Clinical trial NCT02100228
Conditions: Atrial Fibrillation
Keywords: apixaban oral anticoagulant non-valvular atrial fibrillation cardioversion
Sponsor: Pfizer
Start date: 2014-07-14; Completion date: 2017-02-08
Enrollment: 1500 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Some people can develop an abnormal heart beat known as "Atrial fibrillation" or "AF" that puts them at risk of developing clots in the heart. Those clots can travel in the blood circulation to the brain and cause a brain attack ("a stroke"). To prevent those clots forming, blood thinners (anti-coagulants) are used. Apixaban is a blood thinner that works by stopping one of the blood substances required for clotting ("Factor Xa"). It is approved and used to prevent clots forming in people with "AF". Other established blood thinners work by stopping clotting substances being made, known as "Vitamin K antagonists" or "VKAs". An example of this type is Warfarin (Coumadin). The good effects of all blood thinners are preventing clots, and they may also have bad effects of increasing the chance of bleeding. People with "AF", abnormal heart beat, may benefit from changing it back to a normal regular rhythm, known medically as "cardioversion". When this is done, people are currently most commonly treated with a "VKA" blood thinner (e.g. warfarin). The purpose of this study is to assess the good and bad effects ("efficacy" and "safety") of apixaban compared with warfarin in people with "AF" in whom an early cardioversion is planned.

Detailed description:

Arms: arm 1: None arm 2: Parenteral heparin and/or locally used oral Vitamin K antagonist e.g. warfarin (excludes other novel oral anticoagulants)
Interventions: intervention 1: Apixaban intervention 2: Parenteral heparin and/or oral Vitamin K antagonist
Intervention descriptions: intervention 1: Oral, 2.5 or 5 mg BID intervention 2: Parenteral heparin and/or locally used oral Vitamin K antagonist e.g. warfarin (excludes other novel oral anticoagulants)

Protocol documents:
Prot_001.pdf: 
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A PHASE IV TRIAL TO ASSESS THE EFFECTIVENESS OF APIXABAN 
COMPARED WITH USUAL CARE ANTICOAGULATION IN SUBJECTS WITH 
NON-VALVULAR ATRIAL FIBRILLATION UNDERGOING CARDIOVERSION
Compound:
PF-04652577/BMS-562247
Compound Name:
Apixaban
US IND Number (Bristol-Myers Squibb):
IND 68,598
European Clinical Trial Database 
(EudraCT) Number:
2014-001231-36
Pfizer Protocol Number:
B0661025
Bristol-Myers Squibb Protocol Number:
CV185-267
Phase:
4
This document contains confidential information belonging to Pfizer/BMS.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not copy 
or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the 
event of any actual or suspected breach of this obligation, Pfizer/BMS must be promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
19-Mar-2014
Not Applicable
Amendment 1
30-Jul-2014
Following Japan Regulatory Authority (PMDA) 
advice, for Japan only, the optional Apixaban loading 
dose has been removed & the inclusion criterion for 
age increased to 20 years for those subjects 
participating in this study in Japan only.
Amendment 2
16-Feb-2015
Modification of the Exclusion Criterion #1 to allow a 
limited period of treatment with an oral anticoagulant 
prior to study entry.  Additional exclusion criterion 
added/edited for safety and clarity.  Minor 
administrative clarifications and template up-dates.
Amendment 3
22-Feb-2016
Main reason for amendment: 
Sections 4.2 and 5.2.3.2: Request from regulatory 
authorities to incorporate the Protocol Administrative 
Changes and Clarifications letter (dated 08-Jul-2015) 
pertaining to sections 4.2 exclusion criteria #6 and 
5.2.3.2 into a substantial protocol amendment. 
Other changes: 
Schedule of Activities: added footnote referring to 
Figure 2 for examples of timing of Visit 3.
Section 3: Added Figure 2 (Examples of timing for 
Visit 3).
Section 4.1 criteria #1: Added that atrial fibrillation 
must be documented by electrocardiogram (ECG) and 
that subjects presenting with atrial flutter with no 
evidence of atrial fibrillation are not eligible for 
enrolment.  
Section 4.1 criteria #2: Corrected age range for 
Korea.
Sections 5.2.2; 6.1.2; 6.2: Incorporating the Protocol 
Administrative Change Letter (dated 25-Nov-2015) 
clarifying the requirement for visual inspection for 
subjects randomized to usual care.
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Section 5.2.3: Added details of apixaban dosing 
period for subject who have spontaneously reverted to 
normal sinus rhythm before cardioversion
Section 5.2.3.2: Incorporation of Protocol Deviation 
Alert Letter dated 10-Jun-2015 prohibiting 
co-administration of parenteral heparin and apixaban.
Section 5.2.3.2: Clarified that INR values will be 
recorded in the CRF. 
Section 5.2.3.2: Rearranged wording pertaining to 
Japan specific requirement. 
Section 5.2.4: Clarified compliance requirements.
Section 5.4: Added that the co-administration of 
parenteral heparin and apixaban is prohibited.
Section 6.1.1: Clarified timing of ECG taken at Visit 
1. 
Section 6.1.2: Added referral to section 5.2.2.
Section 6.2: Added referral to section 5.2.2.
Section 6.3: Referral to Figure 2 for examples of 
timing of Visit 3. 
Section 7.2: Clarified timing of ECG taken at Visit 1.
Section 8:  Updated throughout with required BMS 
safety language.
Section 15.1: Updated Communication of Results by 
Pfizer/BMS.
Minor formatting corrections have been applied 
throughout the protocol.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.
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PROTOCOL SUMMARY
Background and Rationale; Cardioversion (electrical or pharmacological) is an effective 
method of converting atrial fibrillation (AF) to sinus rhythm and should be considered as 
early as possible in order to initiate a long-term rhythm control management strategy for
patients, and avoid irreversible atrial re-modeling.
In a sub-group analysis of ARISTOTLE trial data, 743 cardioversions were performed in 
540 subjects, and the effectiveness of apixaban was demonstrated in the 30 days following
cardioversion.  However, in this study subjects who underwent cardioversion had already 
been chronically anticoagulated either prior to entry or, if treatment-naïve, as part of the trial.  
Thus, there was no information on the effectiveness of apixaban in subjects newly presenting 
with AF who were anticoagulant-naïve and in whom an early cardioversion was indicated, 
eg, with or without an image-guided approach.  This study is being conducted to assess the 
effectiveness of apixaban compared with usual care (parenteral heparin and/or oral 
anticoagulation with Vitamin K antagonist (excluding other novel oral anticoagulants)) in 
subjects with non-valvular AF indicated for early cardioversion and initiation of anti-
coagulation in a real world clinical practice setting.
Objectives and Endpoints; The study objective is to assess the occurrence of clinical 
endpoints in non-valvular AF subjects (ie, without rheumatic mitral valve disease, a 
prosthetic heart valve, or valve repair) indicated for early cardioversion and treated with 
apixaban or usual care (parenteral heparin and/or oral anticoagulation with Vitamin K 
antagonist (excluding other novel oral anticoagulants)). Clinical endpoints include:
occurrence of stroke, systemic embolism, major bleeding, clinically relevant non-major 
bleeding, and death.  Additional information on the cardioversion details (timing, type, 
attempts, and rhythm status), length of in-hospital stay and use of image guidance will also 
be collected.
Study Design; This is a randomized, active controlled, parallel-group, open label study.  
Approximately 1500 subjects will be randomized 1:1 to apixaban or usual care (parenteral 
heparin and/or oral anticoagulation with Vitamin K antagonist (excluding other novel oral 
anticoagulants)). Following randomization, endpoints will be collected during the 30 days 
following the cardioversion or during the 90 days post randomization if cardioversion is not 
performed within that time frame.
Study Treatments; Apixaban or usual care (parenteral heparin and/or oral anticoagulation 
with Vitamin K antagonist (excluding other novel oral anticoagulants)) will be administered 
from randomization up to 30 days following cardioversion or 90 days post randomization if 
cardioversion is not performed.
Statistical Methods; Baseline demographics, endpoints, adverse events and serious adverse 
events (SAEs) will be reported by randomized treatment.  Number of observations and 
proportions will be given for categorical or binary variables, number of observations, mean, 
standard deviation, median minimum and maximum will be given for continuous variables; 
time-to-event data will be displayed using Kaplan-Meier techniques; hazard ratio will be 
calculated.
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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to Study Procedures and Assessments sections of the protocol for detailed information 
on each procedure and assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
wellbeing of the subject.
Procedure
Visit 1 Enrollment
Screening/Randomizationa
Visit 2
Cardioversion
(or planned 
cardioversion)
Visit 3 Follow-Up
(30 days post 
cardioversion (Visit 2) 
or up to 90 days 
following Visit 1)e
Visit Windows
±7 days
Informed Consent
X
Obtain Alternative 
Contact
X
Inclusion/Exclusion
X
Demographics
X
Medical History
X
CHA2DS2-VASc score b
X
Local Laboratory 
Parameters
X
X
X
Electrocardiogram
X (may be obtained on the 
day prior to Visit 1)
X
X
Randomization
X
Cardioversion c
X
Endpoint Assessments d
X
X
Dispense Study Drug
X
X
Collect Study Drug
X
X
Study Drug Compliance 
Check
X
X
Adverse Event 
Assessment
X
X
a.
Screening/Randomization could occur on the same day
b.
CHA2DS2-VASc - Congestive heart failure, hypertension, age, diabetes, stroke, vascular disease, age, 
sex category risk score
c.
Cardioversion details (timing, type, attempts, and rhythm status) and use of image guidance
d.
Endpoints; stroke, systemic embolism, major bleeding, clinically relevant non-major bleeding, and all 
cause death
e.
See Figure 2 for examples of timing of Visit 3.
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TABLE OF CONTENTS
LIST OF FIGURES ...................................................................................................................8
1. INTRODUCTION .................................................................................................................9
1.1. Indication...................................................................................................................9
1.2. Background and Rationale ........................................................................................9
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................11
3. STUDY DESIGN.................................................................................................................12
3.1. Executive Committee ..............................................................................................14
4. SUBJECT SELECTION......................................................................................................14
4.1. Inclusion Criteria.....................................................................................................14
4.2. Exclusion Criteria....................................................................................................15
4.3. Life Style Guidelines...............................................................................................15
4.4. Sponsor Qualified Medical Personnel.....................................................................16
5. STUDY TREATMENTS.....................................................................................................16
5.1. Allocation to Treatment ..........................................................................................16
5.2. Drug Supplies..........................................................................................................17
5.2.1. Formulation and Packaging........................................................................17
5.2.2. Preparation and Dispensing........................................................................17
5.2.3. Administration............................................................................................18
5.2.3.1. Usual Care.................................................................................18
5.2.3.2. Apixaban ...................................................................................19
5.2.4. Compliance.................................................................................................20
5.3. Drug Storage and Drug Accountability...................................................................20
5.4. Concomitant Medications .......................................................................................20
6. STUDY PROCEDURES .....................................................................................................20
6.1. Visit 1 Enrollment, Screening/Randomization (can occur on the same day)..........20
6.1.1. Screening Assessments...............................................................................20
6.1.2. Randomization Assessments ......................................................................21
6.2. Visit 2 Cardioversion ..............................................................................................21
6.3. Visit 3 (30 days (7) Post Cardioversion or 90 days (7) Following 
Enrollment Visit 1 if Cardioversion is not Performed). See Figure 2 for 
Further Examples of Timing of Visit 3. ....................................................................21
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6.4. Subject Withdrawal.................................................................................................22
6.5. Guidelines for Image Guidance (eg, TEE/TOE or CT) Suggesting Atrial 
Thrombus...................................................................................................................22
6.6. Guidelines for Bleeding/Suspected Bleeding..........................................................23
6.7. Treatment Transition Guidelines.............................................................................23
7. ASSESSMENTS..................................................................................................................23
7.1. Demography............................................................................................................24
7.2. Medical History.......................................................................................................24
7.3. CHA2DS2-VASc Score ...........................................................................................24
7.4. Clinical Endpoints...................................................................................................24
7.4.1. Acute Stroke ...............................................................................................24
7.4.2. Systemic Embolism ....................................................................................25
7.4.3. Major Bleeding ...........................................................................................25
7.4.4. Clinically Relevant Non-Major Bleeding...................................................26
7.5. Details of Cardioversion..........................................................................................26
7.6. Length of In-Hospital Stay......................................................................................27
7.7. Collection of Local Clinical Laboratory Parameters...............................................27
8. ADVERSE EVENTS...........................................................................................................27
8.1. Serious Adverse Events...........................................................................................28
8.1.1. Serious Adverse Event Collection and Reporting ......................................29
8.2. Nonserious Adverse Events ....................................................................................30
8.2.1. Nonserious Adverse Event Collection and Reporting................................30
8.3. Laboratory Test Result Abnormalities ....................................................................30
8.4. Pregnancy................................................................................................................31
8.5. Overdose..................................................................................................................31
8.6. Potential Drug Induced Liver Injury (DILI) ...........................................................31
8.7. Other Safety Considerations....................................................................................32
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................32
9.1. Sample Size Determination.....................................................................................32
9.2. Endpoint Analysis ...................................................................................................32
9.3. Data Monitoring Committee ...................................................................................32
9.4. Independent Adjudication .......................................................................................33
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10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................33
11. DATA HANDLING AND RECORD KEEPING .............................................................33
11.1. Case Report Forms/Electronic Data Record .........................................................33
11.2. Record Retention...................................................................................................34
12. ETHICS..............................................................................................................................34
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............34
12.2. Ethical Conduct of the Study ................................................................................34
12.3. Subject Information and Consent..........................................................................35
12.4. Subject Recruitment ..............................................................................................35
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................35
13. DEFINITION OF END OF TRIAL...................................................................................36
13.1. End of Trial in a Member State.............................................................................36
13.2. End of Trial in all other Participating Countries...................................................36
14. SPONSOR DISCONTINUATION CRITERIA ................................................................36
15. PUBLICATION OF STUDY RESULTS..........................................................................36
15.1. Communication of Results by Pfizer/BMS...........................................................36
15.2. Publications by Investigators ................................................................................37
16. REFERENCES ..................................................................................................................39
LIST OF FIGURES
Figure 1 Study Design Schematic............................................................................................13
Figure 2 Examples of Timing of Visit 3..................................................................................13
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1. INTRODUCTION
Apixaban is a novel, orally active, selective inhibitor of the coagulation factor Xa (FXa) 
developed by Bristol-Myers Squibb (BMS) and Pfizer as an anticoagulant and antithrombotic 
agent.  Apixaban is a reversible and highly potent inhibitor of human FXa with a high degree 
of selectivity over other coagulation proteases and structurally related enzymes involved in 
digestion and fibrinolysis.
1.1. Indication
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation
1.2. Background and Rationale
Atrial fibrillation (AF) is the most common cardiac arrhythmia, accounting for approximately 
one third of hospitalizations attributed to cardiac rhythm disturbances, and the life time risk 
of developing AF is 1 in 4 for adults 40 years of age or older.1,2  Cardioversion (electrical or
pharmacological) is an effective method of converting AF to sinus rhythm and should be 
considered as early as possible in order to initiate a long-term rhythm control management 
strategy for subjects, and avoid irreversible atrial re-modeling.
Electrical cardioversion in patients with AF is associated with an increased risk for 
thromboembolic events, which might exceed 5% with inadequate or no oral 
anticoagulation.3,4  Therapeutic oral anticoagulation with a vitamin K antagonist 
(eg, warfarin) will reduce the risk of thromboembolic events during and after cardioversion 
to less than 1%.5-7 Current AF guidelines recommend therapeutic anticoagulation for at least 
3 weeks before and at least 4 weeks after cardioversion for patients with AF of more than 
48 hours duration or with unknown duration.8,9  The guidelines also recommend an 
abbreviated anticoagulation strategy with an image guided approach (eg, transesophageal 
echocardiography (TEE/TOE) or computed tomographic (CT) scan).
The ACUTE study,6 a multicentre, randomized prospective study, compared a TEE-guided 
strategy of abbreviated therapeutic anticoagulation with intravenous unfractionated heparin 
(UFH) (started 24 h before cardioversion) or conventional warfarin (International 
Normalized Ratio (INR) 2.0-3.0, at least 3 weeks before cardioversion) strategy in 
1222 patients with AF of more than 2 days duration planned for electrical cardioversion.  
There was no significant difference between the two treatment groups in the rate of embolic
events within the eight-week study period; however, the rate of hemorrhagic events was 
significantly lower in the TEE group (18 events [2.9 percent] vs. 33 events [5.5 percent], 
probability (p) =0.03). Patients in the TEE group also had a shorter time to cardioversion
(mean [±standard deviation (SD)], 3.0±5.6 vs. 30.6±10.6 days).  The authors conclude that 
the strategy of using TEE to guide treatment may be considered a safe and clinically effective 
alternative to the conventional treatment strategy.
The efficacy and safety of apixaban for the prevention of stroke and systemic embolism in 
AF patients was demonstrated in 2 randomized, double-blind, Phase 3 trials: ARISTOTLE 
(apixaban vs. warfarin; n = 18,201) in patients suitable for Vitamin K antagonist (VKA)
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therapy 10 and AVERROES (apixaban vs. aspirin; n = 5599) in patients unsuitable for VKA 
therapy.11  Both studies were conducted in patients with non-valvular (ie, without rheumatic 
mitral valve disease, a prosthetic heart valve, or valve repair), persistent, paroxysmal, or 
permanent AF or atrial flutter, and 1 or more additional risk factors.
In the ARISTOTLE trial, the rate of the primary outcome (ischemic or hemorrhagic stroke or 
systemic embolism) was 1.27% per year in the apixaban group, compared with 1.60% per
year in the warfarin group (Hazard Ratio (HR) = 0.79; p<0.001 for non-inferiority; p = 0.01 
for superiority) 10  The rates of major or clinically relevant non-major bleeding events was
also reduced by apixaban compared to warfarin, 4.07 %/ year vs. 6.01 %/year, p<0.001.
The AVERROES trial demonstrated a clear efficacy benefit in favor of apixaban and an 
independent Data and Safety Monitoring Board recommended early termination after 
1.1 years of mean study participation.  The rate of primary outcome events (stroke or 
systemic embolism) in patients assigned to apixaban was 1.6% per year, compared to 
3.7% per year among those assigned to aspirin (HR = 0.45; p<0.001).12
Apixaban (Eliquis) has regulatory approval for prevention of stroke and systemic 
embolism in patients with non-valvular AF since November 2012 in the European Union
(EU) and since December 2012 in Canada, Japan and the US.
Apixaban also has marketing authorization in the EU for prevention of venous 
thromboembolic events in adult patients who have undergone elective hip or knee 
replacement surgery since 2011.
In a sub-group analysis of ARISTOTLE data, where 743 cardioversions were performed in 
540 subjects, the effectiveness of apixaban was demonstrated in the 30 days following 
cardioversion, with no stroke or systemic embolism events in either group, 1 and 1 major 
bleeds, and 2 and 2 deaths in the apixaban and warfarin groups, respectively.13
However, in this ARISTOTLE sub-group analysis, subjects who underwent cardioversion
had already been chronically anticoagulated either prior to entry or, if treatment-naïve, as 
part of the trial. Thus, there was no information on the effectiveness of apixaban in subjects 
newly presenting with AF who were anticoagulant-naïve and in whom an early cardioversion 
was indicated, eg, with an image-guided approach or a definite onset of symptoms ≤48 hours.  
An image-guided approach facilitates cardioversion earlier than the conventional minimum 
of 3 weeks of anticoagulation that would normally be required prior to cardioversion.  It is 
expected that most image-guided cardioversions would occur from a few hours to a few days 
after initial presentation.  In subjects with a clearly defined onset of symptoms ≤48 hours, 
guidelines suggest that cardioversion may be performed early without image-guidance.8,9
Therefore, this study is being conducted to assess the effectiveness of apixaban compared 
with usual care (parenteral heparin and/or oral anticoagulation with Vitamin K antagonist 
(excluding other novel oral anticoagulants (NOACs)) in subjects with non-valvular AF
indicated for early cardioversion and initiation of anticoagulation in a real-world, clinical
practice setting.  The image guidance approach in subjects with >48 hours or unknown 
duration and non-guided with symptoms ≤48 hours will be referred to as “early 
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cardioversion” throughout this protocol.  Subjects with symptom onset >48 hours or 
unknown duration and not following an image guided approach are expected to receive the 
conventional anticoagulation strategy (minimum of 3 weeks prior to cardioversion) as per 
guidelines.
The overriding design principle of this study is that of a randomized observational approach, 
sometimes known as a ‘pragmatic study’14, where subjects are managed according to their 
investigator’s usual care following randomization, and in conjunction with the protocol 
directed schedule of activities.
Data from 15 completed or on-going Phase 2/3 studies in over 29,000 subjects provide 
exposure information of apixaban doses ranging from 2.5 mg twice a day (BID) to 20 mg 
once daily (QD) and treatment durations up to approximately 33 months.
The posology of apixaban has been determined from its pharmacokinetic characteristics and 
per the approved local label for the prevention of stroke and systemic embolism in subjects 
with non-valvular AF.  In this protocol, investigators have an option to use a single loading 
dose of 10 mg (or 5 mg, if the subject meets the criteria for dose reduction as per the local 
label) followed by the approved regimen of 5 mg BID (or 2.5 mg BID) starting 12 hours 
later, to rapidly achieve steady-state exposure (see Section 5.2.3.2 for further details) (Japan 
only: the loading dose is not an available option for those subjects participating in Japan). 
Based on simulations of the apixaban concentration versus time profile in AF patients, this 
regimen will result in Day 1 peak plasma concentration (Cmax) and area under the curve 
(AUC) values that are approximately 104% and 93% of steady-state values, respectively.
Further information for apixaban may be found in the approved local label (eg, United States 
Package Insert (USPI), Summary of Product Characteristics (SmPC)).
2. STUDY OBJECTIVES AND ENDPOINTS
The study objective is to assess the occurrence of clinical endpoints in non-valvular AF 
subjects (ie, without rheumatic mitral valve disease, a prosthetic heart valve, or valve repair) 
indicated for cardioversion and treated with apixaban or usual care (parenteral heparin and/or 
oral anticoagulation with Vitamin K antagonist (excluding other NOACs)).
Clinical Endpoints

Stroke.

Systemic embolism.

Major Bleeding.

Clinically Relevant Non-Major Bleeding.

All cause death.
Additional information will also be collected on:
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
Cardioversion details: timing, type, attempts, and rhythm status.

Length of in-hospital stay.

Use of image guidance eg, TEE/TOE or CT.
This protocol will use an independent endpoint adjudication committee wherein, to maintain 
scientific integrity, adjudication of disease-related efficacy endpoints will be performed.  For 
those serious adverse events (SAEs) that are handled as disease-related efficacy endpoints 
(which may include death), the endpoint adjudication committee, in coordination with the 
data monitoring committee (DMC), is responsible for ongoing analysis of these outcomes 
and for informing the sponsor of recommendations made (eg, to continue the study or to stop 
the study).
3. STUDY DESIGN
This is a randomized, active controlled, parallel-group, open label study.
Approximately 1500 subjects will be randomized 1:1 to apixaban or usual care (parenteral 
heparin and/or oral anticoagulation with Vitamin K antagonist (excluding other NOACs)).  
Usual care will be administered as per local practice and/or approved label.
Apixaban or usual care (parenteral heparin and/or oral anticoagulation with Vitamin K 
antagonist (excluding other novel oral anticoagulants (NOACs)) will be administered from 
randomization up to 30 days following cardioversion or 90 days post randomization if 
cardioversion is not performed within that timeframe.
Following randomization, clinical endpoints, cardioversion details (timing, type, attempts, 
and rhythm status), length of in-patient hospital stay and use of image guidance will be 
collected during the 30 days following the cardioversion or during the 90 days post 
randomization if cardioversion is not performed.
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A schematic diagram below (Figure 1) shows the design of the study:
Figure 1 Study Design Schematic
Figure 2 Examples of Timing of Visit 3
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3.1. Executive Committee
The Executive Committee will be composed of a group of clinical experts and sponsor 
representatives, responsible for ensuring that study design, execution and management are of 
the highest quality. The Executive Committee will provide suggestions for potential 
investigators and National Coordinators, will monitor progress of study enrollment, make 
recommendations in collaboration with the sponsor based on the DMC recommendations, 
and oversee the presentation and publication of the trial results.  The membership, roles and 
responsibilities of the committee are further described in the Executive Committee Charter. 
The committee will convene regularly by teleconference and/or face-to-face meetings to 
discuss and report on the ongoing conduct of the study in collaboration with the sponsor.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Subjects with non-valvular atrial fibrillation (as documented by electrocardiogram (ECG)
at Visit 1) indicated for cardioversion and initiation of anticoagulation in accordance with 
the approved local label. Subjects presenting with atrial flutter with no evidence of atrial 
fibrillation are not eligible for enrolment.  
2. Age ≥18 years (Age ≥19 years for Korea only and Age ≥ 20 years for Japan only).
3. Evidence of a personally signed and dated informed consent document indicating that the 
subject (or their legally-recognized representative) has been informed of all pertinent
aspects of the study.
4. The subject is willing to provide contact details for at least one alternate person for study 
staff to contact regarding their whereabouts, should the subject be lost-to-follow-up over 
the course of the study. (Subject to IRB/IEC approval)
5. Female subjects of childbearing potential must agree to use a highly effective method of 
contraception throughout the study and for at least 28 days after the last dose of assigned 
treatment.  A subject is of childbearing potential if, in the opinion of the investigator, she 
is biologically capable of having children and is sexually active.
6. Subjects who are willing and able to comply with scheduled visits, treatment plan, and 
other study procedures.
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4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Subjects having taken more than 48 hours of an anticoagulant (oral and/or parenteral) 
immediately prior to randomization.
2. Contraindications to apixaban or usual care (eg, VKA) in accordance with the approved 
local label.
3. Severe haemodynamically compromised subjects requiring emergent cardioversion.
4. Patients with hemodynamically significant mitral stenosis, mechanical or biological 
prosthetic valve or valve repair.
5. Conditions other than atrial fibrillation that require chronic anticoagulation (eg, a 
prosthetic heart valve).
6. Simultaneous treatment with both aspirin and a thienopyridine (eg, clopidogrel, 
ticlopidine, prasugrel) or simultaneous treatment with both aspirin and ticagrelor. 
7. Pregnant females; breastfeeding females; females of childbearing potential who are 
unwilling or unable to use a highly effective method of contraception as outlined in this 
protocol for the duration of the study and for at least 28 days after last dose of 
investigational product.
8. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
30 days before the current study begins and/or during study participation.  Note: Subjects 
cannot be randomized into this study more than once.
9. Severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
10. Subjects who are investigational site staff members directly involved in the conduct of 
the trial and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are BMS/Pfizer employees directly involved in the conduct 
of the trial.
4.3. Life Style Guidelines
Female subjects who, in the opinion of the investigator, are biologically capable of having 
children and are sexually active, must agree to use a highly effective method of contraception 
consistently and correctly for the duration of the active treatment period and for at least 
28 days after the last dose of investigational product.  The investigator will confirm that the 
subject enters the study already using a contraceptive method from the permitted list of 
highly effective contraceptive methods and has been instructed in its consistent and correct 
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use.  The investigator, at each study visit, will confirm and document consistent and correct 
use.  In addition, the investigator will instruct the subject to call immediately if the selected 
birth control method is discontinued or if pregnancy is known or suspected.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected or implanted hormonal methods of 
contraception are allowed provided the subject remains on the same treatment throughout 
the entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.
2. Correctly placed copper containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
suppository).
4. Male sterilization with appropriately confirmed absence of sperm in the post-vasectomy 
ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy.
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial will be documented in the study contact list located in the Investigator Site File. To 
facilitate access to appropriately-qualified medical personnel on study related medical 
questions or problems, subjects will be provided with a contact card. The contact card will 
contain, at a minimum, protocol and investigational compound identifiers, subject study 
number, contact information for the investigational site and contact details for a help desk in 
the event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The help desk number can also be used by 
investigational staff if they are seeking advice on medical questions or problems, however it 
should only be used in the event that the established communication pathways between the 
investigational site and the study team are not available. It is therefore intended to augment, 
but not replace the established communication pathways between the investigational site and 
study team for advice on medical questions or problems that may arise during the study. The 
help desk number is not intended for use by the subject directly and if a subject calls that 
number they will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
At Visit 1 subjects will be randomized 1:1 to apixaban or usual care (parenteral heparin 
and/or oral anticoagulation with Vitamin K antagonist (excluding other NOACs)).  Treatment 
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group assignment will be managed using a centralized Internet-based or Interactive Voice 
Response System (IVRS).
5.2. Drug Supplies
5.2.1. Formulation and Packaging
Apixaban formulation and packaging details are as follows;
Product
Potency
Primary 
Packaging
Appearance
Storage
BMS-562247-01 
Film Coated 
Tablet
5 mg
200 tablets per 
bottle
Open label
Reddish brown, 
plain, oval 
shaped, shallow 
bi-convex film 
coated tablet
Store at 2-
30°C
BMS-562247-01 
Film Coated 
Tablet
2.5 mg
200 tablets per 
bottle
Open label
Reddish brown, 
plain, oval 
shaped, shallow 
bi-convex film 
coated tablet
Store at 2-
30°C
Usual care will be locally sourced, commercial drug supply provided via the investigator site; 
no packaging or labeling will be performed unless required by local country regulation.
Generally, the sponsor does not intend to cover the cost of usual care in this study.  However, 
the decision to cover the cost of usual care (parenteral heparin and/or oral anticoagulation 
with Vitamin K antagonist (excluding other NOACs)) in each country will be made by the 
sponsor based on local requirements and guidelines.
5.2.2. Preparation and Dispensing
Sites should refer to the local package inserts for usual care (parenteral heparin and/or oral 
anticoagulation with Vitamin K antagonist (excluding other NOACs)) treatment for 
preparation and dispensing information.
Apixaban supplied to the Investigator must be stored in accordance with the clinical label and
Investigators Brochure.  Apixaban supplies must be stored separately from normal 
hospital/practice stocks.  Until dispensed to the subjects, apixaban will be stored in a securely 
locked area, only accessible to authorized study personnel.
Usual care (parenteral heparin and/or oral anticoagulation with Vitamin K antagonist 
(excluding other NOACs)) treatment should be stored in accordance with the local label.
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For subjects randomized to apixaban (or to the usual care arm, where usual care medication 
is stored at study site), the Investigator or delegate should dispense study drug treatment as 
per label and routine clinical practice, and visually confirm the subject has received their 
medicine supply at randomization.
For subjects randomized to the usual care arm, it is acceptable for the site to provide the 
subject with a prescription if this medication is not routinely stocked at the site and if this is 
consistent with routine clinical practice. In these events, visual inspection is ensured by 
review of the provided prescription. 
A treatment log must be completed for either apixaban or usual care as appropriate.
5.2.3. Administration
Apixaban or usual care (parenteral heparin and/or oral anticoagulation with Vitamin K 
antagonist (excluding other NOACs)) will be administered from randomization up to 30 days 
following first cardioversion attempt (or 30 days following Visit 2 in the event a subject has 
spontaneously reverted to normal sinus rhythm before cardioversion) or 90 days post 
randomization if cardioversion is not performed.
Administration details will be recorded in the case report form (CRF).
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong subject, at the wrong time, or at the wrong dosage strength.  Such 
medication errors occurring to a study participant are to be captured on the adverse event 
(AE) page of the CRFs and on the SAE form when appropriate.  In the event of medication 
dosing error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated adverse event(s) is 
captured on an adverse event (AE) CRF page.
5.2.3.1. Usual Care
Usual care (parenteral heparin and/or oral anticoagulation with Vitamin K antagonist 
(excluding other NOACs)) will be administered as per local label/practice/guidelines.8,9
The dosing of the Vitamin K antagonist must be individualized according to the subject’s
sensitivity to the drug as indicated by their INR.  INR monitoring should follow the 
investigators usual practice. All INR values during the study will be recorded in the CRF.
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5.2.3.2. Apixaban
Apixaban will be administered and dose adjusted as per local label for the prevention of 
stroke and systemic embolism in subjects with non-valvular AF with provision of additional 
dosing guidance as detailed below:
If a subject randomized to apixaban is scheduled for an image guided cardioversion strategy,
then at least 5 doses of apixaban 5 mg BID should be administered before the procedure is 
conducted to ensure steady-state exposure.
If the cardioversion must be conducted earlier than 5 doses of apixaban, a single 10 mg 
loading dose (administered as two 5 mg tablets) followed by 5 mg BID should be 
administered to achieve immediate steady-state exposure (Japan only: the loading dose is not 
an available option for those subjects participating in Japan and therefore at least 5 doses of 
apixaban should be administered before the image guided cardioversion is conducted).  The 
cardioversion should not be performed until at least 2 hours following the loading dose 
administration.
If a subject meets the criteria for dose reduction, which are at least two of the following 
characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dl 
(133 micromole/l) then 2.5 mg BID should be administered for at least 5 doses before 
cardioversion is conducted or a 5 mg loading dose followed by 2.5 mg BID (Japan only: the 
loading dose is not an available option for those subjects participating in Japan).  
Investigators should refer to their local label for dose adjustment guidance for subjects with 
severe renal impairment.  For example the SmPC states “Patients with exclusive criteria of 
severe renal impairment (creatinine clearance 15-29 ml/min) should also receive the lower 
dose of apixaban 2.5 mg twice daily”.
A subject receiving an anticoagulant (oral and/or parenteral) 48 hours prior to screening 
may be randomized into the study.  For subjects randomized to apixaban the transition from 
an anticoagulant (oral and/or parenteral) is as follows;

Low molecular weight heparin (LMWH) - apixaban should be started at the time of next 
scheduled dose and no earlier than 12 hours after the previous parenteral anticoagulation
administration.  If an image guided cardioversion must be conducted earlier than 5 doses 
of apixaban, then, as directed above, the loading dose can be utilized.

Unfractionated Heparin (UFH) - apixaban can be started between 0 to 2 hours after 
stopping intravenous unfractionated heparin. If an image guided cardioversion must be 
conducted earlier than 5 doses of apixaban, then, as directed above, the loading dose can 
be utilized.

VKA - the VKA should be discontinued and apixaban started when the INR is below 2.0.  
If image guided cardioversion must be conducted earlier than 5 doses of apixaban, then,
as directed above, the loading dose can be utilized. Details of INR will be recorded in the 
CRF.
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
Oral anticoagulant other than a VKA - discontinue the oral anticoagulant being taken and 
begin apixaban at the next scheduled dose and no earlier than 12 hours after the previous 
oral anticoagulant administration.  If an image guided cardioversion must be conducted 
earlier than 5 doses of apixaban, then, as directed above, the loading dose can be utilized.
5.2.4. Compliance
For subjects randomized to apixaban, compliance based on study drug tablet count will be 
recorded both at the time of cardioversion (Visit 2) and at Visit 3 for all subjects.
For subjects randomized to usual care, compliance is confirmed by ongoing INR monitoring.
In addition, tablet count should be recorded both at the time of cardioversion (Visit 2) and at 
Visit 3 for all subjects where usual care has been dispensed directly by the site.  
5.3. Drug Storage and Drug Accountability
Study drug should be stored in accordance with the label.
Investigators and site staff are reminded to check temperatures as per local practice (ie, 
manually or by using alarm systems to alert of any excursions) and ensure that thermometers 
are working correctly as required for proper storage of apixaban.  Any temperature 
excursions should be reported to the sponsor.
Apixaban must be stored as indicated.  Deviations from the storage requirements, including 
any actions taken, must be documented and reported to the sponsor. Once a deviation is 
identified, apixaban must be quarantined and not used until the sponsor provides 
documentation of permission to use the product.
5.4. Concomitant Medications
Physicians should refer to the local package inserts for apixaban and usual care to guide 
prescribing of concomitant medications. The co-administration of parenteral heparin and 
apixaban is prohibited. 
6. STUDY PROCEDURES
6.1. Visit 1 Enrollment, Screening/Randomization (can occur on the same day)
6.1.1. Screening Assessments
The Investigator or designee will:

Obtain written informed consent.

Obtain alternate contact.

Obtain subject demography.

Obtain relevant medical history.
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
Obtain Congestive heart failure, hypertension, age, diabetes, stroke, vascular disease, age, 
sex category stroke risk score (CHA2DS2-VASc score).

Assess and record local clinical laboratory parameters.

Determine if subject meets inclusion/exclusion criteria, including confirmation of heart 
rhythm status from electrocardiogram (ECG). (ECG taken on the day prior to Visit 1 may 
be used for this assessment). 
6.1.2. Randomization Assessments
The Investigator or designee will:

Randomize subject using a centralized IVRS.

Dispense study drug treatment as per label and routine clinical practice, and visually 
confirm the subject has received their medicine supply, see Section 5.2.2.
6.2. Visit 2 Cardioversion
The Investigator or designee will:

Assess and record clinical endpoints (stroke, systemic embolism, major bleeding, 
clinically relevant non-major bleeding, and all cause death) and whether they meet the 
serious adverse event reporting criteria.

Perform study drug treatment compliance check, see Section 5.2.4.

Assess and record local clinical laboratory parameters, including INR for VKA-treated 
subjects.

Assess and record cardioversion details (timing, type, attempts, and rhythm status), and 
use of image guidance (eg, TEE/TOE or CT).

Assess and record adverse events.

Collect and dispense study drug treatment, if required, as per label and routine clinical 
practice, and visually confirm the subject has received their medicine supply, see  Section 
5.2.2.
6.3. Visit 3 (30 days (7) Post Cardioversion or 90 days (7) Following Enrollment Visit 
1 if Cardioversion is not Performed). See Figure 2 for Further Examples of Timing of 
Visit 3. 
The Investigator or designee will:

Assess and record local clinical laboratory parameters, including INR for VKA-treated 
subjects.
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
Assess and record ECG details

Assess and record clinical endpoints (stroke, systemic embolism, major bleeding, 
clinically relevant non-major bleeding and all cause death) and whether they meet the 
serious adverse event reporting criteria.

Record length of in-hospital stay.

Assess and record adverse events.

Collect study drug treatment.

Perform study drug treatment compliance check, see Section 5.2.4.
6.4. Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  If a subject is lost to follow-up, the enrolling physician (or designee) will attempt to 
contact the alternate contact.
In any circumstance, every effort should be made to document subject outcome, if possible.  
The investigator should inquire about the reason for withdrawal, request the subject to return 
all unused investigational product(s), request the subject to return for a final visit, if 
applicable, and follow up with the subject regarding any unresolved adverse events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
A subject who is withdrawn from the study is expected to be subsequently managed by their 
physician according to their usual practice.  See also Section 6.7.
6.5. Guidelines for Image Guidance (eg, TEE/TOE or CT) Suggesting Atrial Thrombus
The investigator should follow their usual practice, and in accordance with local and national 
guidelines.  Positive TEE/TOE or CT will be submitted for adjudication.
It is expected that in the event of imaging suggesting atrial thrombus, that any cardioversion 
attempt would be deferred for a minimum period of at least 3 weeks of further 
anticoagulation, consistent with local/national guidelines.  It would also be expected that 
repeat imaging would take place prior to consideration of further cardioversion attempts.
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6.6. Guidelines for Bleeding/Suspected Bleeding
For subjects with clinically significant bleeding, the anticoagulant should be discontinued.  
Bleeding should be managed according to local standard of care and may include measures 
such as surgical haemostasis, volume resuscitation, and transfusion of blood products as 
deemed appropriate and in keeping with the treating physician’s clinical judgment.
There is no specific antidote to reduce apixaban activity.  Investigators should refer to the 
local prescribing information for further advice on significant bleeding that may occur on 
apixaban.
6.7. Treatment Transition Guidelines
At the end of the study or upon subject withdrawal it is expected that subsequent 
management and treatment for the subject will be conducted by their physician according to 
their usual practice and preferred treatment.
If switching anticoagulation treatment is required, then this will be managed in accordance 
with the local label.
For example, the USPI states “Switching from warfarin to ELIQUIS: Warfarin should be 
discontinued and ELIQUIS started when the international normalized ratio (INR) is below 
2.0”, “Switching from ELIQUIS to warfarin: ELIQUIS affects INR, so that INR 
measurements during coadministration with warfarin may not be useful for determining the 
appropriate dose of warfarin.  If continuous anticoagulation is necessary, discontinue 
ELIQUIS and begin both a parenteral anticoagulant and warfarin at the time the next dose 
of ELIQUIS would have been taken, discontinuing the parenteral anticoagulant when INR 
reaches an acceptable range” and “Switching between ELIQUIS and anticoagulants other 
than warfarin: Discontinue one being taken and begin the other at the next scheduled dose”.
The SmPC states “Switching from Vitamin K antagonist (VKA) therapy to Eliquis: When 
converting patients from Vitamin K antagonist (VKA) therapy to Eliquis, discontinue 
warfarin or other VKA therapy and start Eliquis when the international normalized ratio 
(INR) is < 2.0” and “Switching from Eliquis to VKA therapy: When converting patients from 
Eliquis to VKA therapy, continue administration of Eliquis for at least 2 days after beginning 
VKA therapy.  After 2 days of coadministration of Eliquis with VKA therapy, obtain an INR 
prior to the next scheduled dose of Eliquis. Continue coadministration of Eliquis and VKA 
therapy until the INR is ≥ 2.0”
For other countries, the local approved label should be referred to for advice.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document as soon as possible the reason for this and any corrective and 
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preventive actions which he/she has taken to ensure that normal processes are adhered to.
The study team will be informed of these incidents in a timely fashion.
7.1. Demography
Age, gender and race will be captured within the CRF at Visit 1.
7.2. Medical History
Pertinent AF and other relevant medical history will be captured within the CRF at Visit 1.  It 
is expected that subjects will have routine work-up at presentation according to the 
investigator’s usual practice, with a minimum expectation of ECG confirmation of AF 
diagnosis.  At Visit 1, an ECG to confirm AF does not need to be repeated for the protocol, if 
it was taken on the day prior to, or the same day as Visit 1.
7.3. CHA2DS2-VASc Score
The CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes, stroke, vascular 
disease, age, sex category) stroke risk score assigns 2 points age over 75 years and for a 
history of stroke or transient ischemic attack (TIA), and 1 point each for recent congestive 
heart failure, a history of hypertension, diabetes, vascular disease, age 65-74 years or sex 
category (ie, female gender). The summed score quantifies the risk of stroke in subjects with 
AF.
The CHA2DS2-VASc score will be assessed and the category scores will be captured within 
the CRF at Visit 1.
7.4. Clinical Endpoints
Clinical endpoints will be assessed by the Investigator to determine whether they meet the 
protocol criteria as described below.  Clinical events meeting the criteria will be recorded on 
the CRF and independently adjudicated.
7.4.1. Acute Stroke
An acute stroke is defined as a new, focal neurological deficit of sudden onset, lasting at least 
24 hours, that is not due to a readily identifiable non-vascular cause (ie, brain tumor, trauma). 
All strokes during the study will be assessed and classified as primary hemorrhagic, non-
hemorrhagic, infarction with hemorrhagic conversion, or unknown, as defined by the 
American College of Cardiology (ACC):

Primary hemorrhagic: a stroke with documentation on imaging [eg, computed
tomographic (CT) scan or magnetic resonance imaging (MRI)] of hemorrhage in the
cerebral parenchyma, or a subdural or subarachnoid hemorrhage. Evidence of
hemorrhagic stroke obtained from lumbar puncture, neurosurgery, or autopsy can also
confirm the diagnosis.

Non-hemorrhagic: a focal neurological deficit that results from a thrombus or embolus 
(and not due to hemorrhage) that appears and is still partially evident at 24 hours.
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
Infarction with hemorrhagic conversion: no evidence of hemorrhage on an initial scan but 
appeared on a subsequent scan.

Unknown type/no imaging performed: the type of stroke could not be determined by
imaging or other means (lumbar puncture, neurosurgery).
7.4.2. Systemic Embolism
Systemic embolism will be judged to occur where there is a clinical history consistent with 
an acute loss of blood flow to a peripheral artery (or arteries), which is supported by evidence 
of embolism from surgical specimens, autopsy, angiography, or other objective testing.
7.4.3. Major Bleeding
Clinically overt bleeding is defined as new onset, visible bleeding or signs or symptoms 
suggestive of bleeding with confirmatory imaging techniques which can detect the presence 
of blood (eg, ultrasound (US), CT, MRI).
The definition of major bleeding described below is adapted from the International Society 
on Thrombosis and Hemostasis (ISTH) definition.
Major bleeding is defined as clinically overt bleeding that is accompanied by one or more of 
the following:

A decrease in hemoglobin (Hgb) of 2 g/dL or more

A transfusion of 2 or more units of packed red blood cells

Bleeding that occurs in at least one of the following critical sites:

Intracranial.

Intra-spinal.

Intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an
intraocular bleed).

Pericardial.

Intra-articular.

Intramuscular with compartment syndrome.

Retroperitoneal.

Bleeding that is fatal.
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7.4.4. Clinically Relevant Non-Major Bleeding
The definition of clinically relevant non-major bleeding will be clinically overt bleeding that 
consists of:

Any bleeding compromising hemodynamics.

Any bleeding leading to hospitalization.

Subcutaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic cause.

Intramuscular hematoma documented by ultrasonography.

Epistaxis that lasted for more than 5 minutes, was repetitive (ie, two or more episodes of 
bleeding more extensive than spots on a handkerchief within 24 hours), or led to an 
intervention (eg, packing or electrocoagulation).

Gingival bleeding occurring spontaneously (ie, unrelated to eating or tooth brushing) or 
lasting for more than 5 minutes.

Hematuria that was macroscopic and was spontaneous or lasted for more than 
24 hours after instrumentation (eg, catheter placement or surgery) of the urogenital tract.

Macroscopic gastrointestinal hemorrhage, including at least one episode of melena or 
hematemesis, if clinically apparent with positive results on a fecal occult-blood test.

Rectal blood loss, if more than a few spots on toilet paper.

Hemoptysis, if more than a few speckles in the sputum and not occurring within the 
context of pulmonary embolism or:

Any other bleeding type considered to have clinical consequences for a subject, such 
as medical intervention, the need for unscheduled contact (visit or telephone call) 
with a physician, or temporary cessation of a study drug; or

Associated with pain or impairment of activities of daily life.
7.5. Details of Cardioversion
The date and time of all attempted cardioversion procedures and rhythm status according to 
ECG analysis will be captured within the CRF at Visit 2 and Visit 3.  The performance of 
ECG monitoring is in accordance with the investigator’s usual practice, and it is expected 
this would be performed pre and post cardioversion procedures at appropriate times.
Attempts are defined as the number of times the subject is admitted for the cardioversion 
procedure and not the number of attempts during a single admission.
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7.6. Length of In-Hospital Stay
Length of in-hospital stay is defined as the number of hours from hospital admission to 
hospital discharge following early cardioversion.
The date and time of all hospital admissions and discharges following cardioversion will be 
captured within the CRF at Visit 2 and 3.
7.7. Collection of Local Clinical Laboratory Parameters
Local clinical laboratory assessments should be performed as part of the routine care for 
subjects undergoing cardioversion at the clinical practice.
From these routine assessments hemoglobin and serum creatinine will be recorded within the 
CRF from Visit 1 to Visit 3.
8. ADVERSE EVENTS
In this clinical protocol adverse and serious adverse event reporting will be managed 
according to the following BMS standard operating definitions and procedures.
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a preexisting medical condition in a clinical investigation subject administered study drug
and that does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug.
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). 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.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject.  (In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more AEs).
BMS will be reporting adverse events to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and Food and 
Drug Administration (FDA) Code of Federal Regulations 21 CFR Parts 312 and 320.
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8.1. Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death;

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);

results in persistent or significant disability/incapacity;

is a congenital anomaly/birth defect;

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention 
[eg, medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room 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 Section 8.6 for the definition of potential 
DILI).
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 
8.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is 
an endpoint; if death occurred due to anaphylaxis, anaphylaxis must be reported) should be 
reported as an SAE (see Section 8.1.1 for reporting details).
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies:

a visit to the emergency room or other hospital department <24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event);

elective surgery, planned prior to signing consent;

admissions as per protocol for a planned medical/surgical procedure;
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
routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy);

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases;

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
8.1.1. Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited 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 discontinuation of dosing.
The investigator should report any SAE that occurs after these time periods and that is 
believed to be related to study drug or protocol-specified procedure.
An SAE report must be completed for any event where doubt exists regarding its 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 must be specified in the narrative section of the SAE 
Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE 
Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms).
The preferred method for SAE data reporting collection is through the electronic case report 
form (eCRF). The paper SAE/pregnancy surveillance forms are only intended as a back-up 
option when the eCRF system is not functioning. In this case, the paper forms are to be 
transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address:  Refer to Contact Information list.
SAE Facsimile Number:  Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is 
the required method for reporting. In the event the electronic system is unavailable for 
transmission, paper forms must be used and submitted immediately. When paper forms are 
used, the original paper forms are to remain on site.
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SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must 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, the SAE report must be updated and submitted within 24 hours to the 
BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
8.2. Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
8.2.1. Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. 
Nonserious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 8.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study 
treatment as appropriate. All identified nonserious AEs must be recorded and described on 
the nonserious AE page of the CRF (paper or electronic).
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
8.3. Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE 
CRF page or SAE Report Form (electronic) as appropriate. Paper forms are only intended as 
a back-up option when the electronic system is not functioning.

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 laboratory term would be used 
by the reporting investigator (eg, anemia versus low hemoglobin value).
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8.4. 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 study exposure, including 
during at least 5 half lives after product administration, the investigator must immediately 
notify the BMS Medical Monitor/designee of this event and complete and forward a 
Pregnancy Surveillance Form to BMS Designee within 24 hours of awareness of the event 
and in accordance with SAE reporting procedures described in Section 8.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety). Please call the BMS Medical Monitor/designee
within 24 hours of awareness of the pregnancy. 
Protocol-required procedures for study discontinuation and follow-up must be performed on 
the subject. 
The investigator must immediately notify the BMS (or designee) Medical Monitor of this 
event and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 
24 hours of awareness of the event and in accordance with SAE reporting procedures 
described in Section 8.1.1.
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to BMS (or designee). Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
8.5. Overdose
All occurrences of overdose must be reported as SAEs (see Section 8.1.1 for reporting 
details).
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 an SAE (see Section 8.1.1 for reporting details).
8.6. Potential Drug Induced Liver Injury (DILI)
Specific criteria for identifying potential DILI have not been identified for this protocol. 
Standard medical practice in identifying and monitoring hepatic issues should be followed.
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 must be reported as SAEs (see Section 8.1.1 for reporting details).
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8.7. Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not
required by protocol should also be recorded as a nonserious or serious AE, as appropriate, 
and reported accordingly.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan, which will be developed in collaboration 
between the Executive Committee and the sponsor.  This document may modify the plans 
outlined in the protocol; however, any major modifications of the endpoint definition and/or 
its analysis will also be reflected in a protocol amendment.
9.1. Sample Size Determination
The study is intended to be descriptive only.  The study will enroll approximately 
1500 subjects.  No power calculation was performed but with a sample size of 1500 subjects, 
and based upon an ARISTOTLE warfarin naive cohort of subjects (the closest analogous 
data-set to this study design), the predicted incidence of stroke and systemic embolism within 
30 days post cardioversion is approximately 0.3% (1 event on apixaban and 3 events on usual 
care).  Similarly, the predicted event rate for major bleeding is approximately 0.45% 
(2 events on apixaban and 5 events on usual care).
For a study of this type, in order to adequately power for statistically significant claims, 
about 480 endpoints would be needed (similar to the ARISTOTLE trial).10  However, due to 
the limited relevant follow-up (30 days following cardioversion or 90 days post 
randomization), and a clinical estimate for event rate of approximately 1% this would require 
approximately 48000 subjects, which would not be a feasible study.
9.2. Endpoint Analysis
This is a descriptive study, and there is no formal pre-defined hypothesis testing.
Baseline demographics, endpoints, AEs and SAEs will be reported by randomized treatment 
arm as per Pfizer/BMS reporting standards and consistent with the therapeutic area standards.  
Number of observations and proportions will be given for categorical or binary variables, 
number of observations, mean, standard deviation, median minimum and maximum will be 
given for continuous variables; time-to-event data will be displayed using Kaplan-Meier 
techniques; hazard ratio will be calculated.
9.3. Data Monitoring Committee
This study will use a Data Monitoring Committee (DMC) independent of the sponsor study 
team.  The sponsor study team will monitor blinded data trends in accordance with the Safety 
Review Plan.
The DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the Charter.  The recommendations made by the DMC to alter the conduct of 
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the study will be forwarded to Executive Committee and the sponsor (Pfizer/BMS) for final 
decision.  The sponsor will forward such decisions, which may include summaries of 
aggregate analyses of endpoint events and of safety data which are not endpoints, to 
regulatory authorities, as appropriate.
9.4. Independent Adjudication
Independent Adjudicator(s) will review and adjudicate all clinical endpoints and positive 
TEE/TOE or CT without awareness of treatment allocation, ie, in a blinded manner.  The 
responsibilities and procedures followed are described in the Adjudication Charter.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer/BMS or its agent will conduct periodic monitoring visits to 
ensure that the protocol and Good Clinical Practices (GCPs) are being followed.  The 
monitors may review source documents to confirm that the data recorded on CRFs is 
accurate.  The investigator and institution will allow Pfizer/BMS monitors/auditors or its 
agents and appropriate regulatory authorities direct access to source documents to perform 
this verification.
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer/BMS, or 
companies working with or on behalf of Pfizer/BMS, and/or to inspection by appropriate 
regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer/BMS and should not be made available in any 
form to third parties, except for authorized representatives of Pfizer/BMS or appropriate 
regulatory authorities, without written permission from Pfizer/BMS.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.
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In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts.
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer/BMS and 
clearly identify those data that will be recorded in the CRF, and for which the CRF will stand 
as the source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer or BMS, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents,
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer and BMS should be prospectively notified.  
The study records must be transferred to a designee acceptable to Pfizer/BMS, such as 
another investigator, another institution, or to an independent third party arranged by 
Pfizer/BMS. Investigator records must be kept for a minimum of 15 years after completion 
or discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer/BMS's written permission before disposing of any 
records, even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer/BMS.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer/BMS in writing immediately 
after the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
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Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
on any sponsor forms, reports, publications, or in any other disclosures, except where
required by laws.
Subject names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer/BMS in order to de-identify the 
trial subject.  In case of data transfer, Pfizer/BMS will maintain high standards of 
confidentiality and protection of subject personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC before use, and available for inspection.
The investigator must ensure that each study subject, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.  The investigator, or a person designated by the investigator, will obtain written 
informed consent from each subject or the subject's legal representative before any study-
specific activity is performed. The investigator will retain the original of each subject's 
signed consent document.
12.4. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer and/or BMS should be informed immediately.
In addition, the investigator will inform Pfizer and/or BMS immediately of any urgent safety 
measures taken by the investigator to protect the study subjects against any immediate 
hazard, and of any serious breaches of this protocol or of ICH GCP that the investigator 
becomes aware of.
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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all other Participating Countries
End of Trial in all other participating countries is defined as Visit 3.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer/BMS.  
In addition, Pfizer/BMS retains the right to discontinue development of apixaban at any time.
If a study is prematurely terminated or discontinued, Pfizer/BMS will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 48 hours.  As directed by Pfizer/BMS, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer/BMS
Pfizer/BMS fulfills its commitment to publicly disclose clinical trial results through posting 
the results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical 
Trials Database (EudraCT), and/or www.pfizer.com, and other public registries in 
accordance with applicable local laws/regulations.
In all cases, study results are reported by Pfizer/BMS in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer/BMS posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer/BMS-
sponsored interventional studies conducted in patients that evaluate the safety and/or efficacy 
of a Pfizer/BMS product, regardless of the geographical location in which the study is 
conducted.  US Basic Results are submitted for posting within 1 year of the primary 
completion date for studies in adult populations or within 6 months of the primary 
completion date for studies in pediatric populations.
Primary Completion Date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
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whether the clinical trial concluded according to the pre-specified protocol or was 
terminated.
EudraCT
Pfizer/BMS posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional 
studies that are in scope of EU requirements. EU basic Results are submitted for posting 
within 1 year of the primary completion date for studies in adult populations or within 
6 months of the primary completion date for studies in pediatric populations. 
www.pfizer.com
Pfizer/BMS posts Public Disclosure Synopses (clinical study report synopses in which any 
data that could be used to identify individual patients has been removed) on www.pfizer.com 
for Pfizer/BMS-sponsored interventional studies at the same time the US Basic Results 
document is posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer/BMS has no objection to publication by an investigator of any information collected or 
generated by the investigator, whether or not the results are favorable to the investigational 
drug.  However, to ensure against inadvertent disclosure of confidential information or 
unprotected Inventions, Investigator will provide Pfizer/BMS an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to 
Pfizer/BMS at least 30 days before they are submitted for publication or otherwise disclosed.
If any patent action is required to protect intellectual property rights, the investigator agrees 
to delay the disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information (other than the study results themselves) before disclosure.
If the study is part of a multi-centre study, the investigator agrees that the first publication is 
to be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, investigator is free to publish separately, subject to the other requirements 
of this section.
For all publications relating to the study, institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
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Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer/BMS and the institution.  In this section entitled Publications by Investigators, the 
defined terms shall have the meanings given to them in the Clinical Study Agreement.
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16. REFERENCES
1.
Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates 
incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients 
with atrial fibrillation: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on practice guidelines. Circulation. 
Mar 15 2011; 123(10):e269-367.
2.
Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial 
fibrillation: the Framingham Heart Study. Circulation. Aug 31 2004;110(9):1042-6.
3.
Arnold AZ, Mick MJ, Mazurek RP, et al. Role of prophylactic anticoagulation for direct 
current cardioversion in patients with atrial fibrillation or atrial flutter. Journal of the 
American College of Cardiology. 1992; 19:851-5.
4.
Weinberg DM, Mancini J. Anticoagulation for cardioversion of atrial fibrillation. The 
American journal of cardiology. 1989; 63:745-6.
5.
Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing 
embolism related to d.C. Electrical conversion of atrial fibrillation. The American 
journal of cardiology. 1969; 23:208-16.
6.
Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to 
guide cardioversion in patients with atrial fibrillation. The New England journal of 
medicine. 2001; 344:1411-20.
7.
Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients 
with atrial fibrillation: An analysis of patients undergoing cardioversion. Circulation. 
2011; 123:131-6.
8.
Camm AJ, Lip GY, De Caterina, R, et al. 2012 focused update of the ESC Guidelines 
for the management of atrial fibrillation. European heart journal. 2012; 33:2719-47.
9.
You JJ, Singer DE, Howard PA, et al. American College of Chest P. Antithrombotic 
therapy for atrial fibrillation: Antithrombotic therapy and prevention of thrombosis, 9th 
ed: American college of chest physicians evidence-based clinical practice guidelines. 
Chest. 2012; 141: e531S-75S.
10.
Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients 
with atrial fibrillation. The New England journal of medicine. 2011; 365:981-92.
11.
Eikelboom JW, O'Donnell M, Yusuf S, et al. Rationale and design of AVERROES: 
apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who 
have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J. Mar 2010;
159 (3):348-53 e341.
12.
Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. 
N Engl J Med. Mar 3 2011; 364 (9):806-17.
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13.
Data-on file with sponsor.
14.
Thorpe KE, Zwarenstein M, Oxman AD, et al. A pragmatic-explanatory continuum 
indicator summary (PRECIS): a tool to help trial designers. J Clin Epi 62 (2009); 464-
75
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Statistical Analysis Plan 
 
 
 
 
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Protocol B0661025/CV185-267 
 
 
 
 
A PHASE IV TRIAL TO ASSESS THE EFFECTIVENESS OF APIXABAN 
COMPARED WITH USUAL CARE ANTICOAGULATION IN SUBJECTS WITH 
NON-VALVULAR ATRIAL FIBRILLATION UNDERGOING CARDIOVERSION 
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
Version: 
3 
 
Author:  
 PhD 
 
Date:  
02-Feb-2017 
PPD
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TABLE OF CONTENTS  
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................4 
2. INTRODUCTION .......................................................................................................................4 
2.1. Study Design ...................................................................................................................4 
2.2. Study Objectives and Endpoints .....................................................................................6 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ........................................6 
4. HYPOTHESES AND DECISION RULES .................................................................................7 
4.1. Statistical Hypotheses .....................................................................................................7 
4.2. Statistical Decision Rules ................................................................................................7 
5. ANALYSIS SETS .......................................................................................................................7 
5.1. Full Analysis Set .............................................................................................................7 
5.2. ‘Per Protocol’ Analysis Set .............................................................................................7 
5.3. Safety Analysis Set ..........................................................................................................8 
5.4. Other Analysis Sets .........................................................................................................8 
5.5. Treatment Misallocations ................................................................................................8 
5.6. Protocol Deviations .........................................................................................................8 
5.6.1. Deviations Assessed Prior to Randomization .....................................................8 
5.6.2. Deviations Assessed Post-Randomization ..........................................................8 
6. ENDPOINTS AND COVARIATES ...........................................................................................8 
6.1. Efficacy Endpoint(s) .......................................................................................................9 
6.2. Safety Endpoints .............................................................................................................9 
6.3. Other Endpoints ...............................................................................................................9 
6.4. Covariates ........................................................................................................................9 
7. HANDLING OF MISSING VALUES ......................................................................................10 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................10 
8.1. Statistical Methods ........................................................................................................10 
8.1.1 
Analyses for Continuous Data ......................................................................10 
8.1.2 
Analyses for Time-to-Event Data ................................................................10 
8.1.3 
Analyses for Binary Endpoints ....................................................................10 
8.2. Statistical Analyses .......................................................................................................10 
8.2.1. Analysis of Primary Endpoints .........................................................................10 
8.2.2. Analysis of Secondary Endpoints .....................................................................10 
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8.2.3. Analysis of Safety Data ....................................................................................11 
8.2.4. Analyses of Clinical Endpoints ........................................................................11 
8.2.5. Other endpoints: ................................................................................................12 
9. REFERENCES ..........................................................................................................................15 
 
APPENDICES ...............................................................................................................................15 
APPENDIX 1. DATA DERIVATION DETAILS ........................................................................15 
Appendix 1.1. Definition of Protocol Deviations that Relate to Statistical 
Analyses/Populations ..................................................................................................15 
Appendix 1.2. Definition of Analysis Populations/Sets ................................................................15 
Appendix 1.3. Further Definition of Endpoints .............................................................................15 
Appendix 2. STATISTICAL METHODOLOGY DETAILS ........................................................15 
Appendix 2.1. Further Details of Interim Analyses .......................................................................15 
Appendix 2.2. Further Details of the Statistical Methods ..............................................................15 
 
1. AMENDMENTS FROM PREVIOUS VERSION(S)  
2. THIS AMENDS VERSION 2 FROM OCT 15 2015 INTRODUCES ADDITIONAL 
SENSITIVITY ANALYSES AS REQUESTED BY THE EXECUTIVE COMMITTEE. 
INTRODUCTION 
Apixaban is a novel, orally active, selective inhibitor of the coagulation factor Xa (FXa) 
developed by Bristol-Myers Squibb (BMS) and Pfizer as an anticoagulant and antithrombotic 
agent. Apixaban is a reversible and highly potent inhibitor of human FXa with a high degree of 
selectivity over other coagulation proteases and structurally related enzymes involved in 
digestion and fibrinolysis.  
2.1. Study Design 
This is a randomized, active controlled, parallel-group, open label study. Approximately 1500 
subjects will be randomized 1:1 to apixaban or usual care (parenteral heparin and/or oral 
anticoagulation with Vitamin K antagonist (excluding other novel oral anticoagulants)). 
Following randomization, endpoints will be collected during the 30 days following the early 
cardioversion or during the 90 days post randomization if cardioversion is not performed within 
that time frame. 
A schematic diagram below (Figure 1) shows the design of the study: 
Figure 1 Study Design Schematic 
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The Schedule of Activities table provides an overview of the protocol visits and procedures. 
Refer to Study Procedures and Assessments sections of the protocol for detailed information on 
each procedure and assessment required for compliance with the protocol. 
 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule 
of activities, in order to conduct evaluations or assessments required to protect the wellbeing of 
the subject. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1 Schedule of Activities 
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2.2. Study Objectives and Endpoints 
The study objective is to assess the occurrence of clinical endpoints in non-valvular AF 
subjects (i.e., without rheumatic mitral valve disease, a prosthetic mechanical heart valve, or 
mitral valve repair) indicated for early cardioversion and treated with apixaban or usual care 
(parenteral heparin and/or oral anticoagulation with Vitamin K antagonist (excluding other 
NOACs)). 
Clinical Endpoints 
 Stroke. 
  Systemic embolism. 
  Major Bleeding. 
  Clinically Relevant Non-Major Bleeding. 
  All cause death. 
Additional information will also be collected on: 
 Cardioversion details: timing, type, attempts, and rhythm status   
 Length of in-hospital stay.  
 Use of image guidance e.g., TEE/TOE or CT. 
This protocol will use independent adjudication of disease-related clinical endpoints. 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
This study will use an Independent Review Committee (IRC) independent of the sponsor study 
team. The IRC, in collaboration with the sponsor (Pfizer/BMS)  and the Executive Committee 
will create a Charter including the interim analysis plan .  
 
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The sponsor study team will monitor blinded data trends in accordance with the Safety Review 
Plan. The IRC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the Charter. The recommendations made by the IRC to alter the conduct of the 
study will be forwarded to Executive Committee and the sponsor (Pfizer/BMS) for final decision. 
The sponsor will forward such decisions, which may include summaries of aggregate analyses of 
endpoint events and of safety data which are not endpoints, to regulatory authorities, as 
appropriate. 
 
The final analysis will be executed after the database release. 
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
This is a descriptive study, and there is no formal pre-defined hypothesis testing.  
Baseline demographics, endpoints, AEs and SAEs will be reported as per Pfizer/BMS reporting 
standards and consistent with the therapeutic area standards. Number of observations and 
proportions will be given for categorical or binary variables, number of observations, mean, 
standard deviation, median minimum and maximum will be given for continuous variables; time-
to-event data will be displayed using Kaplan-Meier techniques; hazard ratio will be calculated.  
4.2. Statistical Decision Rules 
No decision rules will be set, this is a descriptive study. 
5. ANALYSIS SETS 
Adverse events and adjudicated bleeding endpoints (Major Bleeding and Clinically Relevant 
Non-Major Bleeding) will be reported based on the Safety Analysis set. All other data will be 
reported based on the Full Analysis Set as-randomized (using a strict intent-to-treat criterion), 
irrespective of the actual treatment or compliance. 
5.1. Full Analysis Set 
The Full Analysis Set contains all randomized subjects. It will be used under the intent to treat 
principle (subjects will be categorized to the treatment group to which they were assigned by the 
IVRS, regardless of the treatment actually received). 
5.2. ‘Per Protocol’ Analysis Set  
N/A 
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5.3. Safety Analysis Set 
The Safety Analysis Set (as-treated) will consist of all treated subjects (randomized subjects who 
received at least one dose of study drug). For the purpose of safety analyses, subjects will be 
categorized according to the treatment received; subject that received both treatments will be 
counted as apixaban. The reporting will be done as per Pfizer/BMS reporting standards and BMS 
CT SOP 109. 
5.4. Other Analysis Sets 
Prevention-evaluable analyses datasets will be created in order to exclude subjects identified at 
visit 2 through imaging as already having a thrombus; if multiple evaluations took place over 
time for a subject, only the first one will be used. 
The Full Prevention-Evaluable Analysis Set is obtained by excluding thrombus-positive subjects 
from the Full Analysis Set. The Safety Prevention-Evaluable Analysis Set is obtained by 
removing subjects with thrombus from the Safety Analysis Set. The sets of Thrombus Positive-
Full Analysis Set and Thrombus Positive-Safety are the complements of the Full Prevention 
Evaluable and Safety Prevention-evaluable subjects. 
The Modified Full Analysis Set is the subset of the Full Analysis Set of subjects that received at 
least one study drug dose. 
5.5. Treatment Missallocations 
N/A 
5.6. Protocol Deviations 
All significant protocol deviations including eligibility deviations, use of prohibited concomitant 
medications,  subjects receiving the incorrect study drug, or other deviations-as deemed 
significant by the project team will be identified (either from the project database or RightrackII) 
prior to database release, then listed and summarized by deviation type and randomized 
treatment group after database release. The Clinical team will provide before the database lock a 
list of prohibited medications. 
5.6.1. Deviations Assessed Prior to Randomization 
N/A 
5.6.2. Deviations Assessed Post-Randomization 
N/A 
6. ENDPOINTS AND COVARIATES 
Clinical Endpoints 
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 Stroke. 
  Systemic embolism. 
  Major Bleeding. 
  Clinically Relevant Non-Major Bleeding. 
  All cause death. 
 
6.1. Efficacy Endpoint(s) 
N/A 
6.2. Safety Endpoints 
N/A 
6.3. Other Endpoints 
Additional information will also be collected on cardioversion detail, length of in-hospital stay 
and usage of image guidance: 
 Cardioversion details: timing, type, attempts, and rhythm status; 
 Length of in-hospital stay (in hours);  
 Use of image guidance e.g., TEE/TOE or CT;  
 
6.4. Covariates  
We have identified a number of baseline variables of interest:  
 Age (continuous, in years),  
 Hypertension (checkmark, Yes/No), 
 Low Left Ventricular Function (≤40%),  
 Diabetes (Yes/No),  
 Duration of Arrhythmia (in hours) 
 No imputation for missing data will be made on these covariates.  
We will explore the effect of the above-mentioned covariates on all the clinical endpoints. 
Univariate analyses (one predictor at a time) and multivariate analyses (including all covariates 
from above and treatment effect) will be performed for the above mentioned covariates on each 
of the clinical endpoints using Cox proportional hazards models. Interaction tests between 
covariates and allocated treatment will be conducted.  
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7. HANDLING OF MISSING VALUES 
Safety data will be handled according to the BMS safety data conventions (described in 
“Analysis of Safety Data - Reference to BMS CT SOP 109”. This document includes 
descriptions on how to analyze AE data as well as how to handle partial dates, missing dates, and 
unknown end dates when analyzing safety data. 
For the analyses of clinical endpoints, imputation of missing or partial dates for efficacy and 
bleeding events will follow the convention outlined in “Analysis of Safety Data - Reference to 
BMS CT SOP 109”. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods  
8.1.1 Analyses for Continuous Data 
Frequencies, means, standard deviations, and medians will be reported by treatment arms.  
8.1.2 Analyses for Time-to-Event Data  
Summaries will include tabular and graphical summaries of Kaplan-Meier estimates by treatment 
arm as well as hazard ratios of the treatment effect or other covariates, their 95% confidence 
intervals and p-values. 
8.1.3 Analyses for Binary Endpoints 
For binary endpoints, 95% exact confidence intervals of each event rate will be reported by 
treatment group. The relative risk (risk ratios) will also be reported. In the SAS language we will 
use the RELRISK with FMSCORE method option in the EXACT statement of PROC FREQ in 
order to provide exact unconditional confidence limits for the relative risk.  
Other binary data comparisons will be made using Fisher’s exact test. 
8.2. Statistical Analyses  
N/A 
8.2.1. Analysis of Primary Endpoints 
N/A 
8.2.2. Analysis of Secondary Endpoints 
N/A 
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8.2.3. Analysis of Safety Data 
Safety data will be analyzed according to the BMS safety data conventions (described in 
“Analysis of Safety Data - Reference to BMS CT SOP 109”.  
8.2.4. Analyses of Clinical Endpoints 
 Stroke. 
  Systemic embolism. 
  Major Bleeding. 
  Clinically Relevant Non-Major Bleeding. 
  All cause death. 
The following time periods will be defined for reporting clinical endpoints: 
 Pre-cardioversion 
 Post-cardioversion 
 ALL: entire duration (include 30 days follow-up after cardioversion). 
The characterization of stroke, systemic embolism and death will be done based on the 
adjudicated endpoints during the study (according to an intention-to-treat paradigm). Analysis of 
these endpoints will be based on the full analysis set. 
The characterization of bleeding will be done with a focus on adjudicated major bleeding and 
clinically relevant non-major bleeding during the treatment period (according to a safety 
paradigm). Analysis of these endpoints will be based on the safety analysis set.   
The clinical endpoint summaries will include descriptive statistics of individual event rates and 
their exact 95% confidence intervals; however exact risk ratios and corresponding p-values 
comparing the treatment arms will also be presented without any formal testing.   
Sensitivity analysis: If the TEE/TOE or CT procedures will identify subjects with thrombus 
(thrombus-positive), sensitivity analyses of all clinical endpoints will be run on a dataset 
obtained by removing those subjects from the Full Analysis Set. The dataset from which 
thrombus-positive (as per investigator’s assessment) subjects were excluded will be labeled as 
Full Prevention-Evaluable;its complementary set of Thrombus Positive-ITT will be analyzed for 
the endpoints of Stroke, Systemic Embolism, and Death. Sensitivity analyses of bleeding events 
will also be run on a dataset (labeled as Safety Prevention-Evaluable Analysis Set) obtained by 
removing subjects with thrombus (as per investigator’s assessment) from Safety analysis set; its 
complementary set of Thrombus Positive-Safety will be analyzed for the bleeding endpoints. 
The Modified Full Analysis set will be analyzed for the endpoints of Stroke, Systemic 
Embolism, and Death. 
 
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Subgroup analyses: Clinical endpoints and safety (AEs, SAEs) will be reported for each 
subgroup of interest. Subgroups of interest are (please note that bleeding endpoints are based on 
the safety analysis set while the others are based on the full analysis set): 
 “Early Cardioversion” (defined as cardioversion that occurs within 7 days from 
randomization),  
 Image Guidance (TEE/TOE or CT),  
 age (< 65 years old, ≥ 65 years old)  
 gender.  
 For the clinical endpoints (stroke/embolism/death), also analyze by (first) cardioversion 
status: ‘Interventional cardioversion’, no cardioversion, or ‘Spontaneous cardioversion’ 
 For clinical endpoints, breakdown summaries by Apixaban initial dose levels (loading 
dose vs. no loading dose) will be produced. 
We will display graphically the Kaplan-Meier product-limit estimators of the time to  
• 
Composite of  first adjudicated stroke or systemic embolism, 
• 
First Major bleeding event, 
• 
Composite of first major bleeding and clinically relevant non-major bleeding  
• 
All cause death. 
 
8.2.5. Other analyses: 
The full analysis set will be used to summarize data on cardioversion details, length of in-
hospital stay and usage of image guidance. 
 
 Cardioversion details will be summarized by number of attempts (a separate table will be 
presented for each number of attempts). 
 
o The summary for first attempt will be based on the full analysis set. Timing of 
cardioversion will be the time from randomization to the first attempt only, with time 
to first attempt censored at the last day of follow-up if an attempt has not been made.  
o The hazards ratio (and p-value) will be calculated for time from randomization to the 
first attempt at cardioversion, comparing image guided to non-image guided subjects. 
o The second attempt will be summarized based on the subset of the full analysis set 
that already had the first cardioversion, etc.  
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o For each attempt we will summarize the number and proportion of subjects with 
cardioversion attempts and the number and proportion with each rhythm status. 
o Demog/baseline tables will be subset for 1) subjects with no cardioversion attempt, 2) 
subjects with one cardioversion attempt, and 3) subjects with 2 or more cardioversion 
attempts  
 
 Length of in-hospital stay is defined as the number of hours from hospital admission to 
hospital discharge following cardioversion. The date and time of all hospital admissions and 
discharges following cardioversion will be captured within the CRF at Visit 2 and 3. 
Frequency of hospital stay, mean and median duration will be summarized by treatment arm.  
 
 Early cardioversion is defined as cardioversion that occurred within the first 7 days after 
randomization. Frequency and proportions will be reported by treatment arm. 
 
Routine hemoglobin and serum creatinine will be recorded within the CRF from Visit 1 to Visit 
3. The data will be presented in listings without imputations and displaying even multiple 
findings per visit. The lab data will not be summarized. 
Compliance for apixaban will be reported and summarized overall. The compliance formula is: 
#tablets taken / (#of days*2+L) where L=1 if loading dose was given and 0 otherwise. 
INR will be summarized for the usual care arm. Rosendaal’s linear interpolation methodology 
will be used to determine the proportion of time in specified INR range and time to therapeutic 
range (i.e. time from randomization to the first INR greater than or equal to  2. 
Time to withdrawal will be analyzed and displayed as a KM figure. 
For the adjudicated TEEs, we will report the concordance/discordance between investigator’s 
assessment and the adjudicator’s assessment, without regard to treatment arm. Details of the 
adjudicated TEEs will be included in a listing, as well as details of the investigator’s initial TEE 
assessment. 
 
Demogs/baseline characteristics will be summarized for the following groups: 10 mg load vs no 
load, 5 mg load vs. no load, 10 mg load vs 5 mg load 
Demogs/baseline characteristics will be compared for spontaneous vs. interventional 
cardioversion within the Apixaban arm. 
Demogs/baseline characteristics will be compared for spontaneous vs. interventional 
cardioversion within the usual care arm. 
Demogs/baseline characteristics will be compared for spontaneous vs. interventional 
cardioversion in the two treatment arms combined. 
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Demogs/baseline characteristics will be compared for electrical vs. pharmacological vs. both 
cardioversion within the Apixaban arm. 
Demogs/baseline characteristics will be compared for electrical vs. pharmacological vs. both 
cardioversion within the usual care arm. 
Demogs/baseline characteristics will be compared for electrical vs. pharmacological vs. both 
cardioversion in the two treatment arms combined. 
Demogs/baseline characteristics will be compared for subjects with thrombus vs. subjects 
without thrombus. 
The following analyses/comparisons will be performed for each of the clinical endpoints; the 
Full Ananlysis Set will be used for stroke, systemic embolism, and for death, while the safety 
dataset will be used for the bleeding endpoints; 
for the following Apixaban groups: 10 mg load vs no load, 5 mg load vs. no load, 10 mg load vs 
5 mg load 
for spontaneous vs. interventional cardioversion within the Apixaban arm. 
for spontaneous vs. interventional cardioversion within the usual care arm. 
for spontaneous vs. interventional cardioversion in the two treatment arms combined. 
for electrical vs. pharmacological vs. both cardioversion within the Apixaban arm. 
for electrical vs. pharmacological vs. both cardioversion within the usual care arm. 
for electrical vs. pharmacological vs. both cardioversion in the two treatment arms combined. 
for subjects with thrombus vs. subjects without thrombus. 
 
 
 
 
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References  
N/A 
APPENDICES  
Appendix 1. DATA DERIVATION DETAILS 
Appendix 1.1. Definition of Protocol Deviations that Relate to Statistical 
Analyses/Populations 
N/A 
Appendix 1.2. Definition of Analysis Populations/Sets  
N/A 
Appendix 1.3. Further Definition of Endpoints 
N/A   
Appendix 2. STATISTICAL METHODOLOGY DETAILS  
N/A 
Appendix 2.1. Further Details of Interim Analyses 
N/A 
Appendix 2.2. Further Details of the Statistical Methods 
N/A 
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