Clinical trial NCT01877915
Conditions: Heart Failure Coronary Artery Disease
Keywords: Heart Failure Coronary Artery Disease Stroke Myocardial Infarction Anticoagulation
Sponsor: Janssen Research & Development, LLC
Start date: 2013-09-10; Completion date: 2018-04-19
Enrollment: 5081 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effectiveness and safety of rivaroxaban compared with placebo (inactive medication), in reducing the risk of death, myocardial infarction or stroke in participants with heart failure and significant coronary artery disease following an episode of decompensated heart failure.

Detailed description:
This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor participant knows the identity of the assigned treatment), parallel group (each participant group receives different treatments simultaneously), event driven (the study duration is determined by the time taken for a specific number of events to occur), multicenter study to assess the effectiveness and safety of rivaroxaban compared with placebo, in reducing the risk of death, myocardial infarction or stroke in participants with heart failure and significant coronary artery disease following an episode of decompensated heart failure. Participants will be randomly assigned in a 1:1 ratio to receive either rivaroxaban or placebo (each in addition to standard of care for heart failure and coronary artery disease as prescribed by their managing physician). The study will consist of a screening phase, a double-blind treatment phase, and a follow-up after the sponsor-announced global treatment end date (GTED, defined as the date when 1200 primary efficacy outcome events are predicted to have occurred). The double-blind treatment phase is estimated to last for 6 to 54 months. Participants will discontinue study drug after taking both their morning and evening doses on the GTED and will return to the study center for the end-of-study visit (between 15 and 45 days but no sooner than 15 days after the GTED). Patient safety will be monitored throughout the study. The average study duration for participants is expected to be approximately 29 months. The study drug, rivaroxaban, is approved in the United States and in multiple countries around the world for the prevention and treatment of a number of thrombosis-mediated conditions.

Arms: arm 1: Each participant will receive 2.5 mg of rivaroxaban twice daily with standard of care for heart failure and coronary artery disease (as prescribed by the participant's managing physician). arm 2: Each participant will receive matching placebo twice daily with standard of care for heart failure and coronary artery disease (as prescribed by the participant's managing physician).
Interventions: intervention 1: Rivaroxaban intervention 2: Placebo intervention 3: Standard of care for heart failure and coronary artery disease
Intervention descriptions: intervention 1: Each participant, randomly allocated to the rivaroxaban arm, will receive one 2.5 mg tablet of rivaroxaban orally (by mouth) twice daily (once in the morning and once in the evening at approximately the same time each day) until the global treatment end date (GTED) (defined as the date when 1200 primary efficacy outcome events have occurred). Rivaroxaban will be given with standard of care for heart failure and coronary artery disease (as prescribed by the participant's managing physician). intervention 2: Each participant, randomly allocated to the placebo arm, will receive one matching placebo tablet orally twice daily (once in the morning and once in the evening at approximately the same time each day) until the GTED. Placebo will be given with standard of care for heart failure and coronary artery disease (as prescribed by the participant's managing physician). intervention 3: Each participant's standard of care for heart failure and coronary artery disease (as prescribed by the participant's managing physician) should be continued throughout the study.

Protocol documents:
Prot_000.pdf: 
1
Approved, Date: 1 December 2016
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-blind, Event-driven, Multicenter Study Comparing the Efficacy and 
Safety of Rivaroxaban with Placebo for Reducing the Risk of Death, Myocardial Infarction or 
Stroke in Subjects with Heart Failure and Significant Coronary Artery Disease Following an 
Episode of Decompensated Heart Failure
COMMANDER HF Study
Protocol RIVAROXHFA3001; Phase 3
BAY 59-7939/16302
Amendment INT-3
JNJ-39039039; BAY 59-7939 (rivaroxaban)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen 
R&D Ireland; or Janssen Research & Development, LLC. The term “sponsor” is used throughout the 
protocol to represent these various legal entities; the sponsor is identified on the Contact Information page 
that accompanies the protocol.
This compound is approved for marketing in 5 indications.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER:
2013-000046-19     
Status:
Approved
Date:
1 December 2016
Prepared by:
Janssen Research & Development, LLC
ERIS Number:
EDMS-ERI-51867673, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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Approved, Date: 1 December 2016
TABLE OF CONTENTS
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................. 18
TIME AND EVENTS SCHEDULE .............................................................................................................. 25
ABBREVIATIONS ...................................................................................................................................... 29
1.
INTRODUCTION................................................................................................................................ 31
1.1.
Background .................................................................................................................................... 31
1.1.1.
Compound Profile....................................................................................................................... 32
1.1.2.
Heart Failure – Scope of the Problem ........................................................................................ 33
1.1.3.
Clinical Studies in Patients with Heart Failure with Anticoagulants............................................ 34
1.2.
Overall Rationale for the Study...................................................................................................... 38
2.
OBJECTIVES AND HYPOTHESES.................................................................................................. 39
2.1.
Objectives ...................................................................................................................................... 39
2.2.
Hypothesis ..................................................................................................................................... 40
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 40
3.1.
Overview of Study Design.............................................................................................................. 40
3.2.
Study Design Rationale.................................................................................................................. 42
4.
SUBJECT POPULATION.................................................................................................................. 45
4.1.
Inclusion Criteria ............................................................................................................................ 45
4.2.
Exclusion Criteria ........................................................................................................................... 48
4.3.
Prohibitions and Restrictions ......................................................................................................... 50
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 51
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 52
7.
TREATMENT COMPLIANCE............................................................................................................ 53
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 53
9.
STUDY EVALUATIONS .................................................................................................................... 55
9.1.
Study Procedures........................................................................................................................... 55
9.1.1.
Overview..................................................................................................................................... 55
9.1.2.
Screening Phase ........................................................................................................................ 56
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 56
9.1.4.
Follow-up after GTED................................................................................................................. 57
9.2.
Efficacy........................................................................................................................................... 57
9.2.1.
Efficacy Evaluations.................................................................................................................... 57
9.2.2.
Efficacy Outcomes...................................................................................................................... 62
9.3.
Biomarkers ..................................................................................................................................... 62
9.4.
Medical Resource Utilization.......................................................................................................... 62
9.5.
Safety Evaluations and Outcomes................................................................................................. 63
9.5.1.
Safety Evaluations...................................................................................................................... 63
9.5.2.
Safety Outcomes ........................................................................................................................ 65
9.6.
Benefit-Risk Balance...................................................................................................................... 65
9.7.
Sample Collection and Handling.................................................................................................... 65
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 65
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10.1.
Completion ..................................................................................................................................... 65
10.2.
Discontinuation of Study Treatment............................................................................................... 66
10.2.1.
Temporary Discontinuation of Study Treatment......................................................................... 66
10.2.2.
Permanent Discontinuation of Study Treatment......................................................................... 67
10.3.
Withdrawal From the Study............................................................................................................ 68
11.
STATISTICAL METHODS................................................................................................................. 69
11.1.
Analysis Populations and Observational Periods .......................................................................... 69
11.2.
Sample Size Determination ........................................................................................................... 70
11.3.
Efficacy Analyses ........................................................................................................................... 71
11.4.
Biomarker Analyses ....................................................................................................................... 73
11.5.
Medical Resource Utilization Analyses.......................................................................................... 73
11.6.
Safety Analyses ............................................................................................................................. 74
11.7.
Benefit-Risk Analysis ..................................................................................................................... 74
11.8.
Independent Data Monitoring Committees .................................................................................... 75
11.9.
Interim Analysis.............................................................................................................................. 76
12.
ADVERSE EVENT REPORTING ...................................................................................................... 76
12.1.
Definitions ...................................................................................................................................... 77
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 77
12.1.2.
Attribution Definitions.................................................................................................................. 78
12.1.3.
Severity Criteria .......................................................................................................................... 78
12.2.
Special Reporting Situations.......................................................................................................... 79
12.3.
Procedures..................................................................................................................................... 79
12.3.1.
All Adverse Events...................................................................................................................... 79
12.3.2.
Serious Adverse Events ............................................................................................................. 81
12.3.3.
Pregnancy................................................................................................................................... 81
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 82
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 82
13.1.
Procedures..................................................................................................................................... 82
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 82
14.
STUDY DRUG INFORMATION......................................................................................................... 83
14.1.
Physical Description of Study Drugs.............................................................................................. 83
14.2.
Packaging ...................................................................................................................................... 83
14.3.
Labeling.......................................................................................................................................... 83
14.4.
Preparation, Handling, and Storage............................................................................................... 83
14.5.
Drug Accountability ........................................................................................................................ 83
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 83
16.
ETHICAL ASPECTS ......................................................................................................................... 84
16.1.
Study-Specific Design Considerations........................................................................................... 84
16.2.
Regulatory Ethics Compliance....................................................................................................... 84
16.2.1.
Investigator Responsibilities ....................................................................................................... 84
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 85
16.2.3.
Informed Consent ....................................................................................................................... 86
16.2.4.
Privacy of Personal Data ............................................................................................................ 87
16.2.5.
Long-Term Storage of Samples for Future Research ................................................................ 88
16.2.6.
Country Selection ....................................................................................................................... 88
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 88
17.1.
Protocol Amendments.................................................................................................................... 88
17.2.
Regulatory Documentation ............................................................................................................ 88
17.2.1.
Regulatory Approval/Notification ................................................................................................ 88
17.2.2.
Required Prestudy Documentation............................................................................................. 89
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 89
17.4.
Source Documentation................................................................................................................... 90
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17.5.
Case Report Form Completion ...................................................................................................... 90
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 91
17.7.
Record Retention ........................................................................................................................... 91
17.8.
Monitoring ...................................................................................................................................... 92
17.9.
Study Completion/Termination....................................................................................................... 93
17.9.1.
Study Completion ....................................................................................................................... 93
17.9.2.
Study Termination....................................................................................................................... 93
17.10.
On-Site Audits ................................................................................................................................ 93
17.11.
Use of Information and Publication................................................................................................ 94
REFERENCES............................................................................................................................................ 96
INVESTIGATOR AGREEMENT ............................................................................................................... 102
LIST OF ATTACHMENTS
Attachment 1:
The MDRD Formula for Calculation of GFR............................................................... 98
Attachment 2:
Modified Rankin Scale................................................................................................ 99
Attachment 3:
Enoxaparin Equivalent Doses for Given Rivaroxaban Doses.................................. 100
Attachment 4:
Approach to Subjects Requiring Thrombolysis:  Administration of an Adjusted 
Enoxaparin Dose ...................................................................................................... 101
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Efficacy Endpoints in Subjects who had a History of Heart Failure at Baseline in the 
Phase 3 ATLAS ACS 2 TIMI 51 Study ..................................................................................... 33
Table 2:
Summary of the Results Four Recent Prospective Studies in Patients with Heart 
Failure ....................................................................................................................................... 37
FIGURES
Figure 1:
Schematic Overview of the Study Design  (Study RIVAROXHFA3001) .................................. 42
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Approved, Date: 1 December 2016
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
18 April 2013
Amendment INT-1
02 May 2014
Amendment INT-2
05 December 2014
Amendment INT-3
01 December 2016
Amendments are listed beginning with the most recent amendment.
Amendment INT-3 (01 December 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment is to revise the target number of primary efficacy endpoint events. The 
current COMMANDER trial data show a longer than planned enrollment period, a lower than anticipated 
primary efficacy event rate and a higher than anticipated study drug discontinuation rate: Recruitment of 
subjects in the COMMANDER HF (RIVAROXHFA3001) study has been slower than anticipated which has 
subsequently led to a longer double blind treatment phase (was approximately 30 months, now estimated to be 54 
months). Moreover, a lower than initially estimated aggregate primary efficacy event rate (14% vs. a predicted 
17%) and a higher than originally anticipated study drug discontinuation rate (13% vs. a predicted 10%) have been 
observed. The higher discontinuation rate combined with the longer study duration has resulted in a greater 
percentage of subjects being off treatment, diluting the potential treatment effect and thus reducing the study power 
(originally planned to be 90%). In order to better understand the implication of these findings, a blinded simulation 
study based on currently available trial data was performed and showed that an increase in the target number of 
primary efficacy endpoint events (the first occurrence of the composite of all cause death, MI or stroke) may be able 
to potentially counterbalance this problem and maintain the study power. Thus, the target number of primary 
efficacy endpoint events is revised from 984 to 1,200 for the final analysis, and the target number of primary 
efficacy endpoint events for the interim analysis is revised from approximately 500 to approximately 600.
Applicable Section(s)
Description of Change(s)
Rationale: To revise the target number of primary efficacy endpoint events from “984” to “1,200” based on a 
blinded simulation study as described above.
Synopsis (Overview 
of Study Design); 3.1 
Overview of Study 
Design; 3.2 Study 
Design Rationale.
Revised the number of primary efficacy endpoint events from “984” to “1,200”.
Synopsis (Sample 
Size Justification);
11.2 Sample Size 
Determination 
Added the sentence “The study is revised to observe occurrences of the primary efficacy 
event in 1,200 unique randomized subjects based on a blinded simulation study performed 
on currently available trial data (ie, longer enrollment period, lower than anticipated 
primary efficacy event rate, higher than anticipated study drug discontinuation rate). 
Further details are described in the Statistical Analysis Plan (SAP).”
Rationale: To revise the target number of primary efficacy endpoint events from approximately “500” to 
approximately “600” for the interim analysis, to be consistent with the overall changes in the target number of 
primary efficacy endpoint events for the study.
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Approved, Date: 1 December 2016
Applicable Section(s)
Description of Change(s)
11.2 Sample Size 
Determination; 11.3 
Efficacy Analyses; 
11.9 Interim Analysis.
Revised the number of primary efficacy endpoint events from approximately “500” to 
approximately “600”for the interim analysis.
Rationale: To change the estimated duration of the double-blind treatment phase and the average duration of a 
subject in the study, to reflect the overall slower than anticipated recruitment rate for the study.
Synopsis(Overview of 
Study Design); 3.1 
Overview of Study 
Design; 3.2 Study 
Design Rationale; 
Changed the estimated duration of double-blind treatment phase from “6 to 30 months” to 
“6 to 54 months”.
Changed the estimated average duration of a subject in the study from approximately “16 
months” to “29 months”
Rationale: To add a new prohibited therapy, ie, any medication that is contraindicated in patients with heart failure 
in the Prohibitions and Restrictions Section for safety reasons.
4.3 Prohibitions and 
Restrictions (Criterion 
5); 8 Prestudy and 
Concomitant Therapy
(Prohibited 
Therapies).
Added a new prohibited therapy (under Criterion 5):
“Any drug which is contraindicated in patients with heart failure (eg, cilastazol)”
Rationale: To change the stratification factor for the efficacy and safety analyses from “country” to “region” due to 
the increase in the number of enrolling countries and the corresponding smaller sample sizes expected in those 
countries.
Synopsis (Analyses-
Efficacy); 11.3 
Efficacy 
Analyses;11.6 Safety 
Analyses; 11,9 
Interim Analysis.
Changed the stratification by “country” to the stratification by “region” in the log-rank test 
for the primary efficacy analysis.  
Changed the stratification by “country” to the stratification by “region” in a Cox 
proportional hazards model.
Rationale: To add the log-rank test stratified by “country” as one of the sensitivity analyses in the statistical 
analyses plan.
11.3 Efficacy 
Analyses.
Added the log-rank test stratified by country as one of the sensitivity analyses.  
Rationale: To add additional subgroups/populations for the analyses.
Synopsis (Analyses-
Efficacy); 11.3 
Efficacy Analyses.
Added “BNP, NT-proBNP (≤ median vs > median)” for subgroup analyses. 
11.3 Efficacy 
Analyses.
Added the following sentence for sensitivity analyses:
“Additional sensitivity analyses will also be conducted based on subject populations 
enrolled under various versions of the protocol amendments.”
Rationale: To change the safety analyses from “study drug received” to “study drug assigned” based on the fact 
that the COMMANDER HF is a long term study and the incidence of a subject receiving the wrong study drug 
during the entire treatment period will be low. The statistical analysis plan may include sensitivity analyses of
subjects according to study drug received, if needed.
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Approved, Date: 1 December 2016
Applicable Section(s)
Description of Change(s)
11.6 Safety Analyses
Changed the sentence “Subjects will be analyzed according to study drug received” to 
“Subjects will be analyzed according to the study drug assigned”.
Deleted the sentence “If a subject receives both drugs, the subject will be analyzed as 
randomized.”
Rationale: To add additional details for the safety analyses
Synopsis (Analyses-
Safety; 11.6 Safety 
Analyses
Added the sentence “In addition, summary statistics will be provided for all other reported 
bleeding events.”
11.6 Safety Analyses
Added the sentence “The safety outcomes will also be analyzed for other observational 
periods as defined in the SAP.”
Rationale: To delete a sentence describing the interim analysis that is no longer valid based on the blinded 
simulation study performed on currently available trial data.
11.2 Sample Size 
Determination.
Deleted the sentence “The interim analysis will have ~75% power to detect an RRR of 
30% in the primary efficacy endpoint.”
Rationale: To provide additional clarification on the efficacy outcome events
9.2.1 Efficacy 
Evaluations
Deleted “Transient ischemic attack (TIA)” from the evaluation list of outcome events.
Added the sentence “Transient ischemic attack (TIA) is not an outcome event. The date of 
the TIA should be entered in the eCRF.”
Added the phrase “without any information regarding the immediate cause provided” 
under “Death with Unknown Cause”
9.5.1 Safety 
Evaluations; 12.3.1 
All Adverse Events.
Clarified that “traumatic bleeding events resulting in death” are considered as non-
cardiovascular (CV) Serious Adverse Events.
Rationale: To provide more clarity
Synopsis (Overview 
of Study Design); 3.1 
Overview of Study 
Design; 9.1.3 Double-
Blind Treatment 
Phase; 10.2.2 
Permanent 
Discontinuation of 
Study Treatment
Replaced the phrase “these subjects will be strongly encouraged to return for all scheduled 
visits” with the phrase “these subjects should return for all scheduled visits”
Synopsis (Overview 
of Study Design); 3.1 
Overview of Study 
Design.
Replaced the phrase “study drug must be temporarily discontinued and an appropriate 
treatment for the event must be administered.” with the phrase “study drug may be 
temporarily held if necessary or if using other anticoagulant drugs or thrombolytic 
therapy.”
Synopsis (Overview 
of Study Design); 3.1 
Overview of Study 
Design; 16.1 Study-
Specific Design 
Considerations.
Added the following phrase (in italic) to the sentence “the investigator is asked to strongly 
encourage the subjects to allow regular contact (eg, by telephone)… ”
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Approved, Date: 1 December 2016
Applicable Section(s)
Description of Change(s)
Synopsis (Overview 
of Study Design); 3.1 
Overview of Study 
Design.
Added the following phrase (in italic) to the sentence “study medication must be 
permanently discontinued for any intracranial hemorrhage or for any reason listed in 
Section 10.2.2.”
9.5.1 Safety 
Evaluations
Changed the sentence “Blood transfusion and products will be recorded” to “Transfusion 
with blood or blood products will be recorded”
9.1.1 Overview
Replaced the sentence “Approximately 10 mL of blood will be required for the D-dimer 
test” with the sentence “Approximately 3 mL of blood will be required for each D-dimer 
test (Baseline, Week 4 [if applicable])”
Rationale:  Minor errors were noted.
Throughout the 
protocol
Minor grammatical, spelling or formatting changes were made.
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Approved, Date: 1 December 2016
Amendment INT-2 (05 December 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: In many countries, chronic disease exacerbation is now managed in an 
outpatient setting. Recent data indicate that exacerbation of chronic heart failure is being increasingly managed with 
outpatient therapy. The risk of subsequent events (death, myocardial infarction, and stroke) remains high and is 
comparable whether patients are treated in a hospital or in an acute outpatient setting where they receive parenteral 
medications. With input from investigators and heart failure experts, the inclusion criteria have been modified to 
include high-risk patients treated in an outpatient setting with parenteral medications for decompensated heart 
failure.
Applicable Section(s)
Description of Change(s)
Rationale: To include high-risk patients treated in an outpatient setting with parenteral medications for 
decompensated heart failure.
Synopsis (Overview 
of study design, 
Subject population); 
3.1 Overview of 
Study Design; 4.1. 
Inclusion Criteria 
(Criterion 3.2)
The study population was modified to indicate “Eligible subjects must have an episode of 
decompensated heart failure (index event) requiring (a) an overnight stay in a hospital, 
emergency department, or medical observation facility with the capability of treating with 
intravenous medications and observing heart failure patients, or (b) an unscheduled 
outpatient visit to a heart failure management center, where parenteral therapy is required 
for heart failure stabilization.”
Rationale: To add the term and definition for “index event” as an episode of decompensated heart failure and to 
keep the consistency throughout the protocol.
Synopsis (Description 
of the compound); 
1.2. Overall Rationale 
for the Study 
Defined the “index event” by adding the phrase “an episode of decompensated HF, defined 
as the index event”.
Synopsis (Description 
of the compound); 
1.1. Background
Replaced  the phrase “index hospitalization” with “inpatient or outpatient treatment”
4.1. Inclusion Criteria 
(Criterion 3.2)
Replaced the phrase “Exacerbation of chronic HF” with “an episode of decompensated 
HF”.
Throughout the 
protocol
Replaced the phrase “hospitalization for exacerbation of HF”, or “index hospitalization” 
with the “index event” when appropriate. 
Rationale: Based on investigators’ feedback regarding their standard care for follow-up visits after discharge from 
the index event, the randomization period was extended to “up to 30 days after discharge from the facility treating 
the index event”.
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Approved, Date: 1 December 2016
Applicable Section(s)
Description of Change(s)
Synopsis (Overview 
of study design, 
Subject population); 
T&E Schedule, 
(footnote “m”); 3.1 
Overview of Study 
Design (including 
Figure 1, Schematic 
overview of the study 
design); 4.1. Inclusion 
Criteria (Criterion 
3.2); 9.1.2. Screening 
Phase
Changed the randomization period from “up to 14 days after discharge from their index 
hospitalization” to “up to 30 days after discharge from the facility treating the index 
event”. 
Synopsis (Overview 
of study design); T&E 
Schedule (Table, 
footnote “b”); 3.1 
Overview of Study 
Design; 4. Subject 
Population; 9.1.2. 
Screening Phase
Changed the screening period from “will last up to 35 days (up to 21 days during the index 
hospitalization and up to 14 days after discharge from the index hospitalization)” to “may 
last up to 51 days before randomization (21 days maximum for a hospitalization admission 
plus up to 30 days after discharge from the facility treating the index event)”.
T&E Schedule 
(footnote “d”); 4.2. 
Exclusion Criteria 
(NOTE)
Changed the hospital/local laboratory results and imaging studies information collection 
period from “within 21 days of discharge” to “within 51 days (21 days maximum for a 
hospitalization admission plus up to 30 days after discharge from the facility treating the 
index event).”
4.1. Inclusion Criteria 
(Criterion 6.1)
Changed the phrase “2 weeks” into “30 days” for the stay period in a nursing home, 
rehabilitation center or other skilled facility if transferred to these places after discharge.
Rationale: To provide more clarity for BNP or NT-proBNP test 
1.2. Overall Rationale 
for the Study
Added the rationale for including a minimum level of BNP or NT-proBNP as requirement 
for entry into the study. 
Synopsis (Overview 
of study design, 
Subject population); 
3.1 Overview of 
Study Design; 4.1. 
Inclusion Criteria 
(Criterion 16) 
Added the phrases “(preferred assay)” and “during the screening period and before 
randomization” at the end of the sentence “Subjects must also have a BNP level ≥ 200 
pg/mL or NT-proBNP level ≥800 pg/mL (preferred assay) during the screening period and 
before randomization”.
Rationale: To be consistent with languages across rivaroxaban clinical program
4.1. Inclusion Criteria 
(Criterion 12)
Removed the Criterion 12 “A woman must agree not to donate eggs (ova, oocytes) for the 
purposes of assisted reproduction.”
4.1. Inclusion Criteria 
(Criterion 13)
Deleted the phrase “during the study and for 3 months after receiving”.
Rationale: To provide more clarity
T&E Schedule
Switched the Column’s titles “Double-Blind Treatment Phase” and “Treatment Period”
T&E Schedule 
(footnote “u”)
Replaced the word “local” with “hematology”.
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JNJ-39039039; BAY 59-7939 (rivaroxaban)
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Approved, Date: 1 December 2016
Applicable Section(s)
Description of Change(s)
1.2. Overall Rationale 
for the Study; 3.1. 
Overview of Study 
Design
Added the phrase “(Day 1) prior to the first dose of study drug” to clarify the time for 
collecting blood sample for D-dimer data.
2.1. Objectives 
(Secondary 
objectives)
Added the phrase “in reducing the risk of the following outcomes:”
4.1. Inclusion Criteria 
(Criterion 2.1)
Deleted the phrase “documented” and “chronic” in “Subject must have documented
symptomatic chronic HF for at least 3 months prior to screening”, since symptoms of HF 
can be self-reported.
4.3. Prohibitions and 
Restrictions (Criterion
2.1)
Added the word “ASA”
4.3. Prohibitions and 
Restrictions (Criterion 
5.1); 8. Prestudy and 
Concomitant Therapy 
(Prohibited therapies)
Added the phrase “within 4 days before randomization, or during the study” for strong 
inhibitors of cytochrome P450 3A4.
4.3. Prohibitions and 
Restrictions (Criterion 
9)
Added a criterion required by the current protocol template that states “A man who has not 
had a vasectomy and is sexually active with a woman of childbearing potential must use a 
double-barrier method of birth control (see Section 4.1, Inclusion Criteria). All men must 
also not donate sperm until last dose of study drug.”
8. Prestudy and 
Concomitant Therapy
Added “antiplatelet agents, anticoagulants, and ASA use” into the list to be recorded on 
the appropriate page of the eCRF. 
8. Prestudy and 
Concomitant Therapy 
(Required/Allowed 
therapies)
Changed the subsection title from “Allowed Therapies” to “Required/Allowed Therapies”.
3.1. Overveiw of 
Study Design; 8. 
Prestudy and 
Concomitant Therapy 
(Required/Allowed 
therapies); 
Added the phrase “on a routine or as needed basis” to define diuretic use.
9.2.1. Efficacy 
Evaluations (Re-
Hospitalization for 
Worsening of Heart 
Failure)
Added the following content “The investigator will use his/her clinical judgment to 
determine if the primary diagnosis for a re-hospitalization supports worsening HF or if the 
admission is caused by a different cardiovascular event occurring concurrently (e.g., 
cardiac arrhythmia). If the primary reason for the re-hospitalization could be either event, 
the default should be re-hospitalization for worsening HF.”
9.2.1. Efficacy 
Evaluations (Re-
Hospitalization for a 
CV Event)
Added the following content “MI, Stroke, DVT, PE, and spontaneous bleeding events are 
considered cardiovascular events. If any of these are the primary reason for a 
hospitalization, complete both a re-hospitalization for CV event form and the outcome 
event eCRF form.”
9.5.1. Safety 
Evaluations (Bleeding 
outcome evaluation) 
Added the phrase “or permanent study drug discontinuation” onto the list of events to be 
collected and entered on the eCRF bleeding event page.
Clarified the phrase for a greater than 24 hour hospitalization due to non-traumatic 
bleeding 
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Approved, Date: 1 December 2016
Applicable Section(s)
Description of Change(s)
9.5.1. Safety 
Evaluations (Clinical 
Laboratory Tests)
Added the BNP or NT-proBNP values and CK-MB and troponin values, if available, onto 
the list of test results with reference ranges to be obtained from the hospital lab/local lab at 
the time of the index event
10.2. Discontinuation 
of Study Treatment
Added the sentence “If study drug is permanently discontinued prior to GTED and the 
investigator or subject would like to resume study drug, this is permissible and the 
investigator’s site manager should be contacted for instructions.”
10.2.2. Permanent 
Discontinuation of 
Study Treatment
Removed the following content “The investigator will record any adverse events that 
occurred within the 30 days before the discontinuation of study medication and add a 
narrative for any of those adverse events that were serious. The appropriate adverse event 
or serious adverse event sections of the CRF are to be completed.” 
12.3.1. All Adverse 
Events
Deleted the phrase “hospitalization for” in the front of “CV signs or symptoms expected or 
anticipated in this population such as cardiac arrhythmia, chest pain, dyspnea, edema, 
ACS, and TIAs”.
12.3.3. Pregnancy
Added the following content “Because the effect of the study drug on sperm is unknown, 
pregnancies in partners of male subjects included in the study will be reported by the 
study-site personnel within 24 hours of their knowledge of the event using the appropriate 
pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae 
in the infant will be required.”
Reference
Added 3 publications onto the reference list.
Throughout the 
protocol
Changed the phrase “chronic heart failure” to “heart failure” when appropriate.
Removed the wording “legally accepted representative”, since this study would not have 
cases where “legally accepted representative” would be used
Rationale:  Minor errors were noted.
Throughout the 
protocol
Minor grammatical, spelling or formatting changes were made.
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Amendment INT-1 (2 May 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reasons for the amendment are: 1)  to extend the acceptable 
time window of the documented left ventricular ejection fraction (LVEF) from within 3 months before 
randomization to within 1 year before randomization (Inclusion Criterion 4), this change is based on imaging being 
done on a 3 to 12 months basis in routine clinical practice; 2) to require serum brain natriuretic peptide (BNP) or N-
terminal-proBNP (NT-proBNP) level as an inclusion criterion for enrollment in the study, this change is to exclude 
low risk patients who may not have exacerbation of heart failure; 3) to add a new safety measure of collecting 
hemoglobin level at Week 12, at the request of the Independent Data Monitoring Committee (IDMC) and the 
Steering Committee; 4) to change the definition of hospitalization for heart failure (HF) from a minimum of 24-hour 
hospital stay to an overnight stay in a hospital, emergency department, or medical facility with the capability of 
treating with intravenous medications and observing patients with HF; 5) to provide clarification on inclusion and 
exclusion criteria.
Applicable Section(s)
Description of Change(s)
Rationale: Extended the acceptable time window of the documented LVEF based on imaging being done on a 3 to 
12 months basis in routine clinical practice.
Time and Events 
Schedule; 4.1. 
Inclusion Criteria
The acceptable time window of the documented LVEF has been changed from within 3 
months before randomization to within 1 year before randomization.
4.2. Exclusion 
Criteria, Note
Same change as above.
Rationale: Added serum BNP or NT-proBNP level as an inclusion criterion for enrollment in the study, this change 
is to exclude low risk patients who may not have exacerbation of heart failure
Time and Events 
Schedule
A new row has been added to the Time and Event Schedule to collect BNP or NT-proBNP 
level at screening.
Synopsis, Subject 
Population
Requirement for a minimum level of BNP or NT-proBNP level at screening for study 
entry is added.
3.1 Overview of 
Study Design
Added “Subjects must also have a brain natriuretic peptide (BNP) level ≥200 pg/mL or N-
terminal-proBNP (NT-proBNP) level ≥800 pg/mL”
4.1. Inclusion Criteria
A new inclusion criterion has been added to require a minimum BNP or NT-proBNP level 
at screening for study entry.
9.1.1. (Study 
Procedures) Overview
The following text has been added: 
“Blood for BNP or NT proBNP measurements will be drawn prior to randomization as 
part of the inclusion criteria.  If available, BNP or NT-proBNP will be measured by the 
local hospital laboratory.  If local measurements of BNP or NT-proBNP are not available, 
approximately 5 mL of blood will be sent to a local central laboratory for measurement of 
BNP or NT-proBNP (whichever is available at that laboratory).”
Rationale: Added a new safety measure of collecting hemoglobin level at the request of the IDMC and the Steering 
Committee.
Time and Events 
Schedule; 9.1.1. 
(Study Procedures) 
Overview
A new safety measure of collecting hemoglobin level at a local lab at Week 12 (no later 
than Week 24) has been added. Approximately 3-5 mL of blood will be required for the 
hemoglobin test.
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Applicable Section(s)
Description of Change(s)
Rationale: Added the recording of creatine kinase muscle and brain subunit (CK-MB), troponin levels.
Time and Events 
Schedule
A new row and a footnote have been added to the Time and Event Schedule to capture the 
recording of CK-MB and troponin levels if available during the index hospitalization.
9.1.1. (Study 
Procedures) Overview
The following text has been added: 
If available during the index hospitalization, the value of CK-MB, troponin levels should 
be recorded in the local lab section of the eCRF.
Rationale: Clarified when unscheduled visits should be done.
Time and Events 
Schedule
Footnotes have been added to the Time and Events Table to clarify when unscheduled 
visits should occur.
9.1.3. Double-Blind 
Treatment Phase
For outcome events and after a discharge for any re-hospitalization, the following text has 
been deleted:
“where the next scheduled visit is 2 or more months later”
Rationale: Clarified when replacement for lost medication should be dispensed.
Time and Events 
Schedule
Footnotes have been added to the Time and Events Table to clarify that lost medication 
requiring replacement should be dispensed at an unscheduled visit before the next 
scheduled visits.
Rationale: Defined the index hospitalization and re-hospitalization for HF.  Due to a trend in treating patients with 
HF with shorter hospital stays, as well as treating them in out-patient settings, a minimum of overnight stay will be 
required to consider the admission as the index hospitalization.
Synopsis, Overview 
of Study Design;
Synopsis, Subject 
Population; 4.1. 
Inclusion Criteria; 
9.2.1. Efficacy 
Evaluations
The index hospitalization (and re-hospitalization for HF) has been defined as an overnight 
stay (ie, staying past midnight) in a hospital, emergency department, or medical facility 
with the capability of treating with intravenous medications and observing patients with 
HF.
Rationale: Extended screening period after index hospital discharge.
Synopsis, Overview 
of Study Design;
Synopsis, Subject 
Population; Time and 
Events Schedule; 
Section 3.1. Overview 
of Study Design; 
Section 4. Subject 
Population; 9.1.2. 
Screening Phase
Subjects have up to 14 days (changed from 7 days) after discharge to enroll, as a result the 
screening period is extended to 35 days (from 28 days).
Rationale: Clarified the dose of aspirin. 
Synopsis, Overview 
of Study Design; 3.1. 
Overview of Study 
Design; 8. Prestudy 
and Concomitant 
Therapy
The dose of aspirin should be 100 mg or less per day, unless not clinically appropriate.
Rationale: Clarified how missed doses should be taken and documented.
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Applicable Section(s)
Description of Change(s)
Synopsis, Dosage and 
Administration;
6. Dosage and 
Administration;
A missed dose should be taken as soon as possible, up to 6 hours after the scheduled 
dosing time. If >6 hours has elapsed after the scheduled time the dose should be skipped 
and the next dose should be taken at the regular time.  Unintentional stopping of study 
drug for more than 7 consecutive days should be documented.
Rationale: Clarified subjects discharged from the index hospitalization to a nursing home must have a stay of 2 
weeks or less so that subject will be in a home environment at time of randomization.
4.1. Inclusion Criteria
Inclusion Criterion number 6 has been updated to state that if the subject is transferred to a 
nursing home, rehabilitation center or other skilled facility, the stay must be 2 weeks or 
less so that the subject will be in a home environment at the time of randomization.
Rationale: Clarified criteria for  diuretic, angiotensin receptor blocker (ARB), beta-blocker and aldosterone 
antagonist therapy
4.1. Inclusion Criteria
Inclusion Criterion number 7 has been updated to clarify the criteria for diuretic, ARB, 
beta-blocker and aldosterone antagonist therapy.
Rationale: Clarified criteria for safety purposes
4.1. Inclusion Criteria
Added additional instructions for subjects who had been receiving prophylactic
anticoagulation prior to randomization.
Rationale: Clarified the window of cardiac surgeries and procedures.
4.2. Exclusion 
Criteria
Clarification that planned cardiac surgery within 28 days either prior to or after
randomization, excluding PCIs and devices, and implantation of an electrophysiologic 
device such as implantable cardioverter defibrillator or pacemaker planned to occur within 
14 days either prior to or after randomization will exclude subjects from entering the 
study.
Rationale: Clarified the definitions of “ventricular tachycardia”, “significant liver disease”, “severe peptic ulcer 
disease” and “severe thrombocytopenia”.
4.2. Exclusion 
Criteria
Definitions of “ventricular tachycardia”, “significant liver disease”, “severe peptic ulcer 
disease” and “severe thrombocytopenia” are provided.
Rationale: Removed ticagrelor and prasugrel from prohibited medication as the use of these antiplatelet 
medications is increasing in patients undergoing PCI and stent placement. The use of these newer agents will be 
according to labeling.
4.1. Inclusion 
Criteria; 4.3. 
Prohibitions and 
Restrictions; 
Ticagrelor is no longer a prohibited antiplatelet medication. Prasugrel is prohibited only in 
subjects who are ≥75 years old in age, or in subjects with prior TIA or stroke.
8. Prestudy and 
Concomitant Therapy
The following text has been added to Allowed Therapies:
Clopidogrel, ticlopidine, and ticagrelor may be used if indicated.  Prasugrel may also be 
used if indicated, but not in subjects with a prior history of TIA or stroke or those who are 
75 years of age or older. There is limited data on the combined use of rivaroxaban with 
either ticagrelor or prasugrel.  The IDMC will monitor any increased risk to the subjects in 
this study using these combinations.  The use of clopidogrel, ticlopidine, ticagrelor, or 
prasugrel should be prescribed according to the approved labeling for each drug.
Rationale: Clarified the documentation of prestudy and concomitant therapy.
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Approved, Date: 1 December 2016
Applicable Section(s)
Description of Change(s)
8. Prestudy and 
Concomitant Therapy
The following text has been added (in italic) or modified (strikethrough):
Relevant concomitant medications or treatment (eg, antibiotics for sepsis or surgical 
interventions) given for adverse events and chronic use of other prohibited therapies, as 
specified below, will be documented on the appropriate page of the eCRF as well.
Rationale: Clarified the timing of D-dimer collection.
9.3. Biomarkers
Blood will be collected for D-dimer measurement prior to the first dose of study drug, 
instead of prior to randomization.
Rationale: Clarified the reporting of bleeding outcomes.  
9.5.1. Safety 
Evaluations, Bleeding
Outcome Evaluations
To clarify that bleeding events are not reported as adverse events;
To clarify that non-traumatic bleeding events are considered CV in origin. A Re-
hospitalization for CV Event eCRF page is required for subjects who are hospitalized for 
greater than 24 hours for bleeding. In addition, a discharge summary indicating the 
primary reason for admission as bleeding is required;
To add the text in italics: 
“For subjects hospitalized for a bleeding event, the admission hemoglobin and the lowest 
hemoglobin, or hematocrit (if hemoglobin is not available) will be entered on the eCRF as 
well as the final hemoglobin or hematocrit (closest to discharge).”
Rationale: Clarified that hemoglobin, not hematocrit, is to be collected.  
9.5.1. Safety 
Evaluations, Clinical 
Laboratory Tests
Hematocrit has been removed from the hematology panel.
Rationale:  Removed pooling of efficacy data by country.
11.3. Efficacy 
Analyses, Primary 
Endpoint
The following test has been deleted:
If necessary, countries with few events will be pooled. Pooling algorithm will be defined 
in the SAP.
Rationale:  Defined the minimum length of time spent in the hospital for serious adverse events.
12.1.1.  Adverse 
Event Definitions and 
Classifications; 
12.3.2. Serious 
Adverse Event
The minimum length of hospitalization for serious adverse events has been defined as 24 
hours (including time spent both in the emergency department and the in-patient room).
Rationale: Clarified the criteria for collecting adverse events and serious adverse events.
12.3.1. All Adverse 
Events
Clarification of how bleeding events will be captured.
Rationale: Clarified the recording of outcome events and adverse events between ICF signing and randomization.
12.3.1. All Adverse 
Events
The following text has been added:
If any outcome event or adverse event occurs from the time a signed ICF is obtained until 
randomization, this event will be recorded as an adverse event or an SAE on the eCRF.
Rationale: The FDA indicated that the protocol would not qualify for an exception from informed consent 
requirements for emergency research.
16.2.3. Informed 
Consent
The last paragraph of the section regarding emergency consent exception has been deleted.
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Applicable Section(s)
Description of Change(s)
Rationale: Clarified the enoxaparin dose adjustment calculation.
Attachment 3; 
Attachment 4
If additional enoxaparin is needed, the dose would be the desired dose minus the dose 
provided in the table at the specific time point.  
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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SYNOPSIS
STUDY TITLE
A Randomized, Double-blind, Event-driven, Multicenter Study Comparing the Efficacy and Safety of 
Rivaroxaban with Placebo for Reducing the Risk of Death, Myocardial Infarction or Stroke in Subjects 
with Heart Failure and Significant Coronary Artery Disease Following an Episode of Decompensated 
Heart Failure
DESCRIPTION OF THE COMPOUND
Rivaroxaban is an oral, direct acting, Factor Xa (FXa) inhibitor anticoagulant which has been developed
for the treatment of several thrombosis-mediated conditions. The clinical development program for 
rivaroxaban is extensive, with over 70,000 subjects having been studied from Phase 1 through large Phase 
3 studies covering several indications and potential indications. Approximately 40,000 of these subjects 
have received rivaroxaban. Rivaroxaban is marketed under the trade name XARELTO® and has been 
approved for multiple indications worldwide.
Heart Failure (HF) is a prothrombotic disease and thrombosis may be associated with increased morbidity 
and mortality. For the last 15 to 20 years, more research has centered around the hypercoagulable state 
that occurs in HF patients. It has been observed in clinical studies that subjects with HF have higher 
circulating levels of pro-coagulants. In addition, autopsy studies of subjects with HF who died suddenly 
during a clinical trial had a high rate of myocardial infarction (MI) or acute coronary events. Studies and 
guidelines have reported that the prognosis after inpatient or outpatient treatment of an episode of 
decompensated HF is poor with a 50% readmission rate at 6 months and a 25% to 35% mortality rate at 
12 months.
Although the results of previous studies with warfarin have demonstrated that anticoagulation is 
associated with reduced rates of important clinical events in patients with HF, results of these studies have 
not been conclusive. In a recent Phase 3 study of rivaroxaban in acute coronary syndrome (ACS), 
rivaroxaban was shown to reduce the incidence of the primary endpoint (cardiovascular [CV] death, MI, 
or stroke) in a subset of subjects with a history of HF (see Table 1 of the protocol). This supports the 
hypothesis that rivaroxaban may help reduce thrombotic events in patients with HF that can lead to death, 
MI or stroke. Thus, a large prospectively designed study with a novel anticoagulant is warranted to 
adequately address whether or not rivaroxaban can reduce the risk of death, MI, and stroke in patients 
with HF and significant coronary artery disease (CAD), following an episode of decompensated HF, 
defined as the “index event”.
This study is designed to be a pivotal Phase 3 study, with adequate power to determine if the use of the 
Factor Xa inhibitor rivaroxaban in addition to standard HF therapy can reduce the risk of important 
clinical outcome events (ie, all-cause mortality [ACM], MI, and stroke) in patients with HF and 
significant CAD. The addition of another therapeutic approach to reduce the risk of morbidity and 
mortality in HF patients would fulfill a substantial unmet medical need.
OBJECTIVES AND HYPOTHESES
Primary Objective

The primary objective is to demonstrate that rivaroxaban is superior to placebo in subjects with HF 
and significant CAD, who are receiving standard care, in reducing the risk of the composite of ACM, 
MI, or stroke following an index event.
Secondary Objectives
The secondary objectives are to compare rivaroxaban with placebo in addition to standard care in subjects 
with HF and significant CAD following an index event in reducing the risk of the following outcomes:
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
Composite of CV mortality or re-hospitalization for worsening of HF

CV mortality

Re-hospitalization for worsening of HF

Re-hospitalization for CV events
Exploratory Objectives
The exploratory objectives are to compare rivaroxaban with placebo in addition to standard care in 
subjects with HF and significant CAD following an index event.

Selected medical resource utilization (MRU) data on re-hospitalization for CV events and for 
worsening of HF

Symptomatic deep vein thrombosis (DVT)

Symptomatic pulmonary embolism (PE)

Benefit-risk balance 
Safety Objectives
The safety objectives are to compare the occurrence of the following bleeding events with rivaroxaban 
and placebo in addition to standard care in subjects with HF and significant CAD following an index 
event:

The composite of fatal bleeding or bleeding into a critical space (intracranial, intraspinal, intraocular 
[vitreous or retinal], pericardial, intra-articular, retroperitoneal, intramuscular with compartment 
syndrome) with a potential for permanent disability

Bleeding events requiring hospitalization

Major bleeding events using the International Society on Thrombosis and Haemostasis (ISTH) 
bleeding criteria
Overall safety will also be assessed.
Hypothesis
The primary hypothesis of this study is that rivaroxaban 2.5 mg taken orally twice a day (in addition to 
standard care) is superior to placebo (in addition to standard care), in subjects with HF and significant 
CAD following an index event in reducing the risk of the composite of ACM, MI, or stroke. 
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven, 
superiority study of rivaroxaban with clinical outcome assessments in subjects with symptomatic HF (3 
months or longer) and significant CAD. The subject population comprises men and women age 18 and 
over who have a diagnosis of previous MI or significant CAD with a left ventricular (LV) dysfunction 
(left ventricular ejection fraction [LVEF]) ≤40%). Only subjects treated for decompensated HF will be 
eligible for enrollment.
Eligible subjects must have an episode of decompensated HF (index event) requiring (a) an overnight stay 
in a hospital, emergency department, or medical observation facility with the capability of treating with 
intravenous medications and observing HF patients, or (b) an unscheduled outpatient visit to a HF
management center, where parenteral therapy is required for HF stabilization. Subjects must also have a 
brain natriuretic peptide (BNP) level ≥ 200 pg/mL or N-terminal-proBNP (NT-proBNP) level ≥800 
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pg/mL (preferred assay) during the screening period and before randomization. Subjects have up to 30
days after discharge to be randomized if they are in stable condition.
The primary efficacy outcome is the composite of ACM, MI, or stroke. The principal safety outcome is 
the composite of fatal bleeding or bleeding into a critical space (intracranial, intraspinal, intraocular, 
pericardial, intra-articular, retroperitoneal, intramuscular with compartment syndrome) with a potential 
for permanent disability. Additional bleeding outcomes are bleeding events requiring hospitalization, and
ISTH major bleeding events. 
A total of 1,200 primary efficacy outcome events are targeted to demonstrate the superiority of 
rivaroxaban compared with placebo. A sample size of approximately 5,000 subjects will be randomized. 
Subjects who meet all of the inclusion and none of the exclusion criteria will be randomly assigned to 
receive either rivaroxaban or placebo. Randomization will be stratified by country. After randomization, 
subjects will receive double-blind treatment (oral rivaroxaban 2.5 mg or matching placebo b.i.d.). All 
subjects will also receive standard care based on international clinical guidelines for HF and CAD as 
prescribed by their managing physicians. Standard care is expected to include a diuretic, renin angiotensin 
system (RAS) inhibitor/vasodilator therapy (angiotensin-converting enzyme inhibitors, angiotensin 
receptor blockers or hydralazine/nitrates), beta blocker therapy, aldosterone antagonist if indicated, and 
aspirin/acetylsalicylic acid (ASA) (or other antiplatelet agent as appropriate). The dose of ASA should be
100 mg or less per day, unless not clinically appropriate. Dual antiplatelet therapy is allowed where 
indicated.
The study consists of a screening phase, a double-blind treatment phase, and a follow-up after the 
sponsor-announced global treatment end date (GTED, defined as the date when 1,200 primary efficacy 
outcome events are predicted to have occurred) which is also the End of Study (EOS) visit. The screening 
phase may last up to 51 days before randomization (21 days maximum for a hospitalization admission
plus up to 30 days after discharge from the facility treating the index event), followed by an estimated 6 to 
54 months double-blind treatment phase. The average duration of participation for a subject in the study is
expected to be approximately 29 months. 
Subjects are expected to remain in the double-blind treatment phase until the GTED. The date is based on 
site local time. The study sites will be notified of the GTED at which time subjects will be instructed to 
discontinue study drug (after taking both their AM and PM doses on GTED) and return to the study site 
for the EOS visit (30±15 days, but no sooner than 15 days after the GTED). Efficacy and safety outcome 
events will be collected at the EOS visit. 
Subjects who permanently discontinue the study drug before the GTED will complete the Early 
Permanent Study Drug Discontinuation visit as soon as possible after the last dose of study drug. In 
addition, these subjects should return for all scheduled visits, including the EOS visit. If these subjects 
refuse office visits, the investigator is asked to strongly encourage the subjects to allow regular contact 
(eg, by telephone) until study end, according to the TIME AND EVENTS SCHEDULE, either with them, 
or with a close friend, relative, or their primary care physician to determine vital status and if an efficacy 
or safety outcome event has occurred.
A subject will be considered as having completed the double-blind treatment phase, if the subject 
continues taking double-blind study drug until either the announced GTED or within 7 days before the 
death of the subject. If a subject experiences an outcome event such as MI or stroke, study drug may be 
temporarily held if necessary or if using other anticoagulant drugs or thrombolytic therapy. This also 
applies to other efficacy outcome events such as DVT or PE. After the appropriate treatment of the 
outcome event, the investigator may choose to resume study medication for the subject. However, study 
medication must be permanently discontinued for any intracranial hemorrhage or for any reason listed in 
Section 10.2.2.
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Vital status will be collected for all subjects who permanently discontinue study drug early, withdraw 
from the study, or are lost to follow-up, either by telephone or in person at the EOS visit, or if applicable, 
by a review of subject’s medical or public records unless this contact is not allowed by local regulations.
A Steering Committee and an Independent Data Monitoring Committee (IDMC) will be commissioned 
for this study. The IDMC will review unblinded safety data periodically to ensure the safety of study 
subjects. If necessary or requested by the IDMC, subject level unblinded data may be provided to the 
IDMC (see Section 11.8 of the protocol for more details). In addition, the IDMC will review results of the 
planned interim analysis and make a recommendation whether the study should be terminated 
prematurely due to overwhelming benefit or futility (see Section 11.9 of the protocol for more details). No 
independent Clinical Event Committee will be used for adjudication of outcome events in this study.
SUBJECT POPULATION
The subject population comprises men and women age 18 years and older with HF (3 months or longer) 
and significant CAD with LV dysfunction (LVEF ≤40%). Significant CAD is defined as: documented 
previous MI, history of prior coronary artery bypass graft, coronary angiography demonstrating at least 
50% stenosis of one or more arteries, history of percutaneous coronary intervention (PCI) with or without 
stent, or for those with no documented history of MI, electrocardiogram (ECG) evidence (Q waves) with 
corresponding wall motion abnormality on echocardiogram at any point during the index event period to 
randomization. Eligible subjects must have an episode of decompensated HF (index event) requiring (a)
an overnight stay in a hospital, emergency department, or medical observation facility with the capability 
of treating with intravenous medications and observing HF patients, or (b) an unscheduled outpatient visit 
to a HF management center, where parenteral therapy is required for HF stabilization. Subjects must also 
have a BNP level ≥ 200 pg/mL or NT-proBNP level ≥800 pg/mL (preferred assay) during the screening 
period and before randomization. Subjects have up to 30 days after discharge to be randomized if they are 
in stable condition.
DOSAGE AND ADMINISTRATION
Subjects will be randomly assigned in a 1:1 ratio to receive oral rivaroxaban 2.5 mg or placebo b.i.d.
(each in addition to standard of care for HF and CAD as prescribed by their managing physician). 
Randomization will be stratified by country.
All subjects will receive study drug (rivaroxaban or placebo) orally twice daily; once in the morning and 
once in the evening, with or without food, at approximately the same times each day throughout the study. 
Once the GTED is reached, all subjects who are receiving study drug should discontinue study drug (after 
taking both their AM and PM doses on GTED) and complete the EOS visit (refer to TIME AND 
EVENTS SCHEDULE). 
A missed dose should be taken as soon as possible (up to 6 hours after the scheduled dosing time), and the 
next scheduled dose should be taken at the regular time. If >6 hours has elapsed after the scheduled time 
the dose should be skipped and the next dose should be taken at the regular time.  An occasional forgotten
dose need not be recorded. Intentional stopping of study drug by the subject, unintentional stopping of 
study drug for more than 7 consecutive days, or direction to temporarily stop study drug by the 
investigator or other physician will be documented and recorded in the eCRF.
Throughout the study, study drug will be dispensed at appropriate intervals (see the TIME AND 
EVENTS SCHEDULE) to ensure that subjects have adequate quantities of study drug between study 
visits.
Interruption of Study Drug 
Study drug may be interrupted temporarily as necessary for invasive procedures or as medically 
needed (eg, in the setting of a bleeding event or a required prohibited therapy). Regardless of the duration 
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of interruption, subjects may be restarted on study drug, except for those subjects who had an intracranial 
hemorrhage. These will be recorded on the electronic Case Report Form (eCRF).
EFFICACY EVALUATIONS/OUTCOMES
This is a clinical outcome study. The primary efficacy outcome is the composite of ACM, MI, or stroke.
Secondary efficacy outcomes are:

Composite of CV mortality or re-hospitalization for worsening of HF

CV mortality

Re-hospitalization for worsening of HF

Re-hospitalization for CV events
Exploratory outcomes are:

Selected MRU data on re-hospitalizations for CV events and for worsening of HF

Symptomatic DVT

Symptomatic PE
SAFETY EVALUATIONS/OUTCOMES

The principal safety outcome is the composite of fatal bleeding or bleeding into a critical space 
(intracranial, intraspinal, intraocular [vitreous or retinal], pericardial, retroperitoneal, intra-articular, 
intramuscular with compartment syndrome) with a potential for permanent disability. 

Additional bleeding outcomes are bleeding events requiring hospitalization, and ISTH major 
bleeding events.
STATISTICAL METHODS
Sample Size Justification
This is an event driven study. The study was initially designed to observe occurrences of the primary 
efficacy event in 984 unique randomized subjects, on or before the GTED, to have 90% power to detect a 
20% relative risk reduction (RRR, defined as subtracting the hazard ratio [test to control] from 1) in the 
composite of ACM, MI, or stroke at a 5%, 2-sided statistical significance level. A total of approximately 
5000 subjects will be randomized to either the rivaroxaban group or the placebo group in a 1:1 ratio. If the 
event rate is lower than expected, the sample size may be increased by up to 500 subjects.
The above sample size calculation was estimated based on the following assumptions:

Effect size: 20% RRR

Event rate in the placebo arm: 19%/year

Power: 90%

Over all α level: 5%, 2-sided

Permanent premature treatment discontinuation rate: 10%/year

Lost-to-follow-up: 1%/year 

Duration of enrollment period: 24 months, based on a non-uniform enrollment distribution

Duration of study (from First-Patient-Randomization to GTED): 31 months
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The assumptions of RRR and event rate were based on observations from congestive HF subjects (the HF 
subgroup) in the ATLAS ACS 2 TIMI 51 study and review of literature (see Section 11.2 of the protocol 
for more details).
The study is revised to observe occurrences of the primary efficacy event in 1,200 unique randomized 
subjects based on a blinded simulation study performed on currently available trial data (ie, longer 
enrollment period, lower than anticipated primary efficacy event rate, higher than anticipated study drug 
discontinuation rate). Further details are described in the Statistical Analysis Plan (SAP).
Analyses – Efficacy
The primary efficacy analysis endpoint is the time from randomization to the first occurrence of death, 
MI, or stroke. The associated statistical null hypothesis is that there is no difference between treatment 
groups in distribution of the time, and the alternative hypothesis is that there is a difference between 
treatment groups.
The primary statistical hypothesis will be tested using a log-rank test, stratified by region. In addition to 
the final analysis, an interim analysis is planned. The primary analysis will include all events up to and 
including the GTED based on site local time/date (up to the cut-off date in the interim analysis), in all 
randomized subjects with valid informed consent signed. Subjects will be analyzed according to the 
treatment group to which they are randomized, regardless of actual treatment received. The overall α level 
is 5%, 2-sided. A Lan-DeMets α spending function with O’Brien-Fleming type of boundaries will be used 
to preserve the overall type I error rate.
The cumulative event rate derived from Kaplan-Meier estimate will be displayed graphically to evaluate 
the timing of event occurrence and the consistency of the treatment effect over time. The RRR will be 
estimated using a Cox proportional hazards model, stratified by region, with treatment (as randomized) as 
the only covariate.
Homogeneity of treatment effects, both in RRR and direction will be evaluated for the following 
subgroups. 

Age (< 65 vs ≥ 65; < 75 vs ≥ 75 years)

Sex (men vs women)

LVEF (≤30% vs > 30%; ≤ median vs > median)

Estimated glomerular filtration rate (Modification of Diet in Renal Disease formula value <30, 30 to 
<60, 60 to <90, ≥90 mL/min/1.73 m2)

Baseline D-dimer  level by quartile

BNP, NT-proBNP (≤ median vs > median)

History of diabetes (yes vs no)

History of stroke (yes vs no)

History of MI (yes vs no)

Hypertension (yes vs no)

Body Mass Index (<25, 25 to <30, ≥30 kg/m2)

Baseline digoxin use (yes vs no)

Baseline β-blocker use (yes vs no)

Baseline aldosterone inhibitors (yes vs no)
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
Baseline angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)
(yes vs no)

Baseline aspirin use (yes vs no)

Baseline aspirin vs dual antiplatelet use

Baseline thienopyridine use (yes vs no)

NYHA (Class II, III, IV)

Race (White vs others)

Race (White, Asian, other)

Region
If superiority of rivaroxaban over placebo in reducing the risk of the primary efficacy endpoint is 
established, treatment effects in secondary endpoints will be tested subsequently in the hierarchical order: 
1) Composite of CV mortality or re-hospitalization for worsening of HF
2) CV mortality 
3) Re-hospitalization for worsening of HF 
4) Re-hospitalization for CV events
Statistical significance is required before testing the next hypothesis in the hierarchical test procedure.  
These secondary endpoints will be analyzed using time-to-event analysis methods described above for the 
primary endpoint.
Analyses - Safety
Safety analysis will include randomized subjects who receive at least 1 dose or partial dose of study drug.
The analysis methods used for the primary efficacy endpoint will be used for the following safety 
endpoints. However, there are no stopping boundaries defined for these safety endpoints. Instead, nominal 
p-values will be reported.

Principal safety endpoint, which is the composite of fatal bleeding or bleeding into a critical space 
with potential for permanent disability

Bleeding requiring hospitalization

ISTH major bleeding event
In addition, summary statistics will be provided for all other reported bleeding events.
Verbatim terms reported in the CRF by investigators to identify adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). For each MedDRA preferred term, the 
percentage of subjects who experience at least 1 occurrence of the given event will be summarized by 
treatment group. Additional summaries, listings, or subject narratives may be provided, as appropriate.
EUDRACT number: 2013-000046-19
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TIME AND EVENTS SCHEDULE
Period/Phase
Screening
Perioda,b,c,d
Double-Blind Treatment Phase
Follow-Up After
GTED
Baselinea
Treatment Period
Day/Week
Day -51 to 
Day -1
Day 1/
Randomization
Week 4
(Day 28)
Week 12 
(Day 84)
q12wke,f
(q84d)
Early Permanent 
Study Drug
Discontinuation 
End of Studyg
Window
Study Procedure
21 days 
maximum for a 
hospitalization 
admission plus 
up to 30 days 
after discharge
-4/+2 days
-/+4 days
-/+6 days
30±15 days
Screening/Administrative
Informed consent (ICF)
X
Xh
Inclusion/exclusion criteria
X
Xi
Review medical history requirements
(including history of smoking)
X
Demographics, body weight, height, pulse
and blood pressure
X
Preplanned surgical/procedure(s)
X
Xi
Urine or serum pregnancy testj
Xi
Xk
Xk
BNP or NT-proBNPl
X
Study Drug Administration
Randomization
Xm
Record NYHA classification
X
X
X
Record LVEF
Xn
Dispense study drugo
X
X
X
First dose of study drug 
administered in clinicp
X
Study drug administrationq,r
X
X
X
X
Study drug accountability
X
X
X
X
X
X
Safety and Efficacy Assessments
Clinical status review: record outcome 
eventss
X
X
X
X
X
X
X
Adverse events assessmentt
X
X
X
X
X
X
X
Review concomitant medications related to 
subject's HF and CAD
X
X
X
X
X
X
X
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Period/Phase
Screening
Perioda,b,c,d
Double-Blind Treatment Phase
Follow-Up After
GTED
Baselinea
Treatment Period
Day/Week
Day -51 to 
Day -1
Day 1/
Randomization
Week 4
(Day 28)
Week 12 
(Day 84)
q12wke,f
(q84d)
Early Permanent 
Study Drug
Discontinuation 
End of Studyg
Window
Study Procedure
21 days 
maximum for a 
hospitalization 
admission plus 
up to 30 days 
after discharge
-4/+2 days
-/+4 days
-/+6 days
30±15 days
Review antiplatelet, anticoagulant, proton 
pump inhibitors, prothrombin complex 
concentrates, and prohibited medications
X
X
X
X
X
X
X
Medical resource utilization
X
X
X
X
X
Hemoglobinu
Xk,v
Xw
Platelet count, automated
Xk,v
Serum creatinine for eGFRx
Xk,v
Modified Rankin Evaluation, if stroke 
outcome event occurred
Xy
Xy
Xy
Xy
Biomarkers
D-dimer
Xz
Xaa
CK-MB, troponin
Xab
Key: BNP=brain natriuretic peptide; CAD=coronary artery disease; CK-MB=creatine kinase muscle and brain subunit; eGFR=estimated glomerular filtration rate; 
HF=heart failure; GTED=global treatment end date; LVEF= left ventricular ejection fraction; NYHA= New York Heart Association; NT-proBNP=N terminal-
proBNP; q12wk=every 12 weeks.
a
All screening evaluations must be completed before randomization. Both screening and baseline evaluations may occur on the day of randomization (defined as 
Day 1).
b
The screening period may last up to 51 days before randomization (21 days maximum for a hospitalization admission plus up to 30 days after discharge from the 
facility treating the index event).
c
Laboratory screening assessments that are part of the standard care performed by the investigator do not need to be repeated if performed within the timeframe 
required by the protocol.
d
Hospital/local laboratory results and imaging studies (within 51 days [21 days maximum for a hospitalization admission plus up to 30 days after discharge from the 
facility treating the index event]) will be used for screening purposes and will serve as the baseline (Day 1) laboratory results.
e
Treatment visit every 12 weeks until the global treatment end date (GTED) when pre-specified number of primary efficacy outcome events is estimated to be reached.
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f
At the GTED subjects will be instructed to stop their study drug and return to the study site 30 Days (±15 days) for the End-of-Study visit. 
Subjects who permanently discontinue the study drug before the GTED will complete the Early Permanent Study Drug Discontinuation visit as soon as possible after 
their last dose of study drug. In addition, every attempt will be made to follow these subjects for all subsequent scheduled visits until EOS.
g
Contact will take place 30±15 days, but no sooner than 15 days after the GTED to assess efficacy and safety outcomes. For subjects who discontinue study drug 
prematurely this contact will take place within the same time frame after the GTED. See Section 9.1.4.
h
If subject is screened and randomized the same day.
i
To be reviewed before randomization.
j
To be performed on all women of childbearing potential. Additional serum or urine pregnancy tests may be performed, as determined necessary by the investigator or 
required by local regulation, to establish the absence of pregnancy at any time during the subject's participation in the study.
k
Use local laboratory results for the inclusion and exclusion clinical laboratory parameters and for early permanent study drug discontinuation or the GTED visits. All 
screening clinical laboratory results must be completed and reviewed before randomization. 
l
Blood for BNP or NT proBNP measurements will be drawn prior to randomization as part of the inclusion criteria.  If available, BNP or NT-proBNP will be measured 
by the local hospital laboratory.  If local measurements of BNP or NT-proBNP are not available, approximately 5 mL of blood will be sent to a local central 
laboratory for measurement of BNP or NT-proBNP (whichever is available at that laboratory).
m
Subjects will be randomized up to 30 days after discharge from the facility treating the index event.
n
Documented within 1 year before randomization. If more than one LVEF is available the most recent one should be used.
o
Study drug will be dispensed on Day 1 after randomization and every scheduled visit thereafter except Week 4 until end of treatment. Lost medication requiring 
replacement should be dispensed at an unscheduled visit before the next scheduled visits.
p
If the first dose of study drug is taken prior to or at 12:00 PM (noon), it is considered the AM dose of the day and a PM dose should also be taken. If it is taken after 
12:00 PM (noon), it is considered the PM dose of the day and another pill should not be taken that day.
q
Subjects will self-administer study drug once in the morning and once in the evening (approximately 12 hours apart), at approximately the same times each day.
r
Subjects who experience any outcome events (except for death and hemorrhagic stroke) may continue to receive blinded study drug and complete all scheduled visits.
s
When an outcome event occurs, or after discharge for any re-hospitalization, an unscheduled visit before the next scheduled visit should be done for clinical status 
review and outcome event recording.
t
See Section 9.5, Safety Evaluations and Outcomes for adverse events that will be recorded. Based upon the severity of the adverse event and clinical judgment of the 
investigator, an unscheduled visit before the next scheduled visit may be needed to assess adverse events.
u
If the subject is re-hospitalized for bleeding at any time after randomization, and a hemoglobin or hematocrit test is done, the result should be recorded on the 
hematology lab page(s) in the eCRF.
v
Test result closest to randomization should be used.
w
If a hemoglobin collection is not done at the local lab at Week 12 (±14 days), it should be collected no later than Week 24 (+ 14 days).
x
Creatinine concentration for eGFR will be calculated by the interactive web response system using the Modification of Diet in Renal Disease formula (Attachment 1).
y
A Modified Rankin Evaluation (Attachment 2) will be obtained between 6 and 18 weeks following a stroke outcome event or at End of Study, whichever occurs first.
z
To be collected from all subjects prior to the first dose of study drug and analyzed by the central laboratory. 
aa
To be collected from approximately 10% of randomly selected subjects within each country and analyzed by the central laboratory.
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ab
If available during the index event, the value of CK-MB and/or troponin should be recorded on the lab page(s) of the eCRF (if more than one test values are available, 
use the highest value).
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ABBREVIATIONS
ACE
angiotensin-converting enzyme
ACEI
angiotensin-converting enzyme inhibitor 
ACM
all-cause mortality
ACS
acute coronary syndrome
AFib
Atrial fibrillation
ARB
angiotensin receptor blockers
ASA
acetylsalicylic acid
BNP
brain natriuretic peptide
CABG
coronary artery bypass graft
CAD
coronary artery disease
CCU
Critical Care Unit
CK-MB
creatine kinase-muscle and brain subunit
CRF
case report form
CV
cardiovascular
DCF
data clarification form
DCM
dilated cardiomyopathy
DVT
deep vein thrombosis
ECG
electrocardiogram
eCRF
electronic case report form
eDC
electronic data capture
EF
ejection fraction
eGFR
estimated glomerular filtration rate
EOS
End-of-Study
ER
emergency room
FXa
Factor Xa
GCP
Good Clinical Practice
GTED
Global Treatment End Date
HF
heart failure
HR
hazard ratio
ICF
informed consent form
ICH
International Conference on Harmonisation
ICU
Intensive Care Unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHD
ischemic cardiomyopathy
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Haemostasis
ITT
Intent-to Treat
IWRS
interactive web response system
LBBB
left bundle branch block
LOS
length of stay
LV
left ventricular
LVEF
left ventricular ejection fraction
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRU
medical resource utilization
NT-proBNP
N-terminal-pro- brain natriuretic peptide
PCC
prothrombin complex concentrates
PCI
percutaneous coronary intervention
Pcr
Plasma creatinine
PE
pulmonary embolism
PQC
Product Quality Complaint
PRO
patient-reported outcome(s)
RAS
renin angiotensin system
RRR
relative risk reduction
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TIA
transient ischemic attack
ULN
upper limit of normal
US
United States
VTE
venous thromboembolism
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1.
INTRODUCTION
Rivaroxaban is an oral, direct acting, Factor Xa (FXa) inhibitor anticoagulant that has been 
developed for the treatment of several thrombosis-mediated conditions. The clinical development 
program for rivaroxaban is extensive, with over 70,000 subjects having been studied from Phase 
1 through multiple large Phase 3 studies covering several indications and potential indications. 
Approximately 40,000 of these subjects have received rivaroxaban. Rivaroxaban is marketed 
under the trade name XARELTO® and has been approved in multiple indications worldwide.
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of rivaroxaban, refer to the latest version of the Investigator's Brochure for rivaroxaban. 
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
There are approximately 5.7 million people in the United States (US) suffering from heart failure 
(HF), and of that number approximately 57,000 die each year as a direct result of HF21. In 
addition, it has been estimated that there are about 6.5 million HF patients in Europe. Despite 
many recent advances in the treatment of HF both pharmacologically (eg, angiotensin-converting 
enzyme [ACE] inhibitors, beta blockers) and with devices (eg, implantable defibrillators), 
morbidity and mortality remain high. Overall, approximately 50% of HF patients die within 
4 years of diagnosis8. It remains the most costly disease with respect to hospitalization in the US. 
The estimated direct cost for HF in the US in 2009 was almost $34 billion15.
For the last 15 to 20 years, research has centered around the hypercoagulable state that occurs in 
HF patients6. It has been observed in clinical studies that subjects with HF have higher 
circulating levels of procoagulants4. In addition, autopsy studies of HF subjects who died 
suddenly during a clinical trial had high rates of MI or acute coronary events27.
Approximately 50% of HF patients have a history of a previous MI and about 70% have known 
significant coronary artery disease (CAD) with sudden death being a major cause of mortality3. 
In a large subgroup of subjects with HF in the ATLAS ACS 2 TIMI 51 trial, it was observed that 
the rivaroxaban dose groups had decreased rates of CV events and death compared with the 
placebo control group, which was consistent with the overall study findings (Clinical Study 
Report ATLAS ACS 2 TIMI 51). Subjects in both groups were taking background therapy of 
aspirin, and most were also taking a thienopyridine. This finding combined with the results of 
previous smaller studies on the hypercoagulable state that occurs in HF provides the basis for the 
exploration of the effect of rivaroxaban in similar patients with significant CAD but without a 
recent acute coronary syndrome (ACS) event. 
Studies and guidelines have reported that the prognosis after an index hospitalization for HF is 
poor with a 50% hospital readmission rate at 6 months and a 25% to 35% mortality rate at 12 
months14. In a review of the CHARM study, subjects were noted to be at a higher risk of death
and re-hospitalization if they were hospitalized for HF exacerbation during the study23. This risk 
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was the greatest over the first 6 months and gradually returned to the risk of non-hospitalized 
subjects in that study after a year. The pathophysiology for this high mortality is not well 
understood, but there may be recurrent thrombotic events that occur as the subjects transition 
back to home care and off anticoagulant therapy received during the hospitalization period. 
Because the period of time after an inpatient or outpatient treatment for HF carries a higher risk 
for HF subjects23,24, it would likely be a period where the benefit of rivaroxaban would be 
detected.
1.1.1.
Compound Profile
As part of the prothrombinase complex, FXa directly converts prothrombin to thrombin. 
Thrombin converts fibrinogen to fibrin and activates platelets leading to clot formation. FXa 
occupies a critical place in the coagulation cascade since it is at the confluence of both the 
intrinsic and extrinsic clotting pathways, and is the key amplification point for the generation of 
thrombin. One molecule of FXa is able to generate more than 1,000 molecules of thrombin due 
to the amplification nature of the coagulation cascade. Selective inhibitors of FXa can terminate 
the amplified burst of thrombin generation and prevent clot formation. 
Rivaroxaban is an oral, direct, FXa inhibitor anticoagulant. Rivaroxaban is rapidly absorbed after 
oral administration, with peak plasma concentrations occurring approximately 2 to 4 hours post 
dose. The elimination pathways of rivaroxaban include both hepatic and renal routes. The 
terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy young subjects (aged 20 to 
45 years) and from 11 to 13 hours in healthy elderly subjects (aged 65 to 83 years). Due to 
rivaroxaban’s multiple elimination pathways, there are few clinically relevant drug-drug 
interactions.
A randomized, multicenter Phase 1 study to evaluate the pharmacokinetics, pharmacodynamics, 
and safety of rivaroxaban (10 mg once daily) in subjects with acute (open-label, active-
controlled) or chronic (double-blind, placebo-controlled) HF was recently conducted12. This 
study had 2 cohorts of subjects with HF (rivaroxaban was administered in addition to current 
congestive HF therapy), 8 subjects with acute decompensated HF (Cohort 1) and 18 subjects 
with chronic, stable, severe HF, NYHA Classes III or IV, (Cohort 2). The study was open-label, 
active-controlled (using enoxaparin as the control) in Cohort 1 and was double-blind, placebo-
controlled in Cohort 2.
In general, the PK profile of rivaroxaban was comparable between the 2 cohorts. During steady 
state, peak plasma concentrations of rivaroxaban were reached between approximately 1 to 4 
hours after administration, irrespective of cohort. Rivaroxaban was eliminated with a half-life of 
7 to 8 hours, on average in both cohorts, which is comparable with data observed in healthy 
subjects (with a half-life of 5 to 9 hours). Compared with healthy subjects, clearance was 
decreased in subjects with HF. This resulted in, on average, approximately a 1.8-fold higher 
plasma exposure (AUC) in subjects diagnosed with HF (when considering both cohorts together) 
as compared with a pooled (single dose) database of healthy subjects (n=345 receiving a single 
dose of 10 mg rivaroxaban; age range: 18 to 80 years). Compared with healthy elderly subjects 
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(age range: 65 to 80 years with mean age: 71 years), AUC∞was approximately 20% higher in 
subjects with HF. 
The proportion of subjects reporting an adverse event or treatment-emergent adverse event was 
comparable between the rivaroxaban and placebo/enoxaparin groups and between the 2 cohorts. 
In the Phase 3 ATLAS ACS 2 TIMI 51 study in which subjects with ACS were treated with 
rivaroxaban or placebo plus standard care antiplatelet therapy, 1694 subjects had a history of HF 
(etiology not specified) at baseline (rivaroxaban 2.5 mg b.i.d.: 562; rivaroxaban 5 mg b.i.d.: 574; 
placebo: 558). The composite endpoint event rate of CV death, MI or stroke was reduced in both 
rivaroxaban dose groups compared to placebo group with no apparent dose response (Table 1).
Table 1:
Efficacy Endpoints in Subjects who had a History of Heart Failure at Baseline in the Phase 3 
ATLAS ACS 2 TIMI 51 Study
CV=cardiovascular; HF=heart failure; Riva=rivaroxaban; MI=myocardial infarction.
Source: ATLAS ACS 2 TIMI 51 Clinical Study Report and post hoc analysis of data from ATLAS ACS 2 TIMI 51.
The safety profile of rivaroxaban has been well established. As to be expected from a compound 
in the anticoagulant class of drugs, bleeding risk is associated with the use of rivaroxaban. Post 
hoc analysis showed that in this same subgroup of subjects with HF treated with rivaroxaban or 
placebo in ATLAS ACS 2 TIMI 51, the incidence of bleeding in the safety population for this 
subgroup was similar. The incidence of non-coronary artery bypass graft (CABG) TIMI major 
bleeding was 0.4%, 1.1%, and 0.5% in the rivaroxaban 2.5 mg group, the rivaroxaban 5 mg 
group, and the placebo group, respectively. The incidence of TIMI life-threatening bleeding was 
also similar at 0.4%, 0.5% and 0.5% in the rivaroxaban 2.5 mg group, the rivaroxaban 5 mg 
group, and the placebo group, respectively.  
1.1.2.
Heart Failure – Scope of the Problem
Heart failure is a major public health problem. In 2004 it was estimated that HF contributed to 
approximately 287,200 deaths in the US22 and was the primary cause of death in approximately 
57,000 patients based upon the most recent AHA statistics21. Heart failure is also the most 
common reason for hospitalizations in the US. The clinical and societal burden of heart disease 
consumes approximately 8.3% of the US health care budget and HF management is a major 
contributor of this burden. In addition, it has been estimated that there are about 6.5 million HF 
patients in Europe25. And if one looks at all the 51 countries represented by the European Society 
of Cardiology (with a population of 900 million people) there are an estimated 15 million 
patients with HF8.
Rivaroxaban
Placebo
Hazard Ratio
2.5 mg b.i.d. 
5 mg b.i.d.
Riva 2.5 mg vs. 
Placebo
Riva 5 mg vs 
Placebo
HF patients 
  (N=562)
(N=574)
(N=558)
CV Death/MI/Stroke 
59 (10.5%) 
64 (11.1%) 
96 (17.2%) 
0.58 (0.42,0.81) 
0.61 (0.44,0.83) 
   CV Death 
23 (4.1%) 
33 (5.7%) 
50 (9.0%) 
0.45 (0.27,0.74) 
0.62 (0.40,0.96) 
   MI 
36 (6.4%) 
32 (5.6%) 
50 (9.0%) 
0.67 (0.44,1.03) 
0.58 (0.37,0.91) 
   Stroke 
  7 (1.2%) 
12 (2.1%) 
10 (1.8%) 
0.69 (0.26,1.81) 
1.12 (0.48,2.61) 
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The numbers of HF patients are increasing due to the aging of the global population and the 
ability of increasing numbers of individuals to survive to an age when HF is likely to become a 
problem. In addition, the availability of improved medical technologies has enabled more 
effective treatment of ACS and conferred improved survival rates in patients following MI, the 
most powerful predictor of LV systolic dysfunction and risk of HF. As a result, the absolute 
numbers of individuals living with compromised cardiac function and clinical HF are expected to 
rise dramatically over the next few decades25. 
Heart failure is a complex disease in which poor cardiac reserve is the result of a complicated 
pathophysiology, which includes poor left ventricular (LV) function, derangement of the renin-
angiotensin system, increased levels of sympathetic stimulation, and increased levels of 
cytokines and other inflammatory markers. Many of these can lead to a hypercoagulable state 
which is seen in HF. Despite advances made in the pharmacologic treatment of HF (ACE 
inhibitors, angiotensin receptor blockers [ARBs], beta blocker therapy, aldosterone inhibition), 
the mortality rate from severe HF remains at 60% within 5 years of diagnosis, and 50% of 
hospitalized patients with HF require readmission within 6 months of discharge3.
1.1.3.
Clinical Studies in Patients with Heart Failure with Anticoagulants
A number of approaches, including retrospective analyses of large HF studies such as SAVE, 
SOLVD, and V-HeFT, single and multicenter chart reviews, as well as prospectively defined, 
blinded interventional studies have attempted to address the question of whether anticoagulation 
can reduce the risk of important clinical events in patients with HF.
The EPICAL study was an observational study in a region of France that followed subjects 
admitted with severe HF and a LV dysfunction that was designed to evaluate treatment and 
prognosis. A post-hoc analysis of data from the 417 subjects in that study showed that the use of 
oral anticoagulants and/or aspirin was associated with 5-year survival rate that was better in 
subjects receiving anticoagulants than those who did not11. These results must be interpreted with 
caution as subjects were not randomized.
Retrospective Analyses
In the V-HeFT I study, the embolic rate in subjects receiving warfarin was similar to that in 
subjects who did not receive warfarin (2.9 v 2.7 events/100 patient-years; p =NS); V-HeFT II 
showed similar findings. In V HeFT I study, aspirin use was found to reduce the incidence of 
thromboembolism from 2.7 to 0.5 events/100 patient-years (p=0.007), whereas V HeFT II 
showed no significant reduction (2.1–1.6 events/100 patient-years; p=0.4810.
The SAVE study reported an 81% risk reduction in stroke among subjects receiving warfarin. 
Aspirin reduced the overall risk of stroke by 56%, with a marked effect (66% risk reduction) in 
subjects with left ventricular ejection fraction (LVEF) <28% (p <0.001)16.
An analysis of the SOLVD database indicated that warfarin use is associated with improved 
survival and reduced morbidity in subjects with HF. This association was primarily due to a 
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reduction in cardiac events1. In addition, the SOLVD investigators reported a 24% reduction in 
sudden death in subjects treated with aspirin monotherapy9.
Prospectively Designed Studies
Four prospectively designed, randomized trials (WASH, WATCH, HELAS and WARCEF) have 
been conducted to assess the effect of anticoagulation or platelet inhibition on outcome in HF 
patients. 
In the WASH study5, HF subjects were randomized to receive warfarin, aspirin, or no 
antithrombotic therapy. Subjects had to have a clinical diagnosis of HF with evidence of LV 
dysfunction on echocardiogram (LVEF < 35%). This was an open label pilot study. The dose of 
aspirin was 300 mg/day and the mean INR was reported as 2.3. Time in therapeutic range (TTR)
was not reported. A total of 279 subjects were randomized into the three arms of the study. No 
significant difference in the primary endpoint of death, non-fatal MI, or non-fatal stroke was 
seen, but there was a significant difference (P < 0.05) in all-cause hospitalization with subjects 
randomized to aspirin having the highest incidence. The study had poor recruitment felt to be due 
to a no antithrombotic arm.
The WATCH study18 was a double-blind, double-dummy study comparing warfarin, aspirin at 
162 mg/day, and clopidogrel 75 mg/day. Warfarin was titrated to an INR of 2.5 to 3.0. Subjects 
had symptomatic HF and an EF < 35%. The primary endpoint was the composite of all-cause 
mortality, MI, or stroke. The majority of subjects were NYHA Class III followed by Class II. 
Only 2% of subjects were Class IV. A total of 1587 subjects were randomized out of a planned 
4500, and the study was terminated early. Because of low enrollment, the power to detect a 20% 
difference dropped from 90% to 41%. The TTR (acceptable INR range 2.0 to 3.5) for subjects on 
warfarin was 70%. There was no statistical difference in the comparisons made between warfarin 
and aspirin, warfarin and clopidogrel, or clopidogrel and aspirin. Hospitalization for HF was 
highest in the aspirin group (22.2%), followed by clopidogrel (18.5%) and warfarin (16.5%). 
Although hospitalization rates were higher in aspirin-treated subjects the absence of difference in 
survival or in the primary endpoint led the authors to avoid making any recommendations against 
the use of aspirin in patients with chronic HF in sinus rhythm.
The HELAS study7 was a double-blind, placebo- and active- controlled study in subjects with 
either ischemic cardiomyopathy (IHD) or dilated cardiomyopathy (DCM). Those with IHD 
received either warfarin or aspirin, while those with DCM received either warfarin or placebo. 
The dose of aspirin was 325 mg/day while the warfarin was titrated to an INR of 2.0 to 3.0. 
Subjects were required to have symptomatic HF and a LVEF of < 35%. Although 6000 subjects 
were planned to be enrolled, only 197 were actually randomized due to slow enrollment. There 
were 115 subjects with IHD randomized, and 82 with DCM randomized. The primary endpoint 
was similar among the four groups, although deaths were lowest in the DCM group receiving 
warfarin.
The WARCEF study13 had a targeted enrollment of 2860 subjects with HF. This was a double 
blind study comparing warfarin (target INR 2.0 to 3.5) to aspirin 325 mg/day. The objective of 
the study was to evaluate whether or not warfarin is superior to aspirin in the prevention of all-
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cause mortality and all stroke (ischemic or hemorrhagic) in subjects with a LVEF ≤35%. The 
study was stopped prematurely due to low enrollment, and this resulted in a power of 67%. The 
study demonstrated that the rate of death, ischemic stroke or intracerebral hemorrhage was 
similar in the warfarin and aspirin groups (7.5% vs 7.9%, respectively). When the individual 
components of the primary endpoint are listed as separate components, it can be seen that, while 
death was not statistically different in either treatment arm, subjects receiving warfarin had a 
significantly lower rate of ischemic strokes than those receiving aspirin. 
Table 2 summarizes the results of these four recent prospective HF studies. It should be noted in 
this table that the incidence of major bleeding was always highest in the warfarin treated 
subjects, ranging from 1.8% compared to 0.9% in the aspirin treated group in the WARCEF 
study to 5.2% versus 3.6% in the aspirin group and 2.1% in the clopidogrel group in the 
WATCH study. 
All of these studies compared warfarin to either aspirin/clopidogrel, placebo, or both. There has 
been no large, randomized, controlled study comparing an anticoagulant plus antiplatelet therapy 
to antiplatelet therapy alone in addition to other standards of care. 
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Table 2:
Summary of the Results Four Recent Prospective Studies in Patients with Heart Failure
Study 
Treatment
N
Primary 
Endpoint
Primary Endpoint %
Hospitalization %a
Death %
Stroke %
Major Bleeding %
W
A
P/Cb
W
A 
P/Cb
W
A
P/Cb
W
A
P/Cb
W
A
P/Cb
WASH5
(2004)
W vs A vsP
279
D/MI/CVA
26
32
26
47
64
48
35
30
21
0
2
2
4
1
0
WATCH18
(2009)
W vs A vs C
1587
D/MI/CVA
19.6
20.7
21.6
16.5
22.2
18.5
17.0
18.0
18.3
3.9
2.7
2.5
5.2
3.6
2.1
HELAS7
(2006)
W vs A (IHD);
W vs P (DCM)
115;
82
D/MI/CVA;
Hosp/PE
15.7;
8.9
14.9;
-
-;
14.8
2.4;
4.4
3.2
-
-;
5.9
13.3;
3
9.6;
-
-;
8.9
2.4;
0
2.1;
-
-;
1.5
4.8;
4.4
0;
-
-;
0
WARCEF13
(2012)
W vs A
2305
D/CVA/
ICH
7.5
7.9
-
20.9
17.5
-
23.5
22.6
-
3
4.9
-
1.8
0.9
-
a) Hospitalization for all causes in WASH, and for HF hospitalization in WATCH, HELAS and WARCEF.
b) This column is placebo except in WATCH where it is clopidogrel and WARCEF where there was no placebo arm.
“-” indicates no data because of study design.
W=Warfarin; A=Aspirin; P=Placebo (or no antithrombotic agent); C=Clopidogrel; IHD= Ischemic cardiomyopathy group; DCM= Dilated cardiomyopathy group; 
D=death; MI=myocardial infarction; CVA=cerebrovascular accident; Hosp=hospitalization; PE =pulmonary embolism; ICH=intracerebral hemorrhage
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1.2.
Overall Rationale for the Study
Heart failure is a prothrombotic disease and thrombosis may be associated with increased 
morbidity and mortality. Although the results of previous studies with warfarin have 
demonstrated that anticoagulation is associated with reduced rates of important clinical events in 
patients with HF, results of these studies have not been conclusive5,11,13,16,18. Thus, a large 
prospectively designed study with a novel anticoagulant is warranted to adequately address 
whether or not rivaroxaban can reduce the risk of important clinical events in patients with HF 
and significant CAD. 
The demonstration in the ATLAS ACS 2 TIMI 51 study that subjects with HF and a recent ACS 
have decreased rates of CV events and mortality with the use of rivaroxaban compared to 
placebo provides evidence for the exploration of rivaroxaban effects in similar patients with 
CAD but without a recent ACS event. Therefore, there is a strong rationale to investigate the use 
of rivaroxaban in addition to standard care in the patient population with HF and significant 
CAD. Patients who experience an exacerbation of HF are at higher risk of death within the first 6 
months after discharge, with the greatest risk being in the first month. The most common cause is 
progression of HF, followed by sudden death. Due to its antithrombotic effect it is postulated that 
rivaroxaban will reduce CV death, MI, and stroke in this population.
Natriueretic peptides, whether BNP or NT-proBNP, have been shown to gauge the severity of 
decompensated HF and may help predict which subjects are at higher risk of future events for
death or rehospitalization.20,28 Thus, as of Amendment 1, all subjects will be required to have a 
minimum level of either BNP or NT-proBNP for entry into the study.
D-dimer data will be collected. D-dimer is a marker of coagulation and has been shown to be 
associated with increased mortality in subjects with chronic HF17. In a pharmacokinetic study of 
rivaroxaban in subjects with chronic HF, after 7 days of receiving rivaroxaban, D-dimer levels 
trended lower than baseline12. Blood for D-dimer levels will be drawn at baseline (Day 1) prior 
to the first dose of study drug from all subjects and at Week 4 from approximately 10% of 
subjects within each country to determine if rivaroxaban exerts any benefit in potentially high 
risk HF subjects. However, this biomarker is not sufficiently validated in this population to be 
used as an entry criterion that would identify a responsive treatment group.  
The proposed study is designed to be a pivotal Phase 3 study, with adequate power to determine 
if the use of the FXa inhibitor rivaroxaban in addition to standard HF therapy can reduce the risk 
of important clinical outcome events (ie, all-cause mortality [ACM], MI, and stroke) in patients 
with HF and significant CAD following an episode of decompensated HF, defined as the “index 
event”. The addition of another therapeutic approach to reduce the risk of increased morbidity 
and mortality in HF patients would fulfill a substantial unmet medical need.
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2.
OBJECTIVES AND HYPOTHESES
2.1.
Objectives
Primary Objective

The primary objective is to demonstrate that rivaroxaban is superior to placebo in 
subjects with HF and significant CAD, who are receiving standard care, in reducing the 
risk of the composite of ACM, MI, or stroke following an index event. 
Secondary Objectives
The secondary objectives are to compare rivaroxaban with placebo in addition to standard care in 
subjects with HF and significant CAD following an index event in reducing the risk of the 
following outcomes:

Composite of CV mortality or re-hospitalization for worsening of HF

CV mortality

Re-hospitalization for worsening of HF

Re-hospitalization for CV events
Exploratory Objectives
The exploratory objectives are to compare rivaroxaban with placebo in addition to standard care 
in subjects with HF and significant CAD following an index event in reducing the risk of the 
following outcomes:

Selected medical resource utilization (MRU) data on re-hospitalization for CV events 
and for worsening of HF

Symptomatic deep vein thrombosis (DVT)

Symptomatic pulmonary embolism (PE)

Benefit-risk balance 
Safety Objectives
The safety objectives are to compare the following bleeding events with rivaroxaban and placebo 
in addition to standard care in subjects with HF and significant CAD following an index event:

The composite of fatal bleeding or bleeding into a critical space (intracranial, intraspinal, 
intraocular [vitreous or retinal], pericardial, intra-articular, retroperitoneal, intramuscular 
(with compartment syndrome) with a potential for permanent disability

Bleeding events requiring hospitalization

Major bleeding events using the International Society on Thrombosis and Haemostasis 
(ISTH) bleeding criteria
Overall safety will also be assessed.
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2.2.
Hypothesis
The primary hypothesis of this study is that rivaroxaban 2.5 mg taken orally twice a day (in 
addition to standard care) is superior to placebo (in addition to standard care), in subjects with 
HF and significant CAD following an index event in reducing the risk of the composite of ACM, 
MI, or stroke. 
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven, 
superiority study of rivaroxaban with clinical outcome assessments in subjects with HF (3 
months or longer) and significant CAD. The subject population comprises men and women aged
18 and over who have a diagnosis of previous MI or significant CAD with a LV dysfunction 
(LVEF) ≤40%). Only subjects treated for decompensated HF will be eligible for enrollment. 
Eligible subjects must have an episode of decompensated HF (index event) requiring (a) an 
overnight stay in a hospital, emergency department, or medical observation facility with the 
capability of treating with intravenous medications and observing HF patients, or (b) an 
unscheduled outpatient visit to a HF management center, where parenteral therapy is required for 
HF stabilization. Subjects must also have a brain natriuretic peptide (BNP) level ≥ 200 pg/mL or 
N-terminal-proBNP (NT-proBNP) level ≥ 800 pg/mL (preferred assay) during the screening 
period and before randomization. Subjects have up to 30 days after discharge to be randomized if 
they are in stable condition.
The primary efficacy outcome is the composite of ACM, MI or stroke. The principal safety 
outcome is the composite of fatal bleeding, or bleeding into a critical space (intracranial, 
intraspinal, intraocular, pericardial, intra-articular, retroperitoneal, intramuscular with 
compartment syndrome) with a potential for permanent disability. Additional bleeding outcomes 
are bleeding events requiring hospitalization, and ISTH major bleeding events.
A total of 1,200 primary efficacy outcome events are targeted to demonstrate the superiority of 
rivaroxaban compared with placebo. A sample size of approximately 5,000 subjects will be 
randomized. If the event rate is lower than expected, the sample size may be increased by up to 
500 subjects. Subjects who meet all of the inclusion and none of the exclusion criteria will be 
randomly assigned to receive rivaroxaban or placebo. Randomization will be stratified by 
country. After randomization, subjects will receive double-blind treatment (oral rivaroxaban 
2.5 mg b.i.d. or matching placebo b.i.d.). All subjects will also receive standard care based on 
international clinical guidelines for HF and CAD as prescribed by their managing physicians. 
Standard care must include a diuretic (either on a routine or as needed basis) and renin 
angiotensin 
system 
(RAS) 
inhibitor/vasodilator 
therapy 
(ACE 
inhibitor, 
ARB 
or
hydralazine/nitrates), and, unless contraindicated, beta blocker therapy, aldosterone antagonist 
therapy (where indicated), and aspirin/acetylsalicylic acid (ASA) (or other antiplatelet agent as 
appropriate). The dose of ASA should be 100 mg or less per day, unless not clinically 
appropriate. Dual antiplatelet therapy is allowed where indicated.
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The study consists of a screening phase, a double-blind treatment phase, and a follow-up after 
the GTED, which is also the EOS visit, and the last contact with the subject. The screening phase 
may last up to 51 days before randomization (21 days maximum for a hospitalization admission 
plus up to 30 days after discharge from the facility treating the index event), followed by an 
estimated 6 to 54 months of double-blind treatment phase. The follow-up after the GTED is 
30±15 days. The average duration of a subject in the study is expected to be approximately 29
months.
Subjects are expected to remain in the double-blind treatment phase until the sponsor-announced
GTED. The date is based on site local time. The study sites will be notified of the GTED, at 
which time subjects will be instructed to discontinue study drug (after taking both their AM and 
PM doses on GTED) and return to the study site for the EOS visit (30±15 days, but no sooner 
than 15 days after the GTED). Efficacy and safety outcomes will be collected at the EOS visit.
Subjects who permanently discontinue the study drug before the GTED will complete the Early 
Permanent Study Drug Discontinuation visit as soon as possible after the last dose of study drug. 
In addition, these subjects should return for all scheduled visits, including the EOS visit. If these 
subjects refuse office visits, the investigator is asked to encourage the subjects to allow regular 
contact (eg, by telephone) until study end, according to the TIME AND EVENTS SCHEDULE,
either with them, or with a close friend, relative, or their primary care physician to determine 
vital status and if an efficacy or safety outcome event has occurred.
A subject will be considered as having completed the double-blind treatment phase if the subject 
continues taking double-blind study drug until either the announced GTED or within 7 days 
before the death of the subject. If a subject experiences an outcome event such as MI or stroke, 
study drug may be temporarily held if necessary or if using other anticoagulant drugs or 
thrombolytic therapy. This also applies to events such as DVT or PE. After the appropriate 
treatment of the outcome event, the investigator may choose to resume study medication for the 
subject. However, study medication must be permanently discontinued for any intracranial 
hemorrhage or for any reason listed in Section 10.2.2.
Vital status will be collected for all subjects who permanently discontinue study drug early, 
withdraw from the study, or are lost to follow-up at the EOS visit either by telephone or in 
person, or if applicable, by a review of subject’s medical or public records unless this contact is 
not allowed by local regulations.
A blood sample for biomarker tests (D-dimer) will be collected at Baseline (Day 1) prior to the 
first dose of study drug from all subjects and Week 4 from 10% of randomly selected subjects 
within each country. An additional plasma sample from these subjects will be stored for up to 1 
year after the end of the study for the possible assessment of additional biomarkers for 
exploratory review of the potential relationship between the markers and study outcome events.
A Steering Committee and an Independent Data Monitoring Committee (IDMC) will be 
commissioned for this study. Refer to Section 11.8, Independent Data Monitoring Committee, 
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for details. No independent Clinical Event Committee will be used for adjudication of outcome 
events in this study.
A diagram of the study design is provided below in Figure 1:
Figure 1:
Schematic Overview of the Study Design
(Study RIVAROXHFA3001)
BID=twice daily; D/C=discontinuation; GTED=Global Treatment End Date; HF=heart failure; R=randomization.
3.2.
Study Design Rationale
Study Population 
Patients with documented HF experience a high rate of CV death, MI, stroke, and 
thromboembolic events. These are important clinical events that profoundly impact patients, and 
constitute a large burden in terms of health care provision. Subjects with HF (3 months or 
longer) and significant CAD have been chosen because the addition of another therapeutic 
approach to reduce the risk of increased morbidity and mortality in these patients would meet an 
unmet medical need. The pharmacology, mechanism of action, and previous clinical studies of 
rivaroxaban suggest it will reduce the risk of the composite outcome. The timing of enrollment 
for these subjects (upon stabilization and at the time of discharge from the facility treating the
index event) has been chosen because there is a high rate of mortality during this period, 
particularly during the first 2 months after discharge23. It is hypothesized that rivaroxaban, by 
reducing the thrombin burden, may help prevent cardiac events in this vulnerable population.
Rivaroxaban 2.5 mg BID 
+ Standard Care
Placebo BID 
+ Standard Care
Screening Period
During Index Event
(21 days maximum for 
a hospitalization 
admission)
Early 
Permanent 
Study Drug 
D/C
Continue 
visits as per 
protocol 
until GTED
(may be 
phone calls)
Global Treatment
End Date
End of Study Visit
R
At discharge 
& up to 30
days post
discharge
from the 
facility 
treating the 
index event
Double-Blind
Treatment Phase
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Blinding, Control, Study Phase/Periods, Treatment Groups
This randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven 
design, is a scientifically rigorous approach for evaluating the efficacy and safety of rivaroxaban 
in subjects with HF (3 months or longer) and significant CAD, and meets the registration 
requirements for a superiority study. 
Randomization will be used to avoid bias in the assignment of subjects to treatment groups, to 
increase the likelihood that known and unknown subject attributes (eg, demographic and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. Randomization will be stratified by country. 
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
clinical outcomes. 
The selection of a dose of 2.5 mg b.i.d. is based primarily on the results of the ATLAS ACS 2 
TIMI 51 study, and the HF patient subgroup analysis where 2.5 mg b.i.d. of rivaroxaban resulted 
in benefit with an acceptable risk profile. Although these results were observed primarily on a 
background of dual antiplatelet therapy (ie, ASA plus clopidogrel) which is expected to represent 
about 10% of the subjects in the current study, the 2.5 mg b.i.d. dose has been selected for the 
following reasons: 
1.
There was no clear additional efficacy advantage for the 5 mg b.i.d dose with ASA only 
(Stratum 1) for the primary efficacy endpoint in either ATLAS ACS TIMI 46 (2.5 mg b.i.d.: 
HR [95% CI] 0.55 [0.23,1.3]; 5.0 mg b.i.d.: HR [95% CI] 0.69 [0.33,1.43]) or ATLAS 
ACS 2 TIMI 51 (2.5 mg b.i.d.: 27 events, HR [95% CI] 0.74 [0.45,1.22]; 5 mg b.i.d.:
24 events, HR [95% CI] 0.64 [0.38,1.07]) and therefore this dose is not being proposed for 
use after ACS.
2.
Bleeding risk would be increased with 5 mg b.i.d, especially for subjects who are likely to 
be receiving antiplatelet therapy.
Placebo has been chosen as the comparator because all subjects should be receiving standard of 
care for their HF and significant CAD. This allows for the evaluation of efficacy and safety of 
rivaroxaban when added to standard care. In addition, there has been no well-controlled study to 
date that demonstrates any other oral anticoagulant in this population reduces mortality or CV 
events.
The length of the treatment period is not fixed; as the study is event-driven and subjects will 
continue treatment until the required number of primary efficacy outcome events (ie, 1,200) has 
been reached. This could be up to approximately 54 months, depending on the rates of 
enrollment and occurrence of primary efficacy outcome events.
Choice of Efficacy Measure
The choice of the primary efficacy outcomes is based on their use in prior rivaroxaban trials for 
primary and secondary prevention of cardiac events such as stroke, MI, or sudden CV death. 
These outcomes are considered acceptable and verifiable outcomes for the evaluation of 
prevention of CV events in HF patients with concomitant significant CAD5,11,13,16,18.
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While it is assumed that only CV death will be affected, ACM will be used as one of the 
outcome measures evaluated because: 1) the difference between ACM and CV death is expected 
to be minimal and, 2) it is an unimpeachable measure which requires no adjudication. The actual 
cause of death, however, will be collected.
Safety Assessment
The principal safety outcome will be the composite of fatal bleeding or bleeding into a critical 
space (intracranial, intraspinal, intraocular [vitreous or retinal], pericardial, retroperitoneal, intra-
articular, intramuscular with compartment syndrome) with a potential for permanent disability.
Another bleeding outcome for this study will be bleeding requiring hospitalization. While this is 
not a standard scale used in recent trials, it will be able to help address the risk/benefit of using 
rivaroxaban in patients with HF. 
In addition to these outcomes, data will be collected to allow for classification of major bleeding 
events using validated ISTH bleeding criteria.
Given the extensive background of existing safety data for rivaroxaban, only adverse events 
leading to discontinuation of study drug and non-CV serious adverse events will be collected and 
reported in this study. All CV events will be collected separately as study outcome events. Refer 
to Section 12.3.1, All Adverse Events for more details.
Biomarker Collection
Serum BNP or NT-proBNP level during the screening phase will be collected to determine 
enrollment eligibility. The use of serum BNP or NT-proBNP level is to exclude low risk subjects 
who may not have decompensated heart failure. Using natriuretic peptides (either BNP or NT-
proBNP) in clinical decisions to make the diagnosis of HF is considered a Class I 
recommendation in the American College of Cardiology Foundation/American Heart 
Association guidelines and a Class IIa recommendation in the European Society of Cardiology
guidelines19,29.
Biomarker samples (D-dimer) will be collected at Baseline (Day1) prior to the first dose of study 
drug from all subjects and at Week 4 from 10% of randomly selected subjects within each 
country.
While D-dimer levels have been noted to be elevated in some HF patients17 the association 
between elevated levels and morbidity and mortality is less clear. By collecting D-dimer it will 
allow analyses to be performed to determine if there is any correlation to outcome events in HF.
Benefit-Risk Analysis
Like other anticoagulant agents, rivaroxaban increases the risk of bleeding. To better understand 
the benefit of adding rivaroxaban to standard of care, a benefit risk assessment will be conducted 
by comparing the excess number of benefit events that are fatal or cause irreversible harm to that 
of risk events of comparable clinical impact. Because the baseline event rates vary between 
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different types of events, the comparisons of benefit and risk with different relative scales is 
difficult. Therefore, the evaluation is based on absolute risk difference, and the results are 
interpreted as the excess numbers of events after treatment of rivaroxaban for a certain period in 
a hypothetical patient population. The basis for these analyses is based on those used in 
publications by Unger26 and Beasley et al2.
Medical Resource Utilization and Health Economics
Treatment of HF with rivaroxaban may result in lower rates of CV re-hospitalization as well as 
the following selected utilization criteria: re-hospitalization for HF, overall CV and worsening 
HF re-hospitalization(s) length of stay (LOS), including emergency room (ER), intensive care 
unit (ICU) cardiac care unit (CCU) LOS and subject discharge destination.
4.
SUBJECT POPULATION
The screening period for eligible subjects may last up to 51 days before randomization (21 days 
maximum for a hospitalization admission plus up to 30 days after discharge from the facility 
treating the index event).
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
into this study.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study.
1.
Subject must be a man or woman 18 years of age or older.
2.
Criterion modified per amendment 
2.1.
Subject must have symptomatic HF for at least 3 months prior to screening.
3.
Criterion modified per amendment 
3.1.
Criterion modified per amendment 
3.2.
Subjects must have an episode of decompensated HF (index event) requiring (a) an 
overnight stay in a hospital, emergency department, or medical observation facility 
with the capability of treating with intravenous medications and observing HF 
patients before randomization, or (b) an unscheduled outpatient visit to a HF
management center, where parenteral therapy is required for HF stabilization. An 
episode of decompensated HF is defined as symptoms of worsening dyspnea or 
fatigue, objective signs of congestion such as peripheral edema or ascites, and/or 
adjustment of pre-hospitalization/outpatient visit HF medications. Subjects are 
eligible for randomization at discharge from the facility treating the index event and 
up to 30 days after discharge if they are in stable condition.
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4.
Criterion modified per amendment 
4.1.
Subject must have a documented LVEF of less than or equal to 40% within 1 year
before randomization. If more than one LVEF is available, the most recent one should 
be used, but it must be less than or equal to 40%. The ejection fraction will be 
determined by one of the following methods: echocardiogram, nuclear multigated 
acquisition (MUGA) scan, cardiac MRI, cardiac CT scan, or left ventriculography.
5.
Subject must have evidence of significant CAD, defined as at least one of the following: 

Documented previous MI

History of prior CABG

Coronary angiography demonstrating at least 50% stenosis of one or more arteries 

History of percutaneous coronary intervention (PCI) with or without stent 

Electrocardiogram (ECG) evidence (pathological Q waves) with corresponding wall 
motion abnormality on echocardiogram for those subjects with no documented history 
of MI, CABG, coronary angiogram or PCI 
6.
Criterion modified per amendment 
6.1.
Criterion modified per amendment
6.2.
Subject must be medically stable in terms of their heart failure clinical status (defined
as ambulatory and receiving no intravenous medications) at the time of randomization. 
The subject must be discharged from the facility treating the index event to a home 
environment. If transferred to a nursing home, rehabilitation center or other skilled 
facility, the stay must be 30 days or less so that the subject will be in a home 
environment at the time of randomization.
7.
Criterion modified per amendment 
7.1.
Subject must be receiving appropriate HF treatment at the appropriate dosing per 
guidelines:  

Diuretic (required for study entry, but may be taken on an as needed basis)

Renin-angiotensin system (RAS) inhibitors such as an ACE inhibitor, or ARB, or 
vasodilator therapy such as hydralazine or nitrates if intolerant to ACE inhibitor 
and ARB (required for study entry)

Beta blocker therapy (if subject is not receiving beta blocker at randomization, it
should be added and titrated during the study, unless not clinically appropriate)

Aldosterone antagonist therapy (if EF is less than or equal to 35%, but may also 
be added if the EF is greater than 35%, and titrated during the study)
If subjects cannot be on all guideline based therapies, the reasons will be collected in 
the case report form (CRF).
8.
Criterion modified per amendment 
8.1.
Subject must be receiving appropriate CAD treatment per guidelines, which should 
include the following (where appropriate): 
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
Aspirin (ASA) at a dose of 100 mg or less per day unless not clinically 
appropriate.

Clopidogrel, ticlopidine, prasugrel and ticagrelor are the only other antiplatelet 
agents that may be used concomitantly if clinically indicated. Dosing should be 
per labeling instructions.
9.
Criterion modified per amendment 
9.1.
Subject must have completed all prophylactic anticoagulation (such as enoxaparin,
warfarin, heparin, etc) before randomization. Study drug should be started no sooner 
than 6 hours after the last dose of LMWH or UFH. In the event that subjects are 
receiving warfarin, the INR should be < 1.2 before the study drug is initiated.
10. Before randomization, a woman must be either: 

Postmenopausal, defined as >45 years of age with amenorrhea for at least 18 months,

If menstruating:

If heterosexually active, practicing a highly effective method of birth control, 
including hormonal prescription oral contraceptives, contraceptive injections, 
contraceptive patch, intrauterine device, double-barrier method [(eg, condoms, 
diaphragm, or cervical cap, with spermicidal foam, cream, or gel)], or male partner 
sterilization, consistent with local regulations regarding use of birth control methods 
for subjects participating in clinical studies, for the duration of their participation in 
the study, or 

Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, 
or otherwise be incapable of pregnancy), or 

Not heterosexually active 
Women must agree to continue using these methods of contraception throughout the study. 
Women using oral contraceptives must agree to use an additional birth control method.
11. A woman of childbearing potential must have a negative serum or urine pregnancy test
before randomization occurs.
12. Criterion deleted per amendment
13. Criterion modified per amendment
13.1
A man who is sexually active with a woman of childbearing potential and has not had 
a vasectomy must agree to use a barrier method of birth control eg, either condom 
with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, 
and all men must also not donate sperm until the last dose of study drug.
14. Subject must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol
15. Each subject must sign an informed consent form (ICF) indicating that he or she understands 
the purpose of and procedures required for the study and are willing to participate in the 
study, including follow-up. (Follow-up is intended to continually assess the vital status and 
any outcome events in subjects who prematurely discontinue from study drug.)
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16. Criterion modified per amendment
16.1. Subjects must have a minimum level of 200 pg/mL BNP or 800 pg/mL NT-proBNP 
(preferred assay) during the screening period and before randomization.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1.
Subject has a bleeding risk: Any condition that, in the opinion of the investigator, 
contraindicates anticoagulant therapy or would have an unacceptable risk of bleeding, such 
as, but not limited to, the following:  

Active internal bleeding  

Clinically significant bleeding, bleeding at a noncompressible site, or bleeding diathesis 
within 28 days of randomization 

Platelet count <90,000/μl at screening 

History of intracranial hemorrhage 

Major surgery, biopsy of a parenchymal organ, or serious trauma (including head 
trauma) within 28 days before randomization

Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg or diastolic 
blood pressure ≥100 mmHg
2.
Criterion modified per amendment 
2.1.
Subject has a severe concomitant disease such as:  

Atrial fibrillation (AFib) or another condition that requires chronic 
anticoagulation (subjects with isolated transient AFib may be allowed at the 
discretion of the treating physician investigator) 

Documented acute MI during index event

Planned cardiac surgery within 28 days either prior to or after randomization, excluding
PCIs and electrophysiologic devices

Implantation of an electrophysiologic device such as implantable cardioverter 
defibrillator or pacemaker planned to occur within 14 days either prior to or after
randomization 

Planned cardiac transplantation or mechanical ventricular assist device 
implantation

Known history of severe valvular disease that is significantly contributing to the 
heart failure (eg, aortic stenosis with a gradient of >40 mmHg or mitral 
regurgitation with regurgitant fraction ≥60%)

Chronic episodes of ventricular tachycardia (sustained > 30 seconds and any 
ventricular tachycardia associated with symptoms)
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
Heart failure due to the following causes: postpartum, infectious (eg, HIV, acute 
myocarditis), substance abuse (eg, cocaine), alcohol, infiltrative disease (eg, 
amyloidosis), or a transient reversible condition (eg, thyrotoxicosis, arrhythmia)  

Cardiogenic shock at the time of randomization  

Estimated glomerular filtration rate (eGFR) <20 mL/min (MDRD method, See 
Attachment 1) at screening or if dialysis is anticipated within 6 months from 
screening

Active malignancy or other condition, other than underlying HF, limiting life 
expectancy to less than 6 months 

Acute endocarditis 

Currently treated with hemofiltration or dialysis 

Known significant liver disease (eg, acute hepatitis, chronic active hepatitis, 
cirrhosis, hepatic disease which is associated with coagulopathy, moderate or 
severe hepatic impairment [corresponding to Child-Pugh B or C])

Anemia (ie, hemoglobin <8 g/dL) at screening 

Known history of severe peptic ulcer disease (ie, history of at least 2 episodes of
upper gastrointestinal bleeding)

History of severe thrombocytopenia (platelet count < 50,000/l)

Known clinical history of HIV 
3.
Subject had a prior stroke within 90 days of randomization.
4.
Subject has been hospitalized longer than 21 days during the index event. The date of 
admission is considered the first day of hospitalization and the date of discharge is 
considered the last day of hospitalization.
5.
Subject has known allergies, hypersensitivity, or intolerance to rivaroxaban or its excipients 
(refer to Investigator's Brochure).
6.
Planned intermittent outpatient treatment with positive inotropic drugs administered 
intravenously.
7.
Subject is currently receiving and has the intention to continue any disallowed therapies as 
noted in Section 8, Prestudy and Concomitant Therapy.
8.
Subject has received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 28 days before the planned first dose of study 
drug or is currently enrolled in an investigational study.
9.
Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant 
while enrolled in this study.
10. Subject has any condition for which, in the opinion of the investigator, participation would 
not be in the best interest of the subject (eg, compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments.
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11. Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, as well 
as family members of the employees or the investigator.
12. At the time of screening, subject will not consider allowing a telephone contact to determine 
any outcome events and/or vital status, up until the end of the study should they prematurely 
discontinue study drug.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
Hospital/local laboratory results and imaging studies (within 51 days [21 days maximum for a 
hospitalization admission plus up to 30 days after discharge from the facility treating the index 
event]) will be used for screening purposes and will serve as the baseline (Day 1) laboratory 
results. There must also be documentation of CAD and HF symptoms (such as EF ≤40% within
1 year). The laboratory results closest to the randomization date should be used. The date of the 
laboratory tests will be collected on the electronic case report form (eCRF). If a subject's status 
changes (including laboratory results or receipt of additional medical records) after screening but 
before first dose of study drug is given such that he or she no longer meets all eligibility criteria, 
then the subject should be excluded from participation in the study. The screening pregnancy 
test, if needed, should be collected on Day 1, prior to randomization and verified as negative for
eligibility. Section 17.4, Source Documentation, describes the required documentation to support 
meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
A woman of childbearing potential who is heterosexually active must remain on a highly 
effective method of birth control (see Section 4.1, Inclusion Criteria).
2.
Criterion modified per amendment 
2.1
Criterion modified per amendment
2.2
Subjects may not take any additional anticoagulant(s) (antiplatelet agents ASA, 
clopidogrel, prasugrel, ticlopidine or ticagrelor are acceptable) concomitantly with 
study medication. Subjects who develop any condition which requires permanent or 
long term anticoagulation (eg, DVT, atrial fibrillation [CHADS2 = 2 or higher]) will be 
discontinued from study drug.
3.
Criterion modified per amendment 
3.1
Prasugrel is prohibited in subjects who are ≥75 years old in age, or in subjects with 
prior TIA or stroke.
4.
Nonsteroidal anti-inflammatory agents (NSAIDs) may be used on a temporary basis, but 
should be avoided for chronic use during the study period. 
5.
Criterion modified per amendment 
5.1
Strong inhibitors of cytochrome P450 3A4, such as but not limited to, ketoconazole, 
itraconazole, telithromycin, clarithromycin and voriconazole or protease inhibitors, are 
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prohibited as concomitant therapy within 4 days before randomization, or during the 
study.
5.2
Criterion added per amendment
5.2.1
Any drug which is contraindicated in patients with heart failure (eg, 
cilastazol)
6.
Strong inducers of cytochrome P450 3A4, such as but not limited to, rifampin/rifampicin, 
rifabutin, rifapentin, phenytoin, phenobarbital, primidone, St. John’s Wort, or 
carbamazepine, are prohibited as concomitant therapy within 4 days before randomization, 
or during the study.
7.
Proton pump inhibitors may be used, however subjects receiving clopidogrel should not 
receive omeprazole or esomeprazole.
8.
Modification of an effective preexisting therapy should not be made for the explicit purpose 
of entering a subject into the study.
9.
A man who has not had a vasectomy and is sexually active with a woman of childbearing 
potential must use a double-barrier method of birth control (see Section 4.1, Inclusion 
Criteria). All men must also not donate sperm until last dose of study drug.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by country. The interactive web response 
system (IWRS) will assign a unique treatment code, which will dictate the treatment assignment 
and matching study drug kit for the subject. The requestor must use his or her own user 
identification and personal identification number when contacting the IWRS, and will then give 
the relevant subject details to uniquely identify the subject. User identification information must 
not be shared.
Approximately 10% of subjects within each country will be randomly selected from whom Week 
4 D-dimer data will be collected. The IWRS will announce if a subject is selected when the 
subject is randomized to study treatment.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, events that contribute to the 
primary and secondary outcomes, treatment allocation, or other specific laboratory data such as 
all D-dimer results) will be handled with special care to ensure that the integrity of the blind is 
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maintained and the potential for bias is minimized. This can include making special provisions, 
such as segregating the data in question from view by the investigators, clinical team, or others 
as appropriate until the time of database lock and unblinding. In addition, eGFR will be 
calculated by the IWRS to ensure eligibility at screening.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. The blind should be broken only if specific emergency 
treatment/course of action would be dictated by knowing the treatment status of the subject. In 
such cases, the investigator may in an emergency determine the identity of the treatment by 
contacting the IWRS. It is recommended that the investigator contact the sponsor or its designee 
if possible to discuss the particular situation, before breaking the blind. Telephone contact with 
the sponsor or its designee will be available 24 hours per day, 7 days per week. In the event the 
blind is broken, the sponsor must be informed as soon as possible. The date, time, and reason for 
the unblinding must be documented by the IWRS in the source document. The documentation 
received from the IWRS indicating the code break must be retained with the subject's source 
documents in a secure manner.
To most effectively preserve clinical study integrity, the treatment assignment of events that 
contribute to the primary and secondary outcomes will remain blinded until the study is 
completed and the database locked. In this way bias is reduced and a truly double-blind, 
placebo-controlled investigation can be carried out. As the events of CV death, MI, stroke, 
symptomatic DVT, and symptomatic PE are considered efficacy outcomes, they will not be 
reported as adverse events or serious adverse events (see Section 12.3.1, All Adverse Events for 
more details).
Subjects who have had their treatment assignment unblinded may continue on study drug unless 
the subject meets a study drug discontinuation criterion. Investigators should not disclose 
treatment assignment to the subject whenever possible, even in a special situation where the 
treatment assignment has been unblinded to the investigator.
An IDMC will review safety data periodically. The IDMC will not be involved with the study 
otherwise. Therefore, unblinded review of safety data by anyone else is unnecessary. IDMC 
responsibility and procedures are outlined in Section 11.9, Interim Analysis. More details will be 
provided in the IDMC charter.
6.
DOSAGE AND ADMINISTRATION
Treatment groups: rivaroxaban and placebo. Subjects will be randomly assigned in a 1:1 ratio to
receive oral rivaroxaban 2.5 mg b.i.d. or placebo b.i.d. (each in addition to standard of care for 
HF and CAD as prescribed by their managing physician). 
All subjects will receive study drug (rivaroxaban or placebo) orally twice daily; once in the 
morning and once in the evening, with or without food, at approximately the same times each 
day throughout the study. The first dose of study drug should be taken in the clinic by the subject 
on the day of randomization. If the first dose is taken prior to or at 12:00 pm (noon), it is 
considered the AM dose of the day and a PM dose should also be taken. If it is taken after 
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12:00 pm (noon), it is considered the PM dose of the day and another pill should not be taken 
that day. Once the GTED is reached, all subjects currently receiving blinded study drug should 
discontinue study drug (after taking both their AM and PM doses on GTED) and complete the 
EOS visit (refer to TIME AND EVENTS SCHEDULE). 
Throughout the study, study drug will be dispensed at appropriate intervals (see the TIME AND 
EVENTS SCHEDULE) to ensure that subjects have adequate quantities of study drug between 
study visits. In addition, study site personnel will instruct subjects on how to store study drug for 
at-home use as indicated for this protocol. For rivaroxaban tablets, no storage restrictions 
(temperature, humidity, light) apply. The storage recommendation for rivaroxaban is at room 
temperature (approximately 15to 30C).
Interruption of Study Drug
Study drug may be interrupted (see Section 10.2.1, Temporary Discontinuation of Study 
Treatment) as necessary for invasive procedures or as medically needed (eg, in the setting of a 
bleeding event or a required prohibited therapy). 
A missed dose should be taken as soon as possible (no later than 6 hours after the scheduled 
dosing time), and the next scheduled dose should be taken at the regular time. If >6 hours have
elapsed after the scheduled time the dose should be skipped and the next dose should be taken at 
the regular time. An occasional forgotten dose need not be recorded. Intentional stopping of 
study drug by the subject, unintentional stopping of study drug for more than 7 consecutive days, 
or direction to temporarily stop study drug by the investigator or other physician will be 
documented and recorded in the eCRF.
7.
TREATMENT COMPLIANCE
The IWRS system will keep track of study drug dispensed to the subjects. Subjects will return 
empty study drug containers and unused study drug at those visits when a new supply of study 
drug is to be received. 
Study drug accountability will be performed at each visit. Subjects should report any 
unintentional interruption or missed doses of 7 consecutive days or more to the study-site 
personnel at each visit. It is understood that subjects may occasionally miss a dose or that a 
subject may be placed on temporary discontinuation (see Section 10.2.1, Temporary 
Discontinuation). 
8.
PRESTUDY AND CONCOMITANT THERAPY
For each subject, the drug identity of all CV therapies, proton pump inhibitors, antiplatelet 
agents, anticoagulants and ASA use taken during the index event through the end of the study 
will be recorded on the appropriate page of the eCRF. Relevant concomitant medications or 
treatment (eg, antibiotics for sepsis or surgical interventions) given for adverse events and use of 
other prohibited therapies, as specified below, will also be documented on the appropriate page 
of the eCRF.
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Required/Allowed Therapies

Subjects must be receiving at a minimum for their HF: a diuretic on a routine or as 
needed basis, and RAS inhibitor/vasodilator therapy (either an ACE inhibitor, ARB, or 
hydralazine/nitrate combination), and, unless contraindicated, the following:
o
Beta blockers, which should be titrated to the maximum dose recommended by 
current guidelines, unless not clinically appropriate. (If beta blockers are not 
prescribed, or the dose is lower than recommended, the reason will be noted in the 
eCRF)
o
Aldosterone 
antagonists, 
which
should 
be 
prescribed 
per 
guideline 
recommendations. (If aldosterone antagonists are not prescribed, or the dose is 
lower than recommended, the reason will be noted in the eCRF)
o
Additional standard care treatments for HF and CAD (except anticoagulants) as 
prescribed by their managing physician are allowed.

Subjects should be receiving antiplatelet therapy as standard care for their CAD. This 
would include aspirin (ASA) up to 100 mg/day, unless not clinically appropriate. 
Clopidogrel, ticlopidine, and ticagrelor may be used if indicated.  Prasugrel may also be 
used if indicated, but not in subjects with a prior history of TIA or stroke or those who 
are 75 years of age or older. There is limited data on the combined use of rivaroxaban 
with either ticagrelor or prasugrel.  The IDMC will monitor any increased risk to the 
subjects in this study using these combinations.  The use of clopidogrel, ticlopidine, 
ticagrelor, or prasugrel should be prescribed according to the approved labeling for each 
drug.

Antiarrhythmic therapy is allowed.

Digoxin is allowed.
Prohibited Therapies
At each visit prohibited medications and the duration of use will be recorded on the eCRF. 
NSAID therapy should be recorded if greater than two weeks during the interval between visits.
Nonsteroidal anti-inflammatory agents may be used on a temporary basis, but should be avoided 
for chronic use during the study period. 
Strong inhibitors of cytochrome P450 3A4, such as but not limited to, ketoconazole,
itraconazole, telithromycin, clarithromycin and voriconazole or protease inhibitors, are 
prohibited as concomitant therapy within 4 days before randomization, or during the study.
Strong inducers of cytochrome P450 3A4, such as but not limited to, rifampin/rifampicin, 
rifabutin, rifapentin, phenytoin, phenobarbital, primidone, St. John’s Wort, or carbamazepine, are 
prohibited as concomitant therapy within 4 days before randomization, or during the study.
Any drug which is contraindicated in patients with heart failure (eg, cilastazol) is prohibited.
Proton pump inhibitors may be used, however subjects receiving clopidogrel should not receive 
omeprazole or esomeprazole. Use of other proton pump inhibitors is allowed.
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Antiplatelet therapy other than aspirin (ASA), clopidogrel, ticlopidine, prasugrel, or ticagrelor is
prohibited. Prasugrel is prohibited in subjects who are ≥75 years old in age, or in subjects with 
prior TIA or stroke.
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a subject into the study.
Also refer to Section 4.3 for additional prohibited therapies.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The TIME AND EVENTS SCHEDULE summarizes the frequency and timing of efficacy, 
MRU, and safety measurements applicable to this study.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
The following MRU data will be collected in all subjects during each study visit: CV 
re-hospitalization, re-hospitalization for HF, overall CV and worsening HF re-hospitalization(s) 
LOS, including LOS in ER, ICU, and CCU and subject discharge destination.
Additional laboratory screening tests are not expected to be performed by the investigator as 
these will likely be part of their index event evaluation. If available during the index event, the 
value of creatine kinase-muscle and brain subunit (CK-MB), troponin, levels should be recorded 
in the local lab section of the eCRF (if more than one test values are available, use the highest 
value). In addition to the hemoglobin collection required at screening, subjects will be required 
to have a local lab hemoglobin collected at Week 12 (±14 days); if not collected at Week 12, it 
should be done no later than Week 24 (+ 14 days). Approximately 3-5 mL of blood will be 
required for the hemoglobin test. In the event that an additional screening lab test is required for 
enrollment, the maximum total blood volume to be collected from such subject will be 
approximately 20 mL, and will be processed locally. Blood for BNP or NT-proBNP 
measurements will be drawn prior to randomization as part of the inclusion criteria. If available, 
BNP or NT-proBNP will be measured by the local hospital laboratory. If local measurements of 
BNP or NT-proBNP are not available, approximately 5 mL of blood will be sent to a local 
central laboratory for measurement of BNP or NT-proBNP (whichever is available at that 
laboratory). In addition, the D-dimer laboratory tests will be performed per study protocol.
Approximately 3 mL of blood will be required for each D-dimer test (Baseline, Week 4 [if 
applicable]).
Information concerning the proper collection, handling and shipping of D-dimer samples can be 
found in the laboratory manual provided to each study site.
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9.1.2.
Screening Phase
The screening period may last up to 51 days before randomization (21 days maximum for a 
hospitalization admission plus up to 30 days after discharge from the facility treating the index 
event). Subjects must be randomized only after discharge. Subjects will be screened using local 
laboratory results for the inclusion and exclusion clinical laboratory parameters, and these values 
will also serve as baseline (Day 1) laboratory values.
9.1.3.
Double-Blind Treatment Phase
Day 1/Day of Randomization
Performance of the screening procedures may extend into Day 1 of the double-blind treatment 
phase, as long as all procedures are completed before randomization on Day 1. If the subject 
meets all of the inclusion and none of the exclusion criteria, he or she is eligible to be randomly 
assigned to receive rivaroxaban or placebo. All screening activities must be completed before 
randomization and the results must be available to the investigator for review to ensure that no 
exclusion criteria are present.
Treatment Visits
Subjects will be instructed to return to the study site according to the visit schedule in the Time 
and Events Schedule. 
Unscheduled Visit
Subjects should be seen by the investigator between scheduled visits for reasons such as:

Adverse event, based upon the severity and clinical judgment of the investigator

Lost medication requiring replacement

Reported outcome event

After a discharge for any re-hospitalization
Early Study Drug Discontinuation/Early Withdrawal from Study
If a subject permanently discontinues treatment before the end of the double-blind treatment 
period (ie, the GTED), the subject should complete the Early Permanent Study Drug 
Discontinuation procedures (see TIME AND EVENTS SCHEDULE). Because the primary 
analysis of the study is based upon the intent-to-treat population (ITT), the subject should return 
for all subsequent site visits and procedures until the EOS visit. It is imperative for the integrity 
of the trial and results to have ongoing outcome event and vital status ascertainment. If a subject 
is unwilling or unable to return for follow-up visits in person, sites should collect as much 
follow-up visit information as possible, including contacting the subject by telephone or by mail 
to determine vital status and if an outcome event has occurred, as agreed to by the subject during 
the initial informed consent process. If applicable, vital status may be obtained by reviewing the 
subject’s medical or public records unless this contact is not allowed by local regulations.
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If the subject withdraws consent for follow-up contact, this must be documented in the source 
document and the subject will be asked to supplement the withdrawal of consent with a signed 
written statement documenting refusal from all subsequent contact.
If a subject temporarily discontinues study drug, and the GTED is announced prior to the subject 
resuming study drug, the subject will then be considered to have been permanently discontinued 
from study drug. The Early Premature Study Drug Discontinuation Visit and EOS Visit for this 
subject will occur on the same day.
9.1.4.
Follow-up after GTED
The date when the targeted number of primary outcome events are predicted to have occurred 
will be known as the GTED. The sponsor will notify all investigative sites of the GTED. The 
sites should contact all subjects and instruct them to stop study drug on the GTED (after taking 
both their AM and PM doses on the GTED) and schedule the EOS visit (30±15 days, but no 
sooner than 15 days after the GTED). A visit is not necessary on GTED. All subjects who 
discontinued study drug early (and are not taking study drug at the time of the GTED) should 
also complete the EOS visit within the same time frame after the GTED.
9.2.
Efficacy
9.2.1.
Efficacy Evaluations
At each visit during the study, the investigator will evaluate the subject for the occurrence of the 
following efficacy outcome events:

Death

Myocardial infarction (MI)

Stroke

Symptomatic PE

Symptomatic DVT

CV and HF re-hospitalization
The investigator will use all available medical records (including hospital records, discharge 
summaries, consultant reports, imaging reports, local laboratory results, an autopsy report, and a 
death certificate) to determine if an outcome event has occurred for a particular subject. Copies 
of these documents must be part of the source documentation for any subject with an outcome 
event in order to verify the outcome event. Transient ischemic attack (TIA) is not an outcome 
event. The date of the TIA should be entered in the eCRF.
The investigator will use his/her medical judgment based upon the definitions below to 
determine if an event has occurred. A manual further delineating the definitions of events will be 
provided to each investigator’s site. The criteria below list documents which must be available to 
the investigator and in the source document to confirm an event. These documents will be 
maintained in the source file and will be verified by the local study monitors. If the study 
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monitor is unable to determine if the source documents are sufficient, the determination will be 
escalated to the Local Trial Manager, or a Country Outcome Advisor, who is an independent 
physician not associated with this study. The sponsor’s clinical group will ensure that all the 
appropriate documents from the investigative site are available and reviewed. All source 
documents and reviewers will remain blinded. These procedures will be outlined in a separate 
document. 
Except for death, an outcome event may not be based on only information verbally obtained. The 
information must be verified by documents listed below for each outcome event. While 
information about a death may be obtained verbally, additional documentation should be 
obtained to classify the cause of death.
The investigator should complete the appropriate eCRF pages as soon as information is received 
regarding an outcome event.
Outcome Event Definitions
Death
Death will be documented as either: Cardiovascular, or Non-Cardiovascular, or with Unknown 
Cause. CV and non-CV deaths should be documented by one of the following:

Hospital discharge summary

Death certificate

Autopsy report

Written communication with the treating physician
Cardiovascular Death
Any death that is not clearly non-CV will be considered a CV death. For example, CV death 
includes deaths due to spontaneous bleeding, MI, stroke, worsening heart failure and 
arrhythmias. Cardiovascular death would include death due to CV procedures and sudden death. 
Sudden death would include any death in which there is abrupt collapse and death during which 
time no other evaluation is made either with ECG monitoring, imaging, or other laboratory 
testing. Unwitnessed death is one in which the subject is discovered dead after last having been 
seen in a stable state. An unwitnessed death would not include death from a chronic, 
deteriorating non-CV illness such as cancer. A death caused by traumatic bleeding would not be 
considered a CV death.
Non-Cardiovascular Death
Any death clearly not related to a CV cause, such as infection, trauma, or cancer.
Death with Unknown Cause
If no information is available regarding the cause of death (other than an oral communication 
from a relative, acquaintance, or representative without any information regarding the immediate 
cause provided) the cause of death will be classified as unknown.
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However, the investigator should record efforts made to obtain information of the cause of death 
in the source documents.
Myocardial Infarction
In the absence of a PCI or CABG, the subject must have at least 2 of the following criteria to 
document an MI: 

Elevated cardiac biomarkers (troponin I or T, or creatine kinase-muscle and brain 
subunit [CK-MB]) greater than the hospital/local lab’s upper limit of normal (ULN)

Development of new pathological Q waves in at least 2 contiguous leads on the ECG

New significant ST changes of either new ST elevation at the J-point in 2 contiguous 
leads, or new horizontal of downsloping ST depression in 2 contiguous leads

New left bundle branch block (LBBB)

Autopsy confirmation (this alone is sufficient)

Cardiology consultation report or discharge summary clearly stating a MI has occurred 
(If the abnormal cardiac biomarker laboratory results are mentioned in the reports, this 
will count as two criteria)
If a subject undergoes PCI, the subject must meet 2 of the criteria below to document a 
post-procedure MI:

Elevated cardiac biomarkers (troponin I or T, or CK-MB) >5 x the hospital/local lab’s 
ULN for samples obtained within 48 hours of the procedure if the baseline values were 
normal, plus either prolonged ischemia (> 20 minutes of chest pain), ischemic ST 
changes or new pathological Q waves, or angiographic evidence of a flow-limiting 
complication, or imaging evidence of new loss of viable myocardium or new regional 
wall abnormality

Development of new pathological Q waves in at least 2 contiguous leads on the ECG

Cardiology consultation report or discharge summary clearly stating a MI has occurred 
(If the abnormal cardiac biomarker laboratory results are mentioned in the reports, this 
will count as two criteria)
After CABG surgery, the subject must meet 1 of the criteria below to document an MI:

Elevated cardiac biomarkers (troponin I or T, or CK-MB) >10 x the hospital/local lab’s 
ULN for samples obtained within 48 hours of the procedure with development of new 
pathological Q waves or a new LBBB on the ECG, or angiographic documented new 
graft or new native coronary artery occlusion, or imaging evidence of new loss of viable 
myocardium or new regional wall abnormality

Cardiology consultation report or discharge summary clearly stating an MI has occurred
(If the abnormal cardiac biomarker laboratory results are mentioned in the reports, this 
will count as two criteria)
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Stroke
Stroke is defined as a new, sudden, focal neurological deficit resulting from a presumed 
cerebrovascular cause that is not reversible within 24 hours and not due to a readily identifiable 
cause such as trauma, a tumor or seizure.
If an event matching this definition lasts less than 24 hours it will be considered a TIA. 
All suspected strokes (including TIA) will require source verification that will become part of the 
subjects source file. Subjects in whom a stroke is diagnosed must have at least two of the 
following criteria:

Autopsy confirmation (this alone is sufficient)

Clinical signs of a stroke which include a focal neurologic deficit which was not present 
at the last visit (The deficit may include hemiparesis, aphasia, apraxia, dysphagia, 
cortical blindness, or ataxia)

Imaging study (MRI or CT scan of head and brain) within two weeks after the onset of 
symptoms that demonstrates a stroke corresponding to the clinical signs and symptoms

Neurology consultation report indicating the occurrence of a stroke

Hospital discharge summary indicating the occurrence of a stroke

Investigator detecting a difference in the neurologic status of the subject which indicates 
a stroke since the previous visit (If no imaging is performed, the investigator’s 
examination must be corroborated by a neurologic consultation)
Investigators will further classify the strokes based upon imaging studies. 

Primary ischemic infarction – stroke without focal collections of intracranial blood [The 
occurrence of hemorrhagic conversion of a primary ischemic infarction will be recorded 
only if there are two or more imaging studies demonstrating progression of the stroke 
from ischemic (or bland) to hemorrhagic]

Primary hemorrhagic – stroke with focal collections of intracerebral blood (The 
diagnosis of primary hemorrhagic stroke can only be made with imaging studies. It may 
include intraventricular hemorrhage)

Subarachnoid hemorrhage – the diagnosis requires documentation by imaging study

Uncertain – no imaging or autopsy available
A Rankin evaluation using the Modified Rankin Scale (Attachment 2) will be obtained by the 
investigator or designee between 6-18 weeks following a stroke or at EOS, whichever occurs 
first.
Other events of intracranial bleeding which will not be considered as strokes as they are usually 
traumatic in nature are:

Subdural hematoma

Epidural hematoma
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These also require documentation by imaging studies and will be recorded on the bleeding event 
eCRF page.
Symptomatic PE
A PE is diagnosed only if the subject has symptoms of PE such as sudden onset of dyspnea, 
chest pain, or fainting, and one of the following criteria are met:

Autopsy confirmation (this alone is sufficient)

High probability ventilation/perfusion lung scan 

Intermediate probability ventilation/perfusion lung scan with a positive D-dimer test

Positive spiral CT scan of the chest

Positive pulmonary arteriogram
Symptomatic DVT
A symptomatic DVT will be diagnosed if the following criteria are met:

Pain, swelling, or other symptoms of DVT in the extremity in question

Positive compression ultrasound OR positive venogram
Re-Hospitalization for Worsening of Heart Failure
Hospitalization for worsening HF requires that subjects be hospitalized (as an inpatient, in 
emergency department, or in a medical facility with the capability of treating with intravenous
medications and observing patients with HF) for an overnight stay or longer, and meet at least 3 
of the following criteria:

Symptoms of dyspnea or fatigue

Objective signs of congestion such as worsening edema, ascites, or rales

Treatment with intravenous diuretics or inotropic agents

Adjustment of pre-hospitalization HF medication 

Discharge summary listing worsening HF as the primary reason for admission 
The primary reason for hospitalization may not be a non-CV event (e.g., infection, cancer, 
non-CV surgery. The investigator will use his/her clinical judgment to determine if the primary 
diagnosis for a re-hospitalization supports worsening HF or if the admission is caused by a 
different cardiovascular event occurring concurrently (e.g., cardiac arrhythmia). If the primary 
reason for the re-hospitalization could be either event, the default should be re-hospitalization for 
worsening HF.
Re-Hospitalization for a CV Event
Hospitalization for a CV Event requires that subjects be hospitalized (in-patient or emergency 
department) for greater than 24 hours and must meet the following criterion: 
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
Discharge summary with primary reason for admission listed as CV in nature (e.g., 
bleeding, arrhythmia, ACS, MI) other than HF which is captured in the HF re-
hospitalization
The primary reason may not be a non-CV event (e.g., infection, cancer, non-CV surgery).
MI, Stroke, DVT, PE, and spontaneous bleeding events are considered cardiovascular events. If 
any of these are the primary reason for a hospitalization, complete both a re-hospitalization for 
CV event form and the outcome event eCRF form.
9.2.2.
Efficacy Outcomes
Primary Efficacy Outcomes
The primary efficacy outcome is the composite of ACM, MI, or stroke.
Secondary Efficacy Outcomes
The secondary outcomes include:

Composite of CV mortality and re-hospitalization for worsening of HF

CV mortality

Re-hospitalization for worsening of HF

Re-hospitalization for CV events
Exploratory Efficacy Outcomes

Selected MRU data on re-hospitalizations for CV events and for worsening of HF

Symptomatic DVT

Symptomatic PE
9.3.
Biomarkers
Serum BNP or NT-proBNP level during the screening phase will be collected to determine 
enrollment eligibility.
Biomarker samples will be collected for evaluation of D-dimer from all subjects at 
randomization, prior to the first dose of study drug. In addition, samples of D-dimer will be 
collected randomly from 10% of subjects within each country at Week 4. When a subject is 
randomized to treatment assignment at the randomization visit, the IWRS will specify if the 
subject is among the biomarker subset at Week 4.
9.4.
Medical Resource Utilization
Medical Resource Utilization data collection will include: re-hospitalization for CV and HF 
causes, overall CV and worsening HF re-hospitalization(s) LOS, including LOS in ER, ICU, and 
CCU and subject discharge destination.
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9.5.
Safety Evaluations and Outcomes
9.5.1.
Safety Evaluations
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the TIME AND EVENTS SCHEDULE: bleeding events, adverse events and 
clinical laboratory tests.
Bleeding Outcome Evaluations
The following will be collected for subjects with bleeding events requiring medical attention,
hospitalization, or permanent study drug discontinuation, and entered on the eCRF bleeding 
event page. Bleeding events are not reported as adverse events (see Section 12.3.1 All Adverse 
Events for further instruction):

Location of the bleeding. Bleeding sites will be entered on the eCRF for all reported 
bleeding events, including any bleeding into a critical space (intracranial, intraspinal, 
intraocular, pericardial, intra-articular, retroperitoneal, intramuscular with compartment 
syndrome) with a potential for permanent disability.

If the bleeding causes hospitalization (or prolongs hospitalization) it will be noted on the 
eCRF (Note that bleeding events will not be captured as adverse events or serious 
adverse events except for traumatic bleeding events resulting in death). Non-traumatic 
bleeding events are considered CV in origin. If non-traumatic bleeding is the primary 
reason for a greater than 24 hour hospitalization, a re-hospitalization for CV Event eCRF 
page must also be completed. In addition, a discharge summary indicating the primary 
reason for admission as bleeding is required.

Fatal bleeding will be collected. A fatal bleeding event is one in which the subject dies 
within 7 days of a bleeding event requiring hospitalization or ISTH major bleeding.

For subjects hospitalized for a bleeding event, the admission hemoglobin and the lowest 
hemoglobin, or hematocrit (if hemoglobin is not available) will be entered on the eCRF 
as well as the final hemoglobin or hematocrit closest to discharge. 

Transfusion with blood or blood products will be recorded.
Bleeding Event Assessment and Classification 
The study will use the ISTH Bleeding Event Classification Scale to assess bleeding events.
An ISTH major bleeding event is defined as overt bleeding that is associated with:

A fall in hemoglobin of 2 g/dL or more (if only hematocrit values are available, a 3% 
decrease will be equivalent to a 1 gram fall in hemoglobin), or

A transfusion of 2 or more units of packed red blood cells or whole blood, or

A critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular,
intramuscular with compartment syndrome, retroperitoneal, or 

A fatal outcome
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Approach to Subjects with a Bleeding Event
If a subject has a serious bleeding event during study drug treatment, the following routine 
measures should be considered: 
Delay the next study drug administration, or discontinue treatment if indicated. Rivaroxaban has 
a plasma half-life of approximately 5 to 9 hours, and in some patients up to 13 hours. Therefore, 
temporary cessation of study drug may allow control of bleeding.
Consider the usual treatment measures for bleeding events, including fluid replacement and 
hemodynamic support, blood transfusion, and fresh frozen plasma, if physical examination and 
laboratory testing suggest benefit could be obtained.
Consider that other causes besides antithrombotic medication can be contributory to the 
seriousness of the bleeding event (i.e., rule out disseminated intravascular coagulation, 
thrombocytopenia, and other coagulopathies; kidney and liver dysfunction; concomitant 
medications, etc.), and treat accordingly.
If bleeding cannot be controlled by these measures, consider administration of 1 of the following 
procoagulants (according to the dosages advised in the package insert):

Activated prothrombin complex concentrate (APCC)

Prothrombin complex concentrate (PCC)

Recombinant factor VIIa (NovoSeven®)

Any products administered to control bleeding should be entered in the eCRF.
Note: Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of 
rivaroxaban. There is currently no scientific rationale for benefit, nor experience with systemic 
hemostatics (eg, desmopressin, aprotinin, tranexamic acid, epsilon amino caproic acid).
Adverse Events
Adverse events reported by the subject to the investigator will be recorded as specified in 
Section 12, Adverse Event Reporting.
Clinical Laboratory Tests
Separate laboratory screening tests are not expected to be performed by the investigator as these 
will likely be part of the subjects’ hospital evaluation. No pre-specified laboratory tests will be 
performed for the duration of the study. However, these subjects are likely to have local 
laboratory tests performed during the regular course of their treatment for HF. Any laboratory 
test along with reference ranges relevant to a serious adverse event or an outcome event should 
be recorded on the appropriate eCRF page.
The following test results with reference ranges will be obtained from the hospital lab/local lab at 
the time of the index event:
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
Hemoglobin

Platelet count

Serum Creatinine (creatinine clearance to be calculated by MDRD formula) 

Serum or urine pregnancy results for women of childbearing potential only

BNP or NT-proBNP values

If available, CK-MB and troponin values
9.5.2.
Safety Outcomes
Overall safety will be assessed for bleeding using the following definitions:

The principal safety outcome is the composite of fatal bleeding or bleeding into a critical 
space 
(intracranial, 
intraspinal, 
intraocular 
[vitreous 
or 
retinal], 
pericardial, 
retroperitoneal, intra-articular, intramuscular with compartment syndrome) with a 
potential for permanent disability. 

Additional bleeding outcomes are bleeding events requiring hospitalization, and ISTH 
major bleeding events.
9.6.
Benefit-Risk Balance
Benefit-risk balance of rivaroxaban will be explored. Refer to Section 11.7, Benefit-Risk 
Analysis for details.
9.7.
Sample Collection and Handling 
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, and shipment of samples (to be collected after screening 
and sent to the central laboratory) are found in the laboratory manual that will be provided for 
sample collection and handling.
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. 
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered as having completed the double-blind treatment period if the subject 
continues taking double-blind study drug until either the GTED or within 7 days before the death 
of the subjects.
A subject will be considered as having completed the study if the subject (regardless of whether 
he/she continues on study drug) is followed according to the visit schedule until the EOS Visit or 
has died.
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Subjects who are taking study drug up until the GTED is announced will stop taking study drug 
after taking their AM and PM doses on the GTED and return to the investigator for the EOS
Visit (30±15 days, but no sooner than 15 days after the GTED).
10.2.
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued before the end of the double-blind treatment 
phase (ie, GTED), this will not result in automatic withdrawal of the subject from the study and 
the subject should continue to be followed for efficacy and safety outcome events. Study drug 
may be temporarily discontinued, or permanently discontinued. If study drug is permanently 
discontinued prior to GTED and the investigator or subject would like to resume study drug, this 
is permissible and the investigator’s site manager should be contacted for instructions.
10.2.1.
Temporary Discontinuation of Study Treatment
Study drug may be temporarily discontinued, however, these interruptions should be kept to a
minimum as much as possible. There is no specific limitation to the duration of a temporary 
study drug discontinuation. Study drug should be temporarily discontinued if the subject: 

Undergoes PCI, CABG, any other interventional procedure (including minor procedures 
such as colonoscopy or dental extractions), or any other medical condition that may 
require temporary interruption or use of therapy due to bleeding risk or use of open-label 
anticoagulants.

Requires use of an anticoagulant on a temporary basis (such as heparin or enoxaparin 
for ACS or PCI).

Experiences a major bleeding event other than intracranial bleeding. For less severe 
bleeding events, investigator discretion is allowed. If possible study drug should be 
resumed when the bleeding event has resolved and the cause has been identified and 
corrected.

Develops a new neurologic deficit or significant alteration in mental status. Once a 
diagnosis is made and appropriate treatment is provided, the study medication may be 
restarted at the discretion of the investigator.

Develops a platelet count less than 50,000/L.

Has a serious adverse event that is considered by the investigator to be possibly related 
to, or exacerbated by, study drug administration.

Requires a prohibited therapy on a temporary basis (see Section 8, Prestudy and 
Concomitant Therapy).
Study drug can be resumed when the investigator considers it safe to do so. Study drug need not 
be discontinued if the subject experiences one of the primary or secondary efficacy outcome
events (except for hemorrhagic stroke or other intracranial bleeding). If a hemorrhagic stroke, or 
other intracranial bleeding occurs, the subject must be permanently discontinued from study 
drug.
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If a subject temporarily discontinues study drug, and the GTED is announced prior to the subject 
resuming study drug, the subject will then be considered to have been permanently discontinued
from study drug.
Discontinuation of Study Drug for Vascular Procedure
Clinical guidance regarding the bolus dose of antithrombin to administer by translating peak 
factor Xa inhibition with oral rivaroxaban to peak factor Xa inhibition with subcutaneous 
enoxaparin can be found in Attachment 3 and Attachment 4. These comparative tables depict the 
approximate equivalent dose of subcutaneous enoxaparin (mg/kg) relative to a given dose of 
rivaroxaban at a given time following its administration and should assist the investigator in 
deciding which dose of enoxaparin or equivalent dose of another antithrombotic agent to 
administer in the event when a subject may have to undergo an emergency interventional 
coronary procedure or pharmacologic reperfusion while receiving study drug. If an urgent 
revascularization is required, consider i.v. administration of 0.5 mg/kg of enoxaparin or its 
antithrombotic equivalent in subjects who undergo PCI. Subjects in whom administration of 
fibrinolytics is considered may require unblinding if the last dose of study drug was taken less 
than 6 hours before initiation of reperfusion therapy. Refer to Attachment 3 and Attachment 4 for 
guidance.
In the event that a subject requires a non-emergency revascularization procedure (PCI or 
CABG), study drug should be stopped approximately 12 hours before the procedure, if possible, 
and appropriate anticoagulant or antiplatelet therapy should be instituted as medically indicated. 
Once the subject has recovered from the PCI or CABG, and assuming no ongoing bleeding risk 
is present, the subject may, at the discretion of the physician, resume study drug approximately 
12 hours after the arterial sheath has been removed (subjects with PCI) or the post-procedural 
drains (subjects with CABG surgery) have been removed and the last dose of parenteral 
anticoagulant therapy has been administered, whichever is later.
10.2.2.
Permanent Discontinuation of Study Treatment
If a subject must be permanently discontinued from study drug before the end of the 
double-blind treatment period, this will not result in automatic withdrawal of the subject from the 
study, and the subject should continue to be followed for efficacy and safety outcome events.
A subject should be discontinued from study drug if:

The investigator believes that for safety reasons (i.e., adverse event) it is in the best 
interest of the subject to stop study drug.

The subject becomes pregnant.

The subject develops any condition which requires permanent anticoagulation (eg, DVT, 
PE, atrial fibrillation [CHADS2 = 2 or higher]).

The subject has a sustained fall in eGFR to below 20 mL/min (by MDRD method). This 
can be obtained by using the IWRS and entering a recent local serum creatinine obtained 
from the subject.
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
The subject requires hemofiltration or dialysis on a permanent basis

The subject requests to discontinue study drug permanently

The subject has a hemorrhagic stroke, or intracranial bleeding

The subject has a heart transplant
If a subject discontinues study treatment permanently before the end of the double-blind 
treatment phase (ie, GTED), the Early Permanent Study Drug Discontinuation assessments as 
outlined in the TIME AND EVENTS SCHEDULE should be conducted.
Because the primary analysis of the study is based upon the ITT population, a subject who 
permanently discontinued study drug treatment should return for all subsequent site visits and 
procedures until the study ends. If a subject is unwilling or unable to return for follow-up visits 
in person, sites should attempt to collect as much follow-up visit information as possible, 
including contacting the subject regularly by telephone or by mail to determine vital status and if 
an outcome event has occurred, until the GTED, as agreed to by the subject during the initial 
informed consent process. Collection of study outcome events and vital status information until 
the announced GTED is critical for this study because the primary analysis of the study is based 
upon the ITT population. Once the GTED is announced the subjects who have prematurely 
discontinued study drug will return to the site (or at least be contacted by telephone) to complete 
the EOS Visit 30±15 days after the GTED. If the subject cannot physically return to the office, a 
telephone contact should be made to collect the required information in lieu of the office visit. If 
applicable, subjects’ medical or public records may be reviewed unless this contact is not 
allowed by local regulations.
If the subject withdraws consent from follow-up contact, this must be documented in the source 
document and the subject will be asked to supplement the withdrawn consent with a signed 
written statement documenting refusal for all subsequent contact.
The eCRF is to be completed to identify the reason for permanent discontinuation of study drug. 
If study drug is terminated for a serious adverse event, expedited reporting (within 24 hours) is 
also required as outlined in Section 12.3.2, Serious Adverse Events.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up (only after all means of all subsequent contact, including locator 
services where permitted by law, up until the EOS visit, will lost to follow up be 
declared). 

Withdrawal of consent (unless specifically refused by the subject, subject contact will be 
made to obtain vital status at the EOS visit).
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
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Study drug assigned to the withdrawn subject may not be assigned to another subject. Subjects 
who withdraw will not be replaced.
If a subject withdraws from study or is lost to follow-up, his or her vital status will be collected 
at the EOS visit either by telephone or in person, or if applicable, by a review of the subject’s 
medical or public records unless this contact is not allowed by local regulations.
Withdrawal of Consent for the Use of Samples in Future Research
A subject may withdraw their consent for biomarker (D-dimer) samples to be used for future 
research. In this case, samples will be destroyed only after they are no longer needed for the 
main study.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
The primary study objective will be addressed by comparing distribution of time to the first 
occurrence of a primary efficacy endpoint between treatment groups. Specifically, the following 
primary statistical hypotheses will be tested.
Null hypothesis H0: there is no difference between treatments in distribution of time from 
randomization to the first occurrence of the primary efficacy endpoint event.
Alternative hypothesis HA: The distributions of time from randomization to the first 
occurrence of the primary efficacy endpoint event are different between the 2 treatment 
groups. 
Analysis methods and decision rules are outlined in Section 11.3 below.
11.1.
Analysis Populations and Observational Periods
Definition of an analysis data set contains these 2 elements: 1) subject population, which specifies 
which subjects will be included in an analysis; and 2) observational period, which specifies the 
time window within which data will be included in an analysis. Key subject populations and 
observational periods are defined below.
Subject Population
Intention-to-treat (ITT) population: This subject population consists of all randomized subjects
with valid informed consent. 
Per-protocol (PP) population: this population is a subset of the ITT population. Subjects with 
major protocol deviations will be excluded from PP population. Major protocol deviations will 
be defined in the Statistical Analysis Plan (SAP).
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Safety population: this population is a subset of the ITT population, consisting of all randomized 
subjects who receive at least one dose or partial dose of study drug.
Observational Period
Up–to-GTED: this observational period includes all data from randomization to the global 
treatment end date, inclusively.
On-treatment: this observational period includes data from the first dose of study drug to 2 days 
after the last dose of the study drug, inclusively.
Post-randomization: this observational period includes all data from randomization to the last 
contact.
Post-first dose of study medication: this observational period includes all data from the first dose 
of study medication to the last contact.
11.2.
Sample Size Determination
This is an event driven study. The study was initially designed to observe occurrences of the 
primary efficacy event in 984 unique randomized subjects, on or before the GTED, to have 90% 
power to detect a 20% relative risk reduction (RRR, defined as subtracting the hazard ratio [test 
to control] from 1) in the composite of ACM, MI, or stroke at a 5%, 2-sided significance level. A 
total of approximately 5,000 subjects will be randomized to either the rivaroxaban group or the 
placebo group in a 1:1 ratio. If the event rate is lower than expected, the sample size may be 
increased by up to 500 subjects.
The above sample size calculation was estimated based on the following assumptions.

Effect size: 20% RRR

Event rate in the placebo arm: 19%/year

Power: 90%

Over all α level: 5%, 2-sided

Permanent premature treatment discontinuation rate: 10%/year

Lost-to-follow-up: 1%/year 

Duration of enrollment period: 24 months (based on a non-uniform enrollment 
distribution. The distribution will be described in the SAP.)

Duration of study (from First-Patient-Randomization to GTED): 31 months
The assumptions of RRR and event rate are based on observations from subjects with congestive 
HF (the HF subgroup) in the ATLAS ACS 2 TIMI 51 study and review of literature. Observed 
data from the HF subgroup in study ATLAS ACS 2 TIMI 51 are summarized in Table 1. Note 
that the study population in this study is slightly different from the HF subgroup in the ATLAS 
ACS 2 TIMI 51 study. The subject population in the present study will have HF with significant 
CAD.
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Based on historical data, the mortality rate in this study was expected to be higher than the 
observed mortality rate in TIMI 51 ATLAS 2 study. Therefore, an event rate of 19%/year was
used in sample size calculation.
The study is revised to observe occurrences of the primary efficacy event in 1,200 unique 
randomized subjects based on a blinded simulation study performed on currently available trial 
data (ie, longer enrollment period, lower than anticipated primary efficacy event rate, higher than 
anticipated study drug discontinuation rate). Further details are described in the SAP.
An interim analysis will be conducted when the primary efficacy events are observed in 
approximately 600 unique subjects (see Section 11.9 for more details).
11.3.
Efficacy Analyses
Primary Endpoint
The primary efficacy analysis endpoint is the time from randomization to the first occurrence of 
death, MI, or stroke. The associated statistical null hypothesis is that there is no difference 
between treatment groups in distribution of the time, and the alternative hypothesis is that there 
is a difference between treatment groups.
The primary statistical hypothesis will be tested using a log-rank test, stratified by region. In 
addition to the final analysis, the primary statistical hypothesis will be tested in an interim 
analysis when approximately 600 primary efficacy events are observed. The primary analysis 
will be based on the analysis set defined by ITT subject population and the up-to-GTED 
observational period (up to the cut-off date to be specified for the interim analysis). Subjects will 
be analyzed according to the treatment group to which they are randomized, regardless of actual 
treatment received. The overall α level is 5%, 2-sided. A Lan-DeMets α spending function with 
O’Brien-Fleming type of boundaries will be used to preserve the overall type I error rate. If the 
log-rank test statistics crosses the stopping boundary, and the log-rank statistic is less than 0, ie, 
the observed number of events in the rivaroxaban group is less than the expected number of 
events under the null hypothesis, it will be concluded that the study has demonstrated that 
efficacy of rivaroxaban is superior to that of placebo in prevention of ACM, MI, and stroke.
It is expected that risk of death will be the highest shortly after discharge from the index events. 
Therefore, the cumulative event rate derived from Kaplan-Meier estimate will be displayed 
graphically to evaluate the timing of event occurrence and the consistency of the treatment effect 
over time.
The RRR will be estimated using a Cox proportional hazards model, stratified by region, with 
treatment (as randomized) as the only covariate. The point estimate and corresponding 95% 
confidence interval (CI) for the hazard ratio (HR, rivaroxaban to placebo) will be reported. The 
plausibility of proportional hazards assumption will be assessed by visually comparing the plot 
of the log of cumulative hazard between treatments, and formally tested by adding a treatment by 
logarithm-transformed time interaction into the Cox model. A p-value greater than 0.05 for the 
interaction term will be interpreted as no evidence against the proportional hazard assumption.
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A number of sensitivity analyses will be conducted to assess the robustness of the primary 
efficacy analysis. These include a log-rank test stratified by country, an unstratified log-rank test, 
repeating analyses mentioned above for analysis set defined by the on-treatment observational 
period and the per-protocol subject population, and analysis set defined by the post-
randomization observational period and the ITT subject population. Additional sensitivity 
analyses will also be conducted based on subject populations enrolled under various versions of 
the protocol amendments. Additional post-hoc analyses may be conducted to investigate 
unexpected results. 
Relative risk reductions on components of the primary efficacy endpoint will be evaluated using 
a Cox proportional hazards model as described above.
Extensive efforts will be made to collect complete data for all subjects randomized in this study. 
Subjects will be followed up to the end of the study and will complete all required data 
collection, regardless of their compliance with study drug or visits. For subjects who are lost to 
follow up or withdraw consent, efforts will be made to obtain their vital status at the end of study 
from permitted sources.
Efforts will be made to clean up the missing or partially missing event date for primary and 
secondary efficacy endpoints, as well as key safety endpoints, before database lock. Imputation 
rules for the missing or partially missing date will be specified in SAP.
Homogeneity of treatment effects, both in RRR and direction, in the following subgroups will be 
assessed by subgroup analysis. Analysis methods will be detailed in SAP.

Age (< 65 vs ≥ 65; < 75 vs ≥ 75 years)

Sex (men vs women)

LVEF (≤30% vs > 30%; ≤ median vs > median)

Estimated glomerular filtration rate (Modification of Diet in Renal Disease formula 
value <30, 30 to <60, 60 to <90, ≥90 mL/min/1.73 m2)

Baseline D-dimer level by quartile

BNP, NT-proBNP (≤ median vs > median)

History of diabetes (yes vs no)

History of stroke (yes vs no)

History of MI (yes vs no)

Hypertension (yes vs no)

Body Mass Index (<25, 25 to <30, ≥30 kg/m2)

Baseline digoxin use (yes vs no)

Baseline β-blocker use (yes vs no)

Baseline aldosterone inhibitors (yes vs no)
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
Baseline ACEI or ARB (yes vs no)

Baseline aspirin use (yes vs no)

Baseline aspirin vs dual antiplatelet use

Baseline thienopyridine use (yes vs no)

NYHA (Class II, III, IV)

Race (White vs others)

Race (White, Asian, other)

Region
Secondary Endpoints
If superiority of rivaroxaban over placebo in reducing the risk of the primary efficacy endpoint is 
established, treatment effects in secondary endpoints will be tested subsequently in the 
hierarchical order: 
1) Composite of CV mortality or re-hospitalization for worsening of HF
2) CV mortality 
3) Re-hospitalization for worsening of HF
4) Re-hospitalization for CV events
Statistical significance is required before testing the next hypothesis in the hierarchical test 
procedure. These secondary endpoints will be analyzed using time-to-event analysis described 
above for the primary endpoint. Details will be provided in the SAP.
Exploratory Endpoints
Analysis methods and results for MRU data will be provided in a separate report.  Due to the 
nature of exploration and consideration regarding to type I and type II errors, no statistical testing 
will be conducted for symptomatic DVT and PE. However, the size of treatment effects on these 
endpoints will be estimated using a Cox proportional hazards model, with treatment is the only 
covariate. HRs and 95%CIs will be reported. 
11.4.
Biomarker Analyses
Descriptive summary statistics will be provided for baseline D-dimer level and change from 
baseline at Week 4 visit. Descriptive summary statistics will be provided for baseline BNP and 
NT-proBNP.
11.5.
Medical Resource Utilization Analyses
Analysis methods and results will be described in a separate report.
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11.6.
Safety Analyses
Bleeding Events
The principal safety evaluation endpoint for this study is the composite of fatal bleeding, or 
bleeding into a critical space with potential for permanent disability. Time to the first occurrence 
of the principal safety endpoint will be compared using a Cox proportional hazards ratio model, 
stratified by region, with treatment as the only covariate. The primary analysis will be conducted 
for analysis set defined by the on-treatment observational period and the safety population.
Subjects will be analyzed according to the study drug assigned.
In addition, time to the following bleeding events will be analyzed using the same method.

Bleeding requiring hospitalization

ISTH major bleeding event
The safety outcomes will also be analyzed for other observational periods as defined in the SAP.
In addition, summary statistics will be provided for all other reported bleeding events.
Adverse Events
Because the safety profile of rivaroxaban has been well established in previous large and 
extensive trials, this study will collect limited adverse event data. For adverse events that are 
collected as specified in Section 12, ADVERSE EVENT REPORTING, the verbatim terms 
reported in the CRF by investigators to identify adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). For each MedDRA preferred term, the 
percentage of subjects who report at least 1 occurrence of the given event will be summarized by 
treatment group. Additional summaries, listings, or subject narratives may be provided, as 
appropriate.
Clinical Laboratory Tests
Because the safety profile of rivaroxaban has been well established in previous trials, this study 
will not collect laboratory data routinely. There is no plan to analyze laboratory data. Local lab 
data may be discussed in subject narratives.
11.7.
Benefit-Risk Analysis
Benefit-risk of rivaroxaban vs placebo will be evaluated based on the excess number of events 
between treatments for events intended to be prevented (benefits) and events that may be 
caused (risks). Excess number of events is defined as the difference in event rate times a 
hypothetical population size (e.g., 10,000 patients or person-years). The event rate will be 
calculated based on time-to-first event approach as the following:

Person-year rate, expressed as number of events per 100 person-years exposure time

Kaplan-Meier Product-Limit estimates of cumulative event rates at 1-year
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The primary benefit-risk analysis will be based on a comparison between events that are fatal or 
are likely to cause irreversible harm, where the endpoints are defined to avoid double-counting 
an event as both a benefit and as a risk:
Benefits 
Composite of non-bleeding related death, non-fatal MI, or non-fatal ischemic stroke

Non-bleeding related death 

Non-fatal MI 

Non-fatal ischemic stroke
Risks
Composite of fatal bleeds, non-fatal intracranial hemorrhage, or other non-fatal critical organ 
bleeds

Fatal bleeds

Non-fatal intracranial hemorrhage

Other non-fatal critical organ bleeds (intraspinal, intraocular [vitreous or retinal], 
pericardial, intra-articular, retroperitoneal, intramuscular)
The primary analysis for benefit-risk evaluation will be based on the ITT analysis population, in 
the up-to-GTED observational period. All comparisons between treatments will be based on the 
excess number of events (as defined above) and the corresponding 95% confidence intervals will 
be provided.
11.8.
Independent Data Monitoring Committees
An IDMC will be established to monitor data on an ongoing basis to ensure the continuing safety 
of the subjects enrolled in this study and to meet efficacy objectives. The IDMC will review 
unblinded safety data periodically. If necessary or requested by the IDMC, subject level 
unblinded data may be provided to the IDMC. In addition, the IDMC will review results of the 
planned interim analysis (see Section 11.9 for more details) and make recommendation whether 
the study should be terminated prematurely due to overwhelming benefit or futility.
The IDMC will consist of at least one medical expert in the relevant therapeutic area and at least 
one statistician. The IDMC will be supported by an independent statistical group which is not 
involved with the study otherwise. All unblinded data will be handled by this statistical group 
until the completion of the study. In their first meeting the committee will decide the frequency 
of future meetings, the scope of safety review, elect a chair person, and finalize the charter.
Detailed IDMC responsibilities, authorities, decision guidelines, and procedures will be 
documented in its charter.
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11.9.
Interim Analysis
An interim analysis will be conducted when primary efficacy events have been observed in 
approximately 600 subjects. A log-rank test, stratified by region, will be employed to compare 
the distribution of time to the occurrence of the composite primary efficacy endpoint between the 
2 treatment groups. If all the following conditions are met, the IDMC may recommend 
terminating study early:

the log-rank test statistic crosses the stopping boundary, and

the 2-sided p-value for all-cause mortality is less than 0.05, and

the totality of data suggests an overwhelming benefit of rivaroxaban over placebo
On the other hand, if the conditional power (based on the assumption that the RRR in the 
remaining study is 20%) is 10% or lower, the study may be stopped for futility. Detailed 
stopping guideline will be specified in the IDMC charter.
The Lan-DeMets α spending function approach with O’Brien-Fleming type of boundaries will be 
used in the interim analysis. The α spent in the interim analysis is 0.003 with a corresponding 
critical value of 2.936 (East®, Version 5.3, Cytel Inc.). If the study continues beyond the first 
interim look, the critical value for the final analysis is 1.969. The actual α spent and 
corresponding critical values may slightly vary from aforementioned numbers, depending on the 
actual number of events included in the interim analysis. If the test statistic for the primary 
efficacy endpoint crosses the stopping boundary, the secondary endpoints will be statistically 
tested in the hierarchical order as specified in Section 11.3. This group sequential test procedure 
will control the type I error rate. There will be no adjustment for p-values in the final study 
report.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with these procedures.
Rivaroxaban has been extensively studied in Phase 1 through Phase 3 clinical studies involving 
more than 70,000 patients and its overall adverse event profile has been well described. 
Appropriate information concerning adverse events were systematically collected and submitted 
to regulatory authorities. For the purposes of this study (and after discussion with appropriate 
regulatory agencies) certain non-serious adverse events will not be collected, while certain 
events will be collected as endpoints and therefore not reported as serious adverse events. All 
data on safety and outcomes will be reviewed regularly by an unblinded IDMC. This will be 
explained in Section 12.3.1, All Adverse Events.
Section 12.1.1 describes the usual definitions of adverse events and serious adverse events.
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12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects required adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires a minimum of 24 hours of hospitalization or prolongation of existing 
hospitalization, which may include time spent both in the ER, and the In-Patient Room 

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
For the purposes of this study, efficacy and safety outcome events will not be considered as 
adverse events or serious adverse events (See Section 12.3.1, All Adverse Events). If a serious 
and unexpected non-CV adverse event occurs for which there is evidence suggesting a causal 
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relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study outcome (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For rivaroxaban, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Investigator's Brochure. 
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed below in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
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Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation which
prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor medicinal product

Suspected abuse/misuse of a sponsor medicinal product

Inadvertent or accidental exposure to a sponsor medicinal product

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor medicinal 
product

Medication error involving a sponsor product (with or without subject/patient exposure 
to the sponsor medicinal product, eg, name confusion)
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
12.3.
Procedures
12.3.1.
All Adverse Events
For the purposes of this trial the following outcome events will not be considered as adverse 
events or serious adverse events. These events will be captured on the eCRF and in the database 
as outcomes only and will be waived from unblinding and exempted from expedited reporting:

CV death

MI

stroke

venous thromboembolism (DVT and PE)

hospitalization for heart failure

any CV hospitalization

unstable, worsening, and new angina pectoris

resuscitated cardiac arrest

bleeding events – note that bleeding events requiring medical attention/hospitalization
will be entered on the bleeding page of the eCRF, refer to Section 9.5.1 under Bleeding 
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Outcome Evaluations;
any bleeding event leading to permanent study drug 
discontinuation will also be entered on the bleeding page of the eCRF.

CV signs or symptoms expected or anticipated in this population such as cardiac 
arrhythmia, chest pain, dyspnea, edema, ACS, and TIAs
The following adverse events or serious adverse events will be collected and entered into the 
eCRF, unless they are considered outcome events as specified in the list above. The serious 
adverse events need to be reported to the sponsor within the appropriate timeline as described in 
Section 12.3.2, Serious Adverse Events.

Adverse events leading to permanent study drug discontinuation

All non-CV serious adverse events

Common drug-induced reactions including but not limited to the following adverse 
events should be considered serious:
o
Suspected toxic effect on the bone marrow including severe thrombocytopenia 
(platelet count less than 50,000/mL), severe neutropenia (white blood cell count 
less than 500/mL), pancytopenia, aplastic anemia
o
Suspected hypersensitivity reaction (e.g., anaphylaxis, angioedema, severe 
urticaria, bronchospasm, etc.)
o
Severe skin reactions such as Stevens-Johnson Syndrome
o
Suspected severe liver injury
While one of the primary outcome measures is ACM, any non-CV death (eg, traumatic bleeding 
events resulting in death are considered to be non-CV events) will be reported as a serious 
adverse event.
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure (which may include contact for follow-up of safety. If any outcome 
event or adverse event occurs from the time a signed ICF is obtained until randomization, this 
event will be recorded as an adverse event or an SAE on the eCRF. The last expected visit when 
adverse events will be collected is during the EOS visit [the visit following GTED, which can 
take place 30±15 days after GTED]).
All adverse events, regardless of seriousness, severity, or presumed relationship to study therapy, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported as appropriate, according to 
sponsor instructions.
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The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all serious adverse events that are unlisted (unexpected) and associated 
with the use of the study drug. The investigator (or sponsor where required) must report these 
events to the appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
that approved the protocol unless otherwise required and documented by the IEC/IRB.
12.3.2.
Serious Adverse Events
All non-CV serious adverse events occurring during clinical studies must be reported to the 
appropriate sponsor contact person by study-site personnel within 24 hours of their knowledge of 
the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a member of the study-site 
personnel, and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a 
serious adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts)
Any non-CV event that occurs during the course of a subject's participation in the study which 
requires a minimum of 24 hours of hospitalization (or prolongation of hospitalization), including 
time spent both in the ER, and the In-Patient Room, must be reported as a serious adverse event, 
except hospitalizations for the following:

Social reasons in the absence of an adverse event

Surgery or procedure planned before entry into the study
12.3.3.
Pregnancy 
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel 
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and congenital 
anomaly) are considered serious adverse events and must be reported using the Serious Adverse 
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Event Form. Any subject who becomes pregnant during the study must discontinue further study 
treatment.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported by the study-site personnel within 24 hours of 
their knowledge of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. PQCs may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
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14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
The study drug supplied for this study is rivaroxaban 2.5 mg and matching placebo provided as 
round yellow tablets. Refer to the Investigator's Brochure for a list of excipients.
14.2.
Packaging
The study drug will be supplied in bottles and dispensed in child-resistant packaging.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
For rivaroxaban tablets, no storage restrictions (temperature, humidity, light) apply. The storage 
recommendation for rivaroxaban is at room temperature (approximately 15to 30C).
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects must be instructed to return all original containers, whether empty 
or containing study drug.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the site is an authorized destruction unit and study 
drug supplies are destroyed on site, this must also be documented on the drug return form.
Study drug should be dispensed under the supervision of the investigator or a delegated and 
qualified member of the study-site personnel, or hospital/clinic pharmacist. Study drug will be 
supplied only to subjects participating in the study. Returned study drug must not be dispensed 
again, even to the same subject. Study drug may not be relabeled or reassigned for use by other 
subjects. The investigator agrees neither to dispense the study drug from, nor store it at, any site 
other than the assigned study site agreed upon with the sponsor. Study drug may not be 
transported from one site to another.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure 

Pharmacy manual/site investigational product manual
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
IWRS Manual 

eDC Manual
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during 
the study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only subjects who are fully able to understand the risks, 
benefits, and potential adverse events of the study and provide their consent voluntarily will be 
enrolled.
While no study has definitively proven the benefit of anticoagulation in HF patients with CAD 
after decompensation of their HF, data from a large subgroup of subjects in the rivaroxaban 
ATLAS ACS 2 TIMI 51 study suggest a benefit in reduced risk of death in subjects with ACS 
and heart failure. While ACS subjects will not be included in this study, those included will have 
significant CAD. A placebo control group is considered appropriate as anticoagulation in this 
type of patient has not been definitively proven effective in reducing the risk of death, MI, or 
stroke. In addition, all subjects will be receiving standard HF therapy, including antiplatelet 
therapy where appropriate. 
Rivaroxaban has been studied in over 70,000 patients for treating or preventing thrombotic 
associated diseases. Because the safety profile of rivaroxaban and the risk of bleeding with its 
use are well known, blood draws were kept to a minimum in this fragile group of subjects.
Subjects will undergo all other treatments and diagnostic tests according to the standard of care 
in their locality, thus making this study minimally intrusive in their regular routine health care. 
Subjects will be strongly encouraged to remain in the clinical study should their study drug be 
discontinued prematurely due to an adverse event, or other reasons, in order to assess the vital 
status and determine if outcome events may have occurred. If these subjects refuse office visits, 
the investigator is asked to encourage the subjects to allow regular contact (eg, by telephone)
until study end, according to the TIME AND EVENTS SCHEDULE, either with them, or with a 
close friend or relative, or their primary care physician to determine vital status and if an efficacy 
or safety outcome event has occurred.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable 
regulatory and country-specific requirements.
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Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principals that originated in the Declaration of 
Helsinki, and that the clinical study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents:

Final protocol and, if applicable, amendments

Sponsor-approved informed consent form (and any other written materials to be 
provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any), the informed consent form, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments

Revision(s) to informed consent form and any other written materials to be provided to 
subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB
(at least annually)
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
Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
investigational drug

New information that may adversely affect the safety of the subjects or the conduct of 
the study

Deviations from or changes to the protocol to eliminate immediate hazards to the 
subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Annual Safety Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or trial conduct), the amendment and applicable informed 
consent form revisions must be submitted promptly to the IEC/IRB for review and approval 
before implementation of the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this clinical study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The consent form must be signed before performance of any 
study-related activity. The consent form that is used must be approved by both the sponsor and 
by the reviewing IEC/IRB and be in a language that the subject can read and understand. The 
informed consent should be in accordance with principals that originated in the Declaration of 
Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and sponsor 
policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow up if needed and that their records 
may be accessed by health authorities and authorized sponsor staff without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
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signing the informed consent form the subject is authorizing such access, and agrees to allow 
his/her study physician or health authorities to re-contact the subject for the purpose of obtaining 
consent for additional safety evaluations, if needed to obtain information about his or her 
survival status. Where permitted by law, a locator may be used.
The subject will be given sufficient time to read the informed consent form and the opportunity 
to ask questions. After this explanation and before entry into the study, consent should be 
appropriately recorded by means of the subject's personally dated signature. After having 
obtained the consent, a copy of the informed consent form must be given to the subject.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the informed consent form after the oral consent of the subject is 
obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, pharmacodynamic, biomarker, PK, or immunogenicity research is not 
conducted under standards appropriate for the return of data to subjects. In addition, the sponsor 
cannot make decisions as to the significance of any findings resulting from exploratory research. 
Therefore, exploratory research data will not be returned to subjects or investigators, unless 
required by law or local regulations. Privacy and confidentiality of data generated in the future 
on stored samples will be protected by the same standards applicable to all other clinical data.
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16.2.5.
Long-Term Storage of Samples for Future Research
Biomarker samples collected in this study will be stored for up to 1 year following the 
completion of the last subject for the study (or according to local regulations). Samples will be 
used for exploratory evaluations of the effects of rivaroxaban on D-dimer levels and its potential 
relationship to responders in this heart failure study. The research may begin at any time during 
the study or the post-study storage period.
Subjects may withdraw their consent for their samples to be stored for research (refer to Section 
10.3, Withdrawal From the Study (Withdrawal From the Use of Samples in Future Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
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17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), 
written IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, 
and if applicable, subject compensation programs. This approval must clearly identify 
the specific protocol by title and number and must be signed (or sealed, where 
appropriate per local regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and 
the applicable laws and regulations. If accompanied by a letter of explanation, or 
equivalent, from the IEC/IRB, a general statement may be substituted for this list. If an 
investigator or a member of the study-site personnel is a member of the IEC/IRB, 
documentation must be obtained to state that this person did not participate in the 
deliberations or in the vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated 
copy of current laboratory normal ranges for these tests, if applicable

Local laboratory documentation demonstrating competence and test reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
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and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of signed informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable. Inclusion/Exclusion criteria should be documented with 
the PI or authorized delegate signature that the subject is eligible for participation. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
The following data will be recorded directly into the CRF and will be considered source data: 

Race

History of smoking

Blood pressure and pulse/heart rate 

Height and weight 
17.5.
Case Report Form Completion
Case report forms are provided for each subject in printed or electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site from the source documents onto an electronic CRF, and transmitted in a secure 
manner to the sponsor within the timeframe agreed upon between the sponsor and the study site. 
The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study site personnel must complete the CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
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All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
an authorized member of the study-site personnel must adjust the CRF (if applicable) and 
complete the query.
The investigator must verify that all data entries in the CRFs are accurate and correct.
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in 3 
different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool)

Study site manager can generate a query for resolution by the study-site personnel

Clinical data manager can generate a query for resolution by the study-site personnel
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review CRFs for accuracy and completeness during 
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform
the 
investigator/institution as to when these documents no longer need to be retained.
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If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
A streamlined approach to monitoring will be implemented in this study that utilizes an
algorithm to analyze data query rates to identify sites requiring additional training, and remote 
data surveillance that monitors subject characteristics, events and clinical and laboratory data at 
the level of each participating site. This seems particularly appropriate since the primary efficacy 
outcome for this study is the clinical composite outcome of ACM, stroke or MI, and not a 
surrogate outcome.
The sponsor will perform on-site monitoring visits as frequently as necessary with all sites being 
monitored at least at the start and at the end of the study. The monitor will record dates of the 
visits in a study site visit log that will be kept at the study site. At these visits, the monitor will 
compare the data entered into the CRFs with the hospital or clinic records (source documents). 
The nature and location of all source documents will be identified to ensure that all sources of 
original data required to complete the CRF are known to the sponsor and study-site personnel
and are accessible for verification by the sponsor study-site contact. If electronic records are 
maintained at the study site, the method of verification must be discussed with the study-site 
personnel. Monitors will also review all source documentation which will be used for 
verification of protocol specified event outcomes based on pre-defined criteria (see Outcome 
Event Definitions with Section 9.2.1)
Remote data surveillance will be performed in multiple ways. First, a control based statistical 
process predicated on a set of predefined parameters (eg, the mean number of critical queries 
generated from the CRF per subject per day of the study, the number of missing forms per 
subject) will be calculated and a pre-specified upper limit will be defined for these parameters 
over time. Sites that exceed the upper limit for these parameters during a specified observational 
period may be subject to an additional monitoring visit. Second, the decision to monitor a site 
will be made following review of clinical demographic data, key site performance data (such as 
time to enter CRF data, time to report serious adverse events) and key outcome variable data. 
Key subject demographic data, site performance data, and key outcome data will be monitored 
remotely as part of routine data surveillance on a monthly basis for all sites and be compared to 
the results seen overall for that country and region. Sites identified as having subjects with data 
that deviates substantially from the norm may also be subject to additional in-person monitoring 
visits, and these data will be used to supplement the data from the statistical process control for 
reviewing query generation.
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Remote monitoring of scanned or faxed imaging reports, laboratory results and other source 
documents will be used by the monitors, local trial managers and other clinical staff on an 
ongoing basis to also verify protocol specified events outcomes based on pre-defined criteria (see 
Outcome Event Definitions with Section 9.2.1).
Findings from this review of eCRFs and source documents will be discussed with the study-site 
personnel. The sponsor expects that, during monitoring visits, the relevant study-site personnel
will be available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees.
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Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding rivaroxaban or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory biomarker research data, generated as 
a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the clinical study will be used by 
the sponsor in connection with the continued development of rivaroxaban, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Study subject identifiers will not be 
used in publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
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investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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REFERENCES
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survival: a cohort analysis from the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol. 1998; 
31(4):749-53.
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Beasley BN, Unger EF, Temple R. Anticoagulant Options--Why the FDA Approved a Higher but not a Lower 
Dose of Dabigatran. N Engl J Med 2011; 364(19): 1788-90.
3.
Bettari L, Fiuzat M, Becker R, Felker GM, Metra M, and O'Connor CM. Circ Heart Fail. Thromboembolism 
and antithrombotic therapy in patients with heart failure in sinus rhythm: current status and future directions. 
2011; 4(3):361-8.
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Chong AY, Freestone B, Patel J, Lim HS, Hughes E, Blann AD, Lip GY. Endothelial activation, dysfunction, 
and damage in congestive heart failure and the relation to brain natriuretic peptide and outcomes. Am J 
Cardiol. 2006; 97(5):671-5.
5.
Cleland JG, Findlay I, Jafri S, Sutton G, Falk R, Bulpitt C, Prentice C, Ford I, Trainer A, Poole-Wilson PA. 
The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies 
for patients with heart failure. Am Heart J. 2004; 148(1):157-64.
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Cleland JG. Anticoagulant and antiplatelet therapy in heart failure. Curr Opin Cardiol. 1997; 12(3):276-87. 
7.
Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK; HELAS investigators. Efficacy of 
antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Fail. 2006; 8(4):428-32.
8.
Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al; ESC 
Committee for Practice Guidelines (CPG). ESC Guidelines for the diagnosis and treatment of acute and 
chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 
2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of 
the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 
2008; 29(19):2388-442.
9.
Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejection fraction and risk of thromboembolic events 
in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left 
ventricular dysfunction trials. J Am Coll Cardiol. 1997; 29(5):1074-80.
10.
Dunkman WB, Johnson GR, Carson PE, Bhat G, Farrell L, and Cohn JN. Incidence of thromboembolic events 
in congestive heart failure. The V-HeFT VA Cooperative Studies Group. Circulation. 1993; 87(6 Suppl):VI94-
101.
11.
Echemann M, Alla F, Briançon S, Juillière Y, Virion JM, Mertès PM, et al; EPICAL Investigators. 
Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine. Antithrombotic therapy is associated with 
better survival in patients with severe heart failure and left ventricular systolic dysfunction (EPICAL study). 
Eur J Heart Fail. 2002; 4(5):647-54.
12.
Gheorghiade M, Thyssen A, Zolynas R, Nadar VK, Greenberg BH, Mehra M, Sun X, Tian H, Plotnikov AN, 
and Burton P. Pharmacokinetics and pharmacodynamics of rivaroxaban and its effect on biomarkers of 
hypercoagulability in patients with chronic heart failure. J Heart Lung Transplant. 2011; 30:218-26. 
13.
Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, et al; WARCEF 
Investigators. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med. 2012; 
366(20):1859-69.
14.
Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al - 2005 Writing Group 
Members; Jessup M, Abraham WT, Donald EC, Feldman AM, Francis GS, Ganiats TG, et al - 2009 Focused 
Update Writing Group Members. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for 
the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with 
the International Society for Heart and Lung Transplantation. Circulation. 2009;119:e391-479.
15.
Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al; for the American Heart 
Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2009 
update: a report from the American Heart Association Statistics Committee and Stroke Statistics 
Subcommittee. Circulation. 2009; 119:e1-e161.
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16.
Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, Lamas GA, Moyé LA, Goldhaber SZ, and 
Pfeffer MA. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med. 1997; 
336(4):251-7.
17.
Marcucci R, Gori AM, Giannotti F, Baldi M, Verdiani V, Del Pace S, Abbate R. Markers of hypercoagulability 
and inflammation predict mortality in patients with heart failure. J Thromb Haemost. 2006; 4 (5): 1017-1022.
18.
Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M, Jafri SM, Krol WF, O'Connor 
CM, Schulman KA, Teo K, Warren SR; WATCH Trial Investigators. Randomized trial of warfarin, aspirin, 
and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart 
Failure (WATCH) trial. Circulation. 2009; 119(12):1616-24. 
19.
McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca 
C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu 
BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, 
Zeiher A; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute 
and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart 
Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure 
Association (HFA) of the ESC. Eur Heart J. 2012; 33:1787-847. 
20.
Neuhold S, Huelsmann M, Strunk G, Stoiser B, Struck J, Morgenthaler NG, Bergmann A, Moertl D, Berger R, 
Pacher R. Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type natriuretic 
peptide in patients with chronic heart failure. JACC. 2008; 52(4):266-72.
21.
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al; on behalf of the American 
Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-
2012 update: a report from the American Heart Association. Members, 2012. Circulation. 2012; 125(1):e2-
e220.
22.
Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al; American Heart Association Statistics 
Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2008 update: a report from 
the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008; 
117(4):e25-146.
23.
Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ, Granger CB, Yusuf S, et al; Candesartan in Heart 
failure: Assessment of Reduction in Mortality and morbidity (CHARM) Investigators. Influence of nonfatal 
hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 
2007; 116(13):1482-7.
24.
Skali H, Dwyer EM, Goldstein R, Haigney M, Krone R, Kukin M, Lichstein E, McNitt S, Moss AJ, Pfeffer 
MA, and Solomon SD. Prognosis and response to therapy of first inpatient and outpatient heart failure event in 
a heart failure clinical trial: MADIT-CRT. Eur J Heart Fail. 2014; 16(5):560-5.
25.
Tendera M. Epidemiology, treatment, and guidelines for the treatment of heart failure in Europe. European 
Heart Journal Supplements. 2005; 7 (Supplement J): J5–J9.
26.
Unger EF. Weighing Benefits and Risks – The FDA’s Review of Prasugrel. N Engl J Med. 2009; 361:942-945.
27.
Uretsky BF, Thygesen K, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, Packer M, Poole-Wilson PA, 
Ryden L. Acute coronary findings at autopsy in heart failure patients with sudden death: results from the 
assessment of treatment with lisinopril and survival (ATLAS) trial. Circulation. 2000; 102(6):611-6.
28.
van Veldhuisen DJ, Linssen JCM, Jaarsma T, van Gilst VH, Hoes AW, Tijssen JGP, Paulus WJ, Voors AA, 
Hillege HL. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced 
ejection fraction. JACC. 2013; 61(14):498-506.
29.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, 
Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, 
Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline 
for the management of heart failure: executive summary: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:1810-52. 
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Attachment 1: The MDRD Formula for Calculation of GFR
The Modification of Diet in Renal Disease (MDRD) study was a multicenter, controlled trial that 
evaluated the effect of dietary protein restriction and strict blood pressure control on the 
progression of renal disease.1 During the baseline period, serum creatinine and several variables 
were measured in 1,628 patients with chronic renal disease. The objective was to develop an 
equation that would predict GFR.
From this study, it was determined that older age and female sex were independent predictors of 
GFR, reflecting the well-known relation of age and sex to muscle mass. GFR was further 
adjusted for body surface area so that neither height nor weight was an independent predictor of 
adjusted GFR. African American ethnicity was an independent predictor of higher GFR as on 
average, black persons have greater muscle mass than whites.
The final MDRD Study prediction equation for GFR is as follows with Pcr being serum or 
plasma creatinine in mg/dL:
GFR (mL/min/1.73 m2) = 186 x (Pcr)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if African American)
The GFR is expressed in mL/min/1.73m2.
For this study the MDRD GFR will be calculated upon randomization and as needed by the IWRS, 
dependent upon variables provided by the investigative sites.
1.
Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum 
creatinine: a new prediction equation. Ann Intern Med. 1999; 130:461-470.
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Attachment 2: Modified Rankin Scale
Score
Description
0
No symptoms at all
1
No significant disability despite symptoms: able to carry out all usual duties and 
activities
2
Slight disability: unable to carry out all previous activities but able to look after 
own affairs without assistance
3
Moderate disability: requiring some help, but able to walk without assistance
4
Moderately severe disability: unable to walk without assistance and unable to 
attend to own bodily needs without assistance
5
Severe disability: bedridden, incontinent and requiring constant nursing care and 
attention
6
Patient death
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Attachment 3: Enoxaparin Equivalent Doses for Given Rivaroxaban Doses
Equivalent SQ Dose of Enoxaparin in mg/kg For a Given Dose of Rivaroxaban and a Given Time 
Following Its Administration
Time
Placebo
2.5 mg Rivaroxaban
3 h
0
0.15 mg/kg
6 h
0
0.1 mg/kg
For example, this table would be interpreted to mean that 3 hours after a 2.5 mg dose of 
rivaroxaban, the anticoagulation status would be similar to 0.15 mg/kg of enoxaparin at that 3 
hour time point. If additional enoxaparin is needed, the dose would be the desired dose minus the 
dose provided in the table at the specific time point.  In the example above for the 0.5 mg/kg 
dose of enoxaparin at 3 hours following a rivaroxaban dose, the dose of enoxaparin would be 
0.35 mg/kg (0.5 – 0.15 mg/kg).
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Attachment 4: Approach to Subjects Requiring Thrombolysis: 
Administration of an Adjusted Enoxaparin Dose
Approach to the Subject Requiring Thrombolysis
If a subject requires thrombolysis, it may be necessary to unblind the subject and administer a 
reduced enoxaparin dose with the adjustment in mg/kg shown below:
Subjects who are less than 6 hours from the last dose of study medication may need to be unblinded 
at the discretion of the investigator (refer to the shaded zone of the table). Do not unblind subjects 
who fall into the white zone and treat with full dose antithrombin (0.5 mg/kg enoxaparin or 
equivalent):
Time
Placebo
2.5 mg Rivaroxaban
3 h
0
0.15 mg/kg
6 h
0
0.1 mg/kg
9 h
0
0
For example, this table would be interpreted to mean that 3 hours after a 2.5 mg dose of 
rivaroxaban, the anticoagulation status would be similar to 0.15 mg/kg of enoxaparin at that 3 
hour time point. If additional enoxaparin is needed, the dose would be the desired dose minus the 
dose provided in the table at the specific time point.  In the example above for the 0.5 mg/kg 
dose of enoxaparin at 3 hours following a rivaroxaban dose, the dose of enoxaparin would be 
0.35 mg/kg (0.5 – 0.15 mg/kg).
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INVESTIGATOR AGREEMENT
NCT01877915

SAP_001.pdf: 
1
Approved, Date:12 December 2017
Janssen Research & Development
Statistical Analysis Plan
A Randomized, Double-blind, Event-driven, Multicenter Study Comparing the Efficacy and
Safety of Rivaroxaban with Placebo for Reducing the Risk of Death, Myocardial Infarction or
Stroke in Subjects with Heart Failure and Significant Coronary Artery Disease Following an
Episode of Decompensated Heart Failure
Protocol RIVAROXHFA3001; Phase 3
JNJ-39039039; BAY 59-7939   
Amendment 2.0
Status:
Approved
Date:
12 December 2017
Prepared by:
Janssen Research & Development, LLC  
Document No.:
EDMS-ERI-54766356, 4.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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Statistical Analysis Plan RIVAROXHFA3001
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Approved, Date:12 December 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
SAP AMENDMENT ...................................................................................................................................... 4
ABBREVIATIONS ...................................................................................................................................... 15
1.
INTRODUCTION................................................................................................................................ 16
1.1.
Trial Objectives .............................................................................................................................. 16
1.2.
Trial Design .................................................................................................................................... 17
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 19
1.4.
Sample Size Justification ............................................................................................................... 19
1.5.
Randomization and Blinding .......................................................................................................... 21
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 21
2.1.
Subject-Level Trial Milestone Dates .............................................................................................. 21
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 22
2.3.
Analysis Sets.................................................................................................................................. 22
2.3.1.
Efficacy Analysis Set .................................................................................................................. 24
2.3.1.1.
Main Efficacy Analysis Set ...................................................................................................... 24
2.3.1.2.
Sensitivity Efficacy Analysis Sets ............................................................................................ 24
2.3.1.3.
Additional Analysis Sets .......................................................................................................... 24
2.3.2.
Safety Analysis Set..................................................................................................................... 24
2.4.
Definition of Subgroups.................................................................................................................. 25
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 26
4.
SUBJECT INFORMATION................................................................................................................ 27
4.1.
Demographics and Baseline Characteristics ................................................................................. 27
4.2.
Disposition Information................................................................................................................... 28
4.3.
Treatment Compliance................................................................................................................... 28
4.4.
Extent of Exposure......................................................................................................................... 29
4.5.
Protocol Deviations ........................................................................................................................ 29
4.6.
Prior and Concomitant Medications ............................................................................................... 30
5.
EFFICACY ......................................................................................................................................... 30
5.1.
Analysis Specifications................................................................................................................... 30
5.1.1.
Level of Significance................................................................................................................... 30
5.1.2.
Data Handling Rules................................................................................................................... 30
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 31
5.2.1.
Definition..................................................................................................................................... 31
5.2.2.
Analysis Methods........................................................................................................................ 31
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 34
5.3.1.
Definition..................................................................................................................................... 34
5.3.2.
Analysis Methods........................................................................................................................ 34
5.4.
Other Efficacy Variable(s) .............................................................................................................. 34
5.4.1.
Definition..................................................................................................................................... 34
5.4.2.
Analysis Methods........................................................................................................................ 35
5.5.
Additional Efficacy Analyses .......................................................................................................... 35
6.
SAFETY............................................................................................................................................. 35
6.1.
Bleeding Events ............................................................................................................................. 35
6.2.
Other Adverse Events.................................................................................................................... 37
6.3.
Clinical Laboratory Tests................................................................................................................ 37
6.4.
Vital Signs and Physical Examination Findings ............................................................................. 38
7.
BENEFIT/RISK ASSESSMENT ........................................................................................................ 38
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8.
HEALTH ECONOMICS ..................................................................................................................... 40
REFERENCES............................................................................................................................................ 41
ATTACHMENTS......................................................................................................................................... 42
Attachment 1.
The assumption of enrollment used in the original sample size calculation 
and the observed enrollment up to June 2016 on which the simulation study 
was based................................................................................................................... 42
Attachment 2.
Template of CONSORT Statement 2010 flow diagram ............................................. 43
Attachment 3.
Disallowed concomitant medications ......................................................................... 44
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Approved, Date:12 December 2017
SAP AMENDMENT
SAP Version 
Issue Date
Original SAP
June 10, 2013
Amendment 1.0
February 01, 2017
Amendment 2.0
December 12, 2017
Amendments are listed beginning with the most recent amendment.
Amendment 2.0
The principal rationale for the SAP Amendment 2.0 is the addition of a supporting analysis suggested by the 
trial’s Steering Committee, and to clarify the definition of an analysis subpopulation. Secondarily, the Amendment 
will also add a recently approved medication to the list of baseline therapies, address differences in adverse event
(AE) reporting in one country (Japan), clarify text and correct minor grammatical errors.
Applicable Section(s)
Description of Change(s)
Rationale: To add a supporting analysis suggested by the trial’s Steering Committee.
5.3.2. Analysis 
Methods
Added the sentence “A supporting analysis of time to the first occurrence of all-cause 
mortality (ACM) or re-hospitalization for worsening of HF will also be performed using 
the same analysis method as for the primary efficacy endpoint.”.
Rationale: To clarify the definition of a subpopulation.
2.4. Definition of 
Subgroups; 5.5. 
Additional Efficacy;
Analyses; 6.1. 
Bleeding Events
Changed the phrase “subjects who complete treatment at GTED and are scheduled for 
EOS visit (Office/Phone)” to “Subjects who complete the double-blind treatment period 
and have the EOS visit (Office/Phone)”
Rationale: To add a new medication “angiotensin receptor-neprilysin inhibitor” (ARNI) to the list of baseline
therapies. ARNIs are currently being coded to ANGIOTENSIN II ANTAGONISTS, OTHER COMBINATIONS in 
this study since this term is not yet available in the current WHODRUG coding dictionary.
ABBREVIATION; 
4.1. Demographics and 
Baseline 
Characteristics
Added “ARNI, angiotensin receptor-neprilysin inhibitors” to the abbreviation list.
Added “Baseline ARNI use” as a sub-bullet of “Baseline ARB use” in the list of 
demographics and baseline characteristics to be summarized.
Rationale: To reflect the current Standardized Medication Name and Medication Class in the WHODRUG coding 
dictionary for spironolactone and epleronone.
2.4. Definition of 
Subgroups; 4.1. 
Demographics and 
Baseline 
Characteristics
Replaced “mineralocorticoid receptor antagonist” with “aldosterone antagonists”.
Rationale: To clarify the definition of the ITT population i.e., the same subject randomized twice will only be 
counted once in the ITT population.
2.3. Analysis Sets
Added the word “unique” into the sentence of: 
Intention-to-treat (ITT) population: This subject population consists of all randomized 
unique subjects who have a signed valid informed consent.
NCT01877915


JNJ-39039039; BAY 59-7939 (rivaroxaban)
Statistical Analysis Plan RIVAROXHFA3001
5
Approved, Date:12 December 2017
Applicable Section(s)
Description of Change(s)
Rationale: To add fragile subjects as a subgroup.
2.4. Definition of 
Subgroups
Added a subgroup:
•
Fragile subjects (yes vs no; fragile subjects are those with age > 75 years or weight ≤
50 kg or baseline eGFR < 50 mL/min)
Rationale: No more countries will be added to the study.
2.4. Definition of 
Subgroups
Deleted the text “(Regions will be updated if additional countries are included in this 
study.)”.
Rationale: To clarify the analysis sets used for evaluation of the primary and secondary efficacy endpoints.  
2.3.1.1. Main Efficacy 
Analysis Set; 2.3.1.2, 
Sensitivity Efficacy 
Analysis Set
Changed the word “Primary” in the section heading, “Primary Efficacy Analysis Set”, to 
“Main” and the word “Secondary” in the section heading, “Secondary Efficacy Analysis 
Sets”, to “Sensitivity”.
Rationale: To describe the additional analysis sets previously defined in multiple places in the document in one
section.  
2.3.1.3. Additional 
Analysis sets
Added a separate Section (2.3.1.3) to describe the additional analysis sets.
Rationale: To clarify the definitions of the observation periods used for the safety analyses.  
2.3. Analysis Set; 
2.3.2. Safety Analysis 
Set
Added the paragraphs:
“The main safety analysis set is defined by the On-treatment observation period and the 
safety subject population. The sensitivity safety analysis set is defined by the post-first 
dose of study drug observation period and the safety subject population. Subjects will be 
analyzed according to the treatment assigned.”;
“Bleeding events and adverse events will be analyzed and summarized based on both the 
main and sensitivity safety analysis sets.”;
“In addition, the same additional analysis sets defined in Section 2.3.1.3 will also be used 
for the summaries of safety events. Details are described in Section 6.1.”.
Moved the paragraph below from Section 2.3.2 to Section 2.3:
“Post-first dose of study drug: This observation period starts from the day of the first dose 
of study drug and ends on the day of last contact, inclusively. Because subjects will be 
asked to take their first dose of study drug on the randomization day, while they are still 
in investigators’ offices, for most of subjects, this observation period will be identical to 
post-randomization observation period.”.
Deleted the two paragraphs:
“In addition to observation periods defined in Section 2.3.1, the following observation 
period is defined specifically for the safety analysis.”;
“Bleeding events will be analyzed based on the analysis set defined by the on-treatment 
observation period and the safety subject population. Subjects will be analyzed according 
to the treatment assigned. As a sensitivity analysis, bleeding events will also be analyzed 
based on the analysis set defined by the post-first dose of study drug observation period 
and the safety subject population.  AEs reported by investigators will be summarized 
based on the analysis set defined by the on-treatment observation period and separately by 
the post-first dose of study drug observation period and the safety subject population.”.
NCT01877915


JNJ-39039039; BAY 59-7939 (rivaroxaban)
Statistical Analysis Plan RIVAROXHFA3001
6
Approved, Date:12 December 2017
Applicable Section(s)
Description of Change(s)
Rationale: To clarify the definition of a baseline therapy.
4.1. Demographics and 
Baseline 
Characteristics
Added the text “or implantable defibrillator or combination” to the bullet of “Cardiac 
resynchronization therapy”.
Rationale: While the number of subjects who permanently discontinue study drug will be reported, the data 
collected are insufficient to support an analysis of the conversion from a temporary to a permanent study drug
discontinuation.
4.2. Disposition
Information
Deleted the two paragraphs:
“It is possible that a temporary study drug interruption can become a permanent study 
drug discontinuation due to events that occur after the start of the temporary study drug
interruption, such as diagnosis of atrial fibrillation that requires permanent anticoagulant 
therapy or announcement of GTED while a subject is on temporary study drug stoppage. 
The number of subjects who permanently discontinue the study drug after a temporary 
study drug interruption may be summarized if there are sufficient observations.
“The same method will be used to summarize information of discontinuations from the 
study if data is sufficient.”
Rationale: To clarify the wording.
2.3.1. Analysis Sets
5.1.1. Level of 
Significance
Clarified the definition of the “Per-Protocol (PP) population: This population is a subset 
of the ITT population, consisting of subjects who do not have a major protocol deviation 
in the following categories …”.
Clarified the main, sensitivity and additional analysis sets for the efficacy, principal safety
(bleeding) and adverse event analyses
Replaced the sentence “If p value for a hypothesis is greater than that significant level, all 
remaining hypotheses after this hypothesis in the fixed sequence will not be rejected.” 
with “If an individual test during any step is not statistically significant, further treatment 
comparison may continue (i.e., reporting of p-values) but significance will not be 
claimed.”.
Rationale: To reflect the planned missing data analysis.
5.2.2. Analysis 
Methods
Added “on the primary efficacy analysis” to the first sentence of the paragraph starting 
“The potential impact of missing data …”.
Deleted the phrase “If the missing observation are substantial,” in the same paragraph.
Rationale: To describe additional analyses for Japan subjects based on Japan-specific reporting of bleeding events
and adverse events.
6.1. Bleeding Events
6.2. Other Adverse 
Events
Added a sentence: “For Japan subjects only, summary statistics will be provided for non-
major clinically relevant bleeding events and minimal bleeding events.”.
Added a paragraph “Based on specific safety reporting requirements from the 
Pharmaceuticals and Medical Devices Agency, AE data from Japan may not be directly 
comparable with those collected from non-Japan sites. Therefore, the AE data from Japan 
sites may be summarized separately from AE data from non-Japan sites in the respective 
reported safety tables.”.
Rationale: To reflect the intent of the protocol and current data reporting requirements.
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JNJ-39039039; BAY 59-7939 (rivaroxaban)
Statistical Analysis Plan RIVAROXHFA3001
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Approved, Date:12 December 2017
Applicable Section(s)
Description of Change(s)
6.4. Vital Signs and 
Physical Examination 
Findings
Revised the section wording to “Targeted medical history and vital signs are obtained at 
baseline only and summarized as baseline characteristics. Physical examinations are not 
required as part of study procedures. Available data may be discussed in subject 
narratives.”.
Rationale: To reflect that a fatal or non-fatal MI and a fatal or non-fatal ischemic stroke may be counted in the 
Benefit outcome.
7. Benefit/Risk 
Assessment
Added a sentence to the Benefit outcome discussion “As a supporting measure, the 
composite of non-bleeding related death, MI (fatal, non-fatal) or ischemic stroke (fatal, 
non-fatal) may also be evaluated.”.
Rationale: To move the text to the appropriate subsection due to formatting error in previous version.
5.1.1. Leve of 
Significance; 5.1.2. 
Data Handling Rules
2.2. Pooling Algorithm 
for Analysis Centers; 
2.3 Analysis Set
Moved the text “Confidence intervals (CIs) are calculated at the 95% nominal confidence 
level. In addition, repeated CI (RCI), which adjusts for the interim analysis, will also be 
provided in the clinical study report (CSR)” to the bottom of Section 5.1.1.
Moved the text “No pooling algorithm for analysis centers will be used. The primary 
efficacy analysis will be stratified by region defined in Section 2.4.” to Section 2.2.
Rationale:  Consistency and minor errors were noted.
Throughout the SAP
Consistency with protocol and minor grammatical, spelling or formatting changes were 
made.
Amendment 1.0
The overall rationale for the SAP Amendment 1.0: is due to changes in the Study Protocol (Amendments 1, 2, 3) 
and FDA feedback on the planned statistical methods.
Applicable Section(s)
Description of Change(s)
Rationale: To indicate that changes made in this document are based on changes made in the protocol amendments.
1. Introduction
Added the texts “originally” and “all its amendments” in the sentence “This SAP is based 
on …”.
Rationale: To include high-risk patients treated in an outpatient setting with parenteral medications for 
decompensated heart failure.
1.1. Trial Objectives
Replaced the phrase “following a recent hospitalization for exacerbation of HF” with 
“following an episode of decompensated HF (index event)”.
Replaced the phrase “a recent hospitalization for exacerbation of HF” with “index event”.
Rationale: To clarify the definition of the bleeding events requiring hospitalization.
1.1. Trial Objectives
Added the text “(caused a hospitalization or prolongation of an existing hospitalization)”.
Throughout the 
document where the 
study population is 
described
Deleted the term “chronic” or replaced “chronic” with “symptomatic”.
Replaced the phrase “a recent hospitalization for exacerbation of HF” with “an episode of 
decompensated HF”.
Rationale: Protocol Amendment INT-3 increases the target number of primary efficacy events from 984 to 1,200 
and increases the target number of primary efficacy events from 500 to 600 for the interim analysis (IA).
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JNJ-39039039; BAY 59-7939 (rivaroxaban)
Statistical Analysis Plan RIVAROXHFA3001
8
Approved, Date:12 December 2017
Applicable Section(s)
Description of Change(s)
1.2 Trial Design; 2.1.
Subject-Level Trial 
Milestone Dates
Replaced “984” with “1,200”.
1.2 Trial Design; 1.4. 
Sample Size 
Justification; 3. 
INTERIM ANALYSIS 
AND DATA 
MONITORING 
COMMITTEE 
REVIEW; 5.2.2.
Analysis Methods
Changed “500±50” to “approximately 600”.
1.4. Sample Size 
Justification
Added:
The study is revised to observe occurrences of the primary efficacy event in 1,200 unique 
randomized subjects based on a simulation study performed on currently available trial 
data, i.e., longer enrollment period, lower than anticipated primary efficacy event rate, 
higher than anticipated study drug discontinuation rate: 
• Event rate in the placebo arm: approximately 16%/year based on the observed 
combined event rate at 14%/year (assumed 20% of RRR remains) 
• Early permanent study drug discontinuation rate: approximately 13%/year
• Duration of enrollment period: approximately 48 months (projected)
The simulation study estimated that the duration of study may extend to approximately 54 
months based on the fact that the original goal of enrolling a total of 5,000 subjects 
remains unchanged and all subjects would be observed for approximately 6 months after 
the last subject is enrolled.
With a 20% effect size and overall α level of 5% (2-sided), 1,200 number of primary 
efficacy events will produce a statistical power of approximately 80%.
Deleted the sentence “The interim analysis will have approximately 75% power to detect 
an RRR of 30% in the primary efficacy endpoint.”
Rationale: To be consistent with the wording used in Protocol Amendment INT-3.
NCT01877915


JNJ-39039039; BAY 59-7939 (rivaroxaban)
Statistical Analysis Plan RIVAROXHFA3001
9
Approved, Date:12 December 2017
Applicable Section(s)
Description of Change(s)
1.2. Trial Design
Deleted the sentences “The screening phase will last up to 28 days (up to 21 days during 
the index hospitalization and up to 7 days after discharge from the index hospitalization), 
followed by an estimated 6 to 30 months double-blind treatment phase.”
Added the sentences “The screening phase may last up to 51 days before randomization 
(21 days maximum for a hospitalization admission plus up to 30 days after discharge from 
the facility treating the index event), followed by an estimated 6 to 54 months of double-
blind treatment phase.” and “Note that the screening period in Japan may last up to 60 
days before randomization (up to 30 days for a hospitalization admission plus up to 30 
days after discharge from the facility treating the index event).”
Deleted the sentence “If the rate of efficacy events is lower than the estimated used in 
sample size calculation, the sample size may increase up to 5500 subjects.”
Added a phrase “as soon as possible after the last dose of study drug” at the end of
sentence “Subjects who permanently discontinue study drug …”.
Deleted the sentence “A subject will be instructed to discontinue study drug temporarily 
for an outcome event such as an MI or ischemic stroke.”
Added the sentences: “If a subject experiences an outcome event such as MI or stroke, 
study drug may be temporarily held if necessary or if using other anticoagulant drugs or 
thrombolytic therapy” and “This also applies to other efficacy outcome events such as 
DVT or PE.”  
Added the phrase “or for any reason listed in Section 10.2.2 of the protocol.” at the end of 
sentence “After appropriate treatment of the event, …”.
Rationale: The process of outcome event document verification has evolved over time.
1.2. Trial Design
Deleted the sentences “Unless otherwise specified, outcome events hereafter refer to 
events with adequate supporting documentation per protocol; and all-reported events refer 
to outcome events reported by investigators, regardless of adequacy of supporting
documentation.” and “Supporting documentation will be reviewed, and the adequacy of 
documentation will be determined before database lock and captured in database.”
Added the sentence “The details of outcome event reporting and verification are described
in the Investigator Manual for Outcome Events and the Sponsor Outcome Event 
Verification Process Manual.”
Rationale: To clarify that the D-dimer collected at both baseline and Week 4 are not being shared with investigators 
nor with sponsor’s clinical study team to avoid any bias in treating the subjects.
1.5. Randomization 
and Blinding; 6.3.
Clinical Laboratory
Tests
Add the sentence “Complete D-dimer data will not be available until after the database 
lock.”
Deleted the paragraph “While the personnel at the study site may be aware of subjects 
randomly selected, Week 4 D-dimer value will only be available to the sponsor after data 
unblinding because of the potential of treatment assignment unblinding. Week 4 D-dimer 
results will not be given to the subject or the investigator. Therefore, collection of Week 4 
D-dimer data will not unblind treatment assignment.”
Rationale: To capture all relevant data collection for the last contact date.
NCT01877915


JNJ-39039039; BAY 59-7939 (rivaroxaban)
Statistical Analysis Plan RIVAROXHFA3001
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Approved, Date:12 December 2017
Applicable Section(s)
Description of Change(s)
2.1. Subject-Level 
Trial Milestone Dates
Added the sentence “If a subject completes the randomization visit but no further visits 
and no other data is recorded on the eCRF, the randomization date will be considered as 
the last contact date.”
Added the phrase “and the death date is missing” to the sentence “For subjects who died 
during the study ….”.
Rationale: In line with MPD category text for subjects excluded from per-protocol analysis set.
2.3.1. Efficacy 
Analysis Set(s) 
Changed the phrase “Subjects with the following major protocol deviations will be 
excluded from the PP population:” to “Subjects with a subset of major protocol deviations 
in the following categories will be excluded from the PP population (see FRM-15949 for 
the specific major protocol deviations that are exclusions from the PP population and 
identification/review process):”
Deleted:
• Not meeting key inclusion or exclusion criteria
• Taking incorrect study drug
• Not permanently discontinuing study drug according to the protocol
• Treatment compliance rate < 75% (see Section 4.3 for details)
• Having been taking prohibited concomitant therapies as specified in the protocol for 
an extended period (≥30 consecutive days or 20% of treatment period on a continuous 
basis, whichever is shorter).  A list of prohibited concomitant medications is in 
Attachment 3.
Added: 
• Entered but did not satisfy criteria
• Received a disallowed concomitant treatment
• Received wrong treatment or incorrect dose (includes subjects with treatment 
compliance rate < 75% calculated according to a formula described in Section 4.3)
• Developed withdrawal criteria but not withdrawn
• Other (as appropriate) 
Rationale: To change the safety analyses from “study drug received” to “study drug assigned” based on the fact that 
the COMMANDER HF is a long term study and the incidence of a subject receiving the wrong study drug during 
the entire treatment period will be low.
2.3.2. Safety Analysis 
Set; 6.1. Bleeding 
Events
Change the sentence “Subjects will be analyzed according to the actual treatment 
received” to “Subjects will be analyzed according to the treatment assigned”. 
Deleted the sentence “If a subject receives both rivaroxaban and placebo, the subject will 
be analyzed according to the treatment assigned”.   
Rationale: To be consistent with the subgroups defined in the protocol and to define regions with more countries.  
2. 4. Definition of 
Subgroups
Deleted “History of percutaneous coronary intervention (PCI) or coronary artery bypass 
graft (CABG) (yes vs no)”, “Cardiac resynchronization therapy (yes vs no)”, “aldosterone 
inhibitors”, “White, Asian, Black, and others”.
Added “Baseline BNP or NT-proBNP (≤median vs > median), “mineralocorticoid 
receptor antagonist”.
Expended regions with more countries enrolling subjects.
Rationale: To change the stratification factor for the efficacy and safety analyses from “country” to “region” due to
the increase in the number of enrolling countries and the corresponding smaller sample sizes expected in those
countries.
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Statistical Analysis Plan RIVAROXHFA3001
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Approved, Date:12 December 2017
Applicable Section(s)
Description of Change(s)
Section 3. INTERIM 
ANALYSIS AND 
DATA 
MONITORING 
COMMITTEE 
REVIEW; 5.2.2 
Analysis Methods; 6.1.
Bleeding Events
Replace “stratified by pooled countries” with “stratified by region”.
Rationale: To add common baseline demographics and baseline characters appropriate for the study population.  
4.1. Demographics and 
Baseline 
Characteristics
Deleted “History of CABG”, “aldosterone inhibitors”.
Added “Height”, “Weight”, “mineralocorticoid receptor antagonist use”, “Baseline BNP 
or NT-proBNP”.
Added the phrase “Additionally, evidence of coronary artery disease will be summarized.”
Rationale: To plan for proper analyses for subject disposition information.
4.2. Disposition 
Information
Added the sentence “The same method will be used to summarize discontinuation from 
the study.”
Deleted the phrases: “These permanent early study drug discontinuations will be included 
in the summary of early permanent discontinuation of study drug with all other early 
permanent drug discontinuations. For these early permanent study drug discontinuations, 
an additional summary will be provided to show reasons of temporary study drug 
discontinuations immediately preceding these early permanent study drug 
discontinuations.  Details are specified in the DPS.”  
Added the sentence “The number of subjects who permanently discontinue the study drug 
after a temporary study drug interruption may be summarized if there are sufficient 
observations.”
Rationale: Study drug compliance will be calculated based on the days of study drug taken due to difficulties of 
obtaining reliable pill counts information.
4.3. Treatment 
Compliance
Replaced the compliance formula based on the pill counts information with the formula 
based on the days of study drug taken.
Deleted the phrases: “If a pill count is impossible for a bottle due to reasons such as lost 
bottle or bottle not returned, it will be assumed that the compliance rate during the period 
that the bottle is intended to cover is the same as the compliance rate during the rest of the 
study. This is equivalent to excluding the period with missing pill count from the 
compliance rate calculation”.
Added the sentence “If the dose date prior to a treatment interruption is missing, the same 
imputation rule for imputing the last dose date descripted in Section 2.1 will be used to 
impute the dose date.”
Rationale: The MPD category text was revised to reflect the database terminology.
NCT01877915


JNJ-39039039; BAY 59-7939 (rivaroxaban)
Statistical Analysis Plan RIVAROXHFA3001
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Approved, Date:12 December 2017
Applicable Section(s)
Description of Change(s)
4.5. Protocol 
Deviations. 
Deleted:
• Not meeting inclusion or exclusion criteria
• Receiving incorrect medication kits
• Not permanently discontinuing study drug as per protocol
• Having been taking prohibited concomitant therapies for an extended period (≥ 30 
consecutive days or 20% of treatment period on a continuous basis whichever is
shorter). A list of prohibited concomitant medications is provided in Attachment 3.
Added:
• Entered but did not satisfy criteria
• Received a disallowed concomitant treatment
• Developed withdrawal criteria but not withdrawn (includes subjects with treatment 
compliance rate < 75% calculated according to a formula described in Section 4.3)
• Received wrong treatment or incorrect dose
• Other (as appropriate)
Rationale: To clearly indicate the stratification factor and analysis sets for sensitivity analyses.
5.2.2 Analysis 
Methods
In the sentence “These include, but are not limited to, …”, added the phrases “a log-rank 
test stratified by country and”; “for the analysis set defined by the up-to-GTED 
observation period and ITT subject population”; and “for the analysis set defined on-
treatment observation period and the safety subject population”.
Added the sentence “The primary efficacy endpoint will also be analyzed for the ITT 
subjects who enrolled under the original protocol and who enrolled under the amended 
protocols for the Up-to-GTED observation period.”
Rationale: To indicate that substantial missing observations will warrant sensitivity analyses. 
5.2.2 Analysis
Methods
Reworded the sentence “Additional details of these sensitivity analyses, including 
specifications for imputation, will be provided in a separate document that will be 
finalized prior to planned interim analysis” to “If the missing observations are substantial, 
additional details of these sensitivity analyses, including specifications for imputation, 
will be provided in a separate document that will be finalized prior to the final database 
lock.”
Rationale: To detail the definition of fatal bleeding and the analysis for other reported bleedings. 
6.1. Bleeding Events
Added the protocol fatal bleeding definition: “A fatal bleeding event is one in which the 
subject dies within 7 days of a bleeding event requiring hospitalization or ISTH major 
bleeding.”
Added 3 exclusive categories of fatal bleeding with regard to how a fatal bleeding event is 
captured on the bleed page of eCRF.
Added the sentence “The number of the subjects with other reported bleeding events will 
be summarized by treatment group and bleeding site.”
Rationale: To clarify the selected lab test collections during the study.
6.3. Clinical 
Laboratory Tests
Added the phrase “during the study other than D-dimer at week 4 (10% of subjects) and 
hemoglobin at week 12 (up to week 24)” to the first sentence.
Rationale: The duration of the study is longer than anticipated
7. Benefit/Risk 
Assessment
Added the sentence “*Because the duration of the trial is longer than anticipated, Kaplan-
Meier Product-Limit estimates of cumulative event rates at 2-years and 3-years may be 
explored.”
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Statistical Analysis Plan RIVAROXHFA3001
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Approved, Date:12 December 2017
Applicable Section(s)
Description of Change(s)
Rationale: To address FDA’s comments on the original study SAP (submitted to the Agency on June 14, 2013; 
FDA comments received on July 30, 2013).
2.2. Pooling Algorithm 
for Analysis Centers
The original pooling strategy was deleted, i.e., countries would not be pooled.
Added the sentence “No pooling algorithm for analysis centers will be used. The primary 
efficacy analysis will be stratified by region defined in Section 2.4.”
2.3.1. Efficacy 
Analysis Set(s)
Added:
Off-treatment: this observation period includes data from 3 days after the last dose of the 
study drug to the last contact date, inclusively.
Day 3 to day 30 after the last dose: the 3rd day after the last dose of study drug to the 30th
day after the last dose of study drug or the last contact day, whichever is earlier.
2.4. Definition of 
Subgroups
Two additional subpopulations were added for summarizing efficacy and safety 
endpoints:
In addition, the number of subjects with efficacy endpoints including components of 
composite efficacy endpoints; the number of subjects with principal safety endpoint and 
its components of fatal bleeding (defined in Section 6.1) and bleeding into a critical space 
with a potential for permanent disability; and the number of subjects with other bleeding 
outcomes of ISTH major bleeding events and bleeding requiring hospitalization will be 
summarized for safety subjects in the following subpopulations:
• Subjects who permanently discontinue study drug for any reason prior to GTED 
• Subjects who complete treatment at GTED and are scheduled for EOS visit 
(Office/Phone)
3. INTERIM 
ANALYSIS AND 
DATA 
MONITORING 
COMMITTEE 
REVIEW
Changed the phrase “at 5%, 2-sided α level” to “at a significant level corresponding to the 
Pocock-type boundary” in the sentence “If the test statistic for the primary efficacy 
endpoint …, secondary endpoints will …”.
5.1.1. Level of 
Significance; 5.3.2 
Analysis methods
Changed the phrase “greater than 0.05” to “greater than that significant level” in the 
sentence “If p-value for a hypothesis is …”.
Changed the phrase “5% significance level” to “a significance level corresponding to the 
Pocock-type boundary”.
Changed ‘0.05 to “corresponding to the Pocock-type boundary”.
Deleted the sentence “In summary, all statistical tests will be conducted at the 0.05 
significance level, except the test for the primary efficacy endpoint.”
Added the sentence “In addition, repeated CI (RCI), which adjusts for the interim 
analysis, will also be provided in the clinical study report (CSR).”
5.2.2. Analysis 
Methods
Added the sentence “In addition, a RCI will be calculated based on the procedure 
described in Jennison and Turnbull (2000), where significance level at the interim 
analysis and the final analysis will be approximately 99.7% and 95.2%, respectively.”
NCT01877915


JNJ-39039039; BAY 59-7939 (rivaroxaban)
Statistical Analysis Plan RIVAROXHFA3001
14
Approved, Date:12 December 2017
Applicable Section(s)
Description of Change(s)
5.5. Additional 
Efficacy Analyses
Added the new section:
5.5. Additional Efficacy Analyses
For all primary, secondary and other efficacy outcome events discussed above, the 
number of subjects with these events will be tabulated for the following analysis sets:
• Off-treatment observation period for subjects who permanently discontinue study drug 
for any reason prior to GTED
• Off-treatment observation period for subjects who complete treatment at GTED and 
are scheduled for EOS visit (Office/Phone)
• Off-treatment observation period for the Safety population.  
• Day 3 to Day 30 after the last dose observation period for subjects who permanently 
discontinue study drug for any reason prior to GTED
• Day 3 to Day 30 after the last dose observation period for subjects who complete 
treatment at GTED and are scheduled for EOS visit (Office/Phone)
• Day 3 to Day 30 after the last dose observation period for the Safety population.
6.1. Bleeding Events
Added:
The number of subjects with above safety outcomes will be tabulated for the following 
analysis sets:
• Off-treatment observation period for subjects who permanently discontinue study drug 
for any reason prior to GTED
• Off-treatment observation period for subjects who complete treatment at GTED and 
are scheduled for EOS visit (Office/Phone)
• Off-treatment observation period for the Safety population.  
• Day 3 to Day 30 after the last dose observation period for subjects who permanently 
discontinue study drug for any reason prior to GTED
• Day 3 to Day 30 after the last dose observation period for subjects who complete 
treatment at GTED and are scheduled for EOS visit (Office/Phone)
• Day 3 to Day 30 after the last dose observation period for the Safety population.
Rationale:  Consistency and minor errors were noted.
Throughout the SAP
Consistency with protocol and minor grammatical, spelling or formatting changes were 
made.
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JNJ-39039039; BAY 59-7939 (rivaroxaban)
Statistical Analysis Plan RIVAROXHFA3001
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Approved, Date:12 December 2017
ABBREVIATIONS
ACEI
angiotensin-converting enzyme inhibitor
ACM
all-cause mortality
AE
adverse event
ARB
angiotensin receptor blocker
ARNI
angiotensin receptor-neprilysin inhibitors
BNP
brain natriuretic peptide
CABG
coronary artery bypass graft
CAD
coronary artery disease
CDF
cumulative distribution function
CEC
Clinical Endpoint Committee
CI
confidence interval
CSR
Clinical Study Report
CV
Cardiovascular
DPS
Data Presentation Specifications
DVT
deep vein thrombosis
ECG
Electrocardiogram
EOS
End-of-Study
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GTED
Global Treatment End Date
HF
heart failure
IDMC
Independent Data Monitoring Committee
ISTH
International Society on Thrombosis and Haemostasis
ITT
Intent-to-Treat
IWRS
interactive web response system
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRU
medical resource utilization
MI
myocardial infarction
NT-proBNP
N-terminal-pro- brain natriuretic peptide
OE
Outcome Event
PCI
percutaneous coronary intervention
PE
pulmonary embolism
PP
Per-Protocol
RCI
Repeated confidence interval
RRR
relative risk reduction
SAP
Statistical Analysis Plan
SC
Steering Committee
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1.
INTRODUCTION
This statistical analysis plan (SAP) specifies definitions of analysis sets, key derived variables 
and statistical methods for analysis of efficacy and safety for the Phase 3 study
RIVAROXAHF3001 (also known as COMMANDER HF). This SAP is based on the Clinical 
Protocol RIVAROXAHF3001, originally finalized on April 18, 2013 and all its amendments.
Titles, mock-ups and programming instructions for all statistical outputs (tables, figures and 
listings) are provided in a separate document entitled Data Presentation Specifications (DPS).
An Independent Data Monitoring Committee (IDMC) will monitor safety during this study, 
review interim efficacy and safety results, and make a recommendation whether the study will be 
continued as planned, or terminated early for overwhelming superiority, futility, or safety.
Safety data will be reviewed by the IDMC periodically and additional details for the planned 
interim analysis are specified in the abbreviated IDMC SAP, which was specifically prepared for 
IDMC use.
1.1.
Trial Objectives
The primary objective is to demonstrate that rivaroxaban is superior to placebo in subjects with 
symptomatic heart failure (HF, 3 months or longer) and significant coronary artery disease 
(CAD), who are receiving standard care, in reducing the risk of the composite of all-cause 
mortality (ACM), myocardial infarction (MI), or stroke following an episode of decompensated 
heart failure (index event).
The secondary objectives are to compare rivaroxaban with placebo in addition to standard care in 
subjects with symptomatic HF and significant CAD following an episode of decompensated 
heart failure (index event) in reducing the risk of the following outcomes:

Composite of cardiovascular (CV) mortality and re-hospitalization for worsening of HF

CV mortality 

Re-hospitalization for worsening of HF 

Re-hospitalization for CV events
The exploratory objectives are to compare rivaroxaban with placebo in addition to standard care
in subjects with symptomatic HF and significant CAD following an index event in reducing the 
risk of the following outcomes:

Selected medical resource utilization (MRU) data on re-hospitalization for CV events and 
for worsening of HF

Symptomatic deep vein thrombosis (DVT)

Symptomatic pulmonary embolism (PE)

Benefit-risk balance
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Note that the plan for analyses of MRU data on CV and HF re-hospitalization will be provided in 
a separate document.  They are not covered in this document.
The safety objectives are to compare the following bleeding events between rivaroxaban and 
placebo in addition to standard care in subjects with symptomatic HF and significant CAD 
following an index event:

The composite of fatal bleeding or bleeding into a critical space (intracranial, intraspinal, 
intraocular [vitreous or retinal], pericardial, intra-articular, retroperitoneal, intramuscular 
(with compartment syndrome) with a potential for permanent disability

Bleeding events requiring hospitalization (caused a hospitalization or prolongation of an 
existing hospitalization)

Major bleeding events using the International Society on Thrombosis and Haemostasis 
(ISTH) bleeding criteria
Overall safety will also be assessed.
1.2.
Trial Design
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven, 
group-sequential, superiority study of rivaroxaban with clinical outcome assessments in subjects 
with symptomatic HF (3 months or longer) and significant CAD. The study consists of a 
screening phase, a double-blind treatment phase, and a follow-up after the sponsor-announced 
global treatment end date (GTED, defined as the date when 1,200 primary efficacy outcome 
events are predicted to have occurred (date is based on site local time). The screening phase may 
last up to 51 days before randomization (21 days maximum for a hospitalization admission plus 
up to 30 days after discharge from the facility treating the index event), followed by an estimated 
6 to 54 months of double-blind treatment phase. Note that the screening period in Japan may last 
up to 60 days before randomization (up to 30 days for a hospitalization admission plus up to 30 
days after discharge from the facility treating the index event). The follow-up after the GTED is 
the End-of-Study (EOS) visit, which occurs 30±15 days after GTED. The primary efficacy 
outcome is the composite of ACM, MI, or stroke. Outcome events will not be centrally 
adjudicated in this study. The decision of no central adjudication for outcome events is based on 
2 considerations: 1) the majority of events are expected to be ACM, for which no adjudication is 
needed; and 2) the confirmation rate by the Clinical Endpoint Committee (CEC) for MI and 
stroke was high in the previous ROCKET AF and ATLAS ACS 2 TIMI 51 studies (ROCKET 
AF: 73% for MI and 85% for stroke; ATLAS ACS 2 TIMI 51: 85% for MI and 85% for stroke).
Since outcome events are not centrally adjudicated, only outcome events with adequate 
supporting documentation per protocol will be included in the main analyses. Reported outcome 
events with inadequate documentation will be included in sensitivity analyses. The details of 
outcome event reporting and verification are described in Investigator Manual for Outcome 
Events and Sponsor Outcome Event Verification Process Manual.
Approximately 5,000 subjects who meet all inclusion criteria and none of exclusion criteria will 
be randomly assigned to the rivaroxaban 2.5 mg b.i.d. arm or the placebo b.i.d. arm in a 1:1 ratio.  
Randomization will be stratified by country. Randomized subjects are expected to remain in the 
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double-blind treatment phase until the sponsor-announced GTED, at which time subjects will be 
instructed to discontinue study drug and return to the study site 30±15 days after GTED for the 
EOS visit. At the EOS visit efficacy and safety outcomes will be collected.  
Subjects who permanently discontinue study drug before GTED will complete the Early 
Permanent Study Drug Discontinuation visit as soon as possible after the last dose of study drug. 
In addition, these subjects should return for all scheduled visits, including the EOS visit. If these 
subjects refuse office visits, the investigator will be asked to encourage the subjects to allow 
regular contact (e.g., by telephone) until study end according to the Time and Events Schedule in 
the protocol, either with them, or with a close friend, relative, or their primary care physician to 
determine vital status and if an efficacy or safety outcome event has occurred.
A subject will be considered as having completed the double-blind treatment phase if the subject 
continues taking double-blind study drug until either the GTED or within 7 days before the death 
of the subject.  If the last dose day cannot be determined in a subject who dies, the last dose day 
will be imputed according to the algorithm presented in Section 2.1, and the above definition will 
be applied to the imputed last dose day. If a subject experiences an outcome event such as MI or 
stroke, study drug may be temporarily held if necessary or if using other anticoagulant drugs or 
thrombolytic therapy. This also applies to other efficacy outcome events such as DVT or PE. 
After appropriate treatment of the event, the investigator may choose to resume study drug for 
the subject. Study drug must be permanently discontinued for any intracranial hemorrhage or for 
any reason listed in Section 10.2.2 of the protocol.
A Steering Committee (SC) and an Independent Data Monitoring Committee (IDMC) will be 
commissioned for this study.  The SC will oversee the study conduct and the IDMC will review 
safety data periodically.  In addition, an interim analysis is planned when primary efficacy events 
have been observed in approximately 600 unique subjects. Depending on interim analysis results, 
the IDMC will make a recommendation whether the study will be continued as planned, or 
terminated early for overwhelming superiority, futility, or safety.
A diagram of the study design is provided below.
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Note: 30 days maximum for a hospitalization for subjects enrolled in Japan  
1.3.
Statistical Hypotheses for Trial Objectives
The primary analysis endpoint for efficacy assessment (referred to as the primary efficacy 
endpoint hereafter) is the time from randomization to the first occurrence of ACM, MI, or stroke.  
The primary objective of the study will be addressed by comparing the distribution of the 
primary efficacy endpoint between the 2 treatment arms. The primary statistical hypotheses are:
Null hypothesis H0: there is no difference between treatment arms in the distribution of the 
primary efficacy endpoint.
Alternative hypothesis HA: the distribution of the primary efficacy endpoint is different 
between the 2 treatment arms.
Analyses endpoints and corresponding statistical hypotheses for secondary efficacy outcomes are 
defined similarly as above.
1.4.
Sample Size Justification
This is an event driven study. The study was designed to observe occurrences of the primary 
efficacy event in 984 unique randomized subjects, on or before the GTED, to have 90% power to 
detect a 20% relative risk reduction (RRR, defined as one minus hazard ratio) in the composite 
of ACM, MI, or stroke at 5%, 2-sided significance level. A total of approximately 5000 subjects 
will be randomly assigned to either the rivaroxaban arm or the placebo arm in a 1:1 ratio.
The above sample size calculation was estimated based on the following additional assumptions:
Rivaroxaban 2.5 mg BID 
+ Standard Care
Placebo BID 
+ Standard Care
Screening Period
During Index Event
(21 days maximum for 
a hospitalization 
admission)
Early 
Permanent 
Study Drug 
D/C
Continue 
visits as per 
protocol 
until GTED
(may be 
phone calls)
Global Treatment
End Date
End of Study Visit
R
At discharge 
& up to 30 
days post
discharge 
from the 
facility 
treating the 
index event
Double-Blind
Treatment Phase
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
Event rate for the composite endpoint in the placebo arm: 19%/year

Permanent premature treatment discontinuation rate: 10%/year

Lost-to-follow-up: 1%/year 

Duration of enrollment period: 24 months (see Attachment 1 for distribution of 
enrollment by month)

Duration of study (from first subject randomized to last EOS visit): 31 months
The assumptions of RRR and event rate were based on observations from HF subjects in the 
ATLAS ACS 2 TIMI 51 study. Observed data from HF subjects of ATLAS ACS 2 TIMI 51 
study are summarized in the table below (Source: Adhoc analyses on file).
Event Rate (%/patient-year)
Hazard Ratio
(95% CI)
Rivaroxaban 2.5 mg bid
Placebo
HF Subjects
(N=562)
(N=558)
ACM/MI/Stroke
9.43
16.64
0.57 (0.41, 0.79)
ACM
3.54
8.31
0.43 (0.26, 0.70)
MI
5.73
8.47
0.67 (0.44, 1.03)
Stroke
1.08
1.60
0.69 (0.26, 1.81)
Based on historical data, the mortality rate in this study was expected to be higher, and the rate of 
MI was expected to be lower, than the observed corresponding rates in ATLAS ACS 2 TIMI 51 
study.  After adjusting for differences in these event rates, an event rate of 19%/year for the 
composite endpoint in the placebo group was used in the sample size calculation.  Event rates in 
the placebo group for the components ACM, MI, and stroke are expected to be approximately 
14%, 4%, and 2% per year, respectively.
Although the RRR observed in ATLAS ACS 2 TIMI 51 study was 43% (95% CI [21%, 59%]), a 
RRR of 20% was assumed in the sample size calculation.  The lower RRR close to the lower 
bound of the 95% CI was used to be conservative because the subject population in the current 
study was considered different from the HF subgroup in ATLAS ACS 2 TIMI 51.  
The study is revised to observe occurrences of the primary efficacy event in 1,200 unique 
randomized subjects based on a simulation study performed on available trial data, i.e., longer 
enrollment period, lower than anticipated primary efficacy event rate, higher than anticipated 
study drug discontinuation rate:

Event rate in the placebo arm: approximately 16%/year based on the observed combined 
event rate at 14%/year (assumed 20% of RRR remains) 

Early permanent study drug discontinuation rate: approximately 13%/year

Duration of enrollment period: approximately 48 months (projected)
The simulation study estimated that the duration of study may extend to approximately 54 
months based on the fact that the original goal of enrolling a total of 5,000 subjects remains 
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unchanged and all subjects would be observed for approximately 6 months after the last subject 
is enrolled.
With an effect size of 20% and overall α level of 5% (2-sided), 1,200 primary efficacy events 
will produce a statistical power of approximately 80%.
An interim analysis will be conducted when primary efficacy events are observed in 
approximately 600 unique subjects (see Section 3 for more details).
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups in a 1:1 ratio, based on a computer-generated randomization schedule 
prepared before the study under the supervision of the sponsor. The randomization will be 
balanced by using randomly permuted blocks and will be stratified by country. The interactive
web response system (IWRS) will assign a unique treatment code, which will dictate the 
treatment assignment and matching study drug kits for the subject. Study subjects, investigators, 
the SC members, and the sponsor study team members are blinded to treatment assignment until 
the completion of the study and data unblinding. The IDMC, whose primary responsibility is to 
ensure subject safety by monitoring data periodically, will have access to unblinded data.  
Measures and procedures to protect against unblinding of treatment assignment and study 
integrity, including data flow and personnel, who have access to unblinded data, are specified in 
the IDMC charter.  
While all subjects will have D-dimer data collected before the first dose of study drug, the 
collection of D-dimer data at week 4 will be limited to a randomly selected subset of 10% of 
subjects within each country. This selection will be done through IWRS and the selection will be 
independent of treatment assignment. Complete D-dimer data will not be available until after the 
database lock.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Subject-Level Trial Milestone Dates
Trial reference start date: the date of randomization of the subject.
Global treatment end date (GTED): The date when 1,200 primary efficacy events are predicted 
to have occurred. The sponsor will notify all investigative sites of the GTED. Subjects will stop 
their study drug after taking the second and final dose of study drug on this date. Because GTED 
is defined based on site local time, the date may be off by 1 day when converted to a central 
time.
First dose date: the date on which the first dose of study drug is taken by the subject. If missing 
or incomplete, the date is set to the earliest logically possible date on or after randomization.
Last dose date: the date on which the last dose is taken by the subject. If the day of last dose 
study drug taken cannot be determined, the last dose day will be assumed to be 32*K days from 
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the last visit at which study drug is dispensed (K is the number of bottles dispensed at that visit), 
capped by GTED, Early Permanent Study Drug Discontinuation visit if applicable, last contact 
day, and the upper bound of the logically possible range if partial date is provided, whichever 
occurs earliest, and no earlier than the first dose date. The number 32 is selected in the 
imputation because a bottle contains 64 tablets, covering 32 days of study drug therapy.
Last contact date (also referred to as trial reference end date): the date of the last trial-related 
procedure.  For survival subjects, it is defined as the maximum of 

Date of last office visit (scheduled or unscheduled visit)

Date of the last follow-up contact (including last date on subject survival status recorded
in eCRF)

Date of the last known outcome event (OE) or adverse event (AE) status or lab sample 
collection reported on the OE or AE or lab electronic case report from (eCRF) pages, 
respectively
If a subject completes the randomization visit but no further visits and no other data is recorded 
on the eCRF, the randomization date will be considered as the last contact date.
The last contact date will be capped by the database lock date. For subjects who died during the 
study and the death date is missing, the trial reference end date is defined as the death date, if 
known, or the database lock date, whichever occurs earlier.  
2.2.
Pooling Algorithm for Analysis Centers
No pooling algorithm for analysis centers will be used. The primary efficacy analysis will be 
stratified by region defined in Section 2.4.
2.3.
Analysis Sets
The definition of an analysis data set consists of these 2 elements: 1) subject population, which 
specifies which subjects will be included in an analysis; and 2) observation period, which 
specifies the time window within which data will be included in an analysis.  Key subject 
populations and observation periods are defined below.
Subject Populations
Intention-to-treat (ITT) population: This subject population consists of all randomized unique 
subjects who have a signed valid informed consent. 
Per-Protocol (PP) population: This population is a subset of the ITT population, consisting of 
subjects who do not have a major protocol deviation in the following categories (see FRM-15949 
for the specific major protocol deviations that are exclusions from the PP population and 
identification/review process):

Entered but did not satisfy criteria

Received a disallowed concomitant treatment
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
Received wrong treatment or incorrect dose (includes subjects with treatment 
compliance rate < 75% calculated according to a formula described in Section 4.3)

Developed withdrawal criteria but not withdrawn

Other (as appropriate)
If appropriate, additional ad hoc exclusion criteria for the PP population may be applied.  
Subjects to be excluded from the PP population will be determined and documented prior to 
database lock, except for those who are excluded from PP due to taking the wrong treatment .  
Because unblinded data are needed to determine whether a subject has taken incorrect study 
drug, subjects excluded from the PP population due to taking any incorrect study drug will be 
determined after data unblinding, according to the pre-specified rule.
Safety population: This population is a subset of the ITT population, consisting of subjects who 
receive at least one dose of study drug.
Observation periods
Up–to-GTED: this observation period includes all data from randomization to the GTED, 
inclusively. For time to event analyses, subjects who do not have events to be analyzed on or 
before the GTED will be censored on the GTED or the last contact date whichever occurs first.
On-treatment: this observation period includes data from the first dose of study drug to 2 days 
after the last dose of the study drug, inclusively. For time to survival event analyses, subjects 
who do not have events to be analyzed for this period will be censored on the last day of the 
period (last dose + 2) or the last contact date whichever occurs first.   
Post-randomization: this observation period includes all data from randomization to the last 
contact day. Last contact day is defined in Section 2.1.  For time to event analyses, subjects who 
do not have events to be analyzed on or before the last contact day will be censored on the last 
contact day.
Post-first dose of study drug: This observation period starts from the day of the first dose of
study drug and ends on the day of last contact, inclusively. Because subjects will be asked to take 
their first dose of study drug on the randomization day, while they are still in investigators’ 
offices, for most of subjects, this observation period will be identical to post-randomization 
observation period.
Off-treatment: this observation period includes data from 3 days after the last dose of the study 
drug to the last contact date, inclusively.
Day 3 to day 30 after the last dose: the 3rd day after the last dose of study drug to the 30th day 
after the last dose of study drug or the last contact day, whichever is earlier.
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2.3.1.
Efficacy Analysis Set
2.3.1.1.
Main Efficacy Analysis Set
The main efficacy analysis set for all efficacy endpoints (primary efficacy, secondary and other 
efficacy analyses) is the analysis set defined by up-to-GTED observation period and the ITT 
subject population. Subjects will be analyzed according to the treatment group they are assigned, 
irrespective of the actual treatment received.
2.3.1.2.
Sensitivity Efficacy Analysis Sets
The following analysis sets will be used to assess the robustness of the primary and secondary
efficacy analyses.

Analysis set defined by the on-treatment observation period and PP population.

Analysis set defined by the on-treatment observation period and the safety subject 
population. Subjects will be analyzed according to the treatment group they are assigned, 
irrespective of the actual treatment received.

Analysis set defined by the post-randomization observation period and the ITT subject 
population.
2.3.1.3.
Additional Analysis Sets
The additional analysis sets are defined by the combination of observation periods: 

Off-treatment

Day 3 to day 30 after the last dose
and, the subpopulations of:

Subjects who permanently discontinue study drug for any reason prior to GTED

Subjects who complete the double-blind treatment period and have the EOS visit 
(Office/Phone)
These analysis sets will be used mainly for the summary statistics for efficacy endpoints and are 
further described in Section 5.5.
2.3.2.
Safety Analysis Set
The main safety analysis set is defined by the On-treatment observation period and the safety 
subject population. The sensitivity safety analysis set is defined by the post-first dose of study 
drug observation period and the safety subject population. Subjects will be analyzed according to 
the treatment assigned.
Bleeding events and adverse events will be analyzed and summarized based on both the main 
and sensitivity safety analysis sets.
In addition, the same additional analysis sets defined in Section 2.3.1.3 will also be used for the 
summaries of safety events. Details are described in Section 6.1.
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2.4.
Definition of Subgroups
Homogeneity of treatment effects, both in RRR and direction will be assessed in the following 
subgroups classified at baseline. 

Age (< 65 vs ≥ 65; < 75 vs ≥ 75 years)

Sex (men vs women)

LVEF (< 30% vs ≥30%; ≤ median vs > median)

Estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease 
formula value <30, 30 to <60, 60 to <90, ≥90 mL/min/1.73 m2)

Baseline D-dimer level by quartile

Baseline BNP or NT-proBNP (≤ median vs > median)

History of diabetes (yes vs no)

History of stroke (yes vs no)

History of MI (yes vs no)

Hypertension (yes vs no)

Body Mass Index (<25, 25 to <30, ≥30 kg/m2)

Baseline digoxin use (yes vs no)

Baseline β-blocker use (yes vs no)

Baseline aldosterone antagonists (yes vs no)

Baseline angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor 
blocker (ARB) (yes vs no)

Baseline aspirin use (yes vs no)

Baseline aspirin only vs dual antiplatelet use

Baseline thienopyridine use (yes vs no)

NYHA (Class II, III, IV)

Fragile subjects (yes vs no; fragile subjects are those with age > 75 years or weight ≤ 50 
kg or baseline eGFR < 50 mL/min)

Race (White vs others; White, Asian, and others)

Region (Eastern Europe [Bulgaria, Czech Republic, Hungary, Latvia, Lithuania, Poland, 
Romania, Russia, Slovakia, Turkey, and Ukraine], Western Europe and South Africa
[Denmark, France, Germany, Greece, Italy, Netherlands, Portugal, South Africa, Spain, 
Sweden, United Kingdom], North America [Canada and USA], Latin America 
[Argentina, Brazil, and Mexico], and Asia Pacific [Australia, China, Japan, Malaysia, 
and South Korea].  
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In addition, the number of subjects with efficacy endpoints including components of composite 
efficacy endpoints; the number of subjects with principal safety endpoint and its components of 
fatal bleeding (defined in Section 6.1) and bleeding into a critical space with a potential for 
permanent disability; and the number of subjects with other bleeding outcomes of ISTH major 
bleeding events and bleeding requiring hospitalization will be summarized for safety subjects in 
the following subpopulations:

Subjects who permanently discontinue study drug for any reason prior to GTED

Subjects who complete the double-blind treatment period and have the EOS visit 
(Office/Phone)
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
An interim analysis will be conducted when primary efficacy events with adequate supporting
documents have been observed in approximately 600 unique subjects. The analysis will be 
carried out by an independent statistical group that supports the IDMC (referred to as statistical 
supporting group [SSG]).  The IDMC will be responsible for the review of the interim analysis 
results.  If early stopping criteria are met, the IDMC may recommend stopping the trial early for 
overwhelming treatment benefits or for futility/feasibility. Early stopping guidelines will be 
established and specified in the IDMC charter, which will be finalized prior to the first safety 
data review and therefore before the interim analysis.  In addition, the IDMC will review safety 
data periodically.  The frequency of safety reviews will also be specified in the IDMC charter. 
In the interim analysis, a log-rank test, stratified by region, will be employed to compare the 
distribution of time to the first occurrence of the composite primary efficacy endpoint between 
the 2 treatment groups.  The Lan-DeMets α spending function approach with O’Brien-Fleming 
type of boundaries will be used in the interim analysis for the primary efficacy endpoint only.  
The α spent in the interim analysis is expected to be 0.003 with a corresponding critical value of 
2.936 (East®, Version 5.3, Cytel Inc.), if the interim analysis involves 600 events.  If the study 
continues beyond the planned interim look, the critical value for the final analysis is 1.969, the 
corresponding α is 0.04895.  The actual α spent and corresponding critical values may be slightly 
different from aforementioned numbers, depending on the actual number of events included in 
the interim analysis.  If the test statistic for the primary efficacy endpoint crosses the stopping 
boundaries either at the interim analysis or at the final analysis, secondary endpoints will be 
tested in a fixed sequence as shown in Section 5.3.1, at a significance level corresponding to the 
Pocock-type boundary.
If the conditional power under the alternative hypothesis (i.e., RRR=20%) is 10% or lower, the 
IDMC may recommend stopping the study for futility.
In order to maintain blinding of randomized treatment assignments and study integrity, measures 
will be taken to ensure the separation between the study team and unblinded data. Data flow and 
parties who have access to unblinded data will be specified in the IDMC charter.
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4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Descriptive statistics (mean, standard deviation, median, inter-quartile range, and range for 
continuous data, and frequency and percentage for categorical data) by treatment group will be 
provided for the following baseline demographics and disease characteristics data 

Age

Sex

Race

Region

Height

Weight

eGFR

eGFR Category [< 30, ≥ 30 - < 60, ≥ 60 - < 90, ≥ 90]

D-dimer

Duration between discharge from index hospitalization to randomization

NYHA classification

LVEF at baseline (or last measurement of LVEF prior randomization)

History of MI

History of stroke

History of PCI

Cardiac resynchronization therapy or implantable defibrillator or combination

Baseline digoxin use 

Baseline β-blocker use

Baseline aldosterone antagonist use

Baseline ACEI use

Baseline ARB use
o
Baseline ARNI use

Baseline aspirin use

Baseline dual antiplatelet use

Baseline thienopyridine use

Baseline BNP or NT-proBNP
Additionally, evidence of coronary artery disease will be summarized. 
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4.2.
Disposition Information
Unless otherwise stated, calculation of durations specified hereafter includes both the start and 
end days.
The number of subjects who permanently discontinue study drug and reasons for discontinuation
will be summarized by treatment group.  The distribution of time to permanent discontinuation 
of study drug, defined as the duration between the first dose and the last dose, will be shown by a 
modified version of Kaplan-Meier plot, where one minus the survival function will be shown.
A similar method will be used to summarize discontinuation from the study.
The primary efficacy analysis of this study will be addressed by data up to GTED. Therefore, 
data from subjects who are followed up until GTED are considered completers. Subjects who 
discontinue from the study prior to GTED without any primary efficacy event data between the 
last contact date and GTED are considered missing for analysis purposes. The fraction of 
follow-up time missing, defined as the ratio of the duration between the day next to the last 
contact date and GTED and the duration between the randomization date and GTED, will be 
summarized. The summary will be further broken down into missing data due to administrative
reasons and missing data due to non-administrative reasons. Discontinuation reasons, such as 
lost-to-follow-up and consent withdrawal, are considered non-administrative.  
A diagram similar to CONSORT Statement 2010 Flow Diagram (Schulz et al, 2010) will be 
provided.  A template of the diagram can be found in Attachment 2.
4.3.
Treatment Compliance
For each subject, the treatment compliance rate is estimated as follows
Compliance rate (%)
=
100 ∗Number of days of taking study drug
Total treatment duration in days (excluding intended treatment interruptions)
where the number of days taking study drug is defined as the total treatment duration (from the 
first dose to the last dose) excluding all interruptions regardless of intentional or not.
Adherence to study regimen for an individual subject is considered acceptable in this study if the
compliance rate is 75% or higher.
For the purpose of compliance rate calculation, interruptions due to AE, outcome events, 
bleeding events, prohibited medication, or surgical/invasive procedures are considered 
intentional interruptions. Interruptions due to other reasons are considered non-intentional. 
Missing doses during intentional interruption periods will not be counted in the compliance rate 
calculation. If the dose date prior to a treatment interruption is missing, the same imputation rule 
for imputing the last dose date descripted in Section 2.1 will be used to impute the dose date.    
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The median, the inter-quartile range, and the range of compliance rate will be summarized by 
treatment.  In addition, if information is sufficient, the compliance rate in each treatment group 
will be depicted by a cumulative distribution function (CDF).
The proportion of subjects with acceptable treatment adherence as defined above will be 
provided.
4.4.
Extent of Exposure
Subject level duration of treatment exposure is defined as the duration between the first dose day 
and last dose day. Note that temporary study drug interruptions are included in this definition.  
The mean, standard deviation, median, the inter-quartile range, and the range of duration of 
treatment exposure will be summarized by treatment. In addition, the duration in each treatment 
group will be depicted by a CDF.
The duration will also be summarized by the following categories:

≤ 90 days

91 – 180 days

181 – 360 days

361 - 540 days

541 – 720 days

721 - 900 days

901 – 1080 days

1081 – 1260 days

> 1260 days  
4.5.
Protocol Deviations
Major protocol deviations will be summarized by treatment group for the all randomized data 
set. The categories of protocol deviations will include the following:

Entered but did not satisfy criteria

Received a disallowed concomitant treatment (Attachment 3)

Received wrong treatment or incorrect dose (includes subjects with treatment 
compliance rate < 75% calculated according to a formula described in Section 4.3)

Developed withdrawal criteria but not withdrawn

Other (as appropriate)
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4.6.
Prior and Concomitant Medications
This study collects limited prior and/or concomitant medications, such as medications related to 
subject’s HF and CAD.  Medication will be classified using the Anatomical Therapeutic 
Chemical (ATC) classification system in WHO drug dictionary. The prevalence of medication 
use by ATC term will be summarized by treatment group and by study phase (prior to 
randomization, during the study drug therapy period, and after last dose of study drug [post-
treatment]). A medication prior to randomization is considered as a prior medication.  A 
medication with a use period overlapping with the study drug therapy period is considered as a 
concomitant medication. A medication that starts after the day of the last dose of study drug is 
considered as a post-treatment medication. Note that a medication can be categorized into 
multiple study phases if its use spans more than one study phase.  In such a case, the medication 
use will be included in more than one summary.
5.
EFFICACY
5.1.
Analysis Specifications
Only outcome events with adequate supporting documentation as specified in the protocol will 
be included in the main analyses described below. All events reported by investigators, 
regardless of adequacy of supporting documentation, will only be included as part of sensitivity 
analyses. The adequacy of documentation will be determined prior to data unblinding.
If it is determined prior to data unblinding that fraud or misconduct occurred at a clinical study 
site during the conduct of the study, all subjects at that site will be excluded from primary 
efficacy analysis. Other findings of noncompliance with Good Clinical Practices (GCP) will be 
assessed to determine whether subjects affected will need to be removed from analyses.  Subjects 
to be excluded from analyses due to fraud or misconduct of a clinical study site will be 
documented prior to data unblinding.
5.1.1.
Level of Significance
The family-wise type I error rate for the primary efficacy endpoint will be controlled at the 5% 
level (2-sided). This is achieved by using the Lan-DeMets α spending function approach. If 
superiority is established for the primary efficacy endpoint, secondary endpoints will be tested in 
a fixed sequence, each at a significance level corresponding to the Pocock-type boundary. If an 
individual test during any step is not statistically significant, further treatment comparison may 
continue (i.e., reporting of p-values) but significance will not be claimed.
Confidence intervals (CIs) are calculated at the 95% nominal confidence level. In addition, 
repeated CI (RCI), which adjusts for the interim analysis, will also be provided in the Clinical 
Study Report (CSR).
5.1.2.
Data Handling Rules
If the date of an outcome event is missing or partially missing, the date at the middle of the 
logically possible range will be imputed as the event date. If there is a tie between 2 such dates, 
(i.e., the number of days within the possible range is an even number), the later date will be used.  
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In the case that it cannot be determined if an event occurs before or after randomization, the 
event is always considered as a post-randomization event and the randomization date is used as 
the start of the logically possible range. On the other hand, in the case that it cannot be 
determined if an event occurs before or after GTED, the occurrence date is always considered 
not later than the GTED. In this case the GTED is the end of the logically possible range.
5.2.
Primary Efficacy Endpoint(s)
5.2.1.
Definition
The primary efficacy endpoint is the time from randomization to the first occurrence of ACM, 
MI, or stroke. Subjects who do not have any of these outcome events will be censored at the end 
of the analysis observation period as defined in Section 2.3.1.
5.2.2.
Analysis Methods
The primary statistical null hypothesis is that there is no difference between treatment groups in 
distribution of the time from randomization to the first occurrence of ACM, MI, or stroke, and 
the alternative hypothesis is that there is a difference in the distribution between treatment 
groups.
The primary statistical hypothesis will be tested using a log-rank test, stratified by region. The 
primary analysis will be based on the analysis set defined by ITT subject population and the 
up-to-GTED observation period (up to the cut-off date to be specified for the interim analysis, 
see details below). Subjects will be analyzed according to the treatment group to which they are 
randomized, irrespective of actual treatment received. The overall α level is 5%, 2-sided. In 
addition to the final analysis, the primary statistical hypothesis will be tested in an interim 
analysis when primary efficacy events are observed in approximately 600 unique subjects. A 
Lan-DeMets α spending function with O’Brien-Fleming type of boundaries will be used to 
preserve the overall type I error rate. If the log-rank test statistic crosses the stopping boundaries, 
and the log-rank statistic is less than 0, (i.e., the observed number of events in the rivaroxaban 
group is less than the expected number of events under the null hypothesis), it will be concluded 
that the study has demonstrated that rivaroxaban is superior to placebo in reducing the risk of the 
composite of ACM, MI, and stroke in the population studied.
It is expected that risk of death will be the highest immediately following the index event or 
following subsequent episodes of re-hospitalization for heart failure. Therefore, the cumulative 
event rate derived from the Kaplan-Meier estimate will be displayed graphically to evaluate the 
timing of event occurrence and the consistency of the treatment effect over time.
The magnitude of the RRR will be estimated using a Cox proportional hazards model, stratified 
by region, with treatment (as randomized by IWRS) as the only covariate. The point estimate and 
corresponding 95% CI, which will be calculated using 95% as the nominal significance level, for 
the hazard ratio (rivaroxaban to placebo) will be reported. In addition, a RCI will be calculated 
based on the procedure described in Jennison and Turnbull (2000), where significance level at 
the interim analysis and the final analysis will be approximately 99.7% and 95.2%, respectively.
The plausibility of the proportional hazards assumption will be assessed by visually comparing 
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the plot of the log of the cumulative hazard function between treatments, and formally tested by 
adding a treatment by logarithm-transformed time interaction into the Cox model. A p-value 
greater than 0.05 for the interaction term will be interpreted as no statistical evidence against the 
proportional hazard assumption. If the p-value is 0.05 or less, post-hoc analyses will be 
conducted to estimate the magnitude of treatment effect by time. These post-hoc analyses 
include, but are not limited to, adding a function of time, such as time interval indicators, by
treatment interaction as covariates to the Cox model. Treatment effects for different time 
intervals, such as < 12 months versus > 12 months, etc., will be reported as appropriate.
Sensitivity analyses will also be conducted to assess the robustness of the primary efficacy 
analysis. These include, but are not limited to, a log-rank test stratified by country and an 
un-stratified log-rank test, repeating analyses mentioned above for the analysis set defined by the 
up-to-GTED observation period and the ITT subject population; for the analysis set defined by 
the on-treatment observation period and the per-protocol subject population; for the analysis set 
defined on-treatment observation period and the safety subject population; and for the analysis 
set defined by the post-randomization observation period and ITT subject population. The 
primary efficacy endpoint will also be analyzed for the ITT subjects who enrolled under the 
original protocol and who enrolled under the amended protocols for the Up-to-GTED 
observation period.
The percentage of events reported by investigators with
adequate
protocol-specified
documentation will be reported.
The RRR for the components of the primary efficacy endpoint will be evaluated using a Cox 
proportional hazards model as described above.
Extensive efforts will be made to collect complete data for all subjects randomized in this study.  
Subjects will be followed up to the end of the study, and all required data will be collected, 
regardless of subjects’ compliance with study drug regimen or visit schedule. For subjects who 
are lost to follow up or who withdraw consent, efforts will be made to obtain their vital status at 
the end of study from permitted sources.  
Although extensive effort will be made to reduce the number of subjects with missing follow-up, 
it is expected that there will be missing vital status and event information in some subjects.  
Sensitivity analyses will be performed to evaluate the potential impact of missing data on 
analysis results and robustness of study conclusions. Distributions of baseline demographics and 
other characteristics will be compared between subjects who complete the study and subjects 
who do not complete the study, accounting for treatment and regardless of treatment, to evaluate 
the plausibility of the non-informative assumption used in the analysis. In addition, reasons of 
early discontinuation from the study will be summarized by treatment group.
The potential impact of missing data on the primary efficacy analysis will be evaluated by 
imputation, where events will be imputed in missing follow-up periods. The imputation will be 
done based on various assumptions for unobservable event rates in missing follow-up periods, 
which may depend on treatment groups and/or reasons of early discontinuation. Additional 
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details of these sensitivity analyses, including specifications for imputation, will be provided in a 
separate document that will be finalized prior to the database lock.
Homogeneity of treatment effects, both in the magnitude and direction of RRR, across subgroups
will be assessed by subgroup analyses. Subgroups to be included in the subgroup analyses are 
defined in Section 2.4.  
Interactions between treatment and baseline covariates with continuous values, such as age and 
D-dimer, will also be evaluated on a continuous scale in addition to categorical scales.
For subgroups specified in Section 2.4, annualized event rates will be provided by treatment and 
by subgroup. If there are at least 10 events in each of the cells defined by combinations of 
treatment and subgroup, statistical testing will be done to test the homogeneity of the treatment 
effect hypothesis. Statistical testing will be conducted for each set of subgroups individually, by 
adding covariate(s) for the subgroup and the corresponding treatment-by-subgroup interaction in 
the Cox proportional hazards model specified above, one at a time, except for the assessment of a 
region effect. An un-stratified Cox model will be used when assessing the homogeneity of 
treatment effect across regions. For subgroups with natural ordering, such as subgroups defined 
by eGFR, Body Mass Index, and NYHA classification, an ordinal covariate will be created to 
indicate subgroups. If a non-monotonic trend is observed, additional subgroup analyses based on 
non-ordinal categories may be further explored. For other subgroups without natural ordering, 
such as subgroups defined by race or region, a set of indicator covariates will be created to 
indicate subgroups. If the p-value for the interaction is greater than 0.05, the test result will be 
interpreted as a lack of statistical evidence for a difference in the treatment effect between the
subgroups. Otherwise, a Gail-Simon test will be performed to assess if the interaction is also 
qualitative. If the p-value from the Gail-Simon test is greater than 0.05, the result will be 
interpreted as a difference in the size of treatment effect between the subgroups with a lack of 
statistical evidence for the difference in the direction of treatment effect (i.e., only quantitative 
but not qualitative interaction). If the p-value is less than or equal to 0.05, it will be interpreted as 
a directional difference in treatment effect between subgroups (i.e., qualitative interaction).  
Given the large number of subgroup analyses explored without multiplicity adjustment, 
observing p-values less than 0.05 due to chance alone is expected. Therefore, results of the 
subgroup analyses will be interpreted with caution.
The above univariate subgroup analyses will be supplemented by a multivariate analysis, which 
will assess the effects of baseline demographics and disease characteristics collectively using an 
un-stratified Cox proportional hazards model that contains main effects of treatment and
subgroups, and interactions between treatment and subgroup (2-way interactions only). This 
approach adjusts for correlations between variables and evaluates the net effects of subgroups. A 
backward selection procedure will be employed. In the backward selection procedure, the 
variable with the largest p-value will be eliminated from the model one at a time. A main effect 
cannot be removed from the model before the corresponding interaction with treatment is 
removed. The backward selection procedure ends when no more covariates can be removed from 
the model with the exit p-value threshold of 0.05.
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5.3.
Secondary Efficacy Endpoints
5.3.1.
Definition
There are 4 secondary efficacy endpoints specified in this study:

Time to the first occurrence of CV death or re-hospitalization for worsening of HF

Time to CV death

Time to re-hospitalization for worsening of HF 

Time to re-hospitalization for CV events
5.3.2.
Analysis Methods
If superiority of rivaroxaban over placebo with respect to the primary efficacy endpoint is 
established, the secondary endpoints will be tested in the sequence specified above. The 
determination of the order is based on clinical relevance and power consideration. Each 
secondary endpoint will be tested using the same analysis methods that are described for the 
primary efficacy endpoint. The significance level of each individual test corresponds to the 
Pocock-type boundary, irrespective of whether the study is completed as planned or stopped 
early at the interim analysis. If p-value for a hypothesis is greater than that significance level, all 
remaining hypotheses after this hypothesis in the fixed sequence will not be rejected.
A supporting analysis of time to the first occurrence of ACM or re-hospitalization for worsening 
of HF will also be performed using the same analysis method as for the primary efficacy 
endpoint.  
As supplemental analyses, the effect size of rivaroxaban versus placebo in terms of
re-hospitalization for worsening of HF and for CV events will also be estimated using 
parametric, semi-parametric, and non-parametric approaches. In contrast to time to the first 
occurrence used in the analyses mentioned above, all occurrences will be included in these
supplemental analyses. A parametric frailty model will be used in the parametric approach. The 
frailty model assumes that events follow a renewal process with a time-independent hazard that 
varies from subject to subject, and the distribution of the subject-dependent hazard follows a 
Gamma distribution, which is treatment specific. The resulting analysis is a generalized linear 
regression model based on negative binomial distribution, where the covariates are duration of 
risk exposure, treatment, and the interaction between them. The semi-parametric approach is the 
Andersen-Gill model (Andersen and Gill, 1982) with a robust estimate for variance that takes 
intra-subject correlation into account (Lin and Wei, 1989). The non-parametric analysis is based 
on the unmatched win-ratio method proposed by Pocock et al (2012).
5.4.
Other Efficacy Variable(s)
5.4.1.
Definition
Analysis of the following efficacy endpoints are considered exploratory:

Time to symptomatic deep vein thrombosis (DVT)
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
Time to symptomatic pulmonary embolism (PE)
5.4.2.
Analysis Methods
The number of symptomatic DVT and PE events is expected to be small. Due to the exploratory 
nature of the analysis and consideration of the type I and type II errors, no statistical testing will 
be conducted for these 2 exploratory endpoints. However, the size of the treatment effects, 
including corresponding 95% CI, of time to DVT and time to PE will be estimated using a Cox 
proportional hazards model with treatment as the only covariate.  Because of the small number of 
events expected, the Cox model is not stratified.  
In order to understand the impact of strokes, the modified Rankin score will be collected within 
6-18 weeks following a stroke or at the end of study, whichever occurs first. The distribution, 
(i.e., frequency and percentage), of the modified Rankin score will be tabulated for stroke events.
5.5.
Additional Efficacy Analyses
For all primary, secondary and other efficacy outcome events discussed above, the number of 
subjects with these events will be tabulated for the following analysis sets:

Off-treatment observation period for subjects who permanently discontinue study drug 
for any reason prior to GTED

Off-treatment observation period for subjects who complete the double-blind treatment 
period and have the EOS visit (Office/Phone)

Off-treatment observation period for the Safety population.  

Day 3 to Day 30 after the last dose observation period for subjects who permanently 
discontinue study drug for any reason prior to GTED

Day 3 to Day 30 after the last dose observation period for subjects who complete the 
double-blind treatment period and have the EOS visit (Office/Phone)

Day 3 to Day 30 after the last dose observation period for the Safety population. 
6.
SAFETY
6.1.
Bleeding Events
The principal safety endpoint for this study is the composite of fatal bleeding or bleeding into a 
critical space with a potential for permanent disability. A fatal bleeding event is one in which the 
subject dies within 7 days of a bleeding event requiring hospitalization or ISTH major bleeding. 
Fatal bleeding events will include those that meet the criteria in the following three exclusive 
categories:

Category 1: Any ISTH major bleeding event considered to be the primary cause of death 
by the investigator (i.e., Question 5 on the BLEED page of the eCRF is answered 'Yes'), 
or
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
Category 2: Any ISTH major bleeding event not considered to be the primary cause of 
death by the investigator (i.e., Question 5 on the BLEED page of the eCRF is answered 
as 'No') but results in death within 7 days, or

Category 3: Any bleeding event that results in a hospital stay and death within 7 days
(i.e., death and either Question 6 or 8 on the BLEED page of the eCRF is answered 'Yes')
The following organs are considered critical:

Intracranial
o
Intraparenchymal
o
Intraventricular
o
Subdural Hemorrhage
o
Subdural
o
Epidural

Intraspinal

Intraocular—other than sub-conjunctival
o
Vitreous
o
Retinal

Pericardial

Intra-articular

Intramuscular with compartment syndrome

Retroperitoneal
Similar to the analyses planned for the primary efficacy endpoint as described above, time to the 
first occurrence of the principal safety endpoint will be compared using a log-rank test and a Cox 
proportional hazards ratio model with treatment as the only covariate. Both the log-rank test and 
Cox proportional hazards models are stratified by region. A plot of cumulative event rate derived 
by Kaplan-Meier estimate will be provided to show event rate and treatment effect by time. The 
analyses will be conducted based on analysis set defined by the on-treatment observation period
and the safety subject population. Subjects will be analyzed according to study drug assigned. 
Significance level is always at the nominal level of 0.05 for safety analyses. There will be no 
adjustment for multiplicity.  The same analysis will be repeated for the post-first dose 
observation period and the safety subject population.
Time to the first occurrence of following bleeding events will be analyzed using the same 
method.

Bleeding requiring hospitalization

ISTH major bleeding
The number of subjects with the above safety outcomes will be tabulated for the following 
observation periods and analysis sets:

Off-treatment observation period for subjects who permanently discontinue study drug 
for any reason prior to GTED
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
Off-treatment observation period for subjects who complete the double-blind treatment 
period and have the EOS visit (Office/Phone)

Off-treatment observation period for the Safety population.  

Day 3 to Day 30 after the last dose observation period for subjects who permanently 
discontinue study drug for any reason prior to GTED

Day 3 to Day 30 after the last dose observation period for subjects who complete the 
double-blind treatment period and are have the EOS visit (Office/Phone)

Day 3 to Day 30 after the last dose observation period for the Safety population.
The number of the subjects with other reported bleeding events will be summarized by treatment 
group and bleeding site. For Japan subjects only, summary statistics will be provided for non-
major clinically relevant bleeding events and minimal bleeding events.
6.2.
Other Adverse Events
Because the safety profile of rivaroxaban has been well established in previous large and 
extensive trials, this study will collect limited AE data (see Section 12 of the study protocol for 
AE data to be collected). For AEs that are collected, the verbatim terms reported in the eCRF by 
investigators to identify adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). For each MedDRA preferred term, the percentage of subjects 
who experience at least 1 occurrence of the given event will be summarized by treatment group.
The difference between treatments in the percentage will be provided. If an AE is reported by 4
or more subjects in the entire safety population, a 95% CI for the difference will also be 
provided.  The 95% CI is calculated based on the normal approximation of binomial data without
continuity correction. This is corresponding to the approach for Tier 2 events (signal detection 
among common events) proposed by Crowe et al (2009). Additional summaries, listings, or 
subject narratives may be provided, as appropriate.
AEs reported by investigators will be summarized based on the analysis set defined by the 
on-treatment observation period and separately by the post-first dose of study drug observation 
period and the safety subject population.
Based on specific safety reporting requirements from the Pharmaceuticals and Medical Devices 
Agency, AE data from Japan may not be directly comparable with those collected from non-
Japan sites. Therefore, the AE data from Japan sites may be summarized separately from AE 
data from non-Japan sites in the respective reported safety tables.
6.3.
Clinical Laboratory Tests
Because the safety profile of rivaroxaban has been well established in previous trials, this study 
will not collect laboratory data during the study other than D-dimer at Week 4 (10% of subjects) 
and hemoglobin at Week 12 (up to Week 24). Complete D-dimer data will not be available until 
after the database lock. There is no plan to analyze laboratory data other than a descriptive 
summary of the hemoglobin and D-dimer data. Local lab data may be discussed in subject 
narratives as appropriate.
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Change from baseline in Week 4 D-dimer, in the 10% of subjects from whom Week 4 D-dimer 
values will be collected, will be summarized by treatment group. A similar approach will be used 
to summarize the hemoglobin data. Mean, standard deviation, median, inter-quartile range, and 
range will be reported.
6.4.
Vital Signs and Physical Examination Findings
Targeted medical history and vital signs are obtained at baseline only and summarized as 
baseline characteristics Physical examinations are not required as part of study procedures. 
Available data may be discussed in subject narratives.
7.
Benefit/Risk Assessment
The section below describes several key elements for benefit-risk assessment, including 1) 
quantification method for benefits and risks, 2) efficacy and safety outcomes included in the 
evaluation, 3) analysis population and observation period, and 4) reporting format of the results.
The benefit-risk analyses described here are primarily intended to structure an integrated 
evaluation of the key benefits and risks in the study. They are complementary to other efficacy 
and safety analyses described elsewhere in this document. The overall benefit-risk profile of the 
study drug will be interpreted in consideration of the analyses described here and the totality of 
the data.
Quantification Methods for Measuring Benefits and Risks
As noted in previous sections, the treatment RRRs for efficacy and safety will be assessed using 
hazard ratios (Cox proportional hazards model). Because of difference in background event rate 
across different types of outcome events, a preferred metric used to evaluate treatment difference 
for benefit/risk assessment purpose is absolute risk differences. For the current benefit-risk 
assessment, the treatment comparison of rivaroxaban vs. placebo will be evaluated based on the 
excess number of events between treatments, including events intended to be reduced (benefits) 
and events that may be caused (risks). The excess number of events is defined as the difference 
in event rates times a hypothetical population size (e.g., 10,000 patients or person-years). The 
event rate will be calculated based on the time-to-first-event using the following approaches:

Person-year rate, expressed as number of events per 100 person-years exposure time

Kaplan-Meier Product-Limit estimates of cumulative event rates at 1-year*
In addition, number-needed-to-treat to benefit (NNT) or harm (NNH) also will be used to 
quantify benefits and risks of the treatment, respectively, which are calculated as the reciprocal 
of the differences in corresponding event rates.
*Because the duration of the trial is longer than anticipated, Kaplan-Meier Product-Limit 
estimates of cumulative event rates at 2-years and 3-years may be explored.
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Efficacy and Safety Outcomes for Benefit-Risk Evaluation
The efficacy and safety outcomes that will be included in benefit-risk evaluation are generally 
consistent with those specified in the efficacy and safety sections of this document, with some 
minor modifications as noted below. The primary efficacy outcome is the composite of ACM, 
MI, or stroke, while the principal safety outcome is the composite of fatal bleeding or bleeding
into a critical space (intracranial, intraspinal [vitreous or retinal], pericardial, intraocular-other 
than sub-conjunctival, intra-articular, retroperitoneal, intramuscular with compartment 
syndrome, retroperitoneal) with a potential for permanent disability. Importantly, for the benefit-
risk calculations, fatal bleeding and hemorrhagic stroke would be counted in both the benefit and 
risk categories (e.g., fatal bleeding will be part of ACM, while hemorrhagic stroke will be part of 
stroke). Therefore, to avoid double-counting an event as both a benefit and as a risk, the 
outcomes for the benefit-risk analysis will be the following:
Benefits
Composite of non-bleeding related death, non-fatal MI, or non-fatal ischemic stroke and each 
component separately:

Non-bleeding related death

Non-fatal MI

Non-fatal ischemic stroke
As a supporting measure, the composite of non-bleeding related death, MI (fatal, non-fatal) or 
ischemic stroke (fatal, non-fatal) may also be evaluated.  
Risks
Composite of fatal bleeding events, non-fatal intracranial hemorrhage, or other bleeding into a 
critical space with a potential for permanent disability and each component separately: 

Fatal bleeding events

Non-fatal intracranial hemorrhage

Non-intracranial hemorrhage, non-fatal bleeding into a critical space with a potential for 
permanent disability
The two composite endpoints listed above will serve as the primary comparison of benefits and 
risks (pairwise comparison), since those events are fatal or are likely to cause irreversible harm
(Unger 2009, Beasley 2011) and arguably represent events of similar clinical importance. In 
addition, components of the composite endpoints and other major efficacy and safety outcomes 
identified in the protocol will also be evaluated in a similar fashion to support the overall 
benefit-risk evaluation.
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Analysis Population and Observation Period
The primary analysis for benefit-risk evaluation will be based on the analysis set defined by the
ITT subject population and the up-to-GTED observation period. However, additional analyses 
using analysis sets defined by other subject populations and/or observation periods as defined in 
the protocol or in this SAP may be performed as supporting analyses.
Note that the benefit-risk analyses are not intended for hypothesis testing. Therefore, no 
multiplicity adjustment will be applied.  When 95% CIs for point estimates of the excess number 
of events are provided as appropriate, nominal statistical significance at the alpha level of 0.05 
(2-sided) will be declared if the confidence interval excludes zero.
The benefit-risk assessment will also be explored for the subgroups specified in Section 2.4.
Note that although primary composite endpoints and analysis set are mentioned above, 
assessment of benefit/risk balance is based on the totality of data. It is unlikely that a clear 
conclusion can be made based on a comparison of a pair of composite endpoints and/or data 
from a typical analysis data set. Those primary composite endpoints and primary analysis data 
set provide a starting point. Results of the analyses do not preclude additional benefit/risk 
assessment in other endpoints and/or analysis population, and they do not carry more weight than 
other additional analyses in the overall benefit/risk assessment.  
Reporting Format of the Results
To facilitate the comparison and interpretation of the results, data will be presented in one of the 
following formats as appropriate:

Table format showing the between-treatment differences in benefits and risks (e.g., 
excess number of events and NNT or NNH)

Kaplan-Meier plots depicting between-treatment differences in benefits and risks over 
time (for the pairwise comparison)

Forest plots for comparing key benefits and risks (as discussed above), as well as other 
main efficacy and safety outcomes measures
8.
HEALTH ECONOMICS
Medical Resource Utilization data will be analyzed and reported in a separate document.
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REFERENCES
1.
Andersen, P.K., Gill, R.D. (1982). Cox regression model for counting processes: A large sample study. Annals 
of Statistics: 10, 1100–1120.
2.
Beasley BN, Unger EF, Temple R (2011). Anticoagulant options ─ why the FDA approved a higher but not a 
lower dose of dabigatran. N Engl J Med;364(19):1788-90.
3.
Crowe BJ, et al (2009).  Recommendations for safety planning, data collection, evaluation and reporting 
during drug, biologic and vaccine development: a report of the safety planning, evaluation, and reporting team. 
Clinical Trials: 6, 430 – 440.
4.
Gail, M. and Simon, R. (1985). Testing for Qualitative Interactions between Treatment Effects and Patient 
Subsets. Biometrics, Vol. 41, No. 2, 361-372
5.
Glimm, E., Maurer, W., and Bretz, F. (2010). Hierarchical testing of multiple endpoints in group-sequential 
trials. Statistics in Medicine, 29 219-228
6.
Jennison, C. and Turnbull, B. W. (2000) Group Sequential Tests with Applications to Clinical Trials, 
Chapman and Hall/CRC, 390 pages
7.
Lin, D. Y. and Wei, L. J. (1989). The Robust Inference for the Proportional Hazards Model. J of American 
Statistical Association: 84, 1074–1078.
8.
Pocock S. J., Ariti C. A., Collier T. J., and Wang D. (2012). The win ratio: a new approach to the analysis of 
composite endpoints in clinical trials based on clinical priorities. European Heart Journal: 33, 176–182.
9.
Schulz KF, Altman DG, Moher D, for the CONSORT Group (2010). CONSORT 2010 Statement: updated 
guidelines for reporting parallel group randomised trials. BMJ: 340:c332
(http://www.bmj.com/content/340/bmj.c332).
10.
Tamhane, A.C, Mehta, C. R., Liu, L. (2010). Testing a Primary and a Secondary Endpoint in a Group 
Sequential Design. Biometrics, 66(4): 1174-1184
11.
Unger EF (2009). Weighing benefits and risks ─ the FDA's review of prasugrel. N Engl J Med;361(10):942-5.
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ATTACHMENTS
Attachment 1. The assumption of enrollment used in the original sample size calculation and the 
observed enrollment up to June 2016 on which the simulation study was based
The table below specifies monthly enrollment assumed in the sample size calculation.
Month
Number of subjects enrolled in the month
Month 1
2
Month 2
5
Month 3
13
Month 4
25
Month 5
50
Month 6
85
Month 7
120
Month 8
160
Month 9
210
Month 10
270
Month 11 and afterward
320
The table below shows the observed subject enrollment up to June 2016
Calendar Month
Number of subject randomized
Sep-13
4
Oct-13
9
Nov-13
51
Dec-13
83
Jan-14
48
Feb-14
91
Mar-14
108
Apr-14
135
May-14
107
Jun-14
112
Jul-14
123
Aug-14
68
Sep-14
78
Oct-14
120
Nov-14
73
Dec-14
71
Jan-15
67
Feb-15
70
Mar-15
61
Apr-15
63
May-15
68
Jun-15
65
Jul-15
53
Aug-15
62
Sep-15
67
Oct-15
109
Nov-15
125
Dec-15
126
Jan-16
125
Feb-16
117
Mar-16
164
Apr-16
161
May-16
137
Jun-16
178
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Attachment 2. Template of CONSORT Statement 2010 flow diagram
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Attachment 3. Disallowed concomitant medications
The following medications are prohibited in this study:
o
Prasugrel is prohibited in subjects who are ≥75 years old in age, or in subjects 
with prior TIA or stroke.
o
Nonsteroidal anti-inflammatory agents (NSAIDs) may be used on a temporary 
basis, but should be avoided for chronic use during the study period.
o
Strong inhibitors of cytochrome P450 3A4, such as but not limited to, 
ketoconazole, itraconazole, telithromycin, clarithromycin and voriconazole or 
protease inhibitors, are prohibited as concomitant therapy within 4 days before 
randomization, or during the study.
o
Any drug which is contraindicated in patients with heart failure (e.g., cilostazol)
o
Strong inducers of cytochrome P450 3A4, such as but not limited to, 
rifampin/rifampicin, rifabutin, rifapentin, phenytoin, phenobarbital, primidone, St. 
John’s Wort, or carbamazepine are prohibited as concomitant therapy within 4 
days before randomization, or during the study.
o
Proton pump inhibitors may be used, however subjects receiving clopidogrel 
should not receive omeprazole or esomeprazole.
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