Safety and Effectiveness of Apixaban Compared to Warfarin in NVAF Patients at Higher Risk of Bleeding.
Conditions: Non-valvular Atrial Fibrillation
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
Safety and effectiveness of apixaban 
compared to warfarin in NVAF patients at 
higher risk of bleeding.
Protocol number
B0661178
Protocol version identifier
Ver.1.0
Date
1 Jun 2022
EU Post Authorization Study (PAS) 
register number
Study not registered
Active substance
B : Blood and blood forming organs
B01: Antithrombotic agents
B01A : Antithrombotic agents
B01AF: Direct factor Xa inhibitors
B01AF02: Apixaban
B : Blood and blood forming organs
B01: Antithrombotic agents
B01A : Antithrombotic agents
B01AA :Vitamin K Antagonist
B01AA03: Warfarin
Medicinal product
Eliquis (Apixaban)
Warfarin
Research question and objectives
Previous RCTs and RWE have shown that 
apixaban is associated with lower risk of 
stroke/SE (effectiveness) and bleeding 
(safety) when compared to warfarin in 
patients with NVAF. However, there are 
limited apixaban data for Japanese elderly 
patients and some patients are prone to bleed 
and several risk factors have been already 
reported. Absolute risk of bleeding is higher 
in these patients and there is little clear 
evidence showing superiority of apixaban 

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over warfarin in population at higher risk of 
bleeding.
Objectives of the present study are:
- To investigate the safety and effectiveness 
of apixaban compared to warfarin in 
Japanese NVAF patients with higher 
bleeding risks
- To generate compliment data for 
ARISTOTLE and support clinicians for 
their appropriate use
Author
Pfizer Japan Inc. 
 
PPD
PPD
PPD

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................3
2. LIST OF ABBREVIATIONS................................................................................................5
3. RESPONSIBLE PARTIES....................................................................................................6
4. ABSTRACT..................................................... ERROR! BOOKMARK NOT DEFINED.
5. AMENDMENTS AND UPDATES.......................................................................................7
6. MILESTONES.....................................................................................................................10
7. RATIONALE AND BACKGROUND................................................................................10
8. RESEARCH QUESTION AND OBJECTIVES .................................................................11
9. RESEARCH METHODS ....................................................................................................12
9.1. Study design ............................................................................................................12
9.2. Setting......................................................................................................................12
9.2.1. Inclusion criteria .........................................................................................13
9.2.2. Exclusion criteria........................................................................................13
9.3. Variables..................................................................................................................14
9.4. Data sources ............................................................................................................15
9.5. Study size ................................................................................................................15
9.6. Data management....................................................................................................15
9.7. Data analysis ...........................................................................................................15
9.8. Quality control.........................................................................................................16
9.9. Limitations of the research methods .......................................................................16
9.10. Other aspects .........................................................................................................16
10. PROTECTION OF HUMAN SUBJECTS ........................................................................16
10.1. Patient information................................................................................................16
10.2. Patient consent.......................................................................................................17
10.3. Patient withdrawal.................................................Error! Bookmark not defined.
10.4. Institutional review board (IRB)/Independent ethics committee (IEC)................17
10.5. Ethical conduct of the study..................................................................................17
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................17
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........17

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13. REFERENCES ..................................................................................................................18
14. LIST OF TABLES.............................................................................................................19
15. LIST OF FIGURES ...........................................................................................................19
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................19
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................19
ANNEX 3. ADDITIONAL INFORMATION.........................................................................19

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ACE
Angiotensin-converting enzyme
AF
Atrial fibrillation
ARB
Angiotensin receptor blocker
CER
Cmparative effectiveness research
DPC
Diagnosis procedure combination
ICD
International Statistical Classification of Diseases 
and Related Health Problems
INR
International normalized ratio
IPTW
Inverse probability treatment weighting
MDV
Medical Data Vision
MI
Myocardial infarction
MR
Mineralocorticoid receptor
NOAC
Non-vitamin K antagonist oral anticoagulant
NSAIDs
Non-steroidal anti-inflammatory drug
NVAF
Non-valvular atrial fibrillation
OAC
Oral anticoagulant
PSM
Propensity score matching
RCT
Randomized control trial
RWD
Real World Data
SAP
Statistical Analysis Plan
SE
Systemic embolism
TIA
Transient ischemic attack

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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Job Title
Affiliation
Address
Pfizer Japan Inc.
 
PPD
PPD
PPD

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4. ABSTRACT
Title: Safety and effectiveness of apixaban compared to warfarin in NVAF patients at higher 
risk of bleeding (CER4)
Version 1.0, (26-May-2022).
Rationale and background: Atrial fibrillation (AF) is characterized by a rapid, irregular 
heartbeat which can cause blood to pool in the atria and increase the risk of the formation of 
blood clots.  It has been reported that AF affects 0.6% to 1.6% of the general population and 
up to 14% in cardiovascular clinics in Japan1-3. An anticoagulation therapy is a critical 
treatment to prevent thromboembolism in non-valvular AF (NVAF) patients. Warfarin, a 
vitamin K antagonist, is the first oral anticoagulant approved for the treatment for prevention 
of thromboembolism in Japan in 1962 and it had long been the only oral anticoagulant until 
the first non-vitamin K antagonist oral anticoagulants (NOACs), dabigatran, was introduced 
with approval for stroke prevention in NVAF patients in March 20114. Apixaban was 
approved in December 2012 in Japan and demonstrated superiority compared to warfarin in 
preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality 
in patients with atrial fibrillation in Phase 3 clinical trial5. Previously we have shown that 
bleeding risks as well as stroke/ systemic embolism (SE) risks are less in real world clinical 
practice in Japan compared to warfarin.6-8  However there are limited apixaban data for 
Japanese NVAF patients with high bleeding risk(s). This study will evaluate the risk of
stroke/SE as well as the risk of bleeding in the real world settings in Japan in patients with 
NVAF who has higher bleeding risk(s).
Research question and objectives: The research questions are: 1) is there any difference in 
the risk of major bleeding and of a composite of (ischemic and hemorrhagic) stroke/SE 
between patients with higher bleeding risk(s) treated with warfarin and those treated with 
apixaban in OAC naïve NVAF patients who start treatment with OACs.
The primary objective is to compare the risk of major bleeding and composite of (ischemic 
and hemorrhagic) stroke/SE in warfarin-apixaban cohorts.
Study design: This is a retrospective, non-interventional observational study using the 
database provided by Medical Data Vision Co. Ltd. (MDV Co. Ltd.) (data set from 1 March, 
2011 to 31 Jun, 2021) designed to evaluate the difference in safety (major bleeding) and 
effectiveness (composite of stroke/SE) in the matched cohorts created by using a propensity 
score matching method or a stabilized IPTW (inverse probability of treatment weighted) 
method. Comparisons of apixaban versus warfarin will be performed.
Population: Data from OAC treatment-naïve Japanese patients with NVAF initiating OAC 
treatment will be used for the analysis. Further information on patient selection, enrollment 
and follow-up time periods are included in Subsection 9.2 below.

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Variables: Index treatment of OACs; outcome measures including major bleeding, 
stroke/SE and demographic and clinical characteristics of the patients.
Data sources: Medical Data Vision database
Study size: The required number of eligible patients for each cohort is estimated in 
Subsection 9.5 below and also in the Statistical Analysis Plan (SAP).
Data analysis: Detailed methodology for data analysis will be described in the SAP.  
Baseline patient demographic information will be compared among the warfarin and 
apixaban by appropriate tests (e.g., t-test, Mann Whitney-U test, chi-square test) based on the 
distribution of the measures. Both propensity score matching (PSM) and stabilized IPTW 
methods will be used to estimate treatment effects of apixaban compared to warfarin. To 
estimate hazard ratio and 95% confidence intervals of apixaban compared to warfarin using 
univariable Cox proportional hazards models (OAC treatment as a single variable) will be 
used. 
Milestones: 
Data extraction from MDV database: Jun. 30 – . Jul 14, 2022; 
Analysis: Jul. 15 – Aug. 17, 2022; 
Final study report: Oct 20, 2022

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5. AMENDMENTS AND UPDATES
None

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6. MILESTONES
Milestone
Planned date
<Completion of feasibility assessment>
17 Mar 2022
Start of data collection 
30 Jun 2022
End of data collection
17 Aug 2022
Final study report
20 Oct 2022
7. RATIONALE AND BACKGROUND
Atrial fibrillation (AF) is characterized by a rapid, irregular heartbeat which can cause blood 
to pool in the atria and increase the risk of the formation of blood clots.  AF affects 0.6% to 
1.6% of the general population and up to 14% in cardiovascular clinics in Japan1-3. AF can be 
categorized into three main categories based on patient characteristics: lone atrial fibrillation
– AF in the absence of overt cardiovascular disease or precipitating illness9 non-valvular AF 
(NVAF) – presence of AF without concurrent rheumatic mitral valve disease or history of 
mitral valve repair or prosthetic heart valve; and secondary AF-AF that occurs in the setting 
of acute myocardial infarction (MI), cardiac surgery, pericarditis, myocarditis, 
hyperthyroidism, pulmonary embolism, pneumonia, or other acute pulmonary disease. 
Anticoagulation therapy is important to prevent thromboembolism in patients with NVAF. 
Warfarin, a vitamin K antagonist, is the first oral anticoagulant approved for the treatment 
and prevention of thromboembolism in Japan in 1962 and it had long been the only oral 
anticoagulant until the first non-vitamin K antagonist oral anticoagulants (NOACs), 
dabigatran, was introduced with approval for NVAF treatment in March 20114. Apixaban 
was approved in December 2012 in Japan and demonsrated superiority compared to walfarin 
in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower 
mortality in patients with atrial fibrillation in Phase 3 clinical trial5. 
Although randomized control trials (RCTs) aimed at head-to-head comparison with placebo 
or a reference drug may provide evidence of safety and efficacy of treatments at the highest 
level, there are potential limitations derived from a limited number of pre-selected patients 
and strict patient eligibility criteria with regard to age, comorbidities, and concomitant 
medications. Accordingly, these studies may not accurately represent what happens when 
drugs are used in general clinical practice. Especially data for Japanese NVAF patients are 
limited due to limited number of Japanese patients recruited in the RCT.  Also patients with 
higher risk from a safety perspective, for instance patients with active caner, are generally 
excluded from RCT and further limited data are exist.
Previously we have shown that bleeding risks as well as stroke/ systemic embolism (SE)
risks are less in real world clinical practice in Japan compared to warfarin6-8, but there are 

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still little data for Japanese NVAF patients who has higher bleeding risks such as componets 
of HAS-BLED risk score factors, active cancer, uncontrolled hypertension etc.  The 
objectives of this study is to compare the risk of incidence of stroke and bleeding among 
NVAF patients with such higher bleeding risk(s) newly prescribed apixaban or warfarin 
using a nation-wide administrative claims database.
8. RESEARCH QUESTION AND OBJECTIVES
The research questions are:
1.
Are there any differences in the risk of major bleeding between apixaban and warfarin
for patients with higher bleeding risk(s) in the general practice settings in Japan?
2.
Are there any differences in the risk of stroke/systemic embolism between apixaban and 
warfarin for patients with higher bleeding risk(s) in the general practice settings in 
Japan?
The primary objective of the study is to compare effectiveness (a composit risk of 
stroke/SE) and safety (major bleeding events) of warfarin and apixaban among NVAF 
patients  with at least one bleeding risk (that is, patients at higher risk of bleeding)  
The secondary objectives are:
1.
to compare the risk of major gastrointestinal or intracranial bleeding between warfarin-
initiators and apixaban-initiators in patients with at least one bleeding risk.
2.
to compare the risk of ischemic stroke, hemorrhagic stroke or SE between warfarin-
initiators and apixaban-initiators in patients with at least one bleeding risk.
Objectives of other exploratory analysis are to explore the risk of major bleeding and 
stroke/SE in the specific populations at higher bleeding risk(s).
In this study, predetermined high bleeding risk subgroups are 1) patients with hypertension 
diagnosis, 2) patients with liver dysfunction, 3) patients with renal dysfunction diagnosis, 4) 
patients with a history of beleeding, 5) patiens with hemorrphagic stroke, 6) patients with
alcohol abuse, 7) patients with concomitamt used of antiplatelet drugs, 8) patients with 
chronic (continuously for longer than 90 days) comcomitant use of NSAID, 9) highly elderly
(> 80 years old) , 10) patients with refractory hypertension, 11) patients with a history of 
peptic ulcer diagnosis, 12) patients with active cancer, 13) patients with diabetes mellitus, 14) 
patients whose body weight is <40kg, 15) patients with polypharmacy.  
In the previous feasibility analysis, we found that the numbers of patients with hemorrhagic 
stroke, alcohol abuse, chronic concomitant used of NSAIDs (for continuously > 90 days), 
and refractory hypertension were less than 2,000. Due to the insufficient statistical power, we 
will not include these subgroups for the future analysis.
Subgroups to be analyzed for exploratory analysis will be described in a SAP.

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9. RESEARCH METHODS 
9.1. Study design
This is a retrospective observational study using data from the MDV database (data set from 
1 March, 2011 to 31 Jun, 2021). Among patients registered in the database patients are 
selected based on the inclusion and exclusion criteria (see blow).. 
Study measures include: (1) for safety evaluation: major bleeding ; (2) for effectiveness 
evaluation: a composite of ischemic stroke, hemorrhagic stroke or SE. 
The primary purpose of this study is to investigate the safety and effectiveness of apixaban 
compared to warfarin in NVAF patients who are prone to bleeding, with at least one known 
risk factor for bleeding. In this study, predetermined high bleeding risk subgroups are 1) 
patients with hypertension diagnosis, 2) patients with liver dysfunction, 3) patients with renal 
dysfunction diagnosis, 4) patients with a history of beleeding, 5) patiens with hemorrphagic 
stroke, 6) patients with alcohol abuse, 7) patients with concomitamt used of antiplatelet drugs, 
8) patients with chronic (continuously for longer than 90 days) comcomitant use of NSAID, 
9) highly elderly (> 80 years old) , 10) patients with refractory hypertension, 11) patients 
with a history of peptic ulcer diagnosis, 12) patients with active cancer, 13) patients with 
diabetes mellitus, 14) patients whose body weight is <40kg, 15) patients with polypharmacy. 
The follow-up period is variable, and will begin on the next day of the index date and 
continue until the earliest of the following scenarios – occurrence of target outcome event 
(details available in Subsection 9.2); discontinuation of apixaban or warfarin; switching from 
apixaban or warfarin; withdrawal from the database.
9.2. Setting
This study uses data from the MDV database, which includes the data used for both inpatient 
and outpatient insurance claims by hospitals according to the Diagnosis Procedure 
Combination (DPC) procedure.
The study population will consist of adults with NVAF who are newly prescribed apixaban 
or warfarin.  Follow-up time period starts from the next day of the index date, and ends 
depending on following outcomes which observed first.  
1.
Major bleeding when the target outcome for the analysis is major bleeding.
2.
Composite of (ischemic or hemorrhagic) stroke and SE when the target outcome for the 
analysis is the composite endpoint.
3.
Discontinuation of apixaban or warfarin:  The index treatment will be considered to be 
"discontinued" if apixaban or warfarin is not prescribed within 45 days after prescription 
refill date (calculated from the last refill date plus days of supply) of apixaban or

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warfarin, even though the patient has >1 medical encounter records after more than 45 
days following the prescription refill date. The supposed prescription refill date is
regarded as the last day of the follow-up for discontinued patients.
4.
Switching from apixaban or warfarin:  The index treatment is regarded as "switched" if 
OAC is prescribed within 45 days after prescription refill date of apixaban or warfarin
when the patient has 1> medical encounter records after more than 45 days following the 
prescription refill date. The switched day is regarded as the last day of the follow-up for 
the switched patients.
5.
Withdrawal from the database:  The patients are regarded as “withdrawal” from the 
database if apixaban or warfarin is not prescribed within 45 days after prescription refill 
date of the apixaban or warfarin and there is no data of the patient on the database after 
prescription refill date. The last medical encounter is regard as the last day of the follow-
up for patients withdrawn from the database.
6.
An elapse of 2 years from the index date without any of the event above.
9.2.1. Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Diagnosed with AF anytime in the baseline period or on the index date, also have 
definitive diagnosis of AF anytime in the baseline period, on the index date, or post-index 
period. 
2. Prescribed apixaban or wararin on or after the day of AF diagnosis. The first observed 
prescription will be used to identify the patient’s index date and treatment cohort
3. No use of the any OACs during the baseline period (the 180 days before the index date) 
4. Age of 18 years or older on the index date.
9.2.2. Exclusion criteria
Patients meeting any of the following criteria will not be included in the study:
1.
Having a diagnosis of valvular atrial fibrillation, post-operative atrial fibrillation, 
rheumatic atrial fibrillation or mechanical-valvular atrial fibrillation during the baseline 
and post-index period
2.
Having a procedure of prosthetic heart valve during the baseline period
3.
Having a cardiac surgery procedure record during the baseline period

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4.
Having a diagnosis of venous thromboembolism during the baseline period
5.
Having a hemodialysis during the baseline period
6.
Female patients with pregnancy during the baseline and follow-up period
7.
Patients prescribed apixaban other than approved daily dose  (<5 mg or >10 mg)
8.
Patients prescribed OACs during baseline period
9.3. Variables
Demographic and clinical characteristics are collected during the baseline period, at the index 
date or during follow-up period.  Detail definition available in SAP.
Variable
Role
Data source(s)
Sex Category
Baseline characteristic
Index date
Age
Baseline characteristic
Index date
Age (> 80y, >90 y)
Sub-group identifier
Index date
CHADS2
Baseline characteristic
Baseline period
CHA2DS2-VASc
Baseline characteristic
Baseline period
Heart failure diagnosis
Baseline characteristic
Baseline period
Coronary heart disease diagnosis 
Baseline characteristic
Baseline period
Peripheral arterial disorder diagnosis 
Baseline characteristic
Baseline period
Myocardial infarction diagnosis
Baseline characteristic
Baseline period
Hyperthyroidism or thyrotoxicosis
Baseline characteristic
Baseline period
Stroke,  TIA or  SE diagnosis 
Baseline characteristic
Baseline period
Renal dysfunction diagnosis
Baseline characteristic
Sub-group identifier
Baseline period
Liver dysfunction diagnosis 
Baseline characteristic
Sub-group identifier
Baseline period
Bleeding diagnosis 
Baseline characteristic
Baseline period
Hypertension diagnosis
Baseline characteristic
Sub-group identifier
Baseline period
Refractory hypertension diagnosis
Sub-group identifier
Baseline period
Diabetes mellitus diagnosis
Baseline characteristic
Sub-group identifier
Baseline period
Cancer diagnosis 
Baseline characteristic
Sub-group identifier
Baseline period
Treated with antiplatelet drug
Baseline characteristic
Baseline period
Treated with antiplatelet drug (>28 d)
Sub-group identifier
Baseline period
Treated with NSAIDs
Baseline characteristic
Baseline period
Treated with NSAIDs (>90 d)
Sub-group identifier
Baseline period
Treated with gastric secretion inhibitor
Baseline characteristic
Baseline period
Treated with statin-based drug
Baseline characteristic
Baseline period
Treated with anti-hypertensives
Baseline characteristic
Baseline period
Treated with anti-arrhythmics
Baseline characteristic
Baseline period
Treated with beta-blockers
Baseline characteristic
Baseline period
Treated with heparins
Baseline characteristic
Baseline period
Cardioversion 
Baseline characteristic
Baseline period
Alcohol abuse
Sub-group identifier
Baseline period
Bleeding diagnosis
Sub-group identifier
Baseline period

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Variable
Role
Data source(s)
Peptic ulcer diagnosis
Sub-group identifier
Baseline period
Hemorrhagic stroke diagnosis
Sub-group identifier
Baseline period
Low body weight (<40 kg)
Sub-group identifier
Baseline period
Polypharmacy
Sub-group identifier
Baseline period
PT-INR (Prothrombin time-international normalized ratio)
potential confounder
Baseline period
Physician specialty
potential confounder
Index date
Hospital size (<500 beds or not)
potential confounder
Index date
Hospitalization status on index date
potential confounder
Index date
Major bleeding
Outcome
Follow-up period
Any bleeding 
Outcome
Follow-up period
Stroke/SE
Outcome
Follow-up period
9.4. Data sources
The analysis will be based on administrative data from MDV Co. Ltd., a longitudinal 
database based on health insurance claims and medical records obtained from the hospitals in 
which the DPC payment system for utilization of both inpatient and outpatient hospital 
claims (percentage of inpatients is about 20%). The database provides claims data from 449 
hospitals (as of Aug 2021) using the DPC system for medical service claims (26% of general 
hospitals in Japan is under the DPC system) including approximately 36.7 million patient
data.
9.5. Study size
All eligible patients are extracted from the database and used for the analysis. In the previous 
study (CER3; conducted based on the data from March 1st, 2011 to July 31st, 2018 for 
apixaban, dabigatran, edoxaban, rivaroxaban and warfarin), 15,902 patients on warfarin, 
22,336 patients on apixaban were eligible for the analysis. The required number of patients 
for the planned analysis and the estimated number of eligible patients for each cohort is 
shown in a SAP.
9.6. Data management 
Data will be securely provided by MDV Co. Ltd (data set from 1 March, 2011 to 31 Jun,
2021). All analyses will be conducted using SAS software (Version 9.0 or higher, SAS 
Institute, Cary, NC, USA) with study results presented in Microsoft Excel tables.
9.7. Data analysis 
Detailed methodology for summary and statistical analyses of data collected in this study will
be documented in a SAP, which will be dated, filed and maintained by the sponsor. The SAP
may modify the plans outlined in the protocol; any major modifications of primary endpoint 
definitions or their analyses would be reflected in a protocol amendment.

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9.8. Quality control
This study is a retrospective analytical study using quality controlled data in a pre-existing 
database, and primary data collection will not be conducted. As for the data provided, quality 
of the data is guaranteed by MDV Co. Ltd., which has professional teams specialized in the 
maintenance and improvement of data quality. All of these processes are consistently 
managed in-house. All of operations for data management in MDV Co. Ltd. are conducted in 
accordance with standard operational procedures of MDV Co. Ltd..
Data analysis will be conducted by Macromill Carenet, Inc. (Tokyo, Japan). The final results 
will be quality checked internally by Macromill Carenet according to their internal 
procedures. For quality assurance of analysis, they will conduct code review of all modules 
of program, descriptive statistics review of all variables and patients row data examination of 
all output results in a test phase.
9.9. Limitations of the research methods
1) Identification of NVAF, bleeding, stroke, TIA and SE events, and high bleeding risk 
factors will be based on insurance claims data, and there is no medical record review to 
adjudicate these diagnosis, which may subject the study of misclassification bias. 2) There is 
no information about the therapeutic range of warfarin therapy or INR monitoring results, 
which are important factors related to the safety and efficacy of warfarin treatment. In Japan, 
it has been pointed out that coagulation status is often sub-optimally controlled by warfarin in 
NVAF patients. 3) This is an observational study and patients with different treatments may 
be incomparable. These differences may impact the comparison between treatment groups. In 
this study, a PSM method or IPTW with stabilized weights will be used to make well 
matched cohorts. Although the cohorts are matched, some differences in patient background 
which are neither available from the database nor included in matching score might still 
affect the results.
9.10. Other aspects
Not applicable
10. PROTECTION OF HUMAN SUBJECTS
10.1. Patient information 
This study involves data that exist in anonymized structured format and contain no patient 
personal information. 

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10.2. Patient consent
As this study involves anonymized structured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required.
10.3. Institutional review board (IRB)/Independent ethics committee (IEC)
Regarding MDV database, IRB/IEC approval is not required since MDV database comprised 
of unlinkable anonymized data.
10.4. Ethical conduct of the study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practice 
described in Ethical Guidelines for Medical and Health Research Involving Human Subjects.  
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (i.e., identify a potential association between) a particular product and 
medical event for any individual.  Thus, the minimum criteria for reporting an adverse event 
(AE) (i.e., identifiable patient, identifiable reporter, a suspect product, and event) cannot be 
met.
This study involves data that exist as structured data by the time of study start. In these data 
sources, individual patient data are not retrieved or validated, and it is not possible to link 
(i.e., identify a potential association between) a particular product and medical event for any 
individual.  Thus, the minimum criteria for reporting an adverse event (AE) (i.e., identifiable 
patient, identifiable reporter, a suspect product, and event) cannot be met.
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if the party responsible for collecting data 
from the participant is aware of any new information which might influence the evaluation of 
the benefits and risks of a Pfizer product, Pfizer should be informed immediately.  
All final data will be shared with BMSKK/BMS. It is also anticipated that results from this 
study will generate at least one study abstract for submission to a medical conference and one 

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manuscript for submission to an international peer-reviewed journal.  The appropriate 
conferences and journal will be decided upon by the alliance medical team. Abstract, 
presentation materials (poster or slide deck) or a manuscript will be reviewed and approved 
both by Pfizer and BMS
13. REFERENCES
1.
Lip GYH, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a 
systematic review of the epidemiology of atrial fibrillation in regions outside North 
America and Europe. Chest 2012;142:1489-1498.
2.
Tomita F, Kohya T, Sakurai M, Kaji T, Yokoshiki H, Sato M, et al. Prevalence and 
clinical characteristics of patients with atrial fibrillation: analysis of 20,000 cases in 
Japan. Jpn Circ J 2000;64:653-658.
3.
Kopecky SL, Gersh BJ, McGoon MD, Whisnant JP, Holmes DR, Jr., Ilstrup DM, et al. 
The natural history of lone atrial fibrillation. A population-based study over three 
decades. N Engl J Med 1987;317:669-674.
4.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. 
Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 
2009;361:1139-1151.
5.
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. 
Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med
2011;365:981-992.
6.
Kohsaka S, Murata T, Izumi N, Katada J, Wang F, Terayama Y. Bleeding risk of 
apixaban, dabigatran, and low-dose rivaroxaban compared with warfarin in Japanese 
patients with non-valvular atrial fibrillation: a propensity matched analysis of 
administrative claims data. Curr Med Res Opin 2017;33:1955-1963.
7.
Kohsaka S, Katada J, Saito K, Terayama Y. Safety and effectiveness of apixaban in 
comparison to warfarin in patients with nonvalvular atrial fibrillation: a propensity-
matched analysis from Japanese administrative claims data. Curr Med Res Opin 
2018;34(9):1627-1634.
8.
Kohsaka S, Katada J, Saito K, Jenkins A, Li B,, Mardekian J, Terayama Y. Safety and 
effectiveness of non-vitamin K oral anticoagulants versus warfarin in real-world patients 
with non-valvular atrial fibrillation: a retrospective analysis of contemporary Japanese 
administrative claims data. Open Heart 2020 Apr 1;7(1):e001232.
9.
Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. 2011 
ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 

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guidelines for the management of patients with atrial fibrillation: a report of the
American College of Cardiology Foundation/American Heart Association Task Force on 
practice guidelines. Circulation 2011;123:e269-367.
10.
14. LIST OF TABLES 
None
15. LIST OF FIGURES
None
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable
ANNEX 3. ADDITIONAL INFORMATION
Not applicable