynolds@hcri.harvard.edu 
Lahey Hospital & Medical Center 
Director of Electrophysiology Research, Division of 
Cardiology 
41 Mall Road, Burlington, MA 01805 
T (781) 744-8863, F (781) 744-5577 
 
 
 
 
 
 
9/2/2015 
_______________________________________ 
 
______________________ 
Christopher Cannon, MD 
 
 
 
 
 
Date 
Co-Principal Investigator 
 
Harvard Clinical Research Institute  
Executive Director, Cardiometabolic Trials 
930-W Commonwealth Ave 
Boston, MA 02215 
T (617) 307-5431, F (617) 307-5605 
christopher.cannon@hcri.harvard.edu 
 
Cardiovascular Division Brigham and Women’s Hospital 
Professor of Medicine, Harvard Medical School 
 
 
 


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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Clinical Investigation Protocol No. _______________ 
 
I have reviewed this protocol for the study entitled:   
 
 The AEIOU Trial: Apixaban Evaluation of Interrupted Or Uninterrupted 
Anticoagulation for  Ablation of Atrial Fibrillation 
 
 
 
I agree to conduct this study according to the requirements described in the protocol.   
 
 
 
Investigator Name (print or type): 
 
Investigator’s Signature: 
 
Date: 
 
Site Number: 
 
 
 
Site Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1 
PROTOCOL SYNOPSIS ...............................................................................9 
2 
INTRODUCTION ........................................................................................18 
2.1 
Overall Risk/Benefit Assessment .................................................................20 
2.2 
Research Hypothesis .....................................................................................20 
2.3 
Study Rationale .............................................................................................21 
2.4 
Study Objectives ...........................................................................................21 
3 
ETHICAL CONSIDERATIONS ................................................................21 
3.1 
Good Clinical Practice ..................................................................................21 
3.2 
Institutional Review Board/Independent Ethics Committee ....................22 
3.3 
Informed Consent .........................................................................................22 
3.4 
Subject Confidentiality .................................................................................24 
4 
INVESTIGATIONAL PLAN ......................................................................25 
4.1 
Study Design and Duration ..........................................................................25 
4.1.1 
Prospective, Randomized Cohort ................................................................25 
4.1.2 
Retrospective, Warfarin Cohort ..................................................................26 
4.2 
Study Population ...........................................................................................26 
4.2.1 
Inclusion Criteria ..........................................................................................26 
4.2.2 
Exclusion Criteria .........................................................................................27 
4.2.3 
Contraception Requirements .......................................................................29 
4.2.4 
Women of Childbearing Potential ...............................................................29 
4.2.5 
Discontinuation of Subjects from Treatment .............................................30 
5 
TREATMENTS ............................................................................................31 
5.1 
Study Treatment: Apixaban ........................................................................31 
5.1.1 
Identification, Packaging, and Labeling .....................................................31 
5.1.2 
Handling and Dispensing .............................................................................31 
5.2 
Drug Ordering and Accountability .............................................................32 
5.2.1 
Apixaban Orders ..........................................................................................32 
5.3 
Randomization ..............................................................................................32 
5.4 
Selection and Timing of Dose for Each Subject .........................................32 
5.4.1 
Uninterrupted Randomized Arm ................................................................33 


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5.4.2 
Interrupted Randomized Arm .....................................................................33 
5.4.3 
Temporary Discontinuation of Apixaban ...................................................33 
5.5 
Blinding/Unblinding .....................................................................................34 
5.6 
Concomitant Treatments .............................................................................34 
5.6.1 
Prohibited and/or Restricted Treatments ..................................................34 
5.6.2 
Other Restrictions and Precautions ............................................................34 
5.7 
Treatment Compliance .................................................................................34 
5.8 
Handling Subjects Withdrawn, Lost to Follow-Up, or Removed 
from the Study ...............................................................................................35 
5.8.1 
Handling of Subject Withdrawals ...............................................................35 
5.8.2 
Handling of Subjects Lost to Follow-Up .....................................................35 
5.8.3 
Removal of Subjects from the Trial or Study Drug ..................................35 
6 
STUDY ASSESSMENTS AND PROCEDURES .......................................37 
6.1 
Study Schematic ............................................................................................37 
6.2 
Time and Events Schedule ...........................................................................38 
6.3 
Study Procedures and Evaluations .............................................................40 
6.3.1 
Informed Consent .........................................................................................40 
6.3.2 
Medical History .............................................................................................40 
6.3.3 
Physical Examination ...................................................................................40 
6.3.4 
Vital Signs ......................................................................................................41 
6.3.5 
Clinical Laboratory Tests ............................................................................41 
6.3.6 
Safety Assessments ........................................................................................42 
6.3.7 
Efficacy and Safety Assessments .................................................................42 
7 
STUDY ACTIVITIES ..................................................................................42 
7.1 
Visit 1: Screening and Enrollment: 0 to 42 Days Prior to the 
Catheter Ablation Procedure .......................................................................43 
7.2 
Visit 2: The Day Prior to the Procedure, the Day of the Procedure 
(Day 0), and the Day of Discharge ...............................................................44 
7.3 
Visit 3: 1-Month Follow-Up/End of Study: Day 30-45 ..............................45 
8 
ADVERSE EVENTS ....................................................................................46 
8.1 
Definition and Causality...............................................................................46 
8.2 
Serious Adverse Events ................................................................................46 
8.2.1 
Serious Adverse Event Collecting and Reporting ......................................48 


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8.2.2 
SAE Reconciliation .......................................................................................49 
8.3 
Non-Serious Events .......................................................................................49 
8.3.1 
Non-Serious Adverse Events (NSAEs) Collecting and Reporting ............49 
8.4 
Laboratory Test Abnormalities ...................................................................49 
8.5 
Pregnancy ......................................................................................................50 
8.6 
Overdose ........................................................................................................50 
8.7 
Potential Drug-Induced Liver Injury .........................................................50 
8.8 
Other Safety Considerations ........................................................................51 
9 
STATISTICAL CONSIDERATIONS ........................................................51 
9.1 
General Statistical Analysis Plan ................................................................51 
9.2 
Sample Size Determination ..........................................................................52 
9.3 
Populations for Analyses ..............................................................................54 
9.4 
Endpoints .......................................................................................................55 
9.4.1 
Definitions ......................................................................................................55 
9.4.2 
Primary Endpoints .......................................................................................55 
9.4.3 
Secondary Endpoints ....................................................................................55 
9.5 
Analyses .........................................................................................................56 
9.5.1 
Demographics and Baseline Characteristics ..............................................56 
9.5.2 
Efficacy Analyses ..........................................................................................56 
9.5.3 
Safety Analyses ..............................................................................................57 
9.5.4 
Other Analyses ..............................................................................................57 
9.5.5 
Addition Analysis: Comparing Prospective Apixaban with 
Retrospective Warfarin Cohorts .................................................................59 
10 
CLINICAL EVENTS COMMITTEE .........................................................59 
11 
STUDY MANAGEMENT ............................................................................60 
11.1 
Regulatory Documentation ..........................................................................60 
11.2 
Compliance with the Protocol ......................................................................60 
11.2.1 
Protocol Deviations .......................................................................................61 
11.3 
Monitoring .....................................................................................................62 
11.3.1 
Initiation of Study Sites ................................................................................62 
11.3.2 
Visits ...............................................................................................................62 
11.3.3 
Study Close-Out ............................................................................................63 


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11.4 
On-Site Inspection and Audits .....................................................................63 
11.5 
Records Retention .........................................................................................63 
11.5.1 
Records Retention .........................................................................................63 
11.5.2 
Study Drug Records .....................................................................................63 
11.6 
Destruction of Investigational Product .......................................................64 
11.7 
Disclosure and Confidentiality ....................................................................64 
12 
GLOSSARY OF TERMS .............................................................................64 
13 
LIST OF ABBREVIATIONS ......................................................................65 
14 
REFERENCES .............................................................................................83 
 
 
 
 
LIST OF APPENDICES 
 
Appendix 1 
US Prescribing Information for Apixaban .....................................68 
Appendix 2 
Bleeding Academic Research Consortium Definition for 
Bleeding .........................................................................................82 
 
 


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1 PROTOCOL SYNOPSIS 
STUDY TITLE 
Apixaban Evaluation of Interrupted Or Uninterrupted Anticoagulation in 
Ablation of Atrial Fibrillation. 
PHASE 
Phase IV 
INTERVENTION 
Apixaban uninterrupted therapy vs. interrupted therapy.  Apixaban dose 
will be 5 mg b.i.d. (per product label, dose adjustment to 2.5 mg b.i.d. will 
be required for subjects with ≥2 of the following characteristics: age ≥80 
years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL). 
PROTOCOL 
NUMBER 
CV185-373 
STUDY DESIGN 
Prospective, multicenter, randomized, open-label clinical trial. The study 
will compare 2 arms:  uninterrupted vs. interrupted therapy with apixaban 
in subjects with planned catheter ablation for the treatment of nonvalvular 
atrial fibrillation (NVAF). 
 
Simultaneously, a retrospective cohort of 300 warfarin-treated 
individuals, identified by chart review, who are matched to the 
prospective randomized subjects, will be identified.  Key demographic 
and outcome variables from each patient record will be documented. The 
outcomes in this group will be compared to the outcomes in the 
randomized, prospective cohort.   
OBJECTIVES 
For the prospective, randomized cohort: to evaluate the efficacy and 
safety of apixaban uninterrupted therapy vs. interrupted therapy during the 
peri- and post-procedural period of catheter ablation. 
 
For the retrospective, warfarin cohort: to assess the efficacy and safety of 
apixaban compared to the current clinical setting (use of warfarin).  
Outcomes derived from the retrospective warfarin cohort will be 
compared to that observed in the combined (both randomized arms) 
prospective cohort, and to that observed in each randomized arm of the 
prospective cohort (warfarin vs. uninterrupted apixaban; warfarin vs. 
interrupted apixaban). 
HYPOTHESES 
A strategy of uninterrupted apixaban will have similar rates of bleeding 
and thrombotic events as an interrupted strategy. 
 
Peri- and post-procedural treatment with apixaban may have a similar risk 


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of thrombotic events but with a decreased risk of bleeding compared with 
current peri- and post-procedure anticoagulation management strategies 
with warfarin. 
SUBJECT 
POPULATIONS 
For the prospective, randomized cohort: Subjects undergoing catheter 
ablation for NVAF.  
 
For the retrospective, warfarin cohort: Patient records identified through 
chart review of individuals who underwent catheter ablation for NVAF on 
or after September 1, 2013 in the enrolling centers, who were treated with 
warfarin, who have documented follow-up in the medical record for ≥ 30 
days post-ablation procedure, and who are matched (prospectively, with 
site personnel blinded to the clinical outcome) to the prospective, 
randomized cohort for age (+/- 5 years), gender, and AF type (paroxysmal 
vs. persistent). 
STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For the prospective, randomized cohort: Subjects undergoing catheter 
ablation for NVAF will be enrolled prospectively.   
Subjects will be treated with apixaban for ≥21 days prior to ablation. 
Apixaban dose will be 5 mg b.i.d.; per product label, dose will be 2.5 mg 
b.i.d. in subjects with ≥2 of the following characteristics: age ≥80 years, 
body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. 
Subjects will be randomized 1:1 to 2 peri-procedural treatment strategies:  
1. Uninterrupted treatment: administer the evening apixaban dose on 
the day prior to the procedure; administer the morning apixaban 
dose on the day of the procedure; administer heparin bolus before 
transseptal puncture to maintain a target activated clotting time 
(ACT) > 300 seconds; administer the evening apixaban dose after 
the procedure if there were no peri-procedural complications that 
necessitate withholding anticoagulation for longer duration. 
2. Interrupted treatment: administer the evening apixaban dose on the 
day prior to the procedure; do not administer the morning 
apixaban dose on the day of the procedure; administer heparin 
bolus before transseptal puncture to maintain a target ACT > 300 
seconds; administer the evening apixaban dose after the procedure 
if there were no peri-procedural complications that necessitate 
withholding anticoagulation for longer duration. 
Subjects will be consented and enrolled at Visit 1 and treated with 
apixaban; for subjects already being treated with apixaban for ≥21 days, it 
is not necessary to wait 21 days between Visit 1 and Visit 2. Eligible 
subjects will be randomized prior to the procedure (Visit 2); 
randomization may take place on the day of the procedure or up to 3 days 


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prior. Subjects not randomized will be considered screen failures. Routine 
monitoring, including pre-procedural transesophageal echocardiography, 
will be performed at the discretion of the investigator.  
 
Randomization of subjects will be stratified only by site. Apixaban 
treatment will be continued for 1 month post-catheter ablation. Visits will 
be at screening/enrollment, pre-procedure, discharge, and at 1 month for 
follow-up. 
 
For the retrospective, warfarin cohort: A chart review will be conducted to 
identify patient records for 300 warfarin-treated individuals who 
underwent ablation for NVAF on or after September 1, 2013 in the 
enrolling centers, who have documented follow-up in the medical record 
for ≥ 30 days post-ablation procedure, and who are matched to the 
subjects from the prospective randomized cohort. Site personnel will 
prospectively review (blinded to the subject’s clinical outcome) matched 
records of patients who meet the applicable inclusion/exclusion criteria 
(see Inclusion/Exclusion Criteria for details) to document key 
demographic and outcome variables. This review will assess the incidence 
of the adjudicated primary endpoint in the current setting. Only pre-
existing data will be collected for the analysis of this cohort. 
NUMBER OF 
SUBJECTS AND 
SITES 
Up to 20 sites in the United States (US) will participate. 
 
For the prospective, randomized cohort: In order to obtain 300 
randomized subjects, it is anticipated that up to 360 subjects will be 
enrolled. 
 
For the retrospective, warfarin cohort: 300 matched patient records will be 
identified via retrospective chart review, with site personnel blinded to the 
subject outcome.  
PRIMARY 
ENDPOINTS 
Primary safety endpoint: The primary safety endpoint is the incidence of 
clinically significant bleeding assessed from the time of randomization 
through 1 month post–catheter ablation. Clinically significant bleeding is 
defined as bleeding meeting Bleeding Academic Research Consortium 
(BARC) criteria type 2 or higher.  See Appendix 2 for BARC definitions.  
 
Primary efficacy endpoint:  The primary efficacy endpoint is the 
incidence of thrombotic events assessed from the time of randomization 
through 1 month post-catheter ablation. Thrombotic events are defined as 


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a composite of non-hemorrhagic stroke and systemic thromboembolic 
events.   
SECONDARY 
ENDPOINTS  
Major Secondary Endpoints 
 
Incidence of a composite of major bleeding (defined as BARC criteria 
type 3 or higher) and thrombotic events assessed from the time of 
randomization and from the time of enrollment through 1 month post–
catheter ablation. 
  
Incidence of a composite of clinically significant bleeding (BARC criteria 
type 2 or higher) and thrombotic events assessed from the time of 
randomization and from the time of enrollment through 1 month post– 
catheter ablation.  
 
See protocol for Additional Secondary Endpoint information. 
 
SUBGROUP 
ANALYSES 
The primary and major secondary endpoints will be assessed for the 
following major subgroups: 
a. Age (<80 and ≥80 years). 
b. CHA2DS2-VASc (Congestive heart failure, hypertension, age, 
diabetes mellitus, stroke or transient ischemic attack or 
thromboembolism, vascular disease, age, sex category) score (< 
median, ≥ median). 
c. HAS-BLED (hypertension, abnormal renal/liver function, stroke, 
bleeding history or predisposition, labile international normalized 
ratio, elderly, drugs/alcohol) and HEMORR2HAGES (hepatic or 
renal disease, ethanol abuse, malignancy, older age, reduced 
platelet count or function, re-bleeding, hypertension, anemia, 
genetic factors, excessive fall risk, stroke) bleeding risk scores  (< 
median, ≥ median). 
d. Baseline antiplatelet therapy vs. no antiplatelet therapy. 
e. Baseline anticoagulation therapy (subjects who are 
anticoagulation-naïve versus subjects on vitamin K antagonists 
versus subjects on novel oral anticoagulants). 
f. Subjects with ≥2 of the following characteristics: age ≥80 years, 
body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. 
g. Apixaban dose. 
 
 


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SAMPLE SIZE 
CONSIDERATIONS 
AND STATISTICAL 
ANALYSES 
 
 
 
Given the nature of the pilot study, it is not powered for the primary 
analyses of comparing randomized treatments on the primary 
endpoints.  The sample size however is based on an evaluation of 
anticipated event rates as compared with current literature, as 
described further below.  While not definitively powered to detect 
differences in the randomized groups, this study should provide useful 
information on this patient population.  
 
For the primary analysis of the comparison of the interrupted versus 
uninterrupted apixaban treatment strategies, the primary efficacy and 
safety endpoint rates and the exact 2-sided 95% confidence intervals 
of the primary efficacy and safety endpoints for each apixaban group 
(and for both apixaban groups combined) and a 2-sided 95% 
confidence interval of the risk difference between the apixaban groups 
(calculated using the Wilson method) will be displayed for apixaban-
treated subjects.  
 
In addition, the secondary analysis of the primary efficacy and safety 
endpoints will compare the rates (from randomization to 1 month 
post-ablation) of clinically significant bleeding events and of 
thrombotic events observed in the apixaban prospective randomized 
cohort (both randomized arms combined and separately by 
randomized arm), compared to that observed in the matched, 
retrospective warfarin cohort.  
 
Sample size justification: 
A tertiary but important current aim of the study is to assess the 
combined thrombotic/bleeding rate for both apixaban groups 
combined via an approach using a comparison to a literature-derived 
boundary. The boundary is derived from the warfarin event rates 
reported in studies assessing novel oral anticoagulants versus warfarin 
in the setting of ablation, and in which 3-month rates were reported. 
This strategy ensures the literature-derived boundary is reflective of 
current standards of care. 
We searched PUBMED for the following search criteria: “(dabigatran 
AND ablation) OR (rivaroxaban AND ablation) OR (apixaban AND 
ablation) OR (novel oral anticoagulants AND ablation).” The search 
yielded 78 titles, of which 12 full-text articles were retrieved for in-
depth review. The following 5 studies were identified: 
 


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Study 
Warfarin 
Group 
Size 
Clinically Significant Bleeding and 
Thrombotic Events* 
Kaseno et al.1 
101 
13 (12.9%) 
Bassiouny et al.2 
623 
24 (3.9%) 
Kaiser et al.3 
135 
12 (8.9%) 
Kim et al.4 
572 
31 (5.4%) 
Yamaji et al.5 
203 
7 (3.4%) 
* Includes thromboembolic events, major clinically significant bleeding events, 
and minor bleeding events. 
A meta-analytic rate of the composite of clinically significant bleeding 
and thrombotic events is calculated to be 5.5% (±1.1%) from a 
random effects meta-analysis (random effects meta-analysis was used 
due to significant heterogeneity among studies).  
Because most events will occur early after the index event, and to 
compare rates at 1 month (rather than 3 months in the literature), we 
will use a composite event rate of 5.0% for the apixaban group. Other 
recent studies, having differing definitions of major bleeding, have 
event rates ranging from 3% to 12%.6-8   As such, a conservative 5% 
rate for the composite seems reasonable.   
An analysis of the two randomized groups of apixaban combined (300 
patients) will be used to assess whether the 1-month rate of the 
composite of clinically significant bleeding and thrombotic events 
(and additionally of the composite of major bleeding and thrombotic 
events) falls below a boundary of 8.7%. Specifically, this study will 
assess the ability of apixaban (in both randomized groups combined) 
in the setting of ablation to meet a boundary of 8.7%, which is an 
absolute increase of 3.7% over the expected rate of 5.0%. 
The following assumptions were used for the sample size calculations: 
• 
Assessment is that the incidence of a composite of clinically 
significant bleeding and thrombotic events (and composite of 
major bleeding and thrombotic events) in the setting of apixaban 
treatment (interrupted and uninterrupted combined) peri- and post-
ablation for NVAF meets the boundary using a 1-sided exact test 
based on the binomial distribution. 
• 
The true apixaban event rate at 1 month is assumed to be 5.0%. 
• 
Type I error (α) = 0.05 (1-sided). 
• 
Power of 80%. 


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A sample size of 300 apixaban subjects in the prospective, 
randomized cohort provides 80% power to meet this boundary, with 
the upper bound of the 1-sided 95% confidence interval of the event 
rate in the study cohort not exceeding 8.7%.  
INCLUSION 
CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For the prospective, randomized cohort: 
1. Signed informed consent. Before any study procedures are performed, 
subjects will have the details of the study described to them, and they 
will be given a written informed consent document to read. Then, if 
subjects consent to participate in the study, they or their legal 
representatives will indicate that consent by signing and dating the 
informed consent document in the presence of study personnel. 
2. >18 years of age. 
3. NVAF with planned catheter ablation treatment. 
4. Planned anticoagulant treatment for a minimum of 1 month after 
catheter ablation. 
5. Subject agrees to all required follow-up procedures and visits. 
6. For women of childbearing potential (WOCBP): 
 Must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]) within 24 hours prior to the start of study 
drug. 
 Must not be breastfeeding 
 Must agree to follow instructions for method(s) of contraception 
for the duration of treatment with the study drug  apixaban plus 5 
half-lives of apixaban (3 days) plus 30 days (duration of ovulatory 
cycle) for a total of 33 days post-treatment completion. 
7. Males who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of 
treatment with the study drug, apixaban, plus 5 half-lives of apixaban 
(3 days) plus 90 days (duration of sperm turnover) for a total of 93 
days post-treatment completion. 
8. Azoospermic males and WOCBP who are continuously not 
heterosexually active are exempt from contraceptive requirements.  
However, WOCBP must still undergo pregnancy testing as described 
in this section. 
 
 
 


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INCLUSION 
CRITERIA 
(CONTINUED) 
 
For the retrospective, warfarin cohort: 
1.  ≥18 years of age, at the time of the historical catheter ablation 
procedure. 
2. NVAF with catheter ablation treatment on or after September 1, 
2013in the enrolling center. 
3. Treatment with a strategy of “uninterrupted warfarin” prior to and 
following catheter ablation (i.e. no peri-procedural bridging with low 
molecular weight heparin). 
4. Medical record includes documentation of follow-up for ≥ 30 days 
post-ablation, i.e. follow-up visit or phone contact (at the facility or 
with other medical provider). 
5. Baseline characteristics in patient record match 1:1 with a subject in 
the prospective, randomized cohort within the same study site, based 
on all of the following criteria: 
 Age (+/– 5 years) 
 Gender  
 AF type (paroxysmal vs. persistent). 
EXCLUSION 
CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For the prospective, randomized cohort: 
1. History of significant bleeding diathesis or coagulopathy or 
inability to accept blood transfusions. 
2. Known hypersensitivity or contraindication to heparin or 
apixaban. 
3. Subjects with mechanical prosthetic heart valves. 
4. History of cerebrovascular accident or transient ischemic attack 
within the last 6 months. 
5. Prior intracranial hemorrhage. 
6. End-stage renal failure (creatinine clearance rate <15 mL/minute 
or on dialysis treatment). 
7. Hepatic disease associated with coagulopathy. 
8. Current or expected systemic treatment with strong dual inducers 
of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (e.g., 
rifampin, carbamazepine, phenytoin, St. John’s wort).  
9. Current or expected systemic treatment with dual antiplatelet 
therapy, other anticoagulants, or fibrinolytics. 
10. Planned or expected surgery, or other invasive procedure that 
would require interruption of anticoagulation within 1 month of 


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EXCLUSION 
CRITERIA 
(CONTINUED) 
the catheter ablation procedure. 
11. Currently enrolled in another investigational device or drug trial 
that has not completed the primary endpoint or that clinically 
interferes with the current study endpoints.  
12. Co-morbid condition(s) that could limit the subject’s ability to 
participate in the trial or to comply with follow-up requirements, 
or that could impact the scientific integrity of the trial. 
13. Platelet count ≤100,000/mm3. 
14. Hemoglobin level <9 g/dL. 
15. Any active bleeding. 
16. Prisoners or subjects who are involuntarily incarcerated. 
17. Subjects who are compulsorily detained for treatment of either a 
psychiatric or physical (e.g., infectious disease) illness. 
 
For the retrospective, warfarin cohort: 
Exclusion criteria 1-15 apply to this study population, applicable at 
the time of the historical catheter ablation procedure. 
 
ESTIMATED 
START DATE, 
ENROLLMENT, 
AND FOLLOW-UP 
Estimated start date is in the third quarter of 2015. The enrollment 
phase is expected to last 10 months. Subjects will be followed from 
enrollment (approximately 0-42 days prior to ablation) to 1 month 
post-procedure. 
 
 
 


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2 INTRODUCTION 
Atrial fibrillation (AF) is the most common significant cardiac rhythm disorder and is associated 
with substantial mortality and morbidity.9 The estimated prevalence of AF is 0.4% to 1% in the 
general population, and increases with age.9,10 AF is also associated with increased morbidity 
and increased risk of thrombotic embolism and death.11-13 The rate of ischemic stroke among 
patients with nonvalvular atrial fibrillation (NVAF) is estimated at 5% per year,14 with 1 of every 
6 strokes occurring in a patient with AF.15 The use of antithrombotic medications can mitigate 
some of the embolic risks associated with AF, and clinical guidelines recommend that 
anticoagulants be used in patients with more than 1 moderate risk factor.14 
Catheter ablation of AF has become a well-established therapeutic approach in symptomatic 
patients.14 However, AF catheter ablation is technically challenging and carries a risk of 
thromboembolic complications, likely associated with the catheters used in the left atrium, 
endothelial denudation, scar formation, and tissue inflammation.16-18 The incidence of 
thromboembolic events associated with AF ablation can be as high as 7%,19 and there are reports 
indicating clinically silent cerebral microembolism detected only by post-procedural 
imaging.20,21 Peri-procedural anticoagulation management in patients undergoing AF ablation 
can mitigate some of these effects, but is associated with a higher bleeding rate.22 Recent 
guidelines suggest that catheter ablation of AF can be executed without warfarin interruption, but 
the level of evidence supporting this recommendation is still low.23 
The field of anticoagulation has changed considerably over the last few years. Considerable 
research has sought to overcome the limitations of available anticoagulant and antithrombotic 
agents, including efforts to develop agents that target specific factors of the coagulation process, 
which in turn may improve efficacy and increase the therapeutic index. Factor Xa (FXa) is a 
primary target, as this factor plays a pivotal role in the coagulation cascade at the junction of the 
intrinsic and extrinsic pathways of the coagulation system. Inhibition of FXa is expected to exert 
anticoagulant and antithrombotic effects by decreasing the conversion of prothrombin to active 
thrombin, thereby diminishing thrombin-mediated activation of the coagulation process, 
including fibrin formation and platelet activation.24 
Novel oral anticoagulants (NOACs) have been studied for treatment of AF in the setting of 
catheter ablation. They have shown to carry a comparable risk-benefit profile to that of 
warfarin.25,26 Apixaban, a novel, orally active, potent, direct selective inhibitor of coagulation 
FXa, reversibly binds to the active site of FXa, and exerts anticoagulant and antithrombotic 
effects by diminishing the conversion of prothrombin to thrombin. It has been shown to reduce 
the risk of stroke, systemic embolism, and bleeding in patients with AF compared with 


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warfarin,27 and reduce the risk of stroke and systemic embolism without increasing the risk of 
bleeding compared with aspirin in patients for whom vitamin K antagonists are not suitable.24 
Considerable uncertainty exists about the optimal strategy for dosing NOAC agents around the 
time of an ablation procedure.  “Uninterrupted” warfarin has become the standard approach 
based on case series and on randomized study (BRUISE CONTROL) of a related procedure28-31 
A series of papers have been published using uninterrupted rivaroxaban, with similar rates of 
bleeding and thrombotic endpoints as warfarin control patients.26  With dabigatran, two strategies 
of interrupted dosing have been evaluated in prior years, where holding one dose was associated 
with increased bleeding, but holding two doses was not. Randomized trials however, are testing 
an uninterrupted strategy.32 33  
With apixaban, the graph below illustrates the level of anticoagulation over time with twice daily 
dosing, which would be that of an “uninterrupted” strategy.  For an “interrupted” strategy, 
holding the dose in the morning of the ablation procedure, thus being between 12-18 hours 
following a dose (if last taken at 8pm the night before) – the level of anticoagulation 
approximates that of rivaroxaban.  Which of these two approaches gives the best overall 
effectiveness for avoiding bleeding and thrombotic complications is unknown.34   
 


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2.1 Overall Risk/Benefit Assessment 
Similar to other NOACs, apixaban is expected to have a risk-benefit profile that is comparable to 
that of warfarin in subjects with NVAF undergoing radiofrequency ablation. In this study, peri- 
and post-procedural treatment with apixaban may reduce procedure-related risk of 
thromboembolic complications but with a decreased risk of bleeding compared with current peri- 
and post-procedure anticoagulation management strategies. 
 
Between the two dosing strategies, it is not known whether the uninterrupted or interrupted 
strategy of apixaban will differ in their rates of clinically significant bleeding or thrombotic 
events. For possible benefits and risks – holding one dose of apixaban could potentially lower the 
risk of bleeding or might increase thrombotic events; conversely, continuing apixaban might lead 
to a higher risk of bleeding but lower rates of thrombotic events.  On balance though, with the 
modest difference in the level of anticoagulation, it is hypothesized that the rates of these events 
will be similar between the two strategies. 
 
2.2 Research Hypothesis 
For the prospective, randomized cohort: 
Among subjects planned to undergo catheter ablation for treatment of NVAF, it is hypothesized 
that the incidence of thrombotic events and bleeding events will be similar between the two arms 
of the study (apixaban uninterrupted therapy vs. apixaban interrupted therapy). To assess this 
hypothesis, the primary efficacy and safety endpoint rates and the exact 2-sided 95% confidence 
intervals of the primary efficacy and safety endpoints for each apixaban group (and for both 
apixaban groups combined) and a 2-sided 95% confidence interval of the risk difference between 
the groups (calculated using the Wilson method) will be presented for apixaban-treated subjects.  
 
Retrospective warfarin cohort: 
It is hypothesized that peri- and post-procedural treatment with apixaban may have similar risk 
of thrombotic events but with a decreased risk of bleeding compared with current peri- and post-
procedure anticoagulation management strategies with warfarin. 
 
A tertiary research hypothesis is: 
The combined clinically significant bleeding and thrombotic event rate (and additionally the 
combined major bleeding/thrombotic event rates) with apixaban peri- and post-procedural 


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treatment (interrupted and uninterrupted combined) will be lower than the literature-based 
boundary of 8.7% at 1 month based on the medical literature. To assess this hypothesis, we will 
compare the 1-sided 95% upper bound of the confidence interval of the rate of clinically 
significant bleeding and thrombotic events to the literature-based boundary. (If interrupted and 
uninterrupted apixaban are considered to be statistically and clinically significantly different on 
the combined bleeding/thrombotic event rate, then this analysis may be carried out separately for 
interrupted and uninterrupted apixaban). 
2.3 Study Rationale 
This post-market, prospective, randomized trial is designed to assess the efficacy and safety of 
apixaban in subjects planned to undergo catheter ablation for treatment of NVAF. This will be 
the first study addressing the safety and efficacy of 2 apixaban treatment strategies 
(uninterrupted versus interrupted) in the setting of NVAF ablation.  It will also assess the 
effectiveness of each strategy for apixaban (uninterrupted, interrupted) versus warfarin and both 
strategies for apixaban combined (uninterrupted plus interrupted) versus warfarin. 
.  
2.4 Study Objectives 
For the prospective, randomized cohort: to evaluate the efficacy and safety of apixaban 
uninterrupted therapy vs. interrupted therapy during the peri- and post-procedural period of 
catheter ablation. 
For the retrospective, warfarin cohort: to assess the efficacy and safety of apixaban compared to 
the current clinical setting (use of warfarin).  Outcomes derived from the retrospective, warfarin 
cohort will be compared to that observed in the combined (both randomized arms) prospective 
cohort, and to that observed in each randomized arm of the prospective cohort (warfarin vs. 
uninterrupted apixaban; warfarin vs. interrupted apixaban). 
 
3 ETHICAL CONSIDERATIONS 
3.1 Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations (CFR), Title 21, Part 50 (21CFR50). 


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The study will be conducted in compliance with the protocol. The protocol, any amendments, 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion before initiation of the study. 
All potential serious breaches must be reported immediately to Harvard Clinical Research 
Institute (HCRI). A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant degree, the 
safety or physical or mental integrity of the subjects of the study or the scientific value of the 
study. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.  
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure; debarment).  
 
3.2 Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator 
should also provide the IRB/IEC with a copy of the product labeling information to be provided 
to subjects, and any updates. HCRI must receive a letter documenting the IRB/EC approval prior 
to initiation of the study. 
The investigator should provide the IRB/IEC with reports, updates, and other information (e.g., 
expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. The investigator is also responsible for informing the 
IRB/EC of the progress of the study and for obtaining annual IRB/EC renewal. The IRB/EC 
must be informed at the time of completion of the study and should be provided with a summary 
of the results of the study by the site principal investigator (PI). The investigator must notify the 
IRB/EC in writing of any serious adverse event or any unexpected adverse event according to 
ICH guidelines. 
 
3.3 Informed Consent 
The following information in this section applies to the prospective, randomized cohort only: 


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The investigator must comply with informed consent regulations (U.S. 21CFR Part 50), 
ICH/GCP Guidelines, the Declaration of Helsinki, and relevant state regulations (i.e., California 
Bill of Rights for California patients). The ICF must be reviewed and approved by the site 
investigator’s designated IRB/EC and by HCRI. The ICF should include all the elements as 
outlined in Section 4.8.10 of the ICH guideline for GCP (E6). Each site must provide HCRI with 
a copy of the study site’s IRB/EC approval letter and the approved ICF. Investigators must 
ensure that subjects or, in situations in which consent cannot be given by subjects, their legally 
acceptable representative, are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which they volunteer to participate. 
Investigators must: 
1. Provide a copy of the consent form and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. The 
language must be non-technical and easily understood. 
2. Allow time necessary for the subject or subject’s legally acceptable representative to 
inquire about the details of the study. 
3. Obtain an informed consent that is signed and personally dated by the subject or the 
subject’s legally acceptable representative and by the person who conducted the informed 
consent discussion.  
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form (ICF) and any other information to be provided to the subjects, prior to the 
beginning of the study, and after any revisions are completed for new information. 
5. If informed consent is initially given by a subject’s legally acceptable representative or 
legal guardian, and the subject subsequently becomes capable of making and 
communicating their informed consent during the study, then consent must additionally 
be obtained from the subject. 
6. Revise the informed consent whenever important new information becomes available that 
is relevant to the subject’s consent. The investigator, or a person designated by the 
investigator, should fully inform the subject or the subject’s legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the subject’s willingness to continue participation in the study. 
This communication should be documented.  
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.  


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Any revisions to the approved ICF must be reviewed and approved by HCRI before submission 
to the IRB/EC. 
 
3.4 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects’ state of 
health will be regarded as confidential. This is detailed in the written information provided to the 
subject. An agreement for disclosure of any such information will be obtained in writing and is 
included in both copies of the ICF signed by the subject. The study data shall not be disclosed to 
a third party without the written consent of the sponsor. 
 
Subject confidentiality will be maintained throughout the clinical study in a way that assures that 
data can always be tracked back to the source data. For this purpose, a unique subject 
identification code (ID number) will be used that allows identification of all data reported for 
each subject. 
 
Data relating to the study might be made available to third parties (for example in case of an 
audit performed by regulatory authorities) provided the data are treated as confidential and that 
the subject’s privacy is guaranteed. 
 
“Protected Health Information” will be treated and maintained in compliance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) privacy rule and applicable local 
laws on the protection of individuals with regard to the processing of personal data and on the 
free movement of such data. 
 
The duration of storage time of personal data at the investigational sites will be in accordance 
with national regulations (see Section 12.2). 
 


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4 INVESTIGATIONAL PLAN 
4.1 Study Design and Duration 
4.1.1 Prospective, Randomized Cohort 
Subjects undergoing ablation for NVAF will be screened for eligibility and those meeting all 
eligibility requirements (see Section 4.2) will be enrolled. Subjects will be consented and 
enrolled at Visit 1. Pre-procedural transesophageal echocardiography will be performed at the 
discretion of the investigator. Subjects will be treated with apixaban for ≥21 days prior to 
ablation; for subjects already being treated with apixaban for ≥21 days, it is not necessary to wait 
21 days between Visit 1 and Visit 2. Eligible subjects will be randomized prior to the procedure 
(Visit 2); randomization may take place on the day of the procedure or up to 3 days prior. 
Subjects not randomized will be considered screen failures. Apixaban dose will be 5 mg b.i.d.; 
per product label, however, the dose will be 2.5 mg b.i.d. in subjects with ≥2 of the following 
characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. 
It is anticipated that up to 360 subjects may be enrolled in order to evaluate a total of 300 
randomized subjects.  Subjects will be randomized in a 1:1 ratio to 2 peri-procedural treatment 
strategies (150 subjects per cohort):  
1. Uninterrupted treatment: administer the evening apixaban dose on the day prior to the 
procedure; administer the morning apixaban dose on the day of the procedure; administer 
heparin bolus before transseptal puncture to maintain a target activated clotting time [ACT] > 
300 seconds; administer the evening apixaban dose after the procedure if there were no peri-
procedural complications that necessitate withholding anticoagulation for longer duration.  
2. Interrupted treatment: administer the evening apixaban dose on the day prior to the 
procedure; do not administer the morning apixaban dose on the day of the procedure; 
administer heparin bolus before transseptal puncture to maintain a target ACT > 300 seconds; 
administer the evening apixaban dose after the procedure if there were no peri-procedural 
complications that necessitate withholding anticoagulation for longer duration. 
Randomized subjects will be stratified by site. Apixaban treatment will be continued for at least1 
month post procedure, until the end of the study. Study visits will be at screening/enrollment, 
pre-procedure/ discharge, and at 1 month for follow-up. Subject participation in the study will 
conclude at the follow-up/end-of-study visit conducted at 1 month post-ablation. 
A Study Schema is shown in Section 6.1 and the Schedule of Events in Section 6.2 


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4.1.2 Retrospective, Warfarin Cohort 
In addition, due to diverse definitions of the components of the primary endpoints in previous 
studies (e.g., clinically significant bleedings), a chart review of 300 warfarin-treated patients who 
underwent catheter ablation for NVAF on or after September 1, 2013 in the enrolling centers and 
who have documented follow-up in the medical record for ≥ 30 days post-ablation procedure will 
be performed to assess the incidence of the adjudicated primary endpoints in the current clinical 
setting. Patient records for warfarin-treated individuals who meet the applicable 
inclusion/exclusion criteria and who are matched 1:1 to a subject in the prospective, randomized 
cohort for age (+/- 5 years), gender and AF type (paroxysmal vs. persistent), will be identified. 
Sites will document key demographic and outcome variables. This review will be performed in a 
blinded manner such that site personnel are blinded to the outcome of each retrospective subject 
during the subject selection process. Only pre-existing data will be collected for the analysis of 
this cohort. 
 
4.2 Study Population 
 
4.2.1 Inclusion Criteria 
Subjects meeting all of the following criteria may be included: 
 
For the randomized, prospective cohort: 
1. Signed informed consent. Before any study procedures are performed, subjects will have the 
details of the study described to them, and they will be given a written informed consent 
document to read. Then, if subjects consent to participate in the study, they or their legal 
representatives will indicate that consent by signing and dating the informed consent 
document in the presence of study personnel. 
2. >18 years of age. 
3. NVAF with planned catheter ablation treatment. 
4. Planned anticoagulant treatment for at least 1 month after the index procedure. 
5. Subject agrees to all required follow-up procedures and visits. 
6. For women of childbearing potential (WOCBP): 


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  Must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the 
start of study drug. 
 Must not be breastfeeding 
 Must agree to follow instructions for method(s) of contraception for the duration of 
treatment with the study drug apixaban, plus 5 half-lives of apixaban (3 days) plus 30 
days (duration of ovulatory cycle) for a total of 33 days post-treatment completion. 
7. Males who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with the study drug apixaban plus 5 half-lives 
of the apixaban (3 days) plus 90 days (duration of sperm turnover) for a total of 93 days post-
treatment completion. 
8. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt 
from contraceptive requirements.  However, WOCBP must still undergo pregnancy testing as 
described in this section. 
 
For the retrospective, warfarin cohort:  
1. ≥18 years of age, at the time of the historical catheter ablation procedure. 
2. NVAF with catheter ablation treatment on or after September 1, 2013 in the enrolling center. 
3. Treatment with a strategy of “uninterrupted warfarin” prior to and following catheter ablation 
(i.e. no peri-procedural bridging with low molecular weight heparin). 
4. Medical record includes documentation of follow-up for ≥ 30 days post-ablation, i.e. follow-
up visit or phone contact (at the facility or with other medical provider). 
5. Baseline characteristics in patient record match 1:1 with a subject in the prospective, 
randomized cohort within the same study site, based on all of the following criteria: 
 Age (+/– 5 years) 
 Gender  
 AF type (paroxysmal vs. persistent). 
 
4.2.2 Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded:  
 
For the randomized, prospective cohort: 
1. History of significant bleeding diathesis or coagulopathy or inability to accept blood 
transfusions. 


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2. Known hypersensitivity or contraindication to heparin or apixaban. 
3. Subjects with mechanical prosthetic heart valves. 
4. History of cerebrovascular accident or transient ischemic attach (TIA) within the last 6 
months. 
5. Prior intracranial hemorrhage. 
6. End-stage renal failure (creatinine clearance rate <15 mL/minute or on dialysis treatment). 
7. Hepatic disease associated with coagulopathy. 
8. Current or expected systemic treatment with strong dual inducers of CYP3A4 and P-
glycoprotein (e.g., rifampin, carbamazepine, phenytoin, St. John’s Wort).  
9. Current or expected systemic treatment with dual antiplatelet therapy, other anticoagulants, 
or fibrinolytics. 
10. Planned or expected surgery, or other invasive procedure that would require interruption of 
anticoagulation within 1 month of the catheter ablation procedure. 
11. Currently enrolled in another investigational device or drug trial that has not completed the 
primary endpoint or that clinically interferes with the current study endpoints.  
12. Co-morbid condition(s) that could limit the subject’s ability to participate in the trial or to 
comply with follow-up requirements, or that could impact the scientific integrity of the trial. 
13. Platelet count ≤100,000/mm3. 
14. Hemoglobin level <9 g/dL. 
15. Any active bleeding. 
16. Prisoners or subjects who are involuntarily incarcerated. 
17. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness. 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study can be used. It is imperative that subjects fully 
meet all eligibility criteria. See Appendix 1 for complete US prescribing information for 
apixaban. 
 
For the retrospective, warfarin cohort: 
Exclusion criteria 1-15 apply to this study population, applicable at the time of the historical 
catheter ablation procedure.  
 


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4.2.3 Contraception Requirements 
The information in this section is applicable to the prospective, randomized cohort subjects only. 
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly. 
At a minimum, subjects must agree to the use of one method of highly effective contraception as 
listed below: 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION  
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirena® by WOCBP 
subject or male subject’s WOCBP partner. Female partners of male subjects participating 
in the study may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug  
• 
IUDs, such as ParaGard® 
• 
Tubal ligation 
• 
Vasectomy 
• 
Complete Abstinence* 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence. 
 
4.2.4 Women of Childbearing Potential 
The information in this section is applicable to the prospective, randomized cohort subjects only. 
A WOCBP is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. 
Menopause is defined as 12 months of amenorrhea in a woman over the age of 45 years in the 


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absence of other biological or physiological causes. In addition, females under the age of 55 
years must have a serum follicle-stimulating hormone (FSH) level >40 mIU/mL to confirm 
menopause. 
Note that females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period to obtain a physiologic FSH level. The 
duration of the washout period is a function of the type of HRT used. The duration of the 
washout period below are suggested guidelines and the investigators should use their judgment 
in checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time during the 
washout period, the woman can be considered postmenopausal: 
 1-week minimum for vaginal hormonal products (rings, creams, gels). 
 4-week minimum for transdermal products. 
 8-week minimum for oral products. 
Other parenteral products may require washout periods as long as 6 months. 
 
4.2.5 Discontinuation of Subjects from Treatment 
The information in this section is applicable to the prospective, randomized cohort subjects only. 
Subjects MUST discontinue investigational product for any of the following reasons: 
 Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
 Any clinical adverse event, laboratory abnormality, or intercurrent illness that, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject. 
 Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness. 
All subjects who discontinue should comply with protocol-specified follow-up procedures 
outlined in Section 5.8.3. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (i.e., is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness). If a subject 
withdraws before completing the study, the reason for withdrawal must be documented 
appropriately. 
 


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5 TREATMENTS 
This section applies to the prospective, randomized cohort subjects only. 
 
5.1 Study Treatment: Apixaban 
Definition of Investigational Product: A pharmaceutical form of an active substance or placebo 
being tested or used as a reference in a clinical study, including products already with a 
marketing authorization but used or assembled (formulated or packaged) in a way different from 
the authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form. In this protocol, the investigational product is apixaban. 
Bristol-Myers Squibb (BMS) will provide apixaban at no cost for this study. 
Definition of Non-Investigational Product: Other medications used in the study as support or 
escape medication for preventative, diagnostic, or therapeutic reasons as components of a given 
standard of care.  
 
5.1.1 Identification, Packaging, and Labeling 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label Type 
Appearance 
Storage Conditions (per 
label) 
Apixaban tablet 
2.5 mg 
Bottles of 60/ 
marketed label 
Yellow, round, biconvex, 
film-coated tablets with 
“893” debossed on one side 
and “2½” on the other side. 
Store at 20°C to 25°C 
(68°F–77°F); excursions 
permitted between 15°C 
and 30°C (59°F–86°F) 
Apixaban tablet 
5 mg 
Bottles of 60/ 
marketed label 
Pink, oval-shaped, 
biconvex, film-coated 
tablets with “894” debossed 
on one side and “5” on the 
other side. 
Store at 20°C to 25°C 
(68°F–77°F); excursions 
permitted between 15°C 
and 30°C (59°F–86°F). 
 
5.1.2 Handling and Dispensing 
The investigational product should be stored in a secure area according to local regulations. The 
investigator is responsible for ensuring that it is dispensed only to study subjects and only from 
official study sites by authorized personnel, as dictated by local regulations. 


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The investigator is responsible for ensuring that the investigational product is stored under the 
appropriate environmental conditions (temperature, light, and humidity), as described below: 
Apixaban film-coated tablets should be stored between 20 °C and 25 °C (68–77 °F), with 
excursions permitted between 15 °C and 30 °C (59–86 °F).  
If concerns regarding the quality or appearance of the investigational product arise, do not 
dispense the investigational product, and contact BMS immediately. 
 
5.2 Drug Ordering and Accountability 
5.2.1 Apixaban Orders 
The HCRI project manager should be contacted for study drug requirements. Details of drug 
accountability, ordering, re-supply, and shipment will be provided in the study manual. 
 
5.3 Randomization 
Before the catheter ablation procedure, subjects will be randomly assigned in a 1:1 ratio to 1 of 2 
peri-procedural treatment strategy cohorts (uninterrupted versus interrupted treatment) via the 
HCRI InForm database and based on a randomization list provided by HCRI and stratified by 
site. Randomization may take place on the day of the procedure, prior to time of the subject’s 
morning dose of apixaban, or it may take place up to 3 days prior to the procedure.   
 
5.4 Selection and Timing of Dose for Each Subject 
Subjects not already taking apixaban will be treated with the recommended dose of apixaban 
from at least 21 days prior to the catheter ablation procedure through 1 month post procedure, 
until the final study visit; however, for subjects already taking apixaban for ≥ 21 days, it will not 
be necessary to wait for 21-42 days for Visit 2 to occur.  The dose of apixaban will be 5 mg b.i.d. 
administered orally. A dose adjustment to 2.5 mg b.i.d. will be required for subjects with 2 or 
more of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine 
≥1.5 mg/dL. Before the procedure, subjects will be randomized to receive uninterrupted or 
interrupted therapy as described below.  After the procedure, subjects will receive the same dose 
of apixaban that they received prior to the procedure, for 1 month. 


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If a dose of apixaban is not taken at the scheduled time, the dose should be taken as soon as 
possible on the same day, then continue with twice daily administration as before.   The dose 
should not be doubled to make up for a missed dose. 
Apixaban can be taken with or without food. Apixaban should not be used if a subject has active 
pathological bleeding. It is not recommended in patients with severe hepatic impairment. 
For complete dosing information, see Appendix 1 for the US prescribing information. 
 
5.4.1 Uninterrupted Randomized Arm 
Subjects randomized to the uninterrupted treatment arm will receive the apixaban dose in the 
morning before the procedure. A heparin bolus will be administered before transseptal puncture 
to maintain a target ACT > 300 seconds.  After the procedure, the subject will be administered 
the evening apixaban dose only if no peri-procedural complications occurred that would 
necessitate withholding anticoagulation for longer duration. Apixaban treatment will then be 
continued for at least 1 month post procedure, until the final study visit. 
 
5.4.2 Interrupted Randomized Arm 
Subjects randomized to the interrupted treatment cohort will NOT receive the apixaban dose in 
the morning before the procedure.  A heparin bolus will be administered before transseptal 
puncture to maintain a target ACT > 300 seconds. After the procedure, the subject will be 
administered the evening apixaban dose only if no peri-procedural complications occurred that 
would necessitate withholding anticoagulation for longer duration. Apixaban treatment will then 
be continued for at least 1 month post procedure, until the final study visit. 
5.4.3 Temporary Discontinuation of Apixaban  
Discontinuing anticoagulants, including apixaban, for active bleeding, elective surgery, or 
invasive procedures, places subjects at an increased risk of thrombosis. Lapses in therapy should 
be avoided and, if anticoagulation with apixaban must be temporarily discontinued for any 
reason (with the exception of temporary discontinuation for subjects randomized to the 
interrupted arm as specified above), therapy should be restarted as soon as possible. Treatment 
continuation after the last visit of the study is at the discretion of the treating physician. 
 


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5.5 Blinding/Unblinding 
This is not a blinded study. 
 
5.6 Concomitant Treatments 
5.6.1 Prohibited and/or Restricted Treatments 
For complete contraindication, interaction, and precaution information, see Appendix 1 for the 
US prescribing information for apixaban. 
 
5.6.2 Other Restrictions and Precautions 
Other than the catheter ablation procedure performed during this study, if possible, apixaban 
should be discontinued 2 to 3 days prior to elective surgery or invasive procedures. If surgery or 
invasive procedures cannot be delayed, exercise appropriate caution taking into consideration an 
increased risk of bleeding. This risk of bleeding should be weighed against the urgency of 
intervention. 
The concomitant use of apixaban with antiplatelet agents increases the risk of bleeding. In 
subjects with NVAF and a condition that warrants mono or dual antiplatelet therapy, a careful 
assessment of the potential benefits against the potential risks should be made before combining 
this therapy with apixaban. 
Use apixaban with caution when co-administered with nonsteroidal anti-inflammatory drugs, 
including aspirin. 
For complete contraindication information, see Appendix 1 for the US prescribing information 
for apixaban. 
 
5.7 Treatment Compliance 
Treatment compliance will be determined by subject self-report. If the subject reports that they 
missed doses of apixaban in the following circumstances, they will be discontinued from 
participation in the study (and classified as screen failures): 
1. If the subject reports missing ≥ 1 dose on the day before the procedure. 


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2. If the subject misses ≥ 4 consecutive doses during the 21 days prior to the catheter 
ablation and there is no transesophageal echocardiography (TEE) planned prior to 
the catheter ablation. 
 
5.8 Handling Subjects Withdrawn, Lost to Follow-Up, or Removed from the 
Study 
5.8.1 Handling of Subject Withdrawals 
Although a subject is not obliged to give his/her reason for withdrawing prematurely, the site PI 
will make a reasonable effort to obtain the reason while fully respecting the subject’s rights. If 
there is a medical reason for withdrawal, the subject will remain under the supervision of the site 
PI until in satisfactory health. Reasonable efforts will be made to contact a subject who fails to 
attend any follow-up appointments, in order to ensure that he/she is in satisfactory health. 
 
5.8.2 Handling of Subjects Lost to Follow-Up 
Every attempt must be made to have all subjects complete the visit schedule. A subject will not 
be considered lost-to-follow-up unless all efforts to obtain compliance are unsuccessful. Study 
sites should attempt to contact these subjects in order to maintain study visit compliance and all 
contact attempts should be documented in both the subject’s medical records and on the study 
electronic case report form (eCRF). At a minimum, the site should make two attempts (at least 3-
5 days apart and on both business and non-business hours) to contact the subject by phone and 
one by certified mail. 
 
5.8.3 Removal of Subjects from the Trial or Study Drug 
Subjects will be informed that they are free to withdraw from the study at any time should they 
so wish without jeopardizing their medical care. The site PI may remove a subject if, in his/her 
opinion, it is in the best interest of the subject. A subject may be withdrawn from the study for 
any of the following reasons: 
 Deviation/noncompliance with the protocol occurs 
 A serious or intolerable adverse event (AE) occurs 
 The Sponsor or site PI terminates the study 


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 Withdrawal of consent - any subject may withdraw his/her consent from the study at any 
time. The site PI should make a reasonable attempt to document the specific reason why 
consent is withdrawn. 
 The site PI or Sponsor decides that discontinuing the trial or discontinuing the subject is 
in the subject’s best interest 
 The subject is lost to follow-up 
A study completion eCRF, which includes the reason for discontinuation, must be completed for 
all subjects. If the subject discontinues prematurely, the study completion eCRF should clearly 
indicate the reason for discontinuation. If the subject discontinues due to an AE, an AE eCRF 
must be completed. The AE must be followed by medical attention to satisfactory resolution and 
all trial data related to the subject will be reported. 
Every effort will be made to continue clinical and laboratory follow-up in subjects who wish to 
withdraw from the study treatment (medication or placebo) or in whom the study medication is 
stopped by the site PI or per individual stopping rules. 
 


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6 STUDY ASSESSMENTS AND PROCEDURES 
This section applies to the prospective, randomized cohort subjects only. 
6.1 Study Schematic 
 


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6.2 Time and Events Schedule 
Table 1 
Schedule of Events for Protocol CV185-373 
Evaluation 
Visit 1 
Screening/ 
Enrollment 
Visit 2 
Pre-Procedure 
and 
Discharge 
Visit 3 
1-Month  
Follow-Up/ 
End of Study1 
Study day 
0 to 42 Days 
before procedure2  
0-3 Days before 
procedure 
Day of procedure, 
Day 0 
Day of discharge 
30 to 45 Days after 
procedure 
Informed consent 
X 
 
 
 
 
Screening/eligibility criteria3 
X4 
 
X4 
 
 
Enrollment 
X 
 
 
 
 
Medical/social history, demographics, baseline 
characteristics 
X 
 
 
 
 
CHA2DS2-VASc 
X 
 
 
 
 
HAS-BLED, HEMORR2HAGES 
X 
 
 
 
 
Physical examination 
X 
 
X5 
X5 
X5 
Vital signs 
X 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
Clinical laboratory tests6 
X 
 
X 
 
 
Catheter ablation procedure 
 
 
X7 
 
 
Administration of  study treatment 
X 
 
X8 
X 
 
Termination of study treatment 
 
 
 
 
X 
Study treatment accountability 
 
 
X 
 
X 
Thrombotic events, bleeding (BARC criteria) 
X 
 
X 
X 
X 
Adverse events 
X 
 
X 
X 
X 
Concomitant medications 
X 
 
X 
X 
X 
End of subject participation 
 
 
 
 
X 


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BARC: Bleeding Academic Research Consortium; CHA2DS2VASc: Congestive heart failure, hypertension, age, diabetes mellitus, stroke or transient ischemic attack or thromboembolism, vascular 
disease, age, sex category score; HAS BLED: hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol bleeding 
risk score; HEMORR2HAGES: hepatic or renal disease, ethanol abuse, malignancy, older age, reduced platelet count or function, rebleeding, hypertension, anemia, genetic factors, excessive fall risk, 
stroke bleeding risk score. 
 
1. In the event of early study withdrawal or treatment discontinuation, an end-of-study visit should be conducted. The reason for early withdrawal/study drug discontinuation must be documented. 
2.  Subjects already taking apixaban for ≥ 21 days do not have to wait for the 21-day window for Visit 2 to occur. 
3. Screening/eligibility criteria are detailed in section 7.1. 
4. Urine or serum pregnancy test will be performed for screening within 24 hours prior to start of study drug and within 24 hours prior to the catheter ablation procedure in WOCBP.  
5. Physical examination to assess any clinically significant changes from screening, including neurological examination. 
6. Clinical laboratory tests are detailed in Section 6.3.5. 
7. Catheter ablation will be performed on the day of Visit 2 (day 0). 
8. Subjects randomized to the uninterrupted treatment cohort will receive the morning dose of study treatment pre-procedure. Subjects randomized to the interrupted treatment cohort will not receive the 
morning dose of study treatment pre-procedure. 
 


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6.3 Study Procedures and Evaluations 
6.3.1 Informed Consent 
Potential study subjects will report to the investigative site for eligibility screening. Before any 
study-specific procedures are conducted, the nature, purpose, potential risks and benefits, and 
requirements of the study must be explained to each potential subject, and the potential subject 
must be given an opportunity to ask questions concerning the study until he or she is satisfied. 
The nature and purpose of informed consent must also be explained to the potential subjects. All 
subjects will be informed in writing of the nature of the protocol and investigational therapy, its 
possible hazards, and their right to withdraw at any time. They will have adequate opportunity to 
ask the appropriate person of the study staff (i.e., site PI or designee) presenting the study about 
any aspect of the study. Once the subject is satisfied that he/she is willing to participate in the 
study, he/she will be asked to sign and date the written ICF. No study procedure is permitted to 
be performed until the ICF is signed. The PI or designee obtaining informed consent from the 
subject will also sign the ICF to confirm that consent has been obtained as required. A copy of 
the signed ICF will be given to the subject. The subject’s medical record should contain written 
documentation indicating that voluntary informed consent was obtained. 
6.3.2 Medical History 
A detailed medical history will be obtained by the PI or designee during the screening visit (visit 
1). This will include information regarding the subject’s full history of medical conditions, 
diagnoses, procedures, treatments, concomitant medications, demographic information, and any 
other noteworthy medical information, with dates of start and finish. Data on baseline 
characteristics, including chronic renal insufficiency (%), gastrointestinal bleeding, and smoking 
will also be collected. Any updates to medical history information that the PI or designee 
becomes aware of will be captured throughout the study. 
6.3.3 Physical Examination 
The PI or a medically qualified designee will perform the physical examinations at the time 
points indicated in the schedule of events (SOE; Section 6.1). A complete physical examination 
will include assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, chest/lungs, 
heart, abdomen, lymph nodes, extremities, targeted neurological examination, and general 
appearance. The physical examination will not include a pelvic, breast, or rectal examination. 
Weight (in kg; assessed in ordinary indoor clothing with shoes off) will be recorded according at 
the time points indicated in the SOE. Height (in cm) will be recorded at screening (visit 1) only. 


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Body mass index (BMI) will be calculated at screening (visit 1) only and is defined as the 
subject’s weight in kilograms divided by the square of the subject’s height in meters (kg/m2). 
If any clinically significant change from screening (visit 1) is noted, it will be reported as an 
adverse event and followed up to resolution or upon reaching a stable end point. 
6.3.4 Vital Signs 
Evaluation of vital signs will be performed by qualified site personnel after the subject has been 
seated for 5 minutes, and will include a measurement of systolic and diastolic blood pressure, 
pulse rate, oral temperature, and respiratory rate. Vital sign measurements will be obtained at all 
visits (visits 1, 2, and 3), as indicated in the SOE. Blood pressure should be taken on the same 
arm throughout the study and will be obtained using a completely automated device consisting of 
an inflatable cuff and an oscillatory detection system. Manual blood pressure readings may be 
obtained in the event of instrument malfunction. Body temperature will be measured with an oral 
thermometer. 
If the PI or medically qualified sub-investigator determines that clinically significant changes 
have occurred in any vital sign measurement, that measurement will be captured as an adverse 
event and repeated at medically appropriate intervals until the value returns to an acceptable 
range, a specific diagnosis is established, or the condition is otherwise explained. 
6.3.5 Clinical Laboratory Tests 
6.3.5.1 Laboratory Parameters 
Subjects will be in a seated or supine position during blood collection. All clinical laboratory 
assessments will be performed by a local clinical laboratory accredited by the College of 
American Pathologists or a certificate of compliance issued by the Center for Medicare & 
Medicaid Services, Clinical Laboratory Improvement Amendments. The laboratory assessments 
will include routine and screening laboratory tests. See Section 6.2 for the SOE. Système 
International (SI) units will be used for all assessments. 
Routine safety laboratory panels will include: 
 Hematology: white blood cell count, hemoglobin, hematocrit, and platelet count. 
 Serum chemistry: glucose, blood urea nitrogen (BUN), creatinine, estimated glomerular 
filtration rate, alkaline phosphatase (AP), aspartate transaminase (AST), alanine 
transaminase (ALT), and total bilirubin. 
Any abnormal hematology, serum chemistry, or test result deemed clinically significant by the PI 
or medically qualified sub-investigator will be reported as an adverse event and repeated as 
appropriate as standard of care, including test results obtained on the final study day. For any test 


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abnormality deemed erroneous or clinically significant, repeat analysis will be performed as per 
standard of care until resolution, or until the PI or medically qualified sub-investigator 
determines that resolution of the laboratory abnormality is not expected. 
6.3.5.2 Sample Collection, Storage, and Shipping 
All blood sampling will be by individual venipuncture or with the use of an in-dwelling venous 
catheter. Blood and urine sample collection and processing procedures will be outlined in a 
separate reference manual to be provided to the site. 
6.3.6 Safety Assessments 
The PI is ultimately responsible for assessing and reporting all AEs as outlined in the protocol. 
The assessment of AEs may be delegated to a medically qualified sub-investigator trained in 
study protocol who is listed on the Food and Drug Administration (FDA) Form 1572 or 
equivalent document, and on the Delegation of Authority form. 
AEs should be volunteered by the subject; solicited from subjects using a standard statement; or 
examination of the subject at a clinic visit, or observations of clinically significant laboratory 
values or special exam abnormal values. AEs will not be solicited by use of a specific list of 
anticipated events. 
All AEs are to be assessed and recorded in a timely manner and followed to resolution or until 
the investigator determines that there is not an anticipated resolution. Each AE is to be 
documented with reference to severity, date of occurrence, duration, treatment, and outcome. 
Each AE is also to be classified as being non-serious or serious (as defined in Section 8.2). In 
addition, the PI or delegated medically qualified sub-investigator must assess whether or not the 
AE is drug-related. Changes in severity and resolution dates should be documented as separate 
events. 
See Section 8 for complete information regarding AEs. 
6.3.7 Efficacy and Safety Assessments 
Thrombotic events will be assessed and are defined as a composite of non-hemorrhagic stroke 
and systemic thromboembolic events. 
Clinically significant bleeding will be assessed and is defined as bleeding meeting BARC criteria 
type 2 or higher. BARC definitions for bleeding are shown in Appendix 2. 
 
7 
STUDY ACTIVITIES 
This section applies to the prospective, randomized cohort subjects only. 


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7.1 
Visit 1: Screening and Enrollment: 0 to 42 Days Prior to the Catheter 
Ablation Procedure 
Visit 1 (screening/enrollment) will occur 0 to 42 days prior to the catheter ablation procedure. 
For subjects not already taking apixaban, Visit 1 will occur 21-42 days prior to the procedure. 
For subjects already taking apixaban for ≥ 21 days, it will not be necessary to wait for 21-42 
days for Visit 2 to occur. The following study evaluations and procedures will be performed at 
this visit: 
 The signed informed consent will be obtained before any screening or other study related 
procedures are initiated. 
 Assignment of a subject number. When a subject signs the ICF, she/he will be assigned a 
unique subject number in numerical sequence, which will be used for the duration of the 
study. The subject number will be recorded in the source document and case report form. 
 Review of the inclusion and exclusion criteria. 
 Recording of the subject’s demographic information, baseline characteristics, and 
comprehensive medical history. 
 Physical examination, including targeted neurological examination. 
 Vital sign measurements (systolic and diastolic blood pressure, pulse, respiration rate, 
oral temperature) after a minimum 5-minute rest in the supine position. 
 Administration of pre-procedure treatment 
 CHA2DS2VASc  (Congestive heart failure, hypertension, age, diabetes mellitus, stroke or 
transient ischemic attack or thromboembolism, vascular disease, age, sex category score) 
 HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or 
predisposition, labile international normalized ratio, elderly, drugs/alcohol bleeding risk 
score) 
 HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older age, 
reduced platelet count or function, rebleeding, hypertension, anemia, genetic factors, 
excessive fall risk, stroke bleeding risk score) 
 Clinical laboratory tests (refer to Section 6.3.5) 
 Urine or serum pregnancy test will be performed for screening within 24 hours prior to 
start of study drug in WOCBP.   
 Dispensation and administration of study treatment, if applicable. 
 Evaluation for clinically significant bleeding and thrombotic events. 


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 Recording of AEs and concomitant medications. 
 
7.2 
Visit 2: The Day Prior to the Procedure, the Day of the Procedure (Day 
0), and the Day of Discharge 
Randomization to 1 of 2 peri-procedural treatment strategies, uninterrupted treatment or 
interrupted treatment, will occur prior to the ablation procedure. It may take place on the day of 
the procedure, prior to time of the subject’s morning dose of apixaban, or up to 3 days prior to 
the procedure, but no visit is required for this.  Visit 1 and randomization may take place on the 
same day for subjects already taking apixaban for ≥ 21 days. 
Visit 2 will occur on the day of the ablation procedure (day 0) and the day of discharge from the 
hospital.  
Pre-procedure study evaluations and procedures will occur on the day of the catheter ablation 
and will include: 
 Brief physical examination to assess any clinically significant changes from screening, 
including targeted neurological examination. 
 Vital sign measurements (systolic and diastolic blood pressure, pulse, respiration rate, 
oral temperature) after a minimum 5-minute rest in the supine position. 
 Routine clinical laboratory tests, including hematology and serum chemistry (using a 
venous blood sample). 
 Urine or serum pregnancy test will be performed within 24 hours of catheter ablation 
procedure in WOCBP. 
 Subjects randomized to the uninterrupted treatment cohort will receive the morning dose 
of study treatment pre-procedure. Subjects randomized to the interrupted treatment cohort 
will not receive the morning dose of study treatment pre-procedure. 
 Evaluation for clinically significant bleeding and thrombotic events. 
 Recording of AEs and any changes to concomitant medications, including dose or 
regimen changes. 
 Drug accountability. 
 
Post-procedure study evaluations and procedures will include: 
 All subjects will receive the evening apixaban dose after the procedure if there were no 
peri-procedural complications that necessitate withholding anticoagulation for longer 
duration 


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 Evaluation for clinically significant bleeding and thrombotic events. 
 Recording of AEs and any changes to concomitant medications, including dose or 
regimen changes. 
 For all subjects, the twice daily apixaban dose will be resumed the day after the catheter 
ablation procedure while the subject remains in the hospital. 
 
Discharge study evaluations and procedures will occur on the day the subject is to be discharged 
from the hospital and will include: 
 Brief physical examination to assess any clinically significant changes from screening, 
including targeted neurological examination. 
 Vital sign measurements (systolic and diastolic blood pressure, pulse, respiration rate, 
oral temperature) after a minimum 5-minute rest in the supine position. 
 Evaluation for clinically significant bleeding and thrombotic events. 
 Recording of AEs and any changes to concomitant medications, including dose or 
regimen changes. 
 Drug accountability. 
 If not already occurring, dispensation and administration of study treatment. 
 
7.3 
Visit 3: 1-Month Follow-Up/End of Study: Day 30-45 
Visit 3 (1-month follow-up/end of study) will occur 1 month after the ablation procedure (day 30 
to 45). The following study evaluations and procedures will be performed at this visit: 
 Brief physical examination to assess any clinically significant changes from screening. 
 Vital sign measurements (systolic and diastolic blood pressure, pulse, respiration rate, 
oral temperature) after a minimum 5-minute rest in the supine position. 
 Termination of study treatment. 
 Study treatment accountability. 
 Evaluation for clinically significant bleeding and thrombotic events. 
 Recording of AEs and any changes to concomitant medications, including dose or 
regimen changes. 
 End of subject participation. 
 


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8 
ADVERSE EVENTS 
This section applies to the prospective, randomized cohort subjects only. 
 
8.1 
Definition and Causality 
An AE is defined as any new untoward medical occurrence or worsening of a pre-existing 
medical condition in a patient or clinical investigation subject administered an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of investigational 
product, whether or not considered related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to assess 
all AEs. The causal relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship.  
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. Adverse events may include: 
 Objective signs observed by the site PI or study personnel. 
 Subjective or objective signs/symptoms. 
 Concomitant disease or accidents. 
 Clinically relevant adverse changes in laboratory parameters observed in a subject in the 
course of a clinical study. 
Pre-existing conditions that worsen in severity or frequency or have new signs/symptoms 
associated with them. 
8.2 
Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence at any dose that:  
 Results in death. 


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 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe). 
 Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
note below for exceptions). 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect. 
 Is an important medical event, defined as a medical event that may not be immediately 
life-threatening or result in death or hospitalization but, based on appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed above. Examples 
of such events include but are not limited to intensive treatment in an emergency 
department or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization. 
 Potential drug-induced liver injury (DILI) is also considered an important medical 
event. See the DILI section below for a definition of a potential DILI event. 
Suspected transmission of an infectious agent (e.g., pathogenic or non-pathogenic) via the study 
drug is an SAE.  
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these 
events must be handled as SAEs. 
SAEs also include events that are medically significant in the site PI’s judgment, including 
medically significant laboratory abnormalities, such as those that warrant stopping study 
treatment for individual subjects. 
 
NOTE: The following hospitalizations are not considered SAEs:  
 A visit to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a life-
threatening event). 
 Elective surgery planned before signing consent. 
 Admissions as per protocol for a planned medical/surgical procedure. 
 Routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy). 
 Medical/surgical admission other than remedying ill health state that was planned before 
study entry. Appropriate documentation is required in these cases. 


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 Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
 
8.2.1 Serious Adverse Event Collecting and Reporting  
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuing dosing. If applicable, SAEs must be collected that relate to 
any later protocol-specific procedure (such as follow-up blood draw). 
The investigator should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specified procedure.  
An SAE Report Form should be completed for any event in which doubt exists regarding its 
status of seriousness. 
If the investigator believes that an SAE is not related to study drug but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
SAEs, whether related or unrelated to the study drug, and pregnancies must be reported to HCRI 
within 24 hours. SAEs must be recorded on the SAE Report Form, pregnancies on a Pregnancy 
Surveillance Form. The site PI or designated personnel should enter the SAEs into the clinical 
database. If in the unlikely event the database is not functioning, the site personnel should email 
or fax the SAE information to HCRI. 
SAE Fax Number: 1-617-307-5626 
SAE Email Address:  AXA14@srcdocs.hcri.net 
If only limited information is initially available, follow-up reports are required. Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported. 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to HCRI (or designee) 
using the same procedure used for transmitting the initial SAE report.  
The site PI must also promptly inform the governing IRB/EC of the SAE per the governing 
IRB/EC’s requirements. All SAEs should be followed to resolution or stabilization. 
 


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8.2.2 SAE Reconciliation 
HCRI Clinical Review and Safety in collaboration with the HCRI Data Management (DM) team 
will reconcile the clinical and safety databases according to the SAE Reconciliation Plan. The 
SAE Reconciliation Plan details the parameters to be reconciled, data format, frequency and 
timing and designated responsibilities for reconciliation.  Updates will be made to the safety 
database if discrepancies are found during reconciliation. A follow-up report will be submitted to 
applicable reportable events as a follow-up Med Watch report following completion of SAE 
reconciliation. SAE reconciliation final approval will occur after all discrepancies are resolved 
and the designated representatives agree that the clinical trial and safety databases are reconciled. 
 
8.3 Non-Serious Events 
A non-serious adverse event (NSAE) is an AE not classified as serious. 
8.3.1 Non-Serious Adverse Events (NSAEs) Collecting and Reporting 
The collection of NSAE information should begin after the subject has signed the informed 
consent form. 
NSAEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for NSAEs that cause interruption or discontinuation of study 
drug, or those that are present at the end of study treatment as appropriate.  
 
8.4 
Laboratory Test Abnormalities 
The following laboratory abnormalities should be captured and reported as appropriate: 
 Any laboratory test result that is clinically significant or meets the definition of an SAE. 
 Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted. 
 Any laboratory test result abnormality that required the subject to receive specific 
corrective therapy.  
It is expected that wherever possible, the clinical rather than the laboratory term will be used by 
the reporting investigator (e.g., use the term anemia rather than low hemoglobin value).  
Other findings related to abnormal laboratory values, ECGs, vital signs, etc., that are not 
considered clinically significant, are not to be recorded on the AE reporting page; they should 
instead be entered in the relevant eCRF page. 


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8.5 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product (apixaban) 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (e.g., dose tapering if 
necessary for subject safety). 
The investigator must immediately notify HCRI of this event via the Pregnancy Surveillance 
Form within 24 hours (to be faxed or emailed to HCRI at 1-617-307-5626 or at 
AXA14@srcdocs.hcri.net) and in accordance with SAE reporting procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, if applicable, offspring information must be reported on a Pregnancy Surveillance 
Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
HCRI. Information on this pregnancy may also be collected on the Pregnancy Surveillance 
Form. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., X-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. 
 
8.6 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs. 
 
8.7 
Potential Drug-Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs. 
Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation >3 times upper limit of normal (ULN). 


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AND 
2. Total bilirubin >2 times ULN, without initial findings of cholestasis (elevated serum AP) 
AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
 
8.8 
Other Safety Considerations 
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious AE, 
as appropriate, and reported accordingly. 
. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
General Statistical Analysis Plan 
 This study will examine results in two groups of randomized, prospective subjects, and one 
group of retrospective, warfarin subjects. For the randomized groups, subjects undergoing 
catheter ablation for NVAF will be enrolled. These subjects will be randomized 1:1 to two peri-
procedural treatment strategies: uninterrupted apixaban or interrupted apixaban. Randomization 
of subjects will be stratified by site. The primary safety endpoint is the incidence of the clinically 
significant bleeding from time of randomization through 1 month post-catheter ablation. The 
primary efficacy endpoint is the incidence of thrombotic events assessed from the time of 
randomization through 1 month post–catheter ablation. The primary analyses will compare the 
two groups of randomized subjects on the incidence rate of these endpoints. Secondary analyses 
will compare all randomized subjects (both arms combined) to the retrospective warfarin control 
group on the incidence rate of these endpoints. The control group is comprised of patient records 
from warfarin-treated individuals (retrospective) who underwent ablation for NVAF on or after 
September 1, 2013 in the enrolling centers, and who are matched to the prospective (apixaban) 
subjects by age (+/-5 years), gender, and type of AF (paroxysmal vs. persistent). For the 
retrospective warfarin group, the process of selecting subjects for matching will be performed by 
site personnel, blinded to the matched subject’s outcome. 
   


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9.2 
Sample Size Determination 
Given the nature of the pilot study, it is not powered for the primary analyses of comparing 
randomized treatments. The sample size however is based on an evaluation of anticipated event 
rates as compared with current literature as described further below.  While not definitively 
powered to detect differences in the randomized groups, this study should provide useful 
information on this patient population. 
For the primary analysis of the comparison of the interrupted versus uninterrupted apixaban 
treatment strategies, the primary efficacy and safety endpoint rates and the exact 2-sided 95% 
confidence intervals of the primary efficacy and safety endpoints for each apixaban group (and 
for both apixaban groups combined) and a 2-sided 95% confidence interval of the risk difference 
between the apixaban groups (calculated using the Wilson method) will be displayed for 
apixaban-treated subjects. It is noted that this is a pilot study and this analysis will have limited 
power.   
The event rate for clinically significant bleeding from the literature is difficult to obtain with the 
protocol specified definition.  Recent registries show rates of major bleeding of approximately 
2%, and minor bleeding of 6-12%.  Minor bleeding has not been consistently defined and is 
difficult to compare across trials. To be conservative, we adopted an event rate of 4% for 
warfarin.  Although in the ARISTOTLE trial comparing warfarin and apixaban in patients with 
AF (not undergoing ablation) the bleeding rate was 20-30% lower with apixaban, we have 
conservatively assumed that the rate will be the same.  As such, the assumed rate of clinically 
significant bleeding for apixaban is 4.0%.  
For the primary analyses on the primary safety endpoint, assuming an evaluable sample size of 
150 per randomized group and an event rate of 4.0% for each of the interrupted and 
uninterrupted apixaban groups, the width of the confidence interval for the risk difference 
between randomized groups will be 10% (i.e., the 95% CI of the risk difference will be -5% to 
+5%).  
In addition, the secondary analysis of the efficacy and safety endpoints will compare the rates 
(from randomization to 1 month post-ablation) of clinically significant bleeding events, and of 
thrombotic events observed in the apixaban prospective randomized cohort, compared to that 
observed in the matched, retrospective warfarin cohort who meet inclusion/exclusion criteria. 
These analyses will be performed on the evaluable population. 
For the secondary analyses of comparing apixaban (both interrupted and uninterrupted 
combined) to warfarin, assuming an evaluable sample size of 300 patients for each of apixaban 
and warfarin cohorts and a clinically significant bleeding event rate of 4% for each of these two 


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groups, the width of the confidence interval for the risk difference between groups will be 6.7%. 
(i.e., the 95% CI of the risk difference to be -3.35% to +3.35%). 
Sample size justification 
A tertiary but important current aim of the study is to assess the combined thrombotic/bleeding 
rate for both groups combined via an approach using a comparison to a literature-derived 
boundary. The literature-based boundary is derived from the warfarin event rates reported in 
studies assessing novel oral anticoagulants versus warfarin in the setting of ablation, and in 
which 3-month rates were reported. This strategy ensures the boundary is reflective of current 
standards of care. 
We searched PUBMED for the following search criteria: “(dabigatran AND ablation) OR 
(rivaroxaban AND ablation) OR (apixaban AND ablation) OR (novel oral anticoagulants AND 
ablation).” The search yielded 78 titles, of which 12 full-text articles were retrieved for in-depth 
review. The following 5 studies were identified: 
 
Study 
Warfarin 
Group 
Size 
Clinically Significant Bleeding and 
Thrombotic Events* 
Kaseno et al.1 
101 
13 (12.9%) 
Bassiouny et al.2 
623 
24 (3.9%) 
Kaiser et al.3 
135 
12 (8.9%) 
Kim et al.4 
572 
31 (5.4%) 
Yamaji et al.5 
203 
7 (3.4%) 
* Includes thromboembolic events, major clinically significant bleeding 
events, and minor bleeding events. 
A meta-analytic rate of the composite of clinically significant bleeding and thrombotic events is 
calculated to be 5.5% (± 1.1%) from a random effects meta-analysis (random effects meta-
analysis was used due to significant heterogeneity among studies). 
Because most events will occur early after the index event, and to compare rates at one month 
(rather than 3 months in the literature), we will use a composite event rate of 5.0% for the 
apixaban group. Other recent studies, having differing definitions of major bleeding, have event 
rates ranging from 3% to 12%.6-8   As such, a conservative 5% rate for the composite seems 
reasonable.   
An analysis of the two groups of apixaban combined (300 subjects) will be used in this tertiary 
analysis to assess if the upper bound of the 1-sided 95% confidence interval of the 1-month rate 


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of clinically significant bleeding and thrombotic events (and additionally of the composite of 
major bleeding and thrombotic events) falls below a boundary of 8.7%. Specifically, this analysis 
will assess whether apixaban (in both randomized groups combined) in the setting of catheter 
ablation can meet a boundary of 8.7%, which is an absolute increase of 3.7% over the expected 
rate of 5.0% obtained from the meta-analysis.  In other words, this analysis will test the 
following null and alternative hypotheses: 
 
 
 
H0: π ≥ 0.087 (or 8.7%) 
 
 
 
H1: π < 0.087 (or 8.7%) 
where π is the true (unknown) apixaban endpoint rate. 
The following assumptions were used for the sample size calculations: 
 Assessment is that the incidence of a composite of clinically significant bleeding and 
thrombotic events (and composite of major bleeding and thrombotic events) in the 
setting of apixaban treatment (interrupted and uninterrupted combined) peri- and 
post-ablation for NVAF meets the literature-based boundary using a 1-sided exact test 
based on the binomial distribution. 
 The true apixaban event rate at 1 month is assumed to be 5.0%. 
 Type I error (α) = 0.05 (1-sided). 
 Power of 80%. 
A sample size of 300 apixaban subjects in the prospective, randomized cohort provides 80% 
power to meet this boundary, with the upper bound of the 1-sided 95% confidence interval of the 
event rate in the study cohort not exceeding 8.7%. It is estimated that up to 360 subjects will be 
enrolled to randomize 300 subjects.  
 
9.3 
Populations for Analyses 
Intention-to-treat (ITT): All subjects randomized to either interrupted or uninterrupted apixaban. 
Evaluable: The subset of the ITT population who experienced a primary endpoint prior to 1 
month (30 days) post–index procedure or who were followed through 1 month (30 days minus an 
allowable 3-day visit window) post–index procedure. This is the primary analysis population for 
the primary endpoint and for efficacy in general. Subjects are analyzed under the treatment to 
which they were randomized. 
Safety: All subjects receiving randomized study treatment. This is the primary analysis 
population for safety. Subjects are analyzed under the treatment received. 


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Historical Control: The retrospective cohort of patient records from 300 warfarin-treated 
individuals who underwent catheter ablation for NVAF in the enrolling centers on or after 
September 1, 2013 and who were matched for age, gender and type of AF (paroxysmal vs. 
persistent) to the 300 prospective apixaban patients. 
 
9.4 
Endpoints 
9.4.1 Definitions 
Thrombotic events are defined as a composite of non-hemorrhagic stroke and systemic 
thromboembolic events.   
 
Clinically significant bleeding is defined as bleeding meeting Bleeding Academic Research 
Consortium (BARC) criteria type 2 or higher.  See Appendix 2 for BARC definitions. 
 
Major bleeding is defined as bleeding meeting BARC criteria type 3 or higher. 
 
9.4.2 Primary Endpoints 
1. The primary safety endpoint is the incidence of clinically significant bleeding assessed 
from the time of randomization through 1 month post–catheter ablation.  
2. The primary efficacy endpoint is the incidence of a thrombotic events assessed from the 
time of randomization through 1 month post–catheter ablation.  
 
9.4.3 Secondary Endpoints 
Major Secondary Endpoints 
1. Incidence of a composite of major bleeding and thrombotic events assessed from the time 
of randomization and from the time of enrollment through 1 month post–catheter 
ablation. 
2. Incidence of a composite of clinically significant bleeding and thrombotic events 
assessed from the time of randomization and from the time of enrollment through 1 
month post– catheter ablation. 
Additional Secondary Endpoints 
The following additional secondary endpoints will be assessed: 


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1. Clinically significant bleeding, major bleeding, and thrombotic events, and the composite 
of both (clinically significant bleeding and thrombotic events; major bleeding and 
thrombotic events) assessed separately in-hospital, and from randomization and from 
enrollment through 1 month post–catheter ablation. 
2. TIAs or non-hemorrhagic strokes from the time of enrollment and from the time of 
randomization through 1 month post–catheter ablation. 
3. Incidence of death and cardiovascular death from the time of enrollment and from the time 
of randomization through 1 month post–catheter ablation. 
 
9.5 
Analyses 
9.5.1 Demographics and Baseline Characteristics 
Descriptive statistics of demographic and baseline characteristics will be presented for 
interrupted apixaban, uninterrupted apixaban, and both apixaban groups combined.  Similar 
descriptive statistics and analyses will be presented for the retrospective warfarin group. Groups 
(apixaban uninterrupted versus interrupted; apixaban versus warfarin) will be compared on 
baseline variables using 2-sample t-test for continuous variables and Fisher’s exact test for 
categorical variables.  
9.5.2 Efficacy Analyses 
The following analyses will be performed on the ITT population and the evaluable population. 
The analyses on the evaluable population are considered the primary analyses. 
9.5.2.1 Primary Efficacy Analyses 
For the primary analysis of the comparison of the interrupted versus uninterrupted apixaban 
treatment strategies, the primary efficacy endpoint rates and the exact 2-sided 95% confidence 
intervals of the primary endpoint for each apixaban group (and for both apixaban groups 
combined) and a 2-sided 95% confidence interval of the risk difference between the groups 
(calculated using the Wilson method) will be presented for apixaban-treated subjects. It is noted 
that this is a pilot study and this analysis will have limited power. 
For the ITT analysis set, there may be missing data on the primary efficacy endpoint due to 
premature withdrawals prior to 1 month post–index procedure. As a supportive analysis to assess 
the sensitivity of results to missing data, analyses on the ITT population will incorporate the 
following approach: Kaplan-Meier rate estimates and 2-sided 95% confidence intervals of the 
Kaplan-Meier estimates and of the difference between Kaplan-Meier estimates will be presented 
for the same apixaban groupings. All ITT subjects will be included in the calculation of the 


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Kaplan-Meier rates; subjects not experiencing the event will be censored at the end of the 1-
month follow-up or time of their premature withdrawal, whichever is earlier. 
9.5.2.2 Major Secondary Efficacy Analyses 
The two major secondary endpoints will be analyzed in a similar manner as the primary efficacy 
endpoints for the evaluable and ITT analysis sets.  
9.5.2.3 Additional Secondary Analyses 
The above-mentioned additional secondary endpoints will be assessed and analyzed in a similar 
manner as the primary and major secondary efficacy endpoints (however, Kaplan-Meier 
estimates will not be calculated for in-hospital endpoints, and subjects included in the calculation 
of in-hospital rates do not need to have 1 month of follow-up). 
 
9.5.3 Safety Analyses 
Analyses will be carried out in a similar manner as for the primary efficacy endpoint.   
 
The following additional safety analyses will be carried out on the safety population: 
The number and percentage of subjects with treatment emergent adverse events (TEAEs) will be 
presented by MedDRA system organ class and preferred term for each apixaban group 
(uninterrupted and interrupted) and both apixaban groups combined. A TEAE is defined as an 
AE starting or worsening in severity on or after start of study treatment. These analyses will be 
repeated for serious TEAEs and for TEAEs leading to premature discontinuation from the study. 
For each apixaban group and both groups combined, descriptive statistics (sample size, median, 
mean, minimum, maximum) of vital signs and of the change from baseline in vital signs will be 
presented at each visit. 
 
9.5.4 Other Analyses 
1. As a tertiary analysis, the combined thrombotic/bleeding rate for both apixaban groups combined 
will be compared to a rate derived from the literature. Based on the above-mentioned meta-
analysis, the expectation for the true combined thrombotic/bleeding endpoint rate at 1 month is 
5.0% for apixaban. However, because strict equality cannot be assessed statistically, this study 
will assess if the 1-month rate of clinically significant bleeding and thrombotic events (and 
additionally of the composite of major bleeding and thrombotic events) falls below 8.7% when 
both treatment arms are combined. Specifically, this tertiary analysis will assess the ability of 
apixaban in the setting of catheter ablation to meet a literature-based boundary of 8.7%, which is 


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an absolute increase of 3.7% over the expected rate of 5.0% obtained from the meta-analysis. In 
other words, this analysis will test the following null and alternative hypotheses: 
 
 
 
H0: π ≥ 0.087 (or 8.7%) 
 
 
 
H1: π < 0.087 (or 8.7%) 
where π is the true (unknown) apixaban endpoint rate.  
The null hypotheses will be tested using all evaluable apixaban subjects (uninterrupted and 
interrupted groups combined) at a 1-sided 0.05 level of significance using an exact test based on 
the binomial distribution. In addition, a 1-sided exact 95% confidence interval of the endpoint 
rate will be presented and the upper bound will be compared to 8.7%. For completeness, a 2-
sided exact 90% confidence interval will also be presented.  Note that, prior to carrying out this 
analysis, the comparability between apixaban groups on this thrombotic/bleeding endpoint will 
be assessed using a 2-sided 95% Wilson confidence interval.  If the confidence interval does not 
contain 0 and if the difference between apixaban groups is considered clinically different, the 
above analyses may be repeated for each of the uninterrupted and interrupted apixaban groups, 
separately. 
2. To assess consistency of sites with respect to the primary efficacy and safety endpoint rates, 
logistic regression will be used to compare sites with respect to the primary endpoints rates for 
the evaluable population. A 0.15 level of significance will be used to determine if a significant 
site effect exists. A P value <0.15 will not necessarily preclude the sites from being pooled for 
the final analysis, but will require further inspection (e.g., endpoint results by site) to assess if 
there is a concern about lack of site poolability.  In addition, logistic regression will be used to 
assess consistency of the interrupted vs. uninterrupted apixaban groups across sites, using a 
logistic regression model with effects for treatment type (interrupted or uninterrupted), site and 
the treatment type-by-site interaction.  The interaction term will be assessed using a 0.15 level of 
significance. 
3. The rates and 2-sided exact 95% confidence intervals of the primary and major secondary 
endpoints will be presented by apixaban group and for both apixaban groups combined within 
the following major subgroups: 
a. Age (<80 and ≥80 years). 
b. CHA2DS2-VASc (Congestive heart failure, hypertension, age, diabetes mellitus, stroke or 
transient ischemic attack or thromboembolism, vascular disease, age, sex category) score 
(< median, ≥ median). 
c. HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or 
predisposition, labile international normalized ratio, elderly, drugs/alcohol) and 


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HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older age, 
reduced platelet count or function, re-bleeding, hypertension, anemia, genetic factors, 
excessive fall risk, stroke) bleeding risk scores (< median, ≥ median). 
d. Baseline antiplatelet therapy vs. no antiplatelet therapy. 
e. Baseline anticoagulation therapy (subjects who are anticoagulation-naïve versus subjects 
on vitamin K antagonists versus subjects on novel oral anticoagulants). 
f. Subjects with ≥2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or 
serum creatinine ≥1.5 mg/dL. 
g. Apixaban dose. 
The purpose of this analysis is to assess consistency of primary and major secondary endpoint 
rates across the various subgroups 
. 
9.5.5 Addition Analysis: Comparing Prospective Apixaban with Retrospective Warfarin 
Cohorts 
The rate of the primary endpoint in apixaban subjects (uninterrupted and interrupted groups 
combined) will be compared with a retrospectively-matched warfarin control group. The control 
group is comprised of patient records from warfarin-treated individuals (retrospective) who meet 
inclusion/exclusion criteria, including having undergone ablation for NVAF in the enrolling 
centers on or after September 1, 2013, who have documented follow-up in the medical record for 
≥ 30 days post-ablation procedure, and who meet the other inclusion/exclusion criteria including 
matched for age, gender and type of AF (paroxysmal vs. persistent). For the warfarin group, 
retrospective chart review will be performed to assess the incidence of the primary endpoint. 
This analysis will compare the 1-month rate of clinically significant bleeding and thrombotic 
events between the two groups in a similar manner as was used to compare apixaban groups.   
 
10 
CLINICAL EVENTS COMMITTEE 
The Clinical Events Committee (CEC) is made up of electrophysiology and non-
electrophysiology cardiologists and other clinical experts as required who are not participants in 
the study. The CEC is charged with the adjudication of pre-specified clinical endpoint events. 
At the onset of the trial, the CEC will establish specific criteria used for the categorization of 
clinical endpoint events, explicit rules outlining the minimum amount of data required for 
adjudication of each event, and the algorithm followed in order to classify a study endpoint 
related clinical event. All members of the CEC will remain blinded to the treatment assignment 


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(for subjects in the prospective, randomized cohort) in their review and adjudication of all 
endpoint events. The CEC will meet regularly to review and adjudicate clinical endpoint events 
for which the required minimum data are available. The procedures by which the CEC will 
operate will be documented in a separate manual. 
 
11 
STUDY MANAGEMENT 
11.1 Regulatory Documentation 
Prior to the start of the study, the following documents must be prepared: 
 A completed and signed Form FDA 1572. If during the course of the study any changes 
occur that are not reflected on the 1572, a new 1572 form must be completed and 
returned to Sponsor/HCRI for submission to the FDA. 
 Current signed curriculum vitae and medical licenses (within 2 years) for the site PI and 
all sub-investigators listed on the 1572. 
 A copy of the original approval for conducting the study by the IRB/EC. Renewals, with 
continuance of the study, must be submitted at yearly intervals or as required by IRB/EC 
policy. 
 A copy of the IRB/EC approved informed consent form. 
 IRB/EC member list and DHHS General Assurance Number (if IRB/EC has an 
Assurance number). 
 Signed Financial Disclosure Form for all personnel listed on the 1572 with a statement of 
non-voting by study staff. 
 The protocol signature page signed and dated by the site PI. 
 
11.2 Compliance with the Protocol 
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, HCRI. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB(s)/IEC(s) of an amendment except when necessary to eliminate an 
immediate hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to: 
 IRB/IEC for review and approval/favorable opinion. 


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 HCRI 
 Regulatory authority(ies), if required by local regulations. 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to HCRI. 
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment. 
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s). 
 
11.2.1 Protocol Deviations 
A protocol deviation is defined as any instance during the conduct of the study in which the site 
PI or other site personnel changed or failed to adhere to the study design or procedures specified 
by the protocol. Examples of protocol deviations may include: a) enrollment of a study subject 
who does not meet all of the inclusion/exclusion criteria specified in the protocol; b) failure to 
obtain a key safety procedure or lab test; or c) enrollment of a patient during a lapse in IRB/EC 
approval of the study. Each Investigator shall conduct this clinical study in accordance with this 
clinical protocol, FDA regulations, Good Clinical Practice, and any conditions of approval 
imposed by their IRB/EC. Failure to comply with and/or inability to meet FDA regulations may 
jeopardize further participation of the Investigator or Investigative Center in this and future 
clinical studies. 
All relevant protocol deviations should be submitted by the site on the applicable eCRF, and will 
be reviewed and assessed for their impact on subject safety by the HCRI. 
 
Major Deviations are defined as any unapproved change in the study procedures or study design 
that are within the site Investigator’s control that may adversely affect the subject’s rights, safety 
or well-being, or the accuracy and reliability of the study data. 
 
Minor Deviations are defined as any unapproved change in the study procedures that are within 
the site Investigator’s control that do not have an impact on the subject’s rights, safety or well-
being, or the accuracy and reliability of the study data. 
 


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Investigators are required to notify HCRI in writing before initiating any deviations from the 
protocol, except where necessary to protect the life or physical well-being of a subject in an 
emergency (in cases of medical emergency, HCRI should be notified within 24 hours of the 
occurrence of the deviation). Prior notification is generally not expected in situations where 
unforeseen circumstances are beyond the PI’s control (e.g., subject did not respond to scheduled 
follow-up, blood sample lost by laboratory, etc.), however, the event is still considered a 
deviation. 
 
11.3 Monitoring 
11.3.1 Initiation of Study Sites 
Prior to subject enrollment, a remote study initiation visit will be conducted at each 
investigational site to ensure the following:  IRB/EC approval has been obtained and 
documented prior to subject screening; the Investigators and study personnel are appropriately 
trained and clearly understand the study; and the Investigators and study personnel accept the 
obligations incurred in undertaking this clinical investigation. 
11.3.2 Visits 
Periodic remote monitoring visits will be performed in accordance with the approved monitoring 
plan throughout the clinical study to ensure that the investigator’s obligations are fulfilled and all 
applicable regulations and guidelines are being followed.  These visits will ensure that the 
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 HCRI and the IRB/EC, drug and 
drug inventory are controlled, and the site PI is executing all agreed-upon activities. 
The site will receive notification prior to each remote monitoring visit during the course of the 
study.  The site PI and/or Sub-Investigator and other appropriately trained study staff are 
expected to be available during the visit. 
HCRI, BMS, or their designees retain the right to remove either the PI or the investigational site 
from the study for issues of non-compliance with the protocol or regulatory requirements.  HCRI 
or its designee will perform the monitoring responsibilities according to its standard operating 
procedures. 
The progress of the study will be monitored by: 
• 
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• 
Frequent telephone or email communications between the PI, site staff, and assigned 
study site monitors. 
11.3.3 Study Close-Out 
Upon completion of the clinical study (when all subjects enrolled have completed the follow-up 
visits, all data have been entered into the EDC system, all queries have been resolved, and final 
electronic signatures have been obtained), a study closeout visit will be conducted.  All unused 
study drugs, and any unused study materials and equipment will be collected and returned to 
BMS for reconciliation.  The study monitor will ensure that the PI’s regulatory files are current 
and complete, and that all outstanding issues from previous visits have been resolved.  Other 
issues that will be discussed with site personnel at this visit include retention of study files, 
possibility of site audits, publication policy, and that the site PI must notify the site’s IRB/EC 
regarding study closure. 
11.4 On-Site Inspection and Audits 
The FDA may request access to all study records for inspection and copying. A representative of 
HCRI or BMS also may use similar auditing procedures. The site PI must agree to permit the 
FDA, the governing IRB/EC, BMS and HCRI access to all study records and original subject 
records for auditing purposes and provide support for these actions. The site PI will be informed 
in advance of this visit. 
11.5 Records Retention  
11.5.1 Records Retention 
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by the sponsor/HCRI, whichever is longer.  
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, IRB). Notice of such 
transfer will be given in writing to HCRI. 
11.5.2 Study Drug Records  
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by the sponsor)is maintained at each study site where 
study drug and non-investigational product(s) is/are inventoried and dispensed. Records or logs 
must comply with applicable regulations and guidelines and should include: 
 Amount received and placed in storage area. 


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 Amount currently in storage area. 
 Label identification number or batch number. 
 Amount dispensed to each subject, including unique subject identifiers. 
 Amount transferred to another area/site for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted). 
 Amount destroyed at study site, if applicable. 
 Amount returned to HCRI/the sponsor. 
 Retain samples for bioavailability/bioequivalence, if applicable. 
 Dates 
and 
initials 
of 
person 
responsible 
for 
investigational 
product 
dispensing/accountability, as per the Delegation of Authority Form. 
 
11.6 Destruction of Investigational Product  
If the study drugs are to be destroyed onsite, it is the investigator’s responsibility to ensure that 
arrangements have been made for disposal, and that procedures for proper disposal have been 
established according to applicable regulations, guidelines, and institutional procedures. 
Appropriate records of the disposal must be maintained. 
 
11.7 Disclosure and Confidentiality 
By signing the protocol, the investigator agrees to keep all information provided by HCRI in 
strict confidence and to request similar confidentiality from his/her staff and the IRB/EC. Study 
documents provided by HCRI (protocols, CRFs and other material) will be stored appropriately 
to ensure their confidentiality. The information provided by and HCRI to the investigator may 
not be disclosed to others without direct written authorization from HCRI, except to the extent 
necessary to obtain informed consent from subjects who wish to participate in the study. 
 
12 
GLOSSARY OF TERMS 
Term 
Definition 
 
 
Expedited safety report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (i.e., not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures.  


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Term 
Definition 
Prospective, randomized 
cohort 
Prospectively enrolled subjects who are randomized to 
uninterrupted vs. interrupted apixaban. 
Retrospective, warfarin 
cohort 
Patient records will be identified via chart review and 
pre-existing data will be collected on these individuals 
who had catheter ablation for NVAF and were treated 
with warfarin (to be compared with prospective cohort). 
 
 
13 
LIST OF ABBREVIATIONS 
ACT 
Activated clotting time 
AE 
Adverse event 
AF 
Atrial fibrillation 
ALT 
Alanine transaminase 
AP 
Alkaline phosphatase 
AST 
Aspartate transaminase 
BARC 
Bleeding Academic Research Consortium 
b.i.d. 
Twice daily 
BMI 
Body mass index 
BMS 
Bristol-Myers Squibb 
BUN 
Blood urea nitrogen 
C 
Celsius 
CEC 
Clinical events committee 
CFR 
Code of Federal Regulations 
CHA2DS2-VASc 
Congestive heart failure, hypertension, age, diabetes mellitus, 
stroke or transient ischemic attack or thromboembolism, 
vascular disease, age, sex category (score) 
cm 
Centimeter 
CYP3A4 
Cytochrome P450 3A4 
DILI 
Drug-induced liver injury 
dL 
Deciliter 
DM 
Data Management 
eCRF 
Electronic case report form 
F 
Fahrenheit 
FDA 
Food and Drug Administration 


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FSH 
Follicle-stimulating hormone 
FXa 
Factor Xa 
g 
Gram 
GCP 
Good Clinical Practice 
HAS-BLED 
Hypertension, abnormal renal/liver function, stroke, bleeding 
history or predisposition, labile international normalized ratio, 
elderly, drugs/alcohol (score) 
HCG 
Human chorionic gonadotropin 
HCRI 
Harvard Clinical Research Institute 
HEMORR2HAGES  
Hepatic or renal disease, ethanol abuse, malignancy, older 
age, reduced platelet count or function, re-bleeding, 
hypertension, anemia, genetic factors, excessive fall risk, 
stroke (score) 
HRT 
Hormone replacement therapy 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IUD 
Intrauterine device 
kg 
Kilogram 
L 
Liter 
mg 
Milligram 
mL 
Milliliter 
mm 
Millimeter 
mol 
Micromole 
NOAC 
Novel oral anticoagulant 
NSAE 
Nonserious adverse event 
NVAF 
Nonvalvular atrial fibrillation 
PI 
Principal investigator 
SAE 
Serious adverse event 
SI 
Système International 
SOE 
Schedule of events 
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 


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ULN 
Upper limit of normal 
US 
United States 
WOCBP 
Woman/women of child-bearing potential 
 
 
 


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 Appendix 1 
US Prescribing Information for Apixaban 


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Appendix 2  Bleeding Academic Research Consortium (BARC) Definition 
for Bleeding 
 
Type 0: no bleeding 
 
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalization, or treatment by a healthcare professional; may include 
episodes leading to self-discontinuation of medical therapy by the patient without consulting a 
healthcare professional  
 
Type 2: any overt, actionable sign of hemorrhage (e.g., more bleeding than would be expected for 
a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria 
for type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, 
medical intervention by a healthcare professional, (2) leading to hospitalization or increased level 
of care, or (3) prompting evaluation  
 
Type 3  
o 
Type 3a  
 
Overt bleeding plus hemoglobin drop of 3 to <5 g/dL* (provided hemoglobin 
drop is related to bleed)  
 
Any transfusion with overt bleeding 
o 
Type 3b  
 
Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin drop is 
related to bleed)  
 
Cardiac tamponade 
 
Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid) 
 
Bleeding requiring intravenous vasoactive agents 
o 
Type 3c  
 
Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal) 
 
Subcategories confirmed by autopsy or imaging or lumbar puncture 
 
Intraocular bleed compromising vision 
 
Type 4: CABG-related bleeding  
o 
Perioperative intracranial bleeding within 48 h 
o 
Reoperation after closure of sternotomy for the purpose of controlling bleeding 
o 
Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period† 
o 
Chest tube output ≥2L within a 24-h period 
 
Type 5: fatal bleeding  
o 
Type 5a  
 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious 
o 
Type 5b  
 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
CABG indicates coronary artery bypass graft. Platelet transfusions should be recorded and reported but are 
not included in these definitions until further information is obtained about the relationship to outcomes. If 
a CABG-related bleed is not adjudicated as at least a type 3 severity event, it will be classified as not a 
bleeding event. If a bleeding event occurs with a clear temporal relationship to CABG (i.e., within a 48-h 
time frame) but does not meet type 4 severity criteria, it will be classified as not a bleeding event.  
* Corrected for transfusion (1 U packed red blood cells or 1 U whole blood = 1 g/dL hemoglobin).  
† Cell saver products are not counted. 
 
Mehran R, Rao SV, Bhatt DL, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials. 
A Consensus Report From the Bleeding Academic Research Consortium. Circulation 2011;123:2736-2747. 


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14 
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Hart RG, Halperin JL. Atrial fibrillation and thromboembolism: a decade of 
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Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent 
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Tung R, Boyle NG. Perioperative anticoagulation in device implantation: 
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Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus 
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Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in Patients with Atrial 
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Shurrab M, Morillo CA, Schulman S, et al. Safety and efficacy of dabigatran 
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Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and Safety of 
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Birnie DH, Healey JS, Wells GA, et al. Pacemaker or Defibrillator Surgery 
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Hussein AA, Martin DO, Saliba W, et al. Radiofrequency ablation of atrial 
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Wazni OM, Beheiry S, Fahmy T, et al. Atrial Fibrillation Ablation in Patients 
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Di Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural Stroke and Bleeding 
Complications in Patients Undergoing Catheter Ablation of Atrial Fibrillation 
With Different Anticoagulation Management: Results From the Role of 
Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients 
Undergoing Catheter Ablation (COMPARE) Randomized Trial. Circulation. June 
24, 2014 2014;129(25):2638-2644. 
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patients-undergoing-ablation.html      
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blation&rank=3  
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Frost C, Song Y, Barrett YC, et al. A randomized direct comparison of the 
pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban. Clinical 
pharmacology : advances and applications. 2014;6:179-187. 
 
 

SAP_000.pdf: 
NCT02608099 
 
  
Clinical Trial Protocol: CV 185-373 
 
The AEIOU Trial: Apixaban Evaluation of Interrupted Or 
Uninterrupted Anticoagulation for Ablation of Atrial Fibrillation  
 
 
Statistical Analysis Plan 
 
 
Version: 
Final 1.0 
 
Author: 
Wen Hsieh 
Senior Statistician, Biostatistics 
Harvard Clinical Research Institute 
930 Commonwealth Avenue 
Boston, Massachusetts 02215 
 
Date:  
Oct. 28, 2016 
 
 
 
 
 
 


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HCRI CONFIDENTIAL 
Page 2 of 23 
Final Version 1.0 
APPROVAL SIGNATURES AND SIGNATURE MEANING: 
Harvard Clinical Research Institute (HCRI) Signatures 
Approvals below indicate that the individual has reviewed and agrees with this document as written.  
Any/All deviations will require amendments to this document. 
Name 
Signature 
Title/Department 
Date 
Matthew Reynolds, MD, 
MSc,  
 
Director, Economics and Quality of Life Research 
Harvard Clinical Research Institute  
 
Director of Electrophysiology Research, Division 
of Cardiology 
Lahey Hospital & Medical Center 
 
 
Christopher P. Cannon, 
MD 
 
Executive Director, Cardiometabolic Trials 
Harvard Clinical Research Institute 
 
Cardiovascular Division Brigham and Women’s 
Hospital 
 
Professor of Medicine, Harvard Medical School 
 
 
 
 
DOCUMENT HISTORY 
 
Revision # 
Author 
Date 
Reviewed/Revis
ed 
Changes + Reason for Changes 
Draft V 0.1 
Wen Hsieh 
05JUL2016 
New Document 
Draft V 0.2 
Wen Hsieh 
01SEP2016 
Updated per review comments 
Final V 1.0 
Wen Hsieh 
28 OCT2016 
Finalized SAP 
 
 
 
 


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Contents 
1. 
LIST OF ABBREVIATIONS................................................................................. 5 
2. 
INTRODUCTION ................................................................................................. 7 
2.1 
Overall Risk/Benefit Assessment ............................................................................ 8 
2.2 
Research Hypothesis ............................................................................................ 9 
2.3 
Study Rationale ................................................................................................... 9 
3. 
STUDY OBJECTIVES ........................................................................................ 10 
4. 
PRIMARY AND SECONDARY EDNPOINTS .................................................... 10 
4.1 
Definitions ........................................................................................................ 10 
4.2 
Primary Endpoints ............................................................................................. 10 
4.3 
Secondary Endpoints .......................................................................................... 10 
5. 
INVESTIGATIONAL PLAN, STUDY DESIGN AND DURATION ..................... 11 
5.1 
Prospective, Randomized Cohort ......................................................................... 11 
5.2 
Retrospective, Warfarin Cohort ........................................................................... 13 
6. 
STATISTICAL METHODOLOGY AND CONSIDERATIONS ........................... 14 
6.1     Determination of Sample Size ............................................................................... 14 
6.2     Analysis Populations ............................................................................................ 15 
6.2.1 Intention-to-Treat (ITT)................................................................................... 15 
6.2.2 Evaluable ...................................................................................................... 15 
6.2.3 Safety ............................................................................................................ 15 
6.2.4 Historical Control .......................................................................................... 15 
6.3 
Data Summaries ................................................................................................ 16 
6.4 
Subject Disposition ............................................................................................ 16 
6.5 
Demography, Baseline Characteristics and Medical History .................................. 17 
6.6 
Efficacy Analyses ............................................................................................... 17 
6.6.1 Primary Efficacy Analyses ............................................................................... 17 
6.6.2 Major Secondary Efficacy Analyses .................................................................. 17 
6.6.3 Additional Secondary Analyses ........................................................................ 18 
6.7 
Safety Analyses .................................................................................................. 18 
6.8 
Other Analyses .................................................................................................. 18 
6.9 
Addition Analysis: Comparing Prospective Apixaban with Retrospective Warfarin 
Cohorts ............................................................................................................. 19 
6.10 
Protocol Deviation ............................................................................................. 20 


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6.11 
Concomitant Medication ..................................................................................... 20 
REFERENCES .............................................................................................................. 21 
 
 
 


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1. LIST OF ABBREVIATIONS  
ACT 
Activated clotting time 
AE 
Adverse event 
AF 
Atrial fibrillation 
ALT 
Alanine transaminase 
AP 
Alkaline phosphatase 
AST 
Aspartate transaminase 
BARC 
Bleeding Academic Research Consortium 
b.i.d. 
Twice daily 
BMI 
Body mass index 
BMS 
Bristol-Myers Squibb 
BUN 
Blood urea nitrogen 
C 
Celsius 
CEC 
Clinical events committee 
CFR 
Code of Federal Regulations 
CHA2DS2-VASc 
Congestive heart failure, hypertension, age, diabetes mellitus, stroke or 
transient ischemic attack or thromboembolism, vascular disease, age, 
sex category (score) 
cm 
Centimeter 
CYP3A4 
Cytochrome P450 3A4 
DILI 
Drug-induced liver injury 
dL 
Deciliter 
DM 
Data Management 
eCRF 
Electronic case report form 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FXa 
Factor Xa 
g 
Gram 
GCP 
Good Clinical Practice 
HAS-BLED 
Hypertension, abnormal renal/liver function, stroke, bleeding history or 
predisposition, labile international normalized ratio, elderly, 
drugs/alcohol (score) 
HCG 
Human chorionic gonadotropin 
HCRI 
Harvard Clinical Research Institute 


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HRT 
Hormone replacement therapy 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IUD 
Intrauterine device 
kg 
Kilogram 
L 
Liter 
mg 
Milligram 
mL 
Milliliter 
mm 
Millimeter 
mol 
Micromole 
NOAC 
Novel oral anticoagulant 
NSAE 
Nonserious adverse event 
NVAF 
Nonvalvular atrial fibrillation 
PI 
Principal investigator 
SAE 
Serious adverse event 
SI 
Système International 
SOE 
Schedule of events 
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 
ULN 
Upper limit of normal 
US 
United States 
WOCBP 
Woman/women of child-bearing potential 
 
 
 
 
 


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2. INTRODUCTION  
Atrial fibrillation (AF) is the most common significant cardiac rhythm disorder and is associated 
with substantial mortality and morbidity.9 The estimated prevalence of AF is 0.4% to 1% in the 
general population, and increases with age.9,10 AF is also associated with increased morbidity 
and increased risk of thrombotic embolism and death.11-13 The rate of ischemic stroke among 
patients with nonvalvular atrial fibrillation (NVAF) is estimated at 5% per year,14 with 1 of every 
6 strokes occurring in a patient with AF.15 The use of antithrombotic medications can mitigate 
some of the embolic risks associated with AF, and clinical guidelines recommend that 
anticoagulants be used in patients with more than 1 moderate risk factor.14 
Catheter ablation of AF has become a well-established therapeutic approach in symptomatic 
patients.14 However, AF catheter ablation is technically challenging and carries a risk of 
thromboembolic complications, likely associated with the catheters used in the left atrium, 
endothelial denudation, scar formation, and tissue inflammation.16-18 The incidence of 
thromboembolic events associated with AF ablation can be as high as 7%,19 and there are reports 
indicating clinically silent cerebral microembolism detected only by post-procedural 
imaging.20,21 Peri-procedural anticoagulation management in patients undergoing AF ablation 
can mitigate some of these effects, but is associated with a higher bleeding rate.22 Recent 
guidelines suggest that catheter ablation of AF can be executed without warfarin interruption, but 
the level of evidence supporting this recommendation is still low.23 
The field of anticoagulation has changed considerably over the last few years. Considerable 
research has sought to overcome the limitations of available anticoagulant and antithrombotic 
agents, including efforts to develop agents that target specific factors of the coagulation process, 
which in turn may improve efficacy and increase the therapeutic index. Factor Xa (FXa) is a 
primary target, as this factor plays a pivotal role in the coagulation cascade at the junction of the 
intrinsic and extrinsic pathways of the coagulation system. Inhibition of FXa is expected to exert 
anticoagulant and antithrombotic effects by decreasing the conversion of prothrombin to active 
thrombin, thereby diminishing thrombin-mediated activation of the coagulation process, 
including fibrin formation and platelet activation.24 
Novel oral anticoagulants (NOACs) have been studied for treatment of AF in the setting of 
catheter ablation. They have shown to carry a comparable risk-benefit profile to that of 
warfarin.25,26 Apixaban, a novel, orally active, potent, direct selective inhibitor of coagulation 
FXa, reversibly binds to the active site of FXa, and exerts anticoagulant and antithrombotic 
effects by diminishing the conversion of prothrombin to thrombin. It has been shown to reduce 
the risk of stroke, systemic embolism, and bleeding in patients with AF compared with 
warfarin,27 and reduce the risk of stroke and systemic embolism without increasing the risk of 
bleeding compared with aspirin in patients for whom vitamin K antagonists are not suitable.24 
Considerable uncertainty exists about the optimal strategy for dosing NOAC agents around the 
time of an ablation procedure.  “Uninterrupted” warfarin has become the standard approach 
based on case series and on randomized study (BRUISE CONTROL) of a related procedure28-31 
A series of papers have been published using uninterrupted rivaroxaban, with similar rates of 
bleeding and thrombotic endpoints as warfarin control patients.26  With dabigatran, two strategies 
of interrupted dosing have been evaluated in prior years, where holding one dose was associated 


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with increased bleeding, but holding two doses was not. Randomized trials however, are testing 
an uninterrupted strategy.32 33  
With apixaban, the graph below illustrates the level of anticoagulation over time with twice daily 
dosing, which would be that of an “uninterrupted” strategy.  For an “interrupted” strategy, 
holding the dose in the morning of the ablation procedure, thus being between 12-18 hours 
following a dose (if last taken at 8pm the night before) – the level of anticoagulation 
approximates that of rivaroxaban.  Which of these two approaches gives the best overall 
effectiveness for avoiding bleeding and thrombotic complications is unknown.34   
 
 
 
2.1 
Overall Risk/Benefit Assessment 
Similar to other NOACs, apixaban is expected to have a risk-benefit profile that is comparable to 
that of warfarin in subjects with NVAF undergoing radiofrequency ablation. In this study, peri- 
and post-procedural treatment with apixaban may reduce procedure-related risk of 
thromboembolic complications but with a decreased risk of bleeding compared with current peri- 
and post-procedure anticoagulation management strategies. 
Between the two dosing strategies, it is not known whether the uninterrupted or interrupted 
strategy of apixaban will differ in their rates of clinically significant bleeding or thrombotic 
events. For possible benefits and risks – holding one dose of apixaban could potentially lower the 
risk of bleeding or might increase thrombotic events; conversely, continuing apixaban might lead 


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to a higher risk of bleeding but lower rates of thrombotic events.  On balance though, with the 
modest difference in the level of anticoagulation, it is hypothesized that the rates of these 
bleeding and thrombotic events will be similar between the two strategies. 
 
 
2.2 
Research Hypothesis 
For the prospective, randomized cohort: 
Among subjects planned to undergo catheter ablation for treatment of NVAF, it is hypothesized 
that the incidence of thrombotic events and bleeding events will be similar between the two arms 
of the study (apixaban uninterrupted therapy vs. apixaban interrupted therapy). To assess this 
hypothesis, the primary efficacy and safety endpoint rates and the exact 2-sided 95% confidence 
intervals of the primary efficacy and safety endpoints for each apixaban group (and for both 
apixaban groups combined) and a 2-sided 95% confidence interval of the risk difference between 
the groups (calculated using the Wilson method) will be presented for apixaban-treated subjects.  
 
Retrospective warfarin cohort: 
It is hypothesized that peri- and post-procedural treatment with apixaban may have similar risk 
of thrombotic events but with a decreased risk of bleeding compared with current peri- and post-
procedure anticoagulation management strategies with warfarin. 
 
A tertiary research hypothesis is: 
The combined clinically significant bleeding and thrombotic event rate (and additionally the 
combined major bleeding/thrombotic event rates) with apixaban peri- and post-procedural 
treatment (interrupted and uninterrupted combined) will be lower than the literature-based 
boundary of 8.7% at 1 month. To assess this hypothesis, we will compare the 1-sided 95% upper 
bound of the confidence interval of the rate of clinically significant bleeding and thrombotic 
events to the literature-based boundary. (If interrupted and uninterrupted apixaban are considered 
to be statistically and clinically significantly different on the combined bleeding/thrombotic 
event rate, then this analysis may be carried out separately for interrupted and uninterrupted 
apixaban). 
 
2.3 
Study Rationale 
This post-market, prospective, randomized trial is designed to assess the efficacy and safety of 
apixaban in subjects planned to undergo catheter ablation for treatment of NVAF. This will be the 
first study addressing the safety and efficacy of 2 apixaban treatment strategies (uninterrupted 
versus interrupted) in the setting of NVAF ablation.  It will also assess the effectiveness of each 
strategy for apixaban (uninterrupted, interrupted) versus warfarin and both strategies for apixaban 
combined (uninterrupted plus interrupted) versus warfarin. 


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3. STUDY OBJECTIVES 
For the prospective, randomized cohort: to evaluate the efficacy and safety of apixaban 
uninterrupted therapy vs. interrupted therapy during the peri- and post-procedural period of 
catheter ablation. 
For the retrospective, warfarin cohort: to assess the efficacy and safety of apixaban compared to 
the current clinical setting (use of warfarin).  Outcomes derived from the retrospective, warfarin 
cohort will be compared to that observed in the combined (both randomized arms) prospective 
cohort, and to that observed in each randomized arm of the prospective cohort (warfarin vs. 
uninterrupted apixaban; warfarin vs. interrupted apixaban). 
 
 
4. PRIMARY AND SECONDARY EDNPOINTS 
4.1 
Definitions 
Thrombotic events are defined as a composite of non-hemorrhagic stroke and systemic 
thromboembolic events.   
Clinically significant bleeding is defined as bleeding meeting Bleeding Academic Research 
Consortium (BARC) criteria type 2 or higher.   
Major bleeding is defined as bleeding meeting BARC criteria type 3 or higher. 
 
4.2 
Primary Endpoints 
Primary safety endpoint: The primary safety endpoint is the incidence of clinically significant 
bleeding assessed from the time of randomization through 1 month post–catheter ablation.  
Primary efficacy endpoint:  The primary efficacy endpoint is the incidence of thrombotic events 
assessed from the time of randomization through 1 month post-catheter ablation.  
 
4.3 
Secondary Endpoints 
 Major Secondary Endpoints 
1. Incidence of a composite of major bleeding and thrombotic events assessed from the time of 
randomization and from the time of enrollment through 1 month post–catheter ablation. 
2. Incidence of a composite of clinically significant bleeding and thrombotic events assessed from 
the time of randomization and from the time of enrollment through 1 month post– catheter 
ablation. 
Additional Secondary Endpoints 
The following additional secondary endpoints will be assessed: 


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1. Clinically significant bleeding, major bleeding, and thrombotic events, and the composite of both 
(clinically significant bleeding and thrombotic events; major bleeding and thrombotic events) 
assessed separately in-hospital, and from randomization and from enrollment through 1 month 
post–catheter ablation. 
2. TIAs or non-hemorrhagic strokes from the time of enrollment and from the time of randomization 
through 1 month post–catheter ablation. 
3. Incidence of death and cardiovascular death from the time of enrollment and from the time of 
randomization through 1 month post–catheter ablation. 
 
5. INVESTIGATIONAL PLAN, STUDY DESIGN AND DURATION 
This is a prospective, multicenter, randomized, open-label clinical trial. The study will compare 
2 arms:  uninterrupted vs. interrupted therapy with apixaban in subjects with planned catheter 
ablation for the treatment of nonvalvular atrial fibrillation (NVAF). 
Simultaneously, a retrospective cohort of 300 warfarin-treated individuals, identified by chart 
review, who are matched to the prospective randomized subjects, will be identified.  Key 
demographic and outcome variables from each patient record will be documented. The outcomes 
in this group will be compared to the outcomes in the randomized, prospective cohort.   
 
5.1 
Prospective, Randomized Cohort 
Subjects undergoing ablation for NVAF will be screened for eligibility and those meeting all 
eligibility requirements will be enrolled. Subjects will be consented and enrolled at Visit 1. Pre-
procedural transesophageal echocardiography will be performed at the discretion of the 
investigator. Subjects will be treated with apixaban for ≥21 days prior to ablation; for subjects 
already being treated with apixaban for ≥21 days, it is not necessary to wait 21 days between 
Visit 1 and Visit 2. Eligible subjects will be randomized prior to the procedure (Visit 2); 
randomization may take place on the day of the procedure or up to 3 days prior. Subjects not 
randomized will be considered screen failures. Apixaban dose will be 5 mg b.i.d.; per product 
label, however, the dose will be 2.5 mg b.i.d. in subjects with ≥2 of the following characteristics: 
age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. 
It is anticipated that up to 360 subjects may be enrolled in order to evaluate a total of 300 
randomized subjects. Up to 20 sites in the United States (US) will participate. Subjects will be 
randomized in a 1:1 ratio to 2 peri-procedural treatment strategies (150 subjects per cohort):  
1. Uninterrupted treatment: administer the evening apixaban dose on the day prior to the procedure; 
administer the morning apixaban dose on the day of the procedure; administer heparin bolus 
before transseptal puncture to maintain a target activated clotting time [ACT] > 300 seconds; 
administer the evening apixaban dose after the procedure if there were no peri-procedural 
complications that necessitate withholding anticoagulation for longer duration.  
2. Interrupted treatment: administer the evening apixaban dose on the day prior to the procedure; do 
not administer the morning apixaban dose on the day of the procedure; administer heparin bolus 
before transseptal puncture to maintain a target ACT > 300 seconds; administer the evening 


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apixaban dose after the procedure if there were no peri-procedural complications that necessitate 
withholding anticoagulation for longer duration. 
Randomized subjects will be stratified by site. Apixaban treatment will be continued for at least1 
month post procedure, until the end of the study. Study visits will be at screening/enrollment, 
pre-procedure/ discharge, and at 1 month for follow-up. Subject participation in the study will 
conclude at the follow-up/end-of-study visit conducted at 1 month post-ablation. 
A Study Schema is shown in the figure and Schedule of Events is shown in the table below. 
 
 
 
Schedule of Events for Protocol CV185-373 
Evaluation 
Visit 1 
Screening/ 
Enrollment 
Visit 2 
Pre-Procedure 
and 
Discharge 
Visit 3 
1-Month  
Follow-Up/ 
End of 
Study1 
Study day 
0 to 42 Days 
before 
procedure2  
0-3 Days 
before 
procedure 
Day of 
procedure, 
Day 0 
Day of 
discharge 
30 to 45 Days 
after 
procedure 
Informed consent 
X 
 
 
 
 
Screening/eligibility criteria3 
X4 
 
X4 
 
 
Enrollment 
X 
 
 
 
 


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Medical/social history, 
demographics, baseline 
characteristics 
X 
 
 
 
 
CHA2DS2-VASc 
X 
 
 
 
 
HAS-BLED, HEMORR2HAGES 
X 
 
 
 
 
Physical examination 
X 
 
X5 
X5 
X5 
Vital signs 
X 
 
X 
X 
X 
Randomization 
X 
Clinical laboratory tests6 
X 
 
X 
Catheter ablation procedure 
 
 
X7 
 
 
Administration of  study treatment 
X 
 
X8 
X 
Termination of study treatment 
 
X 
Study treatment accountability 
 
X 
X 
Thrombotic events, bleeding 
(BARC criteria) 
X 
 
X 
X 
X 
Adverse events 
X 
 
X 
X 
X 
Concomitant medications 
X 
 
X 
X 
X 
End of subject participation 
 
X 
BARC: Bleeding Academic Research Consortium; CHA2DS2VASc: Congestive heart failure, hypertension, age, diabetes mellitus, stroke or 
transient ischemic attack or thromboembolism, vascular disease, age, sex category score; HAS BLED: hypertension, abnormal renal/liver 
function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol bleeding risk score; 
HEMORR2HAGES: hepatic or renal disease, ethanol abuse, malignancy, older age, reduced platelet count or function, rebleeding, hypertension, 
anemia, genetic factors, excessive fall risk, stroke bleeding risk score. 
 
1. In the event of early study withdrawal or treatment discontinuation, an end-of-study visit should be conducted. The reason for early 
withdrawal/study drug discontinuation must be documented. 
2.  Subjects already taking apixaban for ≥ 21 days do not have to wait for the 21-day window for Visit 2 to occur. 
3. Screening/eligibility criteria are detailed in section 7.1 in study protocol. 
4. Urine or serum pregnancy test will be performed for screening within 24 hours prior to start of study drug and within 24 hours prior to the 
catheter ablation procedure in WOCBP.  
5. Physical examination to assess any clinically significant changes from screening, including neurological examination. 
6. Clinical laboratory tests are detailed in Section 6.3.5 in study protocol. 
7. Catheter ablation will be performed on the day of Visit 2 (day 0). 
8. Subjects randomized to the uninterrupted treatment cohort will receive the morning dose of study treatment pre-procedure. Subjects 
randomized to the interrupted treatment cohort will not receive the morning dose of study treatment pre-procedure. 
 
 
5.2 
Retrospective, Warfarin Cohort 
In addition, due to diverse definitions of the components of the primary endpoints in previous 
studies (e.g., clinically significant bleedings), a chart review of 300 warfarin-treated patients who 
underwent catheter ablation for NVAF on or after September 1, 2013 in the enrolling centers and 
who have documented follow-up in the medical record for ≥ 30 days post-ablation procedure will 
be performed to assess the incidence of the adjudicated primary endpoints in the current clinical 
setting. Patient records for warfarin-treated individuals who meet the applicable 
inclusion/exclusion criteria and who are matched 1:1 to a subject in the prospective, randomized 


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cohort for age (+/- 5 years), gender and AF type (paroxysmal vs. persistent), will be identified. 
Sites will document key demographic and outcome variables. This review will be performed in a 
blinded manner such that site personnel are blinded to the outcome of each retrospective subject 
during the subject selection process. Only pre-existing data will be collected for the analysis of 
this cohort. 
 
6. STATISTICAL METHODOLOGY AND CONSIDERATIONS 
6.1     Determination of Sample Size 
Given the nature of the pilot study, it is not powered for the primary analyses of comparing 
randomized treatments. The sample size however is based on an evaluation of anticipated event 
rates as compared with current literature as described further below.  While not definitively 
powered to detect differences in the randomized groups, this study should provide useful 
information on this patient population. 
For the primary analysis of the comparison of the interrupted versus uninterrupted apixaban 
treatment strategies, the primary efficacy and safety endpoint rates and the exact 2-sided 95% 
confidence intervals of the primary efficacy and safety endpoints for each apixaban group (and 
for both apixaban groups combined) and a 2-sided 95% confidence interval of the risk difference 
between the apixaban groups (calculated using the Wilson method) will be displayed for 
apixaban-treated subjects. It is noted that this is a pilot study and this analysis will have limited 
power.   
The event rate for clinically significant bleeding from the literature is difficult to obtain with the 
protocol specified definition.  Recent registries show rates of major bleeding of approximately 
2%, and minor bleeding of 6-12%.  Minor bleeding has not been consistently defined and is 
difficult to compare across trials. To be conservative, we adopted an event rate of 4% for 
warfarin.  Although in the ARISTOTLE trial comparing warfarin and apixaban in patients with 
AF (not undergoing ablation) the bleeding rate was 20-30% lower with apixaban, we have 
conservatively assumed that the rate will be the same.  As such, the assumed rate of clinically 
significant bleeding for apixaban is 4.0%.  
For the primary analyses on the primary safety endpoint, assuming an evaluable sample size of 
150 per randomized group and an event rate of 4.0% for each of the interrupted and 
uninterrupted apixaban groups, the width of the confidence interval for the risk difference 
between randomized groups will be 10% (i.e., the 95% CI of the risk difference will be -5% to 
+5%).  
In addition, the secondary analysis of the efficacy and safety endpoints will compare the rates 
(from randomization to 1 month post-ablation) of clinically significant bleeding events, and of 
thrombotic events observed in the apixaban prospective randomized cohort, compared to that 
observed in the matched, retrospective warfarin cohort who meet inclusion/exclusion criteria. 
These analyses will be performed on the evaluable population. 
For the secondary analyses of comparing apixaban (both interrupted and uninterrupted 
combined) to warfarin, assuming an evaluable sample size of 300 patients for each of apixaban 
and warfarin cohorts and a clinically significant bleeding event rate of 4% for each of these two 


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groups, the width of the confidence interval for the risk difference between groups will be 6.7%. 
(i.e., the 95% CI of the risk difference to be -3.35% to +3.35%). 
Sample size justification 
The following assumptions were used for the sample size calculations: 
• Assessment is that the incidence of a composite of clinically significant bleeding and thrombotic 
events (and composite of major bleeding and thrombotic events) in the setting of apixaban 
treatment (interrupted and uninterrupted combined) peri- and post-ablation for NVAF meets the 
literature-based boundary using a 1-sided exact test based on the binomial distribution. 
• The true apixaban event rate at 1 month is assumed to be 5.0%. 
• Type I error (α) = 0.05 (1-sided). 
• Power of 80%. 
A sample size of 300 apixaban subjects in the prospective, randomized cohort provides 80% 
power to meet this boundary, with the upper bound of the 1-sided 95% confidence interval of the 
event rate in the study cohort not exceeding 8.7%. It is estimated that up to 360 subjects will be 
enrolled to randomize 300 subjects.  
 
 
6.2     Analysis Populations 
The following populations will be used for data analyses: 
 
6.2.1 Intention-to-Treat (ITT) 
All subjects randomized to either interrupted or uninterrupted apixaban. 
6.2.2 Evaluable 
The subset of the ITT population who underwent an index ablation procedure and were followed 
through 1 month (30 days minus an allowable 3-day visit window) post–index procedure or who 
experienced a primary endpoint prior to the 1 month follow-up visit. This is the primary analysis 
population for the primary endpoint and for efficacy in general. Subjects are analyzed under the 
treatment to which they were randomized. 
6.2.3 Safety  
All subjects receiving randomized study treatment. This is the primary analysis population for 
safety. Subjects are analyzed under the treatment received. 
6.2.4 Historical Control 
The retrospective cohort of patient records from 300 warfarin-treated individuals who underwent 
catheter ablation for NVAF in the enrolling centers on or after September 1, 2013 and who were 
matched for age, gender and type of AF (paroxysmal vs. persistent) to the 300 prospective 
apixaban patients.  The time frame for analysis of events will be from the morning of the 
procedure through 30 days of follow-up. 


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6.3 
Data Summaries 
All statistical analyses will be performed after the study has completed and the database has been 
locked. All tables, statistical analyses, figures, and subject data listings will be generated using 
SAS® Version 9.4 or SAS EG Version 6.1 (SAS Institute Inc., Cary, North Carolina, United 
States of America). A subject who withdraws prior to the last planned observation will be 
included in the analyses up to the time of withdrawal.  
Continuous variables will be summarized using descriptive statistics (n, mean, standard deviation 
[SD], median, minimum, and maximum values). Unless otherwise specified, the mean and 
median for a continuous variable will be presented to 1 more decimal place than the original 
(raw) values and the SD will be presented to 2 more decimal places than the original values. The 
minimum and maximum will be presented to the same number of decimal places as the original 
values. 
Categorical variables will be reported as frequency counts (including number missing) and the 
percentage of subjects in corresponding categories. Unless otherwise stated, percentage 
calculations will be based on the number of subjects with non-missing data in each of the 
treatment groups. Percentages will be presented to 1 decimal place. A percentage will not be 
presented against zero counts in the tables.  
Individual subject data will be presented by subject in data listings. Data listings will include all 
data collected from the initial screening visit to the end of study for all subjects enrolled. 
Given the pilot nature of this study, there is no significance level adjustment for multiple 
comparisons. 
 
6.4 
Subject Disposition  
A tabulation of the number and percent of subjects will be presented for the following categories 
for each randomized treatment group: 
• Screened 
• Screen Failure (Percentages are based on number of Screened subjects) 
• Randomization (Percentages are based on number of Screened subjects)  
• Evaluable (Percentages are based on number of Randomized subjects) 
• Number discontinued overall and by Reason for discontinuation (Percentages are based 
on number of Randomized subjects) 
• Number of randomized patients in each study center (Percentages are based on total 
number of Randomized subjects) 
 
 


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6.5 
Demography, Baseline Characteristics and Medical History 
Descriptive statistics of demographic, baseline characteristics (age, gender, race, ethnicity, 
height, weight) and medical history will be presented for interrupted apixaban, uninterrupted 
apixaban, and both apixaban groups combined.  Similar descriptive statistics and analyses will be 
presented for the retrospective warfarin group. Groups (apixaban uninterrupted versus 
interrupted; apixaban versus warfarin) will be compared on baseline variables using 2-sample t-
test for continuous variables and Fisher’s exact test for categorical variables.  
 
6.6 
Efficacy Analyses 
The following analyses will be performed on the ITT population and the evaluable population. 
The analyses on the evaluable population are considered the primary analyses. 
 
6.6.1 Primary Efficacy Analyses 
For the primary analysis of the comparison of the interrupted versus uninterrupted apixaban 
treatment strategies, the primary efficacy endpoint rates and the exact 2-sided 95% confidence 
intervals of the primary endpoint for each apixaban group (and for both apixaban groups 
combined) and a 2-sided 95% confidence interval of the risk difference between the groups 
(calculated using the Wilson method) will be presented for apixaban-treated subjects. It is noted 
that this is a pilot study and this analysis will have limited power. 
For the ITT analysis set, there may be missing data on the primary efficacy endpoint due to 
premature withdrawals prior to 1 month post–index procedure. As a supportive analysis to assess 
the sensitivity of results to missing data, analyses on the ITT population will incorporate the 
following approach: Kaplan-Meier rate estimates and 2-sided 95% confidence intervals of the 
Kaplan-Meier estimates and of the difference between Kaplan-Meier estimates will be presented 
for the same apixaban groupings. All ITT subjects will be included in the calculation of the 
Kaplan-Meier rates; subjects not experiencing the event will be censored at the end of the 1-
month follow-up or time of their premature withdrawal, whichever is earlier. 
 
To assess consistency of results across study sites, logistic regression on the primary endpoint 
with the independent variables of treatment, site and treatment-by-site interaction will be carried 
out on the evaluable analysis set.  Significance of the treatment-by-site interaction will be 
assessed at the 0.15 level of significance.  A non-significant interaction or a significant 
interaction that is only quantitative in nature will support the pooling of patients across study 
sites for the primary efficacy analysis. Sites with less than 10 patients will be pooled with other 
sites by geographic region; this will be done before the blind is broken. 
 
6.6.2 Major Secondary Efficacy Analyses 
The two major secondary endpoints will be analyzed in a similar manner as the primary efficacy 
endpoints for the evaluable and ITT analysis sets.  


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6.6.3 Additional Secondary Analyses 
The above-mentioned additional secondary endpoints will be assessed and analyzed in a similar 
manner as the primary and major secondary efficacy endpoints (however, Kaplan-Meier 
estimates will not be calculated for in-hospital endpoints, and subjects included in the calculation 
of in-hospital rates do not need to have 1 month of follow-up). 
 
 
6.7 
Safety Analyses 
Analyses on the primary safety endpoint (the incidence of clinically significant bleeding assessed 
from the time of randomization through 1 month post–catheter ablation) will be carried out in a 
similar manner as for the primary efficacy endpoint, including the assessment of the treatment-
by-center interaction.   
The following additional safety analyses will be carried out on the safety population: 
The number and percentage of subjects with treatment emergent adverse events (TEAEs) will be 
presented by MedDRA system organ class and preferred term for each apixaban group 
(uninterrupted and interrupted) and both apixaban groups combined. A TEAE is defined as an 
AE starting or worsening in severity on or after start of study treatment. These analyses will be 
repeated for serious TEAEs and for TEAEs leading to premature discontinuation from the study. 
 
6.8 
Other Analyses 
1. As a tertiary analysis, the combined thrombotic/bleeding rate for both apixaban groups combined 
will be compared to a rate derived from the literature. Based on the above-mentioned meta-
analysis, the expectation for the true combined thrombotic/bleeding endpoint rate at 1 month is 
5.0% for apixaban. However, because strict equality cannot be assessed statistically, this study 
will assess if the 1-month rate of clinically significant bleeding and thrombotic events (and 
additionally of the composite of major bleeding and thrombotic events) falls below 8.7% when 
both treatment arms are combined. Specifically, this tertiary analysis will assess the ability of 
apixaban in the setting of catheter ablation to meet a literature-based boundary of 8.7%, which is 
an absolute increase of 3.7% over the expected rate of 5.0% obtained from the meta-analysis. In 
other words, this analysis will test the following null and alternative hypotheses: 
 
 
 
H0: π ≥ 0.087 (or 8.7%) 
 
 
 
H1: π < 0.087 (or 8.7%) 
where π is the true (unknown) apixaban endpoint rate.  
The null hypotheses will be tested using all evaluable apixaban subjects (uninterrupted and 
interrupted groups combined) at a 1-sided 0.05 level of significance using an exact test based on 
the binomial distribution. In addition, a 1-sided exact 95% confidence interval of the endpoint 
rate will be presented and the upper bound will be compared to 8.7%. For completeness, a 2-
sided exact 90% confidence interval will also be presented.  Note that, prior to carrying out this 
analysis, the comparability between apixaban groups on this thrombotic/bleeding endpoint will 
be assessed using a 2-sided 95% Wilson confidence interval.  If the confidence interval does not 


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contain 0 and if the difference between apixaban groups is considered clinically different, the 
above analyses may be repeated for each of the uninterrupted and interrupted apixaban groups, 
separately. 
2. To assess consistency of sites with respect to the primary efficacy and safety endpoint rates, 
logistic regression will be used to compare sites with respect to the primary endpoints rates for 
the evaluable population. A 0.15 level of significance will be used to determine if a significant 
site effect exists. A P value <0.15 will not necessarily preclude the sites from being pooled for 
the final analysis, but will require further inspection (e.g., endpoint results by site) to assess if 
there is a concern about lack of site poolability.    
In addition, logistic regression will be used to assess consistency of the interrupted vs. 
uninterrupted apixaban groups across sites, using a logistic regression model with effects for 
treatment type (interrupted or uninterrupted), site and the treatment type-by-site interaction.  The 
interaction term will be assessed using a 0.15 level of significance. 
3. The rates and 2-sided exact 95% confidence intervals of the primary and major secondary 
endpoints will be presented by apixaban group and for both apixaban groups combined within 
the following major subgroups: 
a. Age (<65 and ≥65 years). 
b. CHA2DS2-VASc (Congestive heart failure, hypertension, age, diabetes mellitus, stroke or 
transient ischemic attack or thromboembolism, vascular disease, age, sex category) score (< 
median, ≥ median). 
c. HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or 
predisposition, labile international normalized ratio, elderly, drugs/alcohol) bleeding risk scores 
(< median, ≥ median). 
d. Baseline antiplatelet therapy vs. no antiplatelet therapy. 
e. Baseline anticoagulation therapy (subjects who are anticoagulation-naïve versus subjects on 
vitamin K antagonists versus subjects on novel oral anticoagulants). 
f. Subjects with ≥2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum 
creatinine ≥1.5 mg/dL. 
g. Apixaban dose. 
The purpose of this analysis is to assess consistency of primary and major secondary endpoint 
rates across the various subgroups 
 
6.9 
Addition Analysis: Comparing Prospective Apixaban with Retrospective Warfarin 
Cohorts 
The rate of the primary endpoint in apixaban subjects (uninterrupted and interrupted groups 
combined) will be compared with a retrospectively-matched warfarin control group. The control 
group is comprised of patient records from warfarin-treated individuals (retrospective) who meet 
inclusion/exclusion criteria, including having undergone ablation for NVAF in the enrolling 
centers on or after September 1, 2013, who have documented follow-up in the medical record for 
≥ 30 days post-ablation procedure, and who meet the other inclusion/exclusion criteria including 


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matched for age, gender and type of AF (paroxysmal vs. persistent). For the warfarin group, 
retrospective chart review will be performed to assess the incidence of the primary endpoint. 
This analysis will compare the 1-month rate of clinically significant bleeding and thrombotic 
events between the two groups in a similar manner as was used to compare apixaban groups.   
 
6.10 
Protocol Deviation 
A protocol deviation is defined as any instance during the conduct of the study in which the site 
PI or other site personnel changed or failed to adhere to the study design or procedures specified 
by the protocol. Failure to comply with and/or inability to meet FDA regulations may jeopardize 
further participation of the Investigator or Investigative Center in this and future clinical studies. 
 
A summary of major and minor protocol deviations for all ITT and evaluable populations will be 
presented for each apixaban group. Subjects will be counted once within each deviation category. 
 
6.11 
Concomitant Medication 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
dictionary. Incidence (number and percent of subjects reporting the medication at least once 
during the study) will be summarized for all concomitant medications. All verbatim descriptions 
and coded terms will be listed for all non-study medications. 
 
 
 


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