Conditions: Acute Coronary Syndromes
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 4614
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if Apixaban is safer than a Vitamin K Antagonist given for 6 months in terms of bleeding in patients with an irregular heart beat (atrial fibrillation) and a recent heart attack or a recent procedure to open up a blood vessel in the heart. All patients would also be taking a class of medicines called P2Y12 inhibitors (such as clopidogrel/Plavix) and be treated for up to 6 months. The primary focus will be a comparison of the bleeding risk of Apixaban, with or without aspirin, versus a Vitamin K antagonist, such as warfarin, with or without aspirin.

Detailed description:
Patients will be recruited from either inpatient coronary care or general medical units, or recruited from outpatient cardiology offices.

Masking:

Apixaban: Open label.

VKA: Open label.

Acetylsalicylic acid film coated tablet: Double Blinded.

Placebo matching Acetylsalicylic acid film coated tablet: Double Blinded.

Arms:
arm 1: 5 mg or 2.5 mg Apixaban tablets orally twice per day arm 2: VKA tablets orally once daily arm 3: 81 mg Acetylsalicylic acid film coated tablet orally once daily arm 4: Placebo matching Acetylsalicylic acid film coated tablet once daily

Interventions: intervention 1: Apixaban intervention 2: vitamin K antagonist intervention 3: Acetylsalicylic acid intervention 4: Acetylsalicylic acid placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_000.pdf: 
Page:
1
Protocol Number:
CV185316
IND Number:
68,598
Ex-US
Non-IND
EUDRACT Number
2014-002004-24
Date:
19-Mar-2015
Revised Date:
21-Aug-2018
Clinical Protocol CV185316
An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of 
Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial 
Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention
Revised Protocol No.: 04
Incorporates amendment(s): 07 and Administrative Letters 03 and 04
Medical Monitor
Ronald Aronson
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
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who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No: 04
Date: 21-Aug-2018
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 04
21-Aug-2018
Incorporates Amendment 07 and Administrative Letters 03 and 04.
Amendment 07
21-Aug-2018
Amendment 07 - (1) Describes the use of hierarchical statistical testing 
to analyze the data for apixaban vs VKA and aspirin vs aspirin placebo; 
(2) Notes the change in the Medical Monitor and his contact information.
Administrative 
Letter 04
26-Mar-2018
Change in Medical Monitor Contact information
Administrative 
Letter 03
21-Nov-2017
Date corrected on title page of protocol
Revised Protocol 03
11-Oct-2017
Incorporates Amendment 05 and Administrative Letter 02
Amendment 05
11-Oct-2017
The purpose of Amendment 05 is to reword inconsistent language in the 
current protocol to clarify the patient eligibility criteria, add an efficacy 
composite endpoint of all-cause death/all-cause re-hospitalization and to 
correct typographical errors. In addition, Amendment 05 lists some of the 
data not specified in the protocol but included in the electronic case 
report form; this data is planned for potential secondary publications.
Administrative 
Letter 02
04-May-2017
Medical Monitor Address Change
Revised Protocol 02
28-Apr-2016
Incorporates Amendment 02 
Amendment 02
28-Apr-2016
The purpose of amendment 02 is to clarify the hypothesis, objectives and 
patient population in regard to patients who have non-valvular atrial 
fibrillation and acute coronary syndrome and/or PCI by adding the word 
“and” in front of “PCI” throughout the protocol, editing the study 
schematic, as well as to add clarifying language to the targeted SAE 
reporting section. Table 4-1 was updated to include BMS study 
medication that will be supplied in some countries where local sourcing 
is not an option. In addition sections 4.3, 4.8, 4.9, and 9.2.2 were updated 
based on the mandatory language in the revised protocol model 
document.
Revised Protocol 01
05-Apr-2016
Incorporates Amendment 01 and Administrative Letter 01
Amendment 01
05-Apr-2016
The purpose of this amendment is to clarify language for the targeted 
SAE reporting, add language referencing stopping guidance in the DMC 
charter, and correct omissions from the original protocol. In the inclusion 
section, wording was changed to accommodate countries where age of 
adulthood is not 18 years of age. 
 
 
Study was originally meant to allow patients who had balloon 
angioplasty, either with or without a stent being placed. Removing the 
word "with a stent" allows balloon angioplasty without stent. Additional 
language on unstable angina entry also added for clarification of the 
population.
In addition, other revisions and/or clarifications are listed below within 
the synopsis and the protocol body. 
1.
Addition of word “and” after ACS in multiple places to clarify 
the population. 
2.
Replaced word antiplatelet with anticoagulant in hypothesis
3.
In study figure 3.1.1 clarified exclusion box for CABG
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Document
Date of Issue
Summary of Change
4.
Corrected exclusion criteria typo for serum creatinine from 133 
micromol/L to 221 micromol/L
5.
Deleted duplicate text for WOCBP who are breastfeeding.
6.
Deleted Aspirin Placebo from Adverse drug reactions.
7.
Added additional subcriteria  under “other criteria”.
8.
Clarified Prohibited/restricted treatments paragraph
9.
Corrected greater than and less than signs 
10. Asterisk added for Visits 1-3 in Short Term Procedure Outline
11. Clarified SAE reporting
12. Added paragraph to DMC
13. Clarified wording for Drug Study Records.
14. Added 2 abbreviation to terms table
15. Corrected any typographical errors.
Administrative 
Letter 01
30-Jun-2015
Removing the version number from of the Investigator Brochure
Original Protocol
19-Mar-2015
Not applicable
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SYNOPSIS
Clinical Protocol CV185316
Protocol Title:An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of 
Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute 
Coronary Syndrome and/or Percutaneous Coronary Intervention
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):  Oral apixaban 5 mg or 2.5 mg tablets given BID or oral vitamin K antagonist (VKA) tablets given once 
daily (titrated for INR goal of 2.0 to 3.0) for the 6 month treatment period . Blinded 81 mg aspirin tablets or blinded 
aspirin placebo tablets given once daily for the 6 month treatment period.
Study Phase: Phase 4
Research Hypothesis:

Apixaban is non-inferior to VKA on the combined outcome of International Society on Thrombosis and 
Haemostasis (ISTH) major bleeding and clinically relevant non-major bleeding (CRNM) in patients with non-
valvular atrial fibrillation (NVAF) who develop acute coronary syndrome (ACS) and/or require percutaneous 
coronary intervention (PCI) with concomitant antiplatelet therapy.

Single antiplatelet therapy with a P2Y12 inhibitor is superior to dual antiplatelet therapy with a P2Y12 inhibitor 
and aspirin on the combined outcome of ISTH major bleeding and/or clinically relevant non-major bleeding in 
patients with NVAF who develop ACS and/or require PCI with concomitant anticoagulant therapy.
Objectives:  
Dual Primary Objectives:

To determine if apixaban is noninferior to VKA (INR target range 2.0-3.0) on the combined endpoint of ISTH 
major and clinically relevant non-major bleeding in patients with NVAF who develop ACS and/or undergo PCI 
with planned concomitant P2Y12 inhibitor therapy.

To determine if anticoagulant plus single antiplatelet therapy with a P2Y12 inhibitor is superior to anticoagulant 
plus dual antiplatelet therapy with a P2Y12 inhibitor and aspirin on the combined outcome of ISTH major and
clinically relevant non-major bleeding in patients with NVAF who develop ACS and/or undergo PCI with 
concomitant anticoagulant therapy.
Secondary Objectives:
To compare apixaban and VKA (with concomitant P2Y12 inhibitor therapy), in patients with NVAF who develop 
ACS and/or undergo PCI, with respect to:

Superiority on ISTH major or clinically relevant non-major (CRNM) bleeding

The composite of all-cause death and all-cause re-hospitalization

Death, stroke, myocardial infarction, stent thrombosis, or urgent coronary revascularization 
To compare aspirin and aspirin placebo (with concomitant P2Y12 inhibitor therapy), in patients with NVAF who 
develop ACS and/or undergo PCI with respect to:

The composite of all-cause death and all-cause re-hospitalization 

Death, stroke, myocardial infarction, stent thrombosis, or urgent coronary revascularization
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Study Design:  
Patients with a recent ACS and/or undergoing PCI with NVAF and planned treatment with P2Y12 inhibitor and oral 
anticoagulation for at least 6 months will be evaluated for eligibility during their ACS or post-PCI hospitalization. 
Randomization can be performed up to 14 days after the ACS or PCI and should take place as early as possible after 
cessation of parenteral anticoagulant and when clinically stable. Both patients with and without prior oral 
anticoagulant treatment can be included in this trial. Patients who are on a VKA prior to randomization will have 
VKA discontinued and will not be dosed with apixaban until the INR is less than 2.0. At the time of enrollment, 
each patient who meets inclusion / exclusion criteria will be randomized via IVRS using a 2 x 2 factorial design to 
either apixaban or VKA and to either aspirin or aspirin placebo. Randomization will be stratified by indication at 
enrollment (ACS vs. PCI).
Overall, the trial will include approximately 1/3 of patients with a recent ACS.
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The randomized treatment period will be 6 months. In-person study visits will occur at 1, 3 and 6 months with a 30 
day post treatment follow up visit. Phone visits will occur during months 2, 4, and 5. INR monitoring will take place 
in accordance with routine care at the respective center but the level of INR control will be collected and centrally 
monitored. To assure study drug compliance and maintain INR in target range, at least monthly phone contacts will 
be scheduled in both the apixaban and VKA arms if in-person visits do not occur.
Study Population:
Males and females 18 years of age (or age of majority) or older with either active or a history of non-valvular atrial 
fibrillation or flutter with the planned or existing use of an oral anticoagulant for prophylaxis of thromboembolism. 
In addition, participants must have had, within the prior 14 days, an acute coronary syndrome (ST-elevation 
myocardial infarction [STEMI], non-ST-elevation myocardial infarction [NSTEMI], or unstable angina with plans 
for at least 6 months of treatment with an approved P2Y12 inhibitor) and/or PCI (with or without stents) with plans 
for at least 6 months of treatment with an approved P2Y12 inhibitor.
Key Exclusion Criteria Include:

Conditions other than atrial fibrillation that require chronic anticoagulation (eg, prosthetic mechanical heart 
valve)

Severe renal insufficiency (serum creatinine > 2.5 mg/dL [221 micromol/L] or a calculated creatinine clearance 
< 30 mL/min

Patients with any history of intracranial hemorrhage

Any contraindications to VKA, apixaban, to intended P2Y12 inhibitors or to aspirin

Recent or planned coronary arterial bypass graft (CABG) for their index ACS event
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
Patients with known ongoing bleeding 

Patients with known coagulopathies
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for BMS-562247
Medication 
Potency 
IP/Non-IP 
Acetylsalicylic acid Film Coated 
Tablet, 81mg
81mg
IP
Placebo for Acetylsalicylic acid 
Film Coated Tablet, 81mg
0mg
IP
apixaban
5mg and 2.5mg
IP
VKA
INR 2.0 - 3.0
IP
P2Y12 inhibitor
As per site’s decision
Non-IP
Study Assessments and Endpoints
Statistical Considerations: 
Sample Size:  4600
This is a 2 x 2 factorial design with dual primary objectives. The sample size is based on the primary set of 
comparisons of Apixaban vs VKA for the primary endpoint of ISTH major or CRNM bleeding.
A total of 357 primary endpoint events and 4600 subjects will provide 77% power for test of non-inferiority (NI) 
using a stratified log rank test of apixaban versus VKA, assuming a NI margin of 1.2, with ISTH major or CRNM 
bleeding event rates in apixaban and VKA groups of 8.1% per half year and 9% per half year, respectively, one-
sided significance level of 0.025, and six month follow up and a 1% per year of loss to follow up. The NI margin 
was selected because an absolute risk difference of 1.8% (20% of VKA event rate of 9%) in bleeding is considered 
to be a clinically meaningful difference.
This sample size will also provide at least 77.5% power for superiority test of apixaban versus VKA assuming a risk 
reduction of 25% and a one-sided significance level of 0.025.
A blinded assessment of the primary endpoint event rate will be performed after 50% of subjects have completed the 
study. The analyses will focus on the aggregate event rate and the sample size may be increased if the aggregate 
event rate is lower than anticipated. The blinded event rates will be estimated by an independent statistician not 
associated with BMS and not otherwise associated with apixaban, and will be provided to the Executive Committee. 
Sample size may be adjusted (depending on availability of resources) to provide sufficient power for both 
non-inferiority and superiority test on the primary endpoint and first secondary endpoint. Up to a maximum of 
8842 subjects may be randomized to maintain appropriate power for both non-inferiority and superiority test on the 
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primary endpoint and first secondary endpoint to avoid the potential of futility in this study using the pre- specified 
rule below:
Sample Size Adjustment for Non-inferiority and Superiority Test on the Primary and Secondary 
Endpoints
Observed blinded 
Event Rate When 50% 
Patient Complete 
Tx/half year
Assumed 
Apixaban Event 
Rate/half year
Assumed Control 
Event Rate/half 
year
# of 
events
Total Sample Size 80% 
Power for both NI and 
superiority
7.6%
0.072
0.08
379
5514
6.65%
0.063
0.07
379
6308
5.7%
0.054
0.06
379
7360
4.75%
0.045
0.05
379
8842
Endpoints:  
Endpoint Definitions:
Primary endpoints (safety): 
The primary endpoint for apixaban versus VKA is 

ISTH major or CRNM bleeding
The primary endpoint for aspirin versus aspirin placebo is 

ISTH major or CRNM bleeding 
Secondary endpoints:
The secondary endpoint for apixaban versus VKA includes 

Superiority on ISTH major or CRNM bleeding

The composite of all-cause death and all-cause re-hospitalization.

The composite endpoints of death, stroke, myocardial infarction, stent thrombosis, urgent coronary 
revascularization 
The secondary endpoint for aspirin versus aspirin placebo includes 

The composite of all-cause death and all-cause re-hospitalization 

The composite endpoints of death, stroke, myocardial infarction, stent thrombosis, urgent coronary 
revascularization 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
Analyses:
Populations for Analyses - Data set descriptions:
The primary safety data set includes all treated subjects who receive at least one dose of study drug.
A secondary data set, the evaluable subject data set, is a set of the primary safety data set and will exclude data from 
subjects with relevant protocol deviations expected to affect the primary safety endpoint. Relevant protocol 
deviations will be pre-specified in the statistical analysis plan. 
The primary safety data set and the evaluable subject data will be used to analyze the primary safety endpoints.  The 
primary safety data set will be used to analyze other safety endpoints.
The intent-to treat population of all randomized subjects will be used to analyze all efficacy endpoints.
The primary set of comparisons between apixaban and VKA
The primary and all secondary endpoints during the treatment period will be compared between apixaban and VKA.
The hierarchical testing strategy described below will be used to compare the effects of apixaban and VKA between 
treatment groups.

Non-inferiority (NI) for the primary endpoint, a composite of ISTH major or CRNM bleeding, will be tested 
first.

If NI is not demonstrated, then nominal p-values will be presented for subsequent comparisons between 
apixaban and VKA

If NI is demonstrated, then superiority for the composite of ISTH major or CRNM bleeding will be tested. 
If superiority is not demonstrated, then nominal P-values will be presented for subsequent comparisons between 
apixaban and VKA.

If the superiority for the composite of ISTH major or CRNM bleeding is demonstrated, then superiority for the 
composite of all-cause death and all-cause re-hospitalization will be tested. If superiority is not demonstrated, 
then nominal p-values will be presented for subsequent comparisons between apixaban and VKA.

If superiority for the composite of all-cause death and all-cause re-hospitalization is demonstrated, then the 
composite of all-cause death and ischemic events will be tested.
All tests will be performed at the one-sided α = 0.025 significance level.
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The secondary set of comparisons between aspirin and aspirin placebo
The analyses for the primary and secondary endpoints for aspirin vs aspirin placebo will be similar to the analyses 
for apixaban vs. VKA. A hierarchical testing strategy at the one-sided α = 0.025 significance level will be used for a 
separate secondary set of comparisons between aspirin and aspirin placebo.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Pre-Randomization Concomitant Medication ......................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage of Study Drug ...................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction or Return of Investigational Product ............................................. 
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4.9 Retained Samples for Bioavailability / Bioequivalence ................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening Period ......................................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.5 Pharmacokinetic Assessments .......................................................................... 
 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Other Assessments ............................................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.1.1.1 Protocol Specific Exceptions to SAE Reporting ............................. 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.3.1 The primary set of comparisons between apixaban and VKA ........ 
8.4.3.2 The secondary set of comparisons between Aspirin and Aspirin 
Placebo ................................................................................................. 
8.4.3.3 Meta-Analysis ................................................................................. 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
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9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
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Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
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5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
Patients with a recent ACS and/or undergoing PCI for another indication with either active or a 
history of NVAF and planned treatment with P2Y12 agent and oral anticoagulation for at least 
six months will ideally be evaluated for eligibility during their ACS or PCI hospitalization. 
Randomization can be performed up to 14 days after the ACS or PCI and should take place as
early as possible after cessation of parenteral anticoagulant and when clinically stable. Both 
patients with and without prior VKA treatment can be included in this trial. Patients who are on a 
VKA prior to randomization will have VKA discontinued and will not be dosed with apixaban 
until the INR is less than 2.0. (Please refer to your country’s approved label language for 
apixaban and VKA.)At the time of enrollment, each patient who meets inclusion/exclusion 
criteria will be randomized via IVRS using a 2 x 2 factorial design to either apixaban or VKA
and to either aspirin or aspirin placebo. Randomization will be stratified by indication at 
enrollment (ACS vs PCI). Overall, the trial will include approximately 1/3 of patients with a 
recent ACS.
Approximately 690 sites will participate in this study, which will be conducted globally, 
including participation of countries located in North America, Europe, Asia and Latin America.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
The study will not have a lead-in period. Screening period will be from time of consent to time 
of randomization.
The treatment period for all agents, including P2Y12 inhibitor, will be 6 months. In-person study 
visits will occur at months 1, 3, 6 (end of treatment) and 30 days post treatment. Phone visits will
occur at months 2, 4 and 5. INR monitoring will take place in accordance with routine care at the 
respective center but the level of INR control will be collected and centrally monitored. To 
assure study drug compliance and maintain INR in target range, at least monthly (via office or 
phone) contact will be scheduled in both the apixaban and VKA arms.
Adverse events assessments and medication compliance will be performed at study visits. 
Laboratory monitoring (hemoglobin,
) and diagnostic testing (ECG, brain CT 
or MRI, echocardiography, other imaging studies) will be assessed following suspected clinical 
events as per standard of care. The following events will be recorded at each visit: bleeding, 
stroke (ischemic and hemorrhagic), myocardial infarction, stent thrombosis, urgent coronary 
revascularization, and all-cause re-hospitalization.
3.2
Post Study Access to Therapy
At the end of the trial (6 months) patients will be treated according to local standards of care.
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Patients will be contacted by telephone 30 days +/- 7 days after the end of treatment study visit 
for additional follow-up. At this contact, bleeding, death/ischemic events, antithrombotic therapy 
and INR values will be assessed.
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the subject receives appropriate standard of care to treat the condition under study.
As the oral anticoagulant is not blinded, investigators will be free to choose at the end of the 
study whether to continue the apixaban or VKA, or transition to alternative agents. Patients 
transitioning from apixaban to vitamin K antagonists should have frequent INR tests during the 
first few weeks of transition, as per local standards. Furthermore, investigators will not be 
routinely provided blinded aspirin/aspirin placebo assignments until after the final study results 
are made public.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects will be required to provide a written informed consent.
2. Target Population
a) Males and females 18 years of age (or age of majority) or older with either active or a 
history of non-valvular atrial fibrillation or flutter with the planned or existing use of an 
oral anticoagulant for prophylaxis of thromboembolism for at least 6 months AND
b) An acute coronary syndrome (ST-elevation myocardial infarction [STEMI], non-ST-
elevation myocardial infarction [NSTEMI], or unstable angina), within the prior 14 days, 
with planned use of an approved P2Y12 inhibitor for at least 6 months AND/OR
c) PCI (with or without stents) within the prior 14 days with planned use of an approved 
P2Y12 inhibitor for at least 6 months.
(If both an ACS event and an elective PCI occur within the same 14 day period, the 
investigator has the option to define the index event for the randomization to the 
interactive voice/web response system. It is recommended to choose the most recent 
event as the index event. However, for the electronic case report form, if a patient 
has both an ACS and PCI within 14 days, both events can be selected.)
3. Subject Re-enrollment:
a) This study does permit the re-enrollment of a subject that has discontinued the study as a 
pre-treatment failure (screen failure). 
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4. Age and Reproductive Status
a) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
b) Women must not be breastfeeding
c) WOCBP must agree to use effective contraception for the duration of treatment with 
study drugs plus
i.
33 days for patients on apixaban
ii.
40 days for patients on VKA
d) Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly. In addition, subjects and their 
partners should utilize two methods of contraception, such as a barrier method and hormonal 
method, especially for subjects randomized to VKA.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Conditions other than non-valvular atrial fibrillation that require chronic anticoagulation 
(eg, mechanical heart valve)
2. Medical History and Concurrent Diseases
a) Severe renal insufficiency (serum creatinine > 2.5 mg/dL [221 micromol/L] or a 
calculated creatinine clearance < 30 mL/min
b) Patients with any history of intracranial hemorrhage
c) Any contraindications to VKA, apixaban, or to intended P2Y12 antagonists or to aspirin
d) Patients who have or will undergo coronary arterial bypass graft (CABG) for their index 
ACS event
e) Women who are pregnant, breastfeeding, or of childbearing potential and unable to use 
an acceptable method of birth control
3. Physical and Laboratory Test Findings
a) Patients with known ongoing bleeding 
b) Patients with known coagulopathies
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4. Allergies and Adverse Drug Reaction
a) Known allergies or sensitivities to apixaban, VKA, aspirin, or to intended P2Y12 
antagonist.
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Subjects who would have compromised ability to comply with study therapy or follow up 
visits
d) Subjects who are participating in other interventional clinical trials of other drugs or 
unapproved devices.
6. Current employees of Pfizer, Bristol-Myers Squibb, or PPD are excluded from 
participation, as well as their spouses and dependent children.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
inclusion criteria and no exclusion criteria.
3.3.3
Women of Childbearing Potential
A Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.
Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal:

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
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3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
During the 6 month treatment period, oral or parenteral anticoagulants (excluding low molecular 
weight heparins (LMWH or unfractionated heparins (UFH) for the purpose of bridging to VKA 
treatment only), including the novel oral anticoagulants (excluding apixaban for those assigned 
to that arm), as well as non-study aspirin, may not be given concurrently. However, transition 
from pre-randomization medications, such as bridging heparin, may be given at the discretion of 
the investigator, to overlap with study treatments.
3.4.2
Pre-Randomization Concomitant Medication
All concomitant medications from 7 days before randomization to end of study should be 
recorded in the electronic case report form.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue study drug will be contacted by telephone 30 days +/- 7 days after 
the end of study visit as detailed in Section 3.2 and Table 5.1-2. The only exception to this 
requirement is when a subject withdraws consent for all study procedures including 
post-treatment study follow-up or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
In this study, bleeding is a key endpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects 
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who discontinue study drug must continue to be followed for collection of outcome and/or 
survival follow-up data as required and in line with Section 5 until death or the conclusion of the 
study.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. 
In the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
Even after multiple unsuccessful contact attempts, no subject should be considered truly lost to 
follow-up until the final conclusion of the CV185316 study, as subjects may unexpectedly 
present themselves well after their scheduled final visit.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
BMS Supplied Study Drugs for CV185316
Product 
Description / Class 
and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open 
Label
Packaging/ Appearance
Storage 
Conditions
(per label)
Acetylsalicylic acid 
film coated tablet
81 mg
IP
blinded
35 tablets/bottle
White to off white, plain, 
round, biconvex film 
coated tablet
Store at 15-25°C 
(59-77°F). Store in 
a tightly closed 
container.
Placebo for 
Acetylsalicylic acid 
film coated tablet
0 mg
IP
blinded
35 tablets/bottle
White to off white, plain, 
round, biconvex film 
coated tablet
Store at 15-25°C 
(59-77°F). Store in 
a tightly closed 
container.
Apixaban
film coated tableta
2.5 mg
IP
Open Label
30 tablets/blister wallet, 
yellow, round, biconvex 
film coated tablets with 
“893” debossed on one side 
and “2 1/2” on the other 
side.
Store at 15-25°C
(59-77°F)
Apixaban
film coated tableta
5 mg
IP
Open Label
56 tablets/blister wallet, 
Pink, oval shaped, biconvex 
film coated tablets with 
“894” debossed on one side 
and “5” on the other side.
Store at 15-25°C
(59-77°F)
Warfarin tabletsa
1 mg
IP
Open Label
40 tablets/blister wallet, 
Pink tablets with a groove 
on one side and “1” on the 
other side.
Store at 15-25°C
(59-77°F)
Protect from light.
Warfarin tabletsa
5 mg
IP
Open Label
40 tablets/blister wallet, 
Yellow tablets with a 
groove on one side and a 
“5” on the other side.
Store at 15-25°C
(59-77°F)
Protect from light.
a Supplied in countries where local sourcing is not permissible.
Apixaban 5 mg and 2.5 mg tablets, as well as VKA and the P2Y12 inhibitors used will be locally 
sourced materials (to be purchased by the sites through local commercial sources) wherever 
possible and not supplied by Bristol-Myers Squibb. Apixaban 5 mg and 2.5 mg tablets as well as 
Warfarin 1 mg and 5 mg tablets listed in Table 4-1 will be supplied in countries where local 
sourcing is not an option.
Locally sourced material should be kept at appropriate storage conditions in accordance with the 
package insert. BMS considers the blinded aspirin and blinded aspirin placebo to be Investigative 
Product (IP) as well as the apixaban and VKA; the P2Y12 inhibitors are considered to be non-IP 
study medications. For this study, apixaban/VKA and aspirin/aspirin-placebo are considered 
“study drugs;” the required P2Y12 inhibitors are considered background medications.
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. In this study, apixaban 2.5 mg and 5 mg 
tablets, as well as the aspirin 81 mg tablets, aspirin placebo, and VKA are considered 
investigational product.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. In this study, the required P2Y12 inhibitor 
(eg, clopidogrel) is considered non-investigational product.
4.3
Storage of Study Drug
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Please refer to Section 9.2.2 for guidance on IP records and documentation.
4.4
Method of Assigning Subject Identification
At the time of enrollment, each subject will be assigned a unique sequential subject number by 
IVRS. The IVRS will be available 24 hours per day, seven days a week. The subject number will 
consist of a unique 5 digit number which is assigned sequentially within a study (starting with 
00001) by the IVRS. This number will be used for identification throughout the study and will 
not be used for any other subject.
Each subject who meets the inclusion/exclusion criteria will be randomly assigned to one of the 
two open label treatment groups: apixaban or VKA, with each treatment arm having an 
allocation probability of a half (0.50). At the same time, subjects will be randomly assigned in a 
blinded fashion to aspirin or matching placebo.
The randomization will be stratified by indication at enrollment (PCI/ACS). 
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4.5
Selection and Timing of Dose for Each Subject
Subjects randomized to apixaban will be dosed at 5 mg bid, unless they meet at least two of the 
following criteria for dose reduction to 2.5 mg BID:

Age 80 years

Weight 60 kg

Serum creatinine 1.5 mg/dL (133 micromol/L)
Subjects randomized to apixaban may have their dosages increased or decreased during the 6 
month treatment period if at least two of the three above criteria change during the study.
Subjects randomized to VKA should be titrated up for an INR target goal of 2.0 to 3.0. Dosages 
of VKA to achieve that range should be per local standards of care and per investigator clinical 
judgment.
Both the oral anticoagulant (apixaban or VKA) and the antiplatelet agents (blinded aspirin once 
daily or blinded placebo once daily) must be started within 24 hours of randomization.
4.6
Blinding/Unblinding
Apixaban or VKA will be open-label. This section will not apply to those agents.
Aspirin (or matching placebo) will be double blinded. Requests for emergency unblinding for 
patient, only, should be made by the investigator(s) to the designated regional medical monitor 
or, if that person cannot be contacted, to the global medical monitor.
4.7
Treatment Compliance
Drug compliance for apixaban and aspirin/aspirin placebo will be defined as between 80% to 
120%. Pill counts, guided by patient-completed drug diaries, will assist completion of the 
appropriate eCRF pages, but actual determination of compliance will be determined by the 
Sponsors. Diary cards must be distributed to subjects, but completion of the cards is at the 
discretion of the subjects.
4.8
Destruction or Return of Investigational Product
For this study, IP (those supplied by BMS, a vendor, or sourced by the investigator) such as 
partially used study drug containers may be destroyed on site. 
If...
Then...
IP supplied by BMS (including its vendors)
Any unused IP supplied by BMS can only be destroyed after 
being inspected and reconciled by the responsible Study Monitor 
unless IP containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or 
biologics).
If IP will be returned, the return will be arranged by the 
responsible Study Monitor.
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If...
Then...
IP sourced by site, not supplied by BMS (or 
its vendors) (examples include IP sourced 
from the sites stock or commercial supply, or 
a specialty pharmacy)
It is the investigator’s or designee’s responsibility to dispose of 
all containers according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of IP provided by BMS (or its vendors). Destruction of non-IP sourced 
by the site, not supplied by BMS, is solely the responsibility of the investigator or designee.
For this study, IP (those supplied by BMS or its vendors such as full or partially used study drug 
containers, vials, syringes) cannot be destroyed on-site. It is, however, the investigator’s or 
designee’s responsibility to arrange for disposal of all empty IP containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. The return of full or partially used IP supplied by BMS or its vendors will be arranged by 
the responsible Study Monitor.
For subjects where the IP is not directly supplied by BMS (e.g., commercially-sourced apixaban 
or VKA dispensed from a pharmacy by a physician’s prescription), leftover medication after the 
6 month treatment period does not need to be returned to the site.
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For subjects where the IP is directly supplied by BMS or one of its vendors, the site obligation is 
to request the subject to return the medication to the site; it is the subject responsibility, not the 
site’s, to comply.
Please refer to Section 9.2.2 for additional guidance on IP records and documentation.
4.9
Retained Samples for Bioavailability / Bioequivalence
Not Applicable.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
Table 5.1-1:
Baseline and Randomization (CV185316)
Procedure
Screening/
Randomization
Visit
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical History
X
Include assessment of alcohol use, tobacco use, prior VKA use, and CHADS-VASC and 
HAS-BLED scores
Safety Assessments
Physical Examination
See Notes
Only if deemed necessary by treating physician.
Results of examination will be documented in patient’s chart, not on CRF
Vital Signs
X
Blood Pressure and Weight
Assessment of Signs and Symptoms
See Notes
Only if deemed necessary by treating physician.
Results of assessment will be documented in patient’s chart, not on CRF
Serious Adverse Events Assessment
See Notes
Refer to section 6.1 of the protocol for SAE definitions applying to this study.
Adverse Events Assessment
N/A
Laboratory Tests
X
Local lab: CBC, chemistry(CHEM7 or equivalent for determination of serum creatinine), 
coagulation (for PT/PTT/INR)
(local lab within 7 days can be used)
Urine Pregnancy Test* (WOCBP only)
X
*If applicable
Serum pregnancy test to be performed only if urine test is positive or un-interpretable
Study Drug
Randomize
X
Dispense Study Drug (administer within 
24 hours of randomization)
X
Those supplied by BMS or sourced by the investigator
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Table 5.1-2:
Short-term Procedural Outline (CV185316)
Procedure
(7 days is allowed)
Visit 1a
(1 monthb)
Visit 2a
(3 monthsb)
Visit 3a
(6 monthsb)
Phone visits
(at 2, 4, and 
5 monthsb)
Phone or In-Person 
Follow-up 
(30 day +/- 7 days 
after End of 
Treatment)
Notes
Safety Assessments
Targeted Physical Examination
X
X
X
Only if deemed necessary by 
treating physician
Vital Signs
X
X
X
Blood pressure and weight
Assessment of Signs and 
Symptoms
X
X
X
X (if in-person visit)
Serious Adverse Event 
Assessment
X
X
X
X
X
Refer to section 6.1 of the protocol 
for SAE definitions applying to this 
study.
Targeted Adverse Events 
Assessment
X
X
X
X
X
See section 6.2
Laboratory Tests
INR for 
VKA
INR for 
VKA
INR for 
VKA
INR for 
VKA
INR for VKA
To be performed locally for VKA
subjects
Urine Pregnancy Test* (WOCBP 
only)
X
X
X
X
X
*If applicable
Serum pregnancy test to be 
performed only if urine test is 
positive or un-interpretable
Bleeding Assessment
CBC, if 
applicable
CBC, if 
applicable
CBC, if 
applicable
CBC, if 
applicable
CBC, if applicable
To be performed locally
Efficacy Assessments
Death/Ischemic Events 
Assessment
Diagnostic 
studies, if 
applicable
Diagnostic 
studies, if 
applicable
Diagnostic 
studies, if 
applicable
Diagnostic 
studies, if 
applicable
Diagnostic studies, if 
applicable
To be performed locally
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Table 5.1-2:
Short-term Procedural Outline (CV185316)
Procedure
(7 days is allowed)
Visit 1a
(1 monthb)
Visit 2a
(3 monthsb)
Visit 3a
(6 monthsb)
Phone visits
(at 2, 4, and 
5 monthsb)
Phone or In-Person 
Follow-up 
(30 day +/- 7 days 
after End of 
Treatment)
Notes
Study Drug
Dispense Study Drug
X
X
Drug Compliance
X
X
X 
X 
At Follow-up Visit, assess transition 
to Oral Anticoagulant (OAC)
a For patients who decline further treatment but still permit follow up, visits 1, 2, and 3 may be performed by telephone
b 30 day months
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5.1.1
Retesting During Screening Period
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
5.2
Study Materials

Urine pregnancy kits (for WOCBP only)

Patient education materials and site support tools

Patient reminder cards (optional) to be used for helping patients remember to take their study 
medications.
5.3
Safety Assessments
No specific safety assessments other than the laboratory tests, clinical assessments of bleeding 
episodes, AEs/SAEs indicated in Table 5.1-1 and Table 5.1-2, are required.
5.3.1
Imaging Assessment for the Study
No radiological assessments are mandated.
5.4
Efficacy Assessments
No specific efficacy assessments are mandated. Clinical judgment should be executed in 
evaluating what diagnostics and tests to order to assess the study’s efficacy endpoints. These 
suspected endpoints should be documented in the appropriate sections of the electronic case 
report form.
5.5
Pharmacokinetic Assessments
Not applicable.
5.7
Outcomes Research Assessments
Time to first all cause re-hospitalization rates would be captured.
5.8
Other Assessments 
Not applicable.
6
ADVERSE EVENTS
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 
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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.)
6.1
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 below)

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.) 
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 abnormalities are not 
always serious by regulatory definition, these events must be handled as SAEs. 
(See Section 6.1.1 for reporting pregnancies). Standard medical practice in identifying and 
monitoring hepatic abnormalities should be followed.
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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

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).

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
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 must be collected
and reported in a timely fashion, including those thought to be associated with protocol-specified 
procedures (exemptions to usual SAE reporting are described in section 6.1.1.1). All SAEs must 
be collected that occur during the screening period and within 30 days of discontinuation of 
dosing. The investigator should expeditiously 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 should 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 should 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 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.
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For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
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 should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.1.1.1
Protocol Specific Exceptions to SAE Reporting
Given the body of safety data already collected on apixaban, only targeted SAE’s need to be 
reported in an expedited fashion. These events include:

All deaths (known and unknown cause)

Life threatening events assessed by investigator as related to study drug (excluding 
endpoints)

All SAEs that are related (as determined by investigator) to study drug (excluding endpoints)

SAE of interest: liver injury (jaundice, hepatitis, liver failure)

Pregnancies

Overdose
So a fatal pneumonia event, for example, regardless of causality, would be reported in the usual 
expedited manner as an SAE. But a non-fatal myocardial infarction would not need to be 
reported as an SAE; this event would be reported in the endpoint pages of the case report form.
Beyond expedited adverse event reporting, clinically important outcome events are being 
systematically collected on the electronic case report form and adjudicated by the blinded 
clinical events adjudication committee. These events to be adjudicated include: 

All deaths and the cause of death

All bleeding events

All ischemic events including death, myocardial infarction, stent thrombosis, and stroke
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
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6.2.1
Nonserious Adverse Event Collection and Reporting
Only NSAE’s that occur after the initiation of study drug and that result in permanent treatment 
discontinuation (including withdrawal from study) should be recorded in the eCRF.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). 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. Reportable 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.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
(For subjects randomized to VKA treatment, INR values outside of the therapeutic range need 
not be reported unless associated with a clinically apparent adverse event, such as bleeding.)
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).
6.4
Pregnancy
If, following initiation of the study drug, 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 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject 
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Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
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 6.1.1. 
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. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional ingestion of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 6.1.1 for reporting details).
6.6
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, except those listed those clinical endpoints in section 6.1.1.1 which are exempt from 
reporting.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
When required, adjudicated events will be submitted to the Data Monitoring Committee (DMC)
and Health Authorities for review on a specified timeframe in accordance with the adjudication 
documentation.
The external academic-led committees for this study will include an executive committee, 
steering committee, and clinical event adjudication committee. The executive committee will be 
a small body comprised of academic and sponsor representatives. The executive committee will 
lead the daily decision making for the study. The steering committee will be a larger body 
comprised of country-level academic leaders, as well as sponsor representatives, and will meet 
periodically at the recommendation of the executive committee. The clinical event adjudication 
committee will be an independent body of clinicians who are not otherwise involved with the 
study and will evaluate clinical events related to the study’s endpoints.
The DMC will consider efficacy events, in addition to safety events, before making any study 
stopping recommendations to the executive committee and study sponsors, as per guidelines set 
forth in the DMC charter.
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This is a 2 x 2 factorial design with dual primary objectives. The sample size is based on the 
primary set of comparisons between Apixaban vs VKA for the primary endpoint of ISTH major 
or CRNM bleeding.
A total of 357 primary endpoint events and 4600 subjects will provide 77% power for test of 
non-inferiority (NI) using a stratified log rank test of apixaban versus VKA, assuming a NI 
margin of 1.2, with ISTH major or CRNM bleeding event rates in apixaban and VKA groups of 
8.1% per half year and 9% per half year, respectively, one-sided significance level of 0.025, six 
month follow up, and a 1% per year of loss to follow up. The NI margin was selected because an 
absolute risk difference of greater than 1.8% (20% of VKA event rate of 9%) in bleeding is 
considered to be a clinically meaningful difference.
This sample size will also provide at least 77.5% power for superiority test of apixaban versus 
VKA assuming a risk reduction of 25% and a two-sided significant level of 0.05.
A blinded assessment of the primary endpoint event rate will be performed after 50% of subjects 
have completed the study. The analyses will focus on the aggregate event rate and the sample 
size may be increased if the aggregate event rate is lower than anticipated. The blinded event 
rates will be estimated by an independent statistician not associated with BMS and not otherwise 
associated with apixaban, and will be provided to the Executive Committee. Sample size may be 
adjusted (depending on availability of resources) to provide sufficient power for both 
non-inferiority and superiority test on the primary endpoint and first secondary endpoint. Up to a 
maximum of 8842 subjects may be randomized to maintain appropriate power for both 
non-inferiority and superiority test on the primary endpoint and first secondary endpoint to avoid 
the potential of futility in this study using the pre-specified rule below. Table 8.1-1 gives a 
guideline for sample size adjustment.
Table 8.1-1:
Sample Size Adjustment for Non-inferiority and 
Superiority Test on the Primary and Secondary 
Endpoints
Observed blinded 
Event Rate When 
50% Patients 
Complete Tx/
half year
Assumed 
Apixaban 
Event Rate/
half year
Assumed 
Control 
Event Rate/
half year
# of 
events
Total Sample 
Size 80% Power 
for both NI and 
superiority
7.6%
0.072
0.08
379
5514
6.65%
0.063
0.07
379
6308
5.7%
0.054
0.06
379
7360
4.75%
0.045
0.05
379
8842
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8.2
Populations for Analyses
The primary safety data set includes all treated subjects who receive at least one dose of study 
drug.
A secondary data set, the evaluable subject data set, is a set of the primary safety data set and 
will exclude data from subjects with relevant protocol deviations expected to affect the primary 
safety endpoint. Relevant protocol deviations will be pre-specified in the statistical analysis plan. 
The primary safety data set and the evaluable subject data will be used to analyze the primary 
safety endpoints.  The primary safety data set will be used to analyze other safety endpoints.
The intention-to-treat population of all randomized subjects will be used to analyze all efficacy 
endpoints.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary endpoint for apixaban versus VKA is 

ISTH major or CRNM bleeding 
The primary endpoint for aspirin versus aspirin placebo is 

ISTH major or CRNM bleeding 
8.3.2
Secondary Endpoint(s)
The secondary endpoint for apixaban versus VKA includes 

Superiority on ISTH major + CRNM bleeding

The composite of all-cause death and all-cause re-hospitalization.

The composite endpoints of death and ischemic events (stroke, myocardial infarction, stent 
thrombosis, urgent coronary revascularization) 
The secondary endpoint for aspirin versus aspirin placebo includes 

The composite of all-cause death and all-cause re-hospitalization 

The composite endpoints of death and ischemic events (stroke, myocardial infarction, stent 
thrombosis, urgent coronary revascularization) 
 
 
 
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distribution and summary statistics for demographic and baseline variables will be 
presented by treatment group and for all subjects combined. The summaries will be tabulated for 
all randomized subjects.
8.4.2
Efficacy Analyses
This study does not have a primary efficacy analysis. The secondary efficacy endpoints are the 
composite of all-cause death and all-cause re-hospitalization and the composite of death and 
ischemic 
events 
(stroke, 
myocardial 
infarction, 
stent 
thrombosis, 
urgent 
coronary 
revascularization).
A Cox proportional hazards model including treatment group as a covariate and stratified by 
indication at enrollment ( PCI/ACS) and antiplatelet use (aspirin placebo and aspirin) will be 
used to model the time to first occurrence of composite death and ischemic events during the 
6- month treatment period. A point estimate and two-sided 95% CI for hazard ratio will be 
calculated. A p-value for the test of equality of rates (HR = 1) will be calculated. 
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8.4.3
Safety Analyses
The term “treatment period” for bleeding endpoints refers to the period between the first 
administration of study drug and two days after the last administration of study drug. 
8.4.3.1
The primary set of comparisons between apixaban and VKA
The primary endpoint will be time to first occurrence of ISTH major or CRNM bleeding during 
the treatment period. Tests using non-inferiority margin will be performed using a Cox 
proportional hazards model including treatment group as a covariate and stratified by indication 
at enrollment ( PCI/ACS) and antiplatelet use (aspirin and aspirin placebo). A point estimate and 
two-sided 95% CI for hazard ratio and a p-value for the test of equality of rates (HR = 1) will be 
calculated. Non-inferiority will be demonstrated if the upper bound of the two-sided 95% CI for 
HR is less than 1.2. Subjects without events during the treatment period will be censored.
Interaction between oral anticoagulant use (apixaban and VKA) and antiplatelet usage (aspirin or 
aspirin placebo) is not expected. This assumption will be examined as described in the statistical 
analysis plan.
The primary analysis will be based on treated subjects, and a sensitivity analysis will be 
performed on the intention-to-treat population.
A hierarchical testing strategy described below will be used to compare the effects of apixaban 
and VKA between treatment groups. 

Non-inferiority (NI) for the primary endpoint, a composite of ISTH major or CRNM 
bleeding, will be tested first.

If
NI is not demonstrated, then nominal p-values will be presented for subsequent 
comparisons between apixaban and VKA

If NI is demonstrated, then superiority for the composite of ISTH major or CRNM bleeding 
will be tested. If superiority is not demonstrated, then nominal P-values will be presented for 
subsequent comparisons between apixaban and VKA.

If superiority for the composite of ISTH major or CRNM bleeding is demonstrated, then 
superiority for the composite of all-cause death and all-cause re-hospitalization will be tested. 
If superiority is not demonstrated, then nominal p-values will be presented for subsequent 
comparisons between apixaban and VKA.

If superiority for the composite of all-cause death and all-cause re-hospitalization is 
demonstrated, then the composite of all-cause death and ischemic events will be tested.
All tests will be performed at the one-sided α = 0.025 significance level.
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8.4.3.2
The secondary set of comparisons between Aspirin and Aspirin 
Placebo
The comparison between the groups treated with aspirin and aspirin placebo is critical in this 
population, in whom accumulating evidence suggests that omission of aspirin is associated with 
less bleeding than “triple” therapy without a loss in efficacy for thromboembolic events.17,18,19
The analyses for the primary and secondary endpoints for aspirin vs aspirin placebo will be 
similar to the analyses for apixaban vs. VKA. A hierarchical testing strategy at the one-sided 
α = 0.025 significance level will be used for a separate secondary set of comparisons between 
aspirin and aspirin placebo.
8.4.3.3
Meta-Analysis
A meta-analysis of trial-level data (WOEST, PIONEER, REDUAL, and AUGUSTUS trials) will  
be done outside of the clinical study report to assess the effects of treatment with different OACs 
and aspirin (and aspirin placebo) on clinical outcomes. The details of the meta-analysis will be 
written in a publication analysis plan.  
8.4.4
Pharmacokinetic Analyses
Not applicable.
.
8.4.6
Outcomes Research Analyses
Time to first all cause re-hospitalization will be assessed as per secondary endpoints.
8.4.7
Other Analyses 
Not applicable.
8.5
Interim Analyses
No interim analysis is planned. Ongoing review of safety will be the mandate of the DMC. 
Details are provided in the DMC charter.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
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If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
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When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
Records for IP (whether supplied by BMS, its vendors, or the site) must substantiate IP integrity 
and traceability from receipt, preparation, administration, and through destruction or return. 
Records must be made available for review at the request of BMS/designee or a Health 
Authority.
If...
Then...
Supplied by BMS (or its vendors):

Records or logs must comply with applicable regulations and 
guidelines and should include

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each subject, including unique 
subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted)

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable 

dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form
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If...
Then...
Sourced by site, and not supplied by 
BMS or its vendors (examples 
include IP sourced from the sites 
stock or commercial supply, or a 
specialty pharmacy)
The investigator or designee accepts responsibility for documenting 
traceability and study drug integrity in accordance with requirements 
applicable under law and the SOPs/standards of the sourcing pharmacy.   
These records should include:

label identification number or batch number 

amount dispensed to and returned by each subject, including unique 
subject identifiers

dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form. The investigator must retain 
a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:
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
External Principal Investigator designated at protocol development

National Coordinating Investigator 

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTA) governing you or your institution’s participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to BMS at 
the earliest practicable time prior to submission or presentation and otherwise within the time 
period set forth in the CTA.
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GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete Abstinence is defined as complete 
avoidance of heterosexual intercourse and is an acceptable form of contraception for 
all study drugs. Female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in the event 
that the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete abstinence is defined as complete 
avoidance of heterosexual intercourse and is an acceptable form of contraception for 
all study drugs. Subjects who choose complete abstinence are not required to use a 
second method of contraception, but female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly effective contraception must 
be discussed in the event that the subject chooses to forego complete abstinence.
Expanded definition Complete abstinence as defined as complete avoidance of 
heterosexual intercourse is an acceptable form of contraception for all study drugs.
This also means that abstinence is the preferred and usual lifestyle of the patient. This 
does not mean periodic abstinence (eg, calendar, ovulation, symptothermal, 
profession of abstinence for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of contraception. Subjects who choose 
complete abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable alternate methods 
of highly effective contraception must be discussed in the event that the subject 
chooses to forego complete abstinence
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LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ACS
acute coronary syndrome
ALT
alanine aminotransferase
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
-HCG
beta-human chorionic gonadotrophin
BID, bid
bis in die, twice daily
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CABG
Coronary arterial bypass graft
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLR
renal clearance
cm
centimeter
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CRNM
Clinically Relevant Non-major
CYP
cytochrome p-450
D/C
discontinue
DAPT
Dual antiplatelet therapy
dL
deciliter
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Term
Definition
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
ESR
Expedited Safety Report
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator Brochure
ICH
International Conference on Harmonisation 
IMP
investigational medicinal products
INR
International Normalization Ratio
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Haemostasis
IU
International Unit
IV
intravenous
kg
kilogram
L
liter
LMWH
Low Molecular Weight Heparin
LDH
lactate dehydrogenase
mg
milligram
Mg++
magnesium
min
minute
mL
milliliter
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Term
Definition
mmHg
millimeters of mercury
g
microgram
N
number of subjects or observations
N/A
not applicable
NI
Non-inferiority
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
NVAF
Non-valvular atrial fibrillation
NSTEMI
Non-ST Elevation Myocardial Infarction
PCI
Percutaneous coronary intervention
PO
per os (by mouth route of administration)
PT
prothrombin time
PTT
partial thromboplastin time
QD, qd
quaque die, once daily
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
STEMI
ST-elevation myocardial infarction
T
time
T-HALF
Half life
UFH
Unfractionated Heparin
VKA
Vitamin K antagonist
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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SAP_001.pdf: 
Official Title of Study: 
An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of 
Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial 
Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention 
 
NCT Number: NCT02415400 
Document Date (Date in which document was last revised): November 28, 2018 


STATISTICAL ANALYSIS PLAN
An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate 
the Safety of Apixaban vs. VKA and Aspirin vs. Aspirin Placebo in Patients with 
Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary 
Intervention
PROTOCOL(S) CV185316
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TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................2
2
STUDY DESCRIPTION ..........................................................................................5
2.1
Study Design ............................................................................................................5
2.2
Treatment Assignment..............................................................................................6
2.3
Blinding and Unblinding...........................................................................................6
2.4
Protocol Amendments...............................................................................................6
2.5
Date Monitoring Committee .....................................................................................7
3
OBJECTIVES ..........................................................................................................8
3.1
Primary.....................................................................................................................8
3.2
Secondary.................................................................................................................8
4
ENDPOINTS............................................................................................................9
4.2
Secondary Endpoint(s)..............................................................................................9
5
SAMPLE SIZE AND POWER...............................................................................10
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................11
6.1
Study Periods..........................................................................................................11
6.2
Treatment Regimens...............................................................................................12
6.3
Populations for Analyses ........................................................................................12
7
STATISTICAL ANALYSES..................................................................................13
7.1
General Methods ....................................................................................................13
7.2
Study Conduct........................................................................................................14
7.3
Study Population ....................................................................................................14
7.3.1.1
Demography and Baseline Characteristics .............................................................14
7.4
Extent of Exposure .................................................................................................15
7.4.1
Study Therapy.........................................................................................................15
7.4.2
INR Control............................................................................................................16
7.4.3
Concomitant Medications.......................................................................................17
7.5
Efficacy..................................................................................................................17
7.5.1
The comparison between apixaban and VKA ..........................................................17
7.5.2
The comparison between aspirin and placebo.........................................................17
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7.6
Safety.....................................................................................................................18
7.6.1
The comparison between apixaban and VKA ..........................................................18
7.6.1.1
Analysis of Primary Safety Endpoints .....................................................................18
7.6.1.2
Sensitivity Analyses for Key Measures ....................................................................19
7.6.1.3
Subgroup Analyses .................................................................................................19
7.6.1.4
Secondary Safety Analyses......................................................................................21
7.6.2
The comparison between aspirin and placebo.........................................................21
7.6.2.1
Primary Safety Analysis..........................................................................................22
7.6.2.2
Subgroup Analyses .................................................................................................22
7.6.2.3
Secondary Safety Analyses......................................................................................23
7.6.3.1
Adverse Events .......................................................................................................24
7.6.3.2
Laboratory Data.....................................................................................................24
7.6.3.3
Vital Signs ..............................................................................................................24
7.7
Pharmacokinetics/Pharmacodynamics ....................................................................24
7.8
Outcomes Research Assessments............................................................................25
7.9           Interim Analyses ........................................................................................................25
8
CONVENTIONS....................................................................................................25
8.1
Safety Data Conventions.........................................................................................25
8.2
Baseline Measurements ..........................................................................................25
8.3
Day Ranges for Analysis of Time Points.................................................................25
8.4
Multiple Measurements ..........................................................................................26
9
CONTENT OF REPORTS .....................................................................................26
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2
STUDY DESCRIPTION
Patient who meets inclusion / exclusion criteria will be randomized via IVRS using a 2 x 2 factorial 
design to either apixaban or VKA and to either aspirin or aspirin placebo. Randomization will be 
stratified by indication at enrollment (ACS vs. PCI). The factorial design will compare open label 
apixaban to open label VKA and compare blinded low-dose aspirin to aspirin placebo, with 
background P2Y12 inhibitor.
2.1
Study Design
Patients with a recent ACS and/or undergoing PCI with either active or a history of NVAF and 
planned treatment with P2Y12 agent and oral anticoagulation will be evaluated for eligibility 
during their ACS or post-PCI hospitalization. Randomization can be performed up to 14 days after 
the ACS or PCI and should take place as early as possible after cessation of parenteral 
anticoagulant and when clinically stable. Both patients with and without prior VKA treatment can 
be included in this trial. Patients who are on a VKA prior to randomization will have VKA 
discontinued and will not be dosed with apixaban for 4 days or until the INR is less than 2.0. At 
the time of enrollment, each patient who meets inclusion / exclusion criteria will be randomized 
via IVRS using a 2 x 2 factorial design to either apixaban or VKA and to either aspirin or placebo. 
Randomization will be stratified by indication at enrollment (ACS vs. PCI). Overall, the trial will 
is planned to enroll at least 1/3 of patients with a recent ACS.
Approximately 500 sites will participate in this study, which will be conducted globally including
participation of countries located in North America, Europe, Asia and Latin America.
The treatment period for all agents, including P2Y12 inhibitor, will be 6 months. Study visits will 
be at 1, 3 and 6 months (end of treatment) and 30 days post treatment. Phone visits will occur at 
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months 2, 4 and 5. INR monitoring will take place in accordance with routine care at the respective 
center but the level of INR control will be collected and centrally monitored. To assure study drug 
compliance and maintain INR in target range, at least monthly contact will be scheduled in both 
the apixaban and VKA arms.
2.2
Treatment Assignment
At the time of enrollment, each subject will be assigned a unique sequential subject number by 
IVRS. The IVRS will be available 24 hours per day, seven days a week. The subject number will 
consist of a unique 5 digit number which is assigned sequentially within a study (starting with 
00001) by the IVRS. This number will be used for identification throughout the study and will not 
be used for any other subject.
Each subject who meets the inclusion/exclusion criteria will be randomly assigned to one of the 
two open label treatment groups: apixaban or VKA, with each treatment arm having an allocation 
probability of a half (0.50). At the same time, subjects will be randomly assigned in a blinded 
fashion to aspirin or matching placebo.
The randomization will be stratified by indication at enrollment (PCI/ACS). 
2.3
Blinding and Unblinding
Apixaban or VKA will be open-label. 
Aspirin (or matching placebo) will be blinded. Requests for emergency unblinding for patient, 
only, should be made by the investigator(s) to the designated regional medical monitor or, if that 
person cannot be contacted, to the global medical monitor.
2.4
Protocol Amendments
Document
Date of Issue
Summary of Change
Revised Protocol 04
21-Aug-2018
Incorporates Amendment 07 and Administrative Letters 03 and 04.
Amendment 07
21-Aug-2018
Amendment 07 - (1) Describes the use of hierarchical statistical testing 
to analyze the data for apixaban vs VKA and aspirin vs aspirin placebo; 
(2) Notes the change in the Medical Monitor and his contact information.
Administrative 
Letter 04
26-Mar-2018
Change in Medical Monitor Contact information
Administrative 
Letter 03
21-Nov-2017
Date corrected on title page of protocol
Revised Protocol 03
11-Oct-2017
Incorporates Amendment 05 and Administrative Letter 02
Amendment 05
11-Oct-2017
The purpose of Amendment 05 is to reword inconsistent language in the 
current protocol to clarify the patient eligibility criteria, add an efficacy 
composite endpoint of all-cause death/all-cause re-hospitalization and to 
correct typographical errors. In addition, Amendment 05 lists some of the 
data not specified in the protocol but included in the electronic case 
report form; this data is planned for potential secondary publications.
Administrative 
Letter 02
04-May-2017
Medical Monitor Address Change
Revised Protocol 02
28-Apr-2016
Incorporates Amendment 02 
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Document
Date of Issue
Summary of Change
Amendment 02
28-Apr-2016
The purpose of amendment 02 is to clarify the hypothesis, objectives and 
patient population in regard to patients who have non-valvular atrial 
fibrillation and acute coronary syndrome and/or PCI by adding the word 
“and” in front of “PCI” throughout the protocol, editing the study 
schematic, as well as to add clarifying language to the targeted SAE 
reporting section. Table 4-1 was updated to include BMS study 
medication that will be supplied in some countries where local sourcing 
is not an option. In addition sections 4.3, 4.8, 4.9, and 9.2.2 were updated 
based on the mandatory language in the revised protocol model 
document.
Revised Protocol 01
05-Apr-2016
Incorporates Amendment 01 and Administrative Letter 01
Amendment 01
05-Apr-2016
The purpose of this amendment is to clarify language for the targeted SAE 
reporting, add language referencing stopping guidance in the DMC 
charter, and correct omissions from the original protocol. In the inclusion 
section, wording was changed to accommodate countries where age of 
adulthood is not 18 years of age. 
 
 
Study was originally meant to allow patients who had balloon 
angioplasty, either with or without a stent being placed. Removing the 
word "with a stent" allows balloon angioplasty without stent. Additional 
language on unstable angina entry also added for clarification of the 
population.
In addition, other revisions and/or clarifications are listed below within the 
synopsis and the protocol body. 
1.
Addition of word “and” after ACS in multiple places to clarify 
the population. 
2.
Replaced word antiplatelet with anticoagulant in hypothesis
3.
In study figure 3.1.1 clarified exclusion box for CABG
4.
Corrected exclusion criteria typo for serum creatinine from 133 
micromol/L to 221 micromol/L
5.
Deleted duplicate text for WOCBP who are breastfeeding.
6.
Deleted Aspirin Placebo from Adverse drug reactions.
7.
Added additional subcriteria  under “other criteria”.
8.
Clarified Prohibited/restricted treatments paragraph
9.
Corrected greater than and less than signs 
10. Asterisk added for Visits 1-3 in Short Term Procedure Outline
11. Clarified SAE reporting
12. Added paragraph to DMC
13. Clarified wording for Drug Study Records.
14. Added 2 abbreviation to terms table
15. Corrected any typographical errors.
2.5
Data Monitoring Committee
This study will be conducted under the monitoring of an independent Data Monitoring Committee 
(DMC), whose activities will be described in a DMC charter. 
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3
OBJECTIVES
3.1
Primary
Dual Primary Objectives:

To determine if apixaban is noninferior to VKA (INR target range 2.0 - 3.0) on the combined 
endpoint of ISTH major bleeding and clinically relevant non-major bleeding in patients with 
NVAF who develop ACS or undergo PCI with concomitant P2Y12 inhibitor therapy

To determine if anticoagulant plus single antiplatelet therapy with a P2Y12 inhibitor is superior 
to anticoagulant plus dual antiplatelet therapy with a P2Y12 inhibitor and aspirin on the 
combined outcome of ISTH major bleeding or clinically relevant non-major bleeding in 
patients with NVAF who develop ACS or undergo PCI with planned concomitant P2Y12 
inhibitor therapy.
3.2
Secondary
To compare apixaban and VKA (with concomitant P2Y12 inhibitor therapy), in patients with 
NVAF who develop ACS and/or undergo PCI, with respect to:

Superiority on ISTH major  or CRNM bleeding

Superiority for the composite of all-cause death and all-cause re-hospitalization

Death, stroke, myocardial infarction, stent thrombosis, urgent coronary revascularization
To compare aspirin and aspirin placebo (with concomitant P2Y12 inhibitor therapy), in patients 
with NVAF who develop ACS and/or undergo PCI, with respect to:

The composite of all-cause death and all-cause re-hospitalization 

Death, stroke, myocardial infarction, stent thrombosis, urgent coronary revascularization
 
 
 
To compare aspirin and aspirin placebo (with concomitant P2Y12 inhibitor therapy), in patients 
with NVAF who develop ACS or undergo PCI, with respect to:
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4
ENDPOINTS
4.1
Primary Endpoints
The dual primary endpoints are: 
The primary endpoint for apixaban versus VKA is time from the first dose to first occurrence of 
confirmed ISTH major and CRNM bleeding (NI analysis)
The primary endpoint for aspirin versus placebo is the time from first dose to first occurrence of 
confirmed ISTH major and CRNM bleeding 
4.2
Secondary Endpoint(s)
The secondary endpoint for apixaban versus VKA includes 

the time from first dose to first occurrence of confirmed ISTH major 
or CRNM bleeding (Superiority analysis)

the time from first dose to first occurrence of the composite of all-
cause death and all-case re-hospitalization

the time from randomization to first occurrence of confirmed 
composite endpoints of death and ischemic events (stroke, 
myocardial infarction, stent thrombosis, urgent revascularization) 
The secondary endpoint for aspirin versus placebo includes 

the time from first dose to first occurrence of the composite of all-
cause death and all-case re-hospitalization

the time from randomization to first occurrence of confirmed 
composite endpoints of death and ischemic events (stroke, 
myocardial infarction, stent thrombosis, urgent revascularization) 
 
 
 
 
 
 
 
 
 
 
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SAMPLE SIZE AND POWER
A total of 357 primary endpoint events and 4600 subjects will provide 77% power for test of NI 
using a stratified log rank test of apixaban versus VKA, assuming a NI margin of 1.2, with major 
or CRNM bleeding event rates in apixaban and VKA groups of 8.1% per half year and 9% per half 
year, respectively, one-sided significance level of 0.025, six month follow up, and a 1% per year 
of loss to follow up. The NI margin was selected because an absolute risk difference of greater 
than 1.8% (20% of VKA event rate of 9%) in bleeding is considered to be a clinically meaningful 
difference.
This sample size will also provide at least 77.5% power for superiority test of apixaban versus 
VKA assuming a risk reduction of 25% and a two-sided significant level of 0.05.
A blinded assessment of primary endpoint event rate will be performed after 50% of subjects have 
completed the study. The analyses will focus on the aggregate event rate and the sample size may 
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be increased if the aggregate event rate is lower than anticipated. The blinded event rates will be 
estimated by an independent statistician not associated with BMS and not otherwise associated 
with apixaban, and will be provided to the Executive Committee. Sample size may be adjusted 
(depending on availability of resources) to provide sufficient power for both non-inferiority and 
superiority test on the primary endpoint and secondary endpoint. Up to a maximum of 8842 
subjects may be randomized to maintain appropriate power for both non-inferiority and superiority 
test on the primary endpoint and secondary endpoint using the pre- specified rule below. Table 
8.1-1 give a guideline for sample size adjustment.
Table 8.1-1:
Sample Size Adjustment for Non-inferiority and Superiority Test 
on the Primary 
Observed blinded 
Event Rate When 50% 
Patients Complete 
Tx/half year
Assumed 
Apixaban Event 
Rate/half year
Assumed 
Control Event 
Rate/half year
# of events
Total Sample Size 80% 
Power for both NI and 
superiority
7.6%
0.072
0.08
379
5514
6.65%
0.063
0.07
379
6308
5.7%
0.054
0.06
379
7360
4.75%
0.045
0.05
379
8842
Assume time to event follow exponential distribution, 6 months fix follow up, 25% risk reduction for 
superiority test, and 10 % risk reduction for NI test. Nquery 2.0 and EAST 5.4 are used for the sample size 
calculation and power calculation of NI and superiority.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
In all listings, summaries and statistical analyses, the term “Intended Treatment Period” will 
refer to the period from the day of randomization through the day of end of 6-month treatment 
visit for the subjects who complete 6-month treatment. For subjects who discontinue treatment 
early:
1. if they complete the 6-month visit,  the “Intended Treatment Period” will be from day 
of randomization to the day of  the 6-month visit
2. if the subjects do not have the 6-month visit, the “Intended Treatment Period” will be 
from the day of randomization to the earlier of the end date of follow up or intended 6-
month treatment for subjects. 
This period will be the basis for the summaries of efficacy.
In all listings, summaries and statistical analyses, the term “Treatment Period” will refer to the 
period from the first day of study medication through: 

2 days after the last dose of study drug when summarizing

bleeding endpoints 
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
30 days after the last dose of study drug when summarizing

deaths (as an outcome of an SAE)

SAEs 

2 days (for non-serious AEs) or 30 days (for SAEs) after the last dose of study drug when 
summarizing

overall AEs 

AEs leading to study drug discontinuation
First dose and last dose of study medication will be defined based on oral anticoagulant and 
antiplatelet separately. This period will be the basis for the summaries of safety.
In all listings and summaries, the term “Follow-up Period” will refer to the period starting the day
of the end of treatment visit to the Follow-up visit or phone call which is 30 ± 7 days.
6.2
Treatment Regimens
The Randomized Subjects Data Set will consist of all randomized subjects. In this data set, subjects 
are categorized to the group to which they were assigned by the IVRS (oral anticoagulant or 
antiplatelet separately), regardless of the treatment actually received. Efficacy endpoints will be 
summarized according to the As Randomized group.  
The Treated Subjects Data Set will consist of all subjects who receive at least one dose of study 
drug and are categorized to the group to which they are assigned by the IVRS (oral anticoagulant 
or antiplatelet separately) unless the same incorrect treatment is received throughout the study, in 
which case the treatment group will be equal to the treatment received. Safety endpoints will be 
summarized according to the As Treated group.  
6.3
Populations for Analyses
The following population will be used for the analyses.
Enrolled Population
The Enrolled Subjects population consists of all subjects who signed informed consent.
Randomized Population for analysis can be defined as:
Randomized Population for oral anticoagulant: consists of all randomized subjects who are 
randomized to oral anticoagulant study drug. 
Randomized Population for antiplatelet: consists of all randomized subjects who are randomized 
to antiplatelet study drug. 
In these populations, subjects are categorized according to the As Randomized group.  The 
intention-to-treat population of all randomized subjects will be used to analyze all efficacy 
endpoints.
Treated Population for analysis can be defined as:
Treated Population for oral anticoagulant: is a subset of the Enrolled Population consisting of all 
subjects who were randomized and received at least one dose of oral anticoagulant study drug. 
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Treated Population for antiplatelet: is a subset of the Enrolled Population consisting of all subjects 
who were randomized and received at least one dose of antiplatelet study drug. 
When summarizing data using these populations, subjects are categorized to the As Treated group.
Evaluable Populations:
is a subset of the Treated Population for oral anticoagulant excluding subjects with protocol 
deviations expected to affect the primary safety endpoint (see Section 7.2). In the case of treatment 
assignment error, the data collected up to the start of incorrect treatment will be included. 
7
STATISTICAL ANALYSES
7.1
General Methods
All analyses will be performed in SASusing version 9.2 or higher. Unless otherwise stated, all 
hypothesis tests will be performed using two-sided tests at the 5% significance level.  
Continuous variables will be summarized using descriptive statistics including means, standard 
deviations, minima, maxima and quartiles, and qualitative or discrete variables will be summarized 
using absolute and relative frequencies. 
Time to Event Analyses
Unless specified, calculation of p-values and construction of point estimates and CIs for HR will 
be based on Cox proportional hazard models. Stratification variables will be included in the model 
as stratification factors. Additional covariates may be included as described in Sections 7.5 and 
7.6. Ties will be handled using Breslow’s methodology. 
Event rates will be estimated and plotted over time using Kaplan-Meier methodology. 
Testing Strategy
A hierarchical testing strategy described below will be used to compare the effects of apixaban 
and VKA between treatment groups. 

Non-inferiority (NI) for the primary endpoint, a composite of ISTH major and CRNM 
bleeding, will be tested first.

If NI is not demonstrated, then nominal p-values will be presented for subsequent comparisons 
between apixaban and VKA

If NI is demonstrated, then superiority for the composite of ISTH major and CRNM bleeding 
will be tested. If superiority is not demonstrated, then nominal P-values will be presented for 
subsequent comparisons between apixaban and VKA.

If superiority for the composite of ISTH major and CRNM bleeding is demonstrated, then 
superiority for the composite of all-cause death and all-cause re-hospitalization will be tested. 
If superiority is not demonstrated, then nominal p-values will be presented for subsequent 
comparisons between apixaban and VKA.
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
If superiority for the composite of all-cause death and all-cause re-hospitalization is 
demonstrated, then the composite of all-cause death and ischemic events will be tested.
All tests will be performed at the two-sided α = 0.05 significance level.
7.2
Study Conduct
Relevant protocol deviations will be identified for all subjects who are randomized. Relevant 
Protocol Deviation Criteria expected to affect the primary safety endpoint are as follows:

Subject randomized but not dosed

Error in treatment assignment resulting in a subject being dosed with an incorrect 
treatment. This deviation will include only subjects who received apixaban (any dose) but 
were assigned by the IVRS to receive VKA or subjects who received VKA but were 
assigned by the IVRS to receive apixaban ( either dose).
7.3
Study Population
All summary tables will be presented by Apixaban /VKA, aspirin/placebo separately if applicable, 
and combination of treatment groups (apixaban/aspirin, apixaban/aspirin placebo, VKA /aspirin, 
VKA /aspirin placebo).  
The number of subjects enrolled into the study, and the number of subjects enrolled but not 
randomized together with the reasons for not being randomized will be summarized. The reasons 
for not being randomized will be taken from the CRF pre-randomization status page. 
The summaries described below will also be presented by indication at enrollment (PCI/ACS).
The number of randomized subjects and the number of subjects discontinuing during intented 
treatment period together with the reasons for discontinuation will be summarized by treatment 
group.  The reasons for discontinuation will be taken from the end-of-treatment visit page of CRF.  
The frequency of subjects enrolled in each country and in each site will be tabulated by randomized 
treatment group and for all randomized subjects combined.
The summary of VKA categories by warfarin and non-warfarin will be presented as well. The non-
warfarin VKAs will be broken down by subcategories.
7.3.1.1
Demography and Baseline Characteristics
Demographic and baseline characteristics will be summarized by randomized treatment group, 
using the Randomized Population for oral anticoagulant and Randomized Population for 
antiplatelet. All summaries will be further tabulated by indication at enrollment (PCI/ACS). 
Continuous variables will be summarized using means, standard deviations, minima, maxima and 
quartiles, and categorical variables will be summarized using absolute and relative frequencies. 
The following demographic and baseline characteristics will be summarized 

Indication at enrollment (where applicable)
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
Apixaban dose at randomization 

Geographic region 

Age

Age group (< 65, 65-<80, 80 years)

Gender

Race 

Ethnicity (for US only)

Weight

Weight group (60, > 60 kg)

Serum Creatinine

CHADS2 Score

CHADSVASC2 score

HASBLED score

Hypertension

Heart failure

Diabetes Mellitus

P2Y12 Concomitant medication 

Prior warfarin/ VKA status

Prior use of Antiplatelet (where applicable)

Prior Oral anticoagulant (where applicable)
7.4
Extent of Exposure
7.4.1
Study Therapy
The summaries described below will be tabulated for the Treated Populations. All summaries will 
be tabulated by treatment group and by indication at enrollment (PCI/ACS).
Length of exposure to study drug is defined as the number of days the subject is known to be on 
study drug. The distribution of the length of exposure to study drug will be presented by treatment 
group; this distribution will be presented by taking into account days without dosing.  The 
distribution categories will be <30 days, 30 to <60 days, 60 to <90 days, 90 to <120 days, 120 to 
<150 days, 150 to <180 days, 180 days.
The length of exposure to study drug will also be summarized by treatment group using means, 
standard deviations, medians, minima and maxima. The total patient-days of exposure to study 
drug (say, T) will be presented for each treatment group and is defined as:


T
N
i
i
1
subject 
for 
(days)
exposure
of
Length 
,
where NT represents the number of subjects receiving treatment T.  
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Treatment compliance (TC) will be summarized for apixaban and aspirin/placebo. The TC will be 
calculated using the following formula (assuming that either on the first day or the last day subjects 
only receives one dose of apixaban):
%
100
1
n 
1)
-
drug
study 
  
of
dose
last 
first to
from
days
of
(Number 
 taken
 tablets
of
number 




TC
  
Where n=1 for aspirin/placebo (QD), and n=2 for apixaban.
The frequency of subjects with at least 80% compliance with apixaban and aspirin/placebo will 
also be summarized.
7.4.2
INR Control
The summaries described below will be tabulated for the Randomized Population for oral 
anticoagulant. 
For subjects who receive VKA, INR control is a more appropriate measure of compliance than pill 
count.  The assessment of INR control will be based on all available INR values. 
INR values will be summarized by visit (see Sections 8.3). These summaries will also be 
graphically displayed using a box plot.
The proportion of time (counted from first INR value recorded on or after dosing on Day 10 until 
the day of discontinuation of study drug without considering interruptions) in which subjects have 
an INR in the following ranges will be summarized:  

INR < 2.0, 2.0 INR 3.0, INR > 3.0
The frequency of subjects with INR in the 2.0-3.0 range for 60%, 65%, 70%, 75%, or 
80% of time will also be summarized.
Only subjects who have received study drug for at least 10 days will be included in these time-
related summaries.  
The INR control measure, proportion of time in each INR interval, is calculated using Rosendaal’s 
method which assumes that the INR value between two measurements varies linearly from the 
first value to the second value. 

let INRi and INRi+1 be the two consecutive INR values

let Di and Di+1 be the dates associated with these two consecutive INR values,               [(Di+1
- Di)=k, k>1]

assuming the linear increase or decrease between the two consecutive INR measurements, 
the unit change per day in INR is m=(INRi+1 - INRi)/ (Di+1 - Di)

the estimated INR value for the date after Di (Di+1) will be INRi + (m*1) 

likewise, the estimated INR value for the date (Di+2) will be INRi + (m*2), etc.; the 
estimated INR value on the date immediately prior to Di+1 will be INRi + (m*(k-1)).
Using Rosendaal’s method1, each subject will have an INR measurement every day, either actual 
or by estimation through linear interpolation. The proportion of time subjects have an INR within 
an interval is the number of days with INR in the interval divided by the total number of days.
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7.4.3
Concomitant Medications
The summaries described below will be tabulated for the Treated Populations. All summaries will 
be tabulated by treatment group and by treatment group and indication at enrollment (PCI/ACS). 
The frequency of subjects receiving P2Y12 concomitant medication will be summarized by 
treatment group and medication class.  
The length of exposure to P2Y12 administered concomitantly with study drug will be summarized 
(using means, standard deviations, medians, minima and maxima) by treatment group. The 
summaries will be presented by drug name. 
7.5
Efficacy
There is no primary efficacy analysis for this study. All analyses described in this section will be 
performed on the Randomized Populations during Intended Treatment Period, and events will be 
confirmed by adjudication. The numbers of efficacy events will be summarized by combination of 
treatment groups (apixaban/aspirin, apixaban/aspirin placebo, VKA /aspirin, VKA /aspirin 
placebo).
Censoring scheme for time to efficacy event analyses: subjects who do not experience an efficacy 
endpoint event will be censored at the earlier of the date of end of Intended Treatment Period, 
death date (when death is not part of the endpoint), or last-contact date (for subjects who withdraw 
consent to be followed up or are lost to follow-up) at the end of Intended Treatment Period.
7.5.1
The comparison between apixaban and VKA 
7.5.1 .1
      Secondary Efficacy Endpoints
The secondary efficacy endpoints are time to first occurrence of composite of all-cause death (will 
use “death” in later sections) and all-cause re-hospitalization and composite death and ischemic 
events (stroke, myocardial infarction, stent thrombosis, urgent coronary revascularization).
A Cox proportional hazards model including treatment group as a covariate and stratified by 
indication at enrollment (PCI/ACS) and antiplatelet (aspirin/placebo) will be used for randomized 
subjects for oral anticoagulant during Intended Treatment Period. A point estimate and two-sided 
95% CI for hazard ratio will be calculated. A p-value for the test of equality (HR = 1) will be 
calculated based on the hierarchical testing strategy.
 
      
 
 
 
 
7.5.2
The comparison between aspirin and placebo
7.5.2 .1
      Secondary Efficacy Endpoint
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The secondary efficacy endpoints are time to first occurrence of all-cause death and all-cause re-
hospitalization and composite death and ischemic events (stroke, myocardial infarction, stent 
thrombosis, urgent coronary revascularization).
A Cox proportional hazards model including treatment group as a covariate and stratified by 
indication at enrollment (PCI/ACS) and anticoagulant treatment group (apixaban/VKA) will be 
used for randomized subjects for antiplatelet during Intended Treatment Period. A point estimate 
and two-sided 95% CI for hazard ratio will be calculated. A p-value for the test of equality (HR = 
1) will be calculated based on the hierarchical testing strategy, similar to the analyses for apixaban 
vs. VKA.
 
      
 
 
 
7.6
Safety
All analyses described in this section will be performed on the Treated Populations during 
treatment period, and bleeding events will be confirmed by adjudication. The numbers of safety 
events will be summarized by combination of treatment groups (apixaban/aspirin, apixaban/aspirin 
placebo, VKA /aspirin, VKA /aspirin placebo).
Censoring scheme for time to event analyses of safety endpoints: subjects who do not experience 
a safety endpoint event will be censored at the earlier of 2 days after discontinuation of study drug, 
death date, or last-contact date (for subjects who withdraw consent to be followed up or are lost to 
follow-up) at the end of the treatment period.  
7.6.1
The comparison between apixaban and VKA 
7.6.1.1
Analysis of Primary Safety Endpoints
NI and Superiority Tests
All analyses described in this section will be performed on the treated subjects for oral 
anticoagulant during the treatment period using safety censoring scheme (considering study drugs 
apixaban/VKA).
The primary objective of the study is to determine if apixaban is NI to VKA for the primary safety 
endpoint (confirmed ISTH major bleeding and CRNM bleeding). Following the sequential testing 
strategy outlined in Section 7.1, if non-inferiority for the primary safety endpoint is demonstrated 
at the one-sided 0.025 significance level then superiority of apixaban relative to VKA for the 
primary safety endpoint will be tested at the one-sided 0.025 significance level.
The analysis of primary safety endpoint will be performed using a Cox proportional hazard model 
including oral anticoagulant treatment group (apixaban/VKA) as a covariate and stratified by 
indication at enrollment (PCI/ACS) and antiplatelet (aspirin/placebo). The treatment effect will be 
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measured by the estimated HR and two-sided 95% CIs for HR. The non-inferiority will be 
demonstrated if the upper bound of two-sided 95% CIs for HR is less than 1.2.
The proportional hazards assumption will be checked by examining the plots of the log(-
log(survival)) versus survival time for each stratum included in the Cox proportional hazards 
model.
Interaction between oral anticoagulant (apixaban/VKA) and antiplatelet (aspirin/placebo) is not 
anticipated, but this assumption will be examined within Cox model including stratification 
variable indication at enrollment (PCI/ACS), and terms of oral anticoagulant treatment group 
(apixaban/VKA), antiplatelet (aspirin/placebo), and oral anticoagulant (apixaban/VKA) by 
antiplatelet (aspirin/placebo) interaction. If quantitative interaction is significant (two sided p-
value < 0.1), then qualitative interaction will be assessed using Gail and Simon test (1985)2.
Event rates will be estimated and Kaplan-Meier curves will be plotted for the time from first dose 
of study medication to first occurrence of ISTH major or CRNM bleeding, by treatment group, by 
treatment group and indication at enrollment (PCI/ACS), and by treatment group and antiplatelet
treatment group. 
7.6.1.2
Sensitivity Analyses for Key Measures
To assess the impact of relevant protocol deviations on the NI assessment, the NI test will also be 
performed on the Evaluable Population during treatment period.
Sensitivity analysis of primary safety endpoint will be performed using randomized subjects for 
oral anticoagulant during treatment period as well.  
7.6.1.3
Subgroup Analyses 
All analyses described in this section will be performed on the Treated Population for oral 
anticoagulant during treatment period using the safety censoring scheme.
Table 7.6.1.3 shows the subgroups of interest for analyses of primary safety assessment. If the 
value of the grouping variable cannot be determined for a subject, the subject will be excluded 
from the corresponding subgroup analysis. For each subpopulation analysis, if, in any treatment 
group, the number of events is 10 for a subgroup, then the grouping variable will not be included 
in the test of treatment by subpopulation interaction.
Table 7.6.1.3:
Subgroups of Interest for Primary Safety Assessments
Grouping Variable
Subgroups
indication at enrollment
PCI
ACS
Apixaban dose*
2.5 mg BID 
5 mg BID 
Geographic region 
North America
Latin America
Europe
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Table 7.6.1.3:
Subgroups of Interest for Primary Safety Assessments
Grouping Variable
Subgroups
Asia/Pacific
Age
< 65 years old
65  to < 80 years old
80  years old
Gender
Male
Female
Race 
White
Black / African American 
Asian
Other
Ethnicity (for US only)
Hispanic/Latino
Not Hispanic/Latino
Weight 
60 kg
> 60 kg
Serum Creatinine
< 1.5 mg/dL
1.5 mg/dL
CHADS2 Score
1
2
3
CHADSVASC2 scores
Low ( 0[male] or 1 [female])
Moderate ( 1 [male])
High ( 2 )
HASBLED score
1
2
3
Diabetes Mellitus
Yes
No
Hypertension requiring 
pharmacological treatment
Yes
No
Heart Failure
Yes
No
Concomitant med (which P2Y12 
agent was the subject on)
Clopidogrel
Prasugrel
Ticlodipine
Ticagrelor
Prior warfarin/VKA status at least 2 
months prior to the study
Experienced
Naive
Antiplatelet
Aspirin
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Table 7.6.1.3:
Subgroups of Interest for Primary Safety Assessments
Grouping Variable
Subgroups
Aspirin placebo
*the control for apixaban 2.5 mg will be subjects in the VKA group who meet criteria of apixaban dose adjustment 
(see section 1); other VKA subjects will be the control for the subjects taking apixaban 5 mg.
Each of these subgroups will be analyzed using a Cox proportional hazards model stratified by 
indication at enrollment (not applicable for the first subgroup listed) and antiplatelet 
(aspirin/placebo) (not applicable for the last subgroup listed) with terms for treatment group. The 
estimated HR and two-sided 95% CIs will be calculated to assess the treatment effect within each 
of the subgroups.  The p-value for the test of the treatment by grouping variable interaction will 
be presented based on a Cox proportional hazards model stratified by indication at enrollment (not 
applicable for the first subgroup listed) and antiplatelet (aspirin/placebo) (not applicable for the 
last subgroup listed with terms for treatment group,) with terms for treatment group, and the 
grouping variable and treatment by grouping variable interaction.
7.6.1.4
Secondary Safety Analyses
The secondary safety endpoint will be superiority on time to first occurrence of confirmed ISTH 
major and CRNM bleeding, and the detailed analysis is as in the previous section.
 
 
 
 
 
 
 
 
 
 
7.6.2
The comparison between aspirin and placebo
The analyses for the primary and secondary endpoints for aspirin vs aspirin placebo will be similar 
to the analyses for apixaban vs. VKA. A hierarchical testing strategy at the one-sided α = 0.025 
significance level will be used for a separate secondary set of comparisons between aspirin and 
aspirin placebo. All analyses described in this section will be performed on the Treated Population 
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for antiplatelet therapy during the treatment period using the safety censoring scheme (considering
study drugs aspirin/placebo).
7.6.2.1
Primary Safety Analysis
The primary safety endpoint will be time to first occurrence of confirmed ISTH major or CRNM 
bleeding. A point estimate and two-sided 95% CIs for hazard ratio using a Cox proportional 
hazards model including antiplatelet (aspirin/placebo) as a covariate, stratified by indication at 
enrollment (PCI/ACS) and oral anticoagulant treatment group (apixaban/VKA) using the treated 
subjects for antiplatelet during treatment period. A p-value for the test of equality (HR = 1) will 
be calculated based on the hierarchical testing strategy. 
7.6.2.2
Subgroup Analyses 
Table 7.6.2.2 shows the subgroups of interest for analyses of primary safety assessment. If the 
value of the grouping variable cannot be determined for a subject, the subject will be excluded 
from the corresponding subgroup analysis. For each subpopulation analysis, if, in any treatment 
group, the number of events is 10 for a subgroup, then the grouping variable will not be included 
in the test of treatment by subpopulation interaction.
Table 7.6.2.2:
Subgroups of Interest for Primary Safety Assessments
Grouping Variable
Subgroups
indication at enrollment
PCI
ACS
Apixaban dose* 
2.5 mg BID 
5 mg BID 
Geographic region 
North America
Latin America
Europe
Asia/Pacific
Age
< 65 years old
65  to < 80 years old
80  years old
Gender
Male
Female
Race 
White
Black / African American 
Asian
Other
Ethnicity (for US only)
Hispanic/Latino
Not Hispanic/Latino
Weight 
60 kg
> 60 kg
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Table 7.6.2.2:
Subgroups of Interest for Primary Safety Assessments
Grouping Variable
Subgroups
Serum Creatinine
< 1.5 mg/dL
1.5 mg/dL
CHADS2 Score
1
2
3
CHADSVASC2 scores
Low ( 0[male] or 1 [female])
Moderate ( 1 [male])
High ( 2 )
HASBLED score
1
2
3
Diabetes Mellitus
Yes
No
Hypertension requiring 
pharmacological treatment
Yes
No
Heart Failure
Yes
No
Concomitant med (which P2Y12 
agent was the subject on)
Clopidogrel
Prasugrel
Ticlodipine
Ticagrelor
Prior warfarin/VKA status at least 2 
months prior to the study
Experienced
Naive
Oral anticoagulant
Apixaban
VKA
*the control for apixaban 2.5 mg will be subjects in the VKA group who meet criteria of apixaban dose adjustment 
(see section 1); other VKA subjects will be the control for the subjects taking apixaban 5 mg.
Each of these subgroups will be analyzed using a Cox proportional hazards model stratified by 
indication at enrollment (not applicable for the first subgroup listed) and oral anticoagulant 
treatment group (apixaban/VKA) (not applicable for the last subgroup listed) with terms for 
treatment group. The estimated HR and two-sided 95% CIs will be calculated to assess the 
treatment effect within each of the subgroups.  The p-value for the test of the treatment by grouping 
variable interaction will be presented based on a Cox proportional hazards model stratified by 
indication at enrollment (not applicable for the first subgroup listed) and oral anticoagulant 
treatment group (apixaban/VKA) (not applicable for the last subgroup listed) with terms for 
treatment group, and the grouping variable and treatment by grouping variable interaction.
7.6.2.3
Secondary Safety Analyses
There is no secondary safety endpoint.
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7.6.3.1
Adverse Events
Only NSAE’s that occur after the initiation of study drug and that result in permanent treatment 
discontinuation will be recorded in the eCRF. All AEs that lead to treatment discontinuation are 
coded and grouped into Preferred Terms (PT) by System Organ Class (SOC), using the Medical 
Dictionary for Regulatory Activities (MedDRA). Listings and summaries will be based on the 
resulting SOCs and PTs.                                                                                                                                     
All reported SAEs will be listed, indicating the subject id, treatment group, age, gender, race, day 
of onset relative to start of dosing, resolution date, investigator-assessment of relationship to study 
drug, investigator-assessment of intensity of event, action taken regarding study drug and whether 
treatment was required for the event.
Summary information (the number and percentage of subjects) regarding SAEs (for serious and 
non-serious events) will be tabulated by SOC, PT and treatment group for:

deaths (outcome of an SAE)

SAEs

AEs leading to study drug discontinuation
All reported AEs and SAEs during follow-up period will be summarized and listed as well.
7.6.3.2
Laboratory Data
Lab data are not systematically collected in the study. All reported marked lab abnormalities during 
treatment period will be listed.
7.6.3.3
Vital Signs 
Vital signs are not systematically collected in the study.
7.7
Pharmacokinetics/Pharmacodynamics
There will be no pharmacokinetic/pharmacodynamic analysis in this study.
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7.8
Outcomes Research Assessments
Time to first all cause re-hospitalization is assessed per secondary endpoint.
7.9           Interim Analyses 
No interim analysis was planned. A blinded assessment of the primary endpoint event rate was 
performed after 50% of subjects have completed the study. The analyses focused on the 
aggregate event rate and the sample size may be increased if the aggregate event rate was lower 
than anticipated. Ongoing review of the safety will be the mandate of the data monitoring 
committee (DMC). Details are provided in the DMC charter.
8
CONVENTIONS
8.1
Safety Data Conventions
Except as noted in Section 7.6, safety data will be handled according to the BMS safety data 
conventions (described in “Analysis of Safety Data - Reference to 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 efficacy and bleeding endpoints, imputation of missing or partial dates for 
efficacy and bleeding events will follow the convention outlined in “Analysis of Safety Data -
Reference to CT SOP 109”, but rather than using the hierarchy “first active study medication date, 
consent date, visit date corresponding to the visit at which the event was reported”, should instead 
use the following hierarchy 

“first active study medication date, randomization date, consent date” for efficacy and bleeding 
endpoints other than death

“last contact date” for death.
8.2
Baseline Measurements
For laboratory measure will follow GBS standard.
8.3
Day Ranges for Analysis of Time Points
Subjects do not always adhere strictly to the visit schedule timing in the protocol. The day ranges 
for the analyses of INR measurements are defined in the following table. Values associated with 
each nominal visit (except for the follow-up period) will be considered from first day of dosing 
until 2 days after discontinuation of VKA.
Table 8.3:
Day Ranges for Analysis of INR Measurements
Nominal Visit
Target Day
Day Ranges 
Month 1
Day 30
Days 11 - 45 
Month 2
Day 61
Days 46 - 76 
Month 3
Day 91
Days 77 - 106
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Nominal Visit
Target Day
Day Ranges 
Month 4
Day 121
Days 107 - 136 
Month 5
Day 152
Days 137 - 167 
Month 6
Day 183
Days 168 - 198
                               
8.4
Multiple Measurements 
INR Values
If multiple INR values are captured in the CRF within the same nominal visit, the INR value 
obtained on the day closest to the target day for that nominal visit will be used; in the case of a tie, 
the measurement obtained at the earlier date and time will be used in the summaries. 
9
CONTENT OF REPORTS
The results of this study will be presented in a standard BMS Clinical Study Report (CSR). The 
complete list of analysis described for the CSR will be generated in the Data Presentation Plan 
(DPP).
 
 
                                                       
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