SAFETY AND EFFECTIVENESS EVALUATION OF PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION TREATED WITH OACS: COMPARISON BETWEEN NOACS AND WARFARIN (CER3)
Conditions: Non-valvular Atrial Fibrillation
Sponsor: Pfizer

<Eliquis>
<B0661120> Safety and effectiveness evaluation of patients with non-valvular atrial fibrillation treated with 
OACs: Comparison between NOACs and warfarin (CER3)
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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Revision
Effective Date
Summary of Revisions
1.1
2018/5/08
Schedule(Milestone) has been revised 
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Study information
Title
Safety and effectiveness evaluation of patients with non-
valvular atrial fibrillation treated with OACs: Comparison 
between NOACs and warfarin (CER3)
Protocol number
B0661120
Protocol version identifier
1.1
Date of last version of protocol
08MAY2018
EU Post Authorisation Study (PAS) 
register number
Not applicable (this study is not PASS)
Active substance
B : Blood and blood forming organs
B01: Antithrombotic agents
B01A : Antithrombotic agents
B01AF: Direct factor Xa inhibitors
B01AF02: Apixaban
Medicinal product
Eliquis (Apixaban)
Research question and objectives
The research questions are: 1) is there any difference in the 
risk of major bleeding and composite of ischemic stroke, 
hemorrhagic stroke or systemic embolism (stroke/SE)
between patients treated with warfarin and those treated 
with one of NOACs (apixaban, dabigatran, edoxaban or 
rivaroxaban) in OAC naïve NVAF patients who start 
treatment with OACs. The primary objective is to compare 
the risk of major bleeding and stroke/SE in warfarin-
apixaban matched cohorts, warfarin-dabigatran matched 
cohorts, warfarin-edoxaban matched cohorts and warfarin-
rivaroxaban matched cohorts.
Author
,
 
PPD
PPD
PPD
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TABLE OF CONTENTS
1. RESPONSIBLE PARTIES.................................................................................................................. 4
2. ABSTRACT......................................................................................................................................... 4
3. AMENDMENTS AND UPDATES ....................................................................................................... 6
4. MILESTONES..................................................................................................................................... 6
5. RATIONALE AND BACKGROUND.................................................................................................... 7
6. RESEARCH QUESTION AND OBJECTIVES.................................................................................... 8
7. RESEARCH METHODS..................................................................................................................... 9
7.1. Study design ......................................................................................................................... 9
7.2. Setting ................................................................................................................................... 9
7.2.1. Inclusion criteria..................................................................................................... 10
7.2.2. Exclusion criteria.................................................................................................... 10
7.3. Variables ............................................................................................................................. 10
7.4. Data sources ....................................................................................................................... 12
7.5. Study size............................................................................................................................ 12
7.6. Data management............................................................................................................... 13
7.7. Data analysis....................................................................................................................... 13
7.8. Quality control ..................................................................................................................... 13
7.9. Limitations of the research methods ................................................................................... 13
7.10. Other aspects.................................................................................................................... 14
8. PROTECTION OF HUMAN SUBJECTS.......................................................................................... 14
8.1. Patient Information and Consent ........................................................................................ 14
8.2. Patient withdrawal ............................................................................................................... 14
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............................. 14
8.4. Ethical Conduct of the Study............................................................................................... 14
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS ................ 14
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS.............................. 15
11. COMMUNICATION OF ISSUES .................................................................................................... 15
12. REFERENCES ............................................................................................................................... 15
13. LIST OF TABLES ........................................................................................................................... 16
14. LIST OF FIGURES ......................................................................................................................... 16
15. ANNEX 1. LIST OF STAND ALONE DOCUMENTS...................................................................... 16
16. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .................................................... 16
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LIST OF ABBREVIATIONS
Abbreviation
Definition
AF
Atrial fibrillation
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
NOAC
Non-vitamin K antagonist oral anticoagulant
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
1. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, 
degree(s)
Title
Affiliation
Address
  
 
 
 
 
2. ABSTRACT
Title: Safety and effectiveness evaluation of patients with non-valvular atrial fibrillation treated with 
OACs: Comparison between NOACs and warfarin (CER3)
Version 1.0, Mar.14, 2018. PIH IM CV/MET Medical Affairs, 
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), 
PPD
PPD
PPD
PPD
PPD
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dabigatran, was introduced with approval for stroke prevention in NVAF patients in March 2011, 
followed by rivaroxaban in January 2012, apixaban in December 2012, and edoxaban in September 
2014 in Japan. NOACs provide more convenient therapeutic options and have been demonstrated at 
least equivalent efficacy compared to warfarin in Phase 3 clinical trials4-7. Apixaban is one of the four 
NOACs marketed in Japan and has been demonstrated superiority versus warfarin in preventing 
stroke or systemic embolism, caused less bleeding, and resulted in lower mortality in patients with 
atrial fibrillation in Phase 3 clinical trial6. However, its safety and effectiveness remains unknown in 
real-world clinical practice in Japan. Previously we have shown in the CER1 study8 that bleeding risks 
are also less in real world clinical practice in Japan compared to warfarin but effectiveness, that is, 
prevention of stroke, has not been evaluated yet. 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 initiated any of 
OACs (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin).
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 
treated with warfarin and those treated with one of NOACs (apixaban, dabigatran, edoxaban or 
rivaroxaban) 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, warfarin-dabigatran cohorts, warfarin-edoxaban 
cohorts and warfarin-rivaroxaban 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 March 1st, 2011 to December 
31st, 2017) designed to evaluate the difference in safety (major and any 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, dabigatran versus warfarin, edoxaban versus warfarin and rivaroxaban 
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 Subsections 7.2 below.
Variables: Index treatment of OACs; outcome measures including major bleeding, any 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 7.5 
below and also in the Statistical Analysis Plan (SAP).
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Data analysis: Detailed methodology for data analysis will be described in the SAP.  Baseline patient 
demographic information will be compared among the warfarin and each NOAC cohorts 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 NOACs compared with warfarin. To estimate hazard ratio and 95% 
confidence intervals of each NOAC compared with warfarin using univariable Cox proportional 
hazards models (OAC treatment as a single variable) will be used. 
Milestones: Data extraction from MDV database: Mar.19 - Mar.26, 2018; Analysis: Apr.01 - Apr.16, 
2018; Manuscript submission: JUL. 30th, 2018.
3. AMENDMENTS AND UPDATES
Amendment 
number
Date
Substantial or 
administrative 
amendment
Protocol 
section(s) 
changed
Summary of 
amendment(s)
Reason
4. MILESTONES
Milestone
Planned date
Start of data collection 
15 MAY 2018
End of data collection
21 MAY 2018
Final study report
1 OCT 2018
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5. 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 2011, followed by rivaroxaban in January 2012, apixaban in 
December 2012, and edoxaban in September 2014 in Japan. 
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. 
Recently, in order to overcome the drawbacks of RCTs and corroborate the evidence from RCTs, 
real-world evaluations of drugs have been conducted. As for anticoagulants, there are some studies 
that have evaluated safety and effectiveness of NOACs such as apixaban, dabigatran, and 
rivaroxaban in the real-world setting and the results were similar to those obtained from RCTs4-7. 
However, these studies are not sufficient, especially for effectiveness evaluation, and real-world data 
(RWD) specific to each country or region are also required. For example, Asian populations, including 
Japanese population, are known to be more prone to intracranial hemorrhage when treated with
warfarin10. Japan is a rapidly aging society with a large proportion of the population aged 75 years or 
older. Unfortunately, there have been few large-scale, real-world studies to investigate safety and 
effectiveness of NOACs in patients with NVAF receiving NOACs versus warfarin in Japan. 
The objective of this study is to compare the risk of incidence of stroke and bleeding among patients 
with NVAF newly prescribed any of NOACs (apixaban, dabigatran, edoxaban or rivaroxaban), versus 
newly prescribed warfarin using a nation-wide administrative claims database.
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This retrospective study is conducted voluntarily by Pfizer. This study will not be conducted as post-
authorization safety study (PASS)
 according to the decision by the business 
process owner
.
6. RESEARCH QUESTION AND OBJECTIVES
The research questions:
1.
Are there any differences in the risk of major bleeding and any bleeding between NOACs and 
warfarin in the general practice settings in Japan?
2.
Are there any differences in the risk of stroke/systemic embolism between NOACs and warfarin 
in the general practice settings in Japan?
The primary objective of the study compare both the risk of stroke/ SE and of bleeding events 
among patients with NVAF initiating treatment with one of NOACs (apixaban, dabigatran, edoxaban 
or rivaroxaban) versus warfarin.
The secondary objectives are 
1.
to compare the risk of major GI bleeding, any GI bleeding, and intracranial Hemorrhage between 
warfarin-initiators and NOAC-initiators
2.
to compare the risk of ischemic stroke, hemorrhagic stroke or SE between warfarin-initiators and 
NOAC-initiators
CCI
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7. RESEARCH METHODS 
7.1. Study design
This is a retrospective observational study using data from the MDV database (data set from March 
1st, 2011 to December 31st, 2017). Among patients registered in the database patients are selected 
based on the inclusion and exclusion criteria (see blow). The first observed prescription of apixaban, 
dabigatran, edoxaban, rivaroxaban or warfarin is used to identify the patient’s index date (date of the 
first prescription of any OACs is defined as “index date”) and treatment cohort. Study measures
include: (1) for safety evaluation: major bleeding and any bleeding; (2) for effectiveness evaluation: a 
composite of ischemic stroke, hemorrhagic stroke or SE.
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 
Section 8.2); discontinuation of the index OAC; switching from the index OAC; withdrawal from the 
database.
7.2. 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, dabigatran, 
edoxaban, rivaroxaban 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.
Any bleeding when the target outcome for the analysis is any bleeding.
4.
Discontinuation of the index OAC:  The index treatment will be considered to be 
"discontinued" if the index OAC is not prescribed within 45 days after prescription refill date
(calculated from the last refill date plus days of supply) of the index OAC, 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.
5.
Switching from the index OAC:  The index treatment is regarded as "switched" if non-index 
OAC is prescribed within 45 days after prescription refill date of the index OAC 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.
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6.
Withdrawal from the database: The patients are regarded as “withdrawal” from the database 
if the index OAC is not prescribed within 45 days after prescription refill date of the index 
OAC 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.
7.2.1. Inclusion criteria
Patients must meet all of the following criteria to be eligible for 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 one of the index OACs (apixaban, dabigatran, edoxaban, rivaroxaban or warfarin) 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.
7.2.2. 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 cardiac surgery procedure record during the baseline period
3.
Having a joint replacement procedure record during the baseline period
4.
Having a procedure of prosthetic heart valve during the baseline period
5.
Having a diagnosis of venous thromboembolism during the baseline period
6.
Female patients with pregnancy during the follow-up period
7.
Patients prescribed “off-label” doses of OACs (per Japanese package insert of each OAC) or 
patients treated with OAC but in “off-label” or “contraindicated” manners.
7.3. Variables
Demographic and clinical characteristics are collected during the baseline period or at the index date.
Table 1: Demographic and clinical information of patients
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Variable
Obtained from
Operational definition
Sex Category
Index date
Dichotomous variable equals 1 if sex is male and 2 if female
Age
Index date
Age (in years) at the index date
Physician specialty
Index date
Dichotomous variable equals 1 if a physician specialty on the 
index date is categorized into a cardiac specialty and 0 if
others. Following specialties will be categorized as the cardiac 
specialty: cardiology stroke, cardiovascular surgery, pediatric
cardiology, neurosurgery, cardiovascular medicine, and 
neurology. If there are ≥1 specialties but including the cardiac 
specialty, the physician specialty will be regarded as the 
cardiac specialty.
Hospital size (<500 beds 
or not)
Index date
Dichotomous variable equals 1 if hospital size on the index 
date is <500 beds and 0 if ≥500 beds.
Hospitalization status on 
index date
Index date
Dichotomous variable equals 1 if hospitalization status is 
inpatient and 0 if outpatient. 
CHADS2
Baseline period
CHADS2 score will be calculated based on age and the 
presence of congestive heart failure, hypertension, diabetes, 
and stroke or TIA.
CHA2DS2-VASc
Baseline period
Score calculated by appointing 1 point each for congestive 
heart failure/left ventricle dysfunction, hypertension, diabetes, 
vascular disease (prior MI, peripheral arterial disease, or aortic 
plaque), age between 65-74, female gender; and 2 points each 
for age >75 years and prior stroke, TIA, or thromboembolism. 
PT-INR (Prothrombin 
time-international 
normalized ratio)
Baseline period
Continuous variable. 
* Only available for patients treated with warfarin
Heart failure diagnosis in 
baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses for 
heart failure ICD-10 or disease codes during the baseline 
period.  
Coronary heart disease
diagnosis in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses for 
coronary heart disease ICD-10 or disease codes during the 
baseline period.  
Peripheral arterial
disorder diagnosis in 
baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses for 
peripheral arterial disorder ICD-10 or disease codes during the 
baseline period.  
Myocardial infarction
diagnosis in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses  for
myocardial infarction ICD-10 or disease codes during the 
baseline period.  
Hyperthyroidism or 
thyrotoxicosis in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses  for
hyperthyroidism ICD-10 or disease codes during the baseline 
period.  
Stroke,  TIA or  SE
diagnosis in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses  for 
Stroke, TIA or systemic embolism ICD-10 or disease codes 
during the baseline period.  
Renal dysfunction
diagnosis in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses  for 
renal dysfunction ICD-10 or disease codes during the baseline 
period.  
Liver dysfunction 
diagnosis in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses  for 
liver dysfunction ICD-10 or disease codes during the baseline 
period.  
Bleeding diagnosis in 
baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses  for
bleeding ICD-10 or disease codes during the baseline period. 
Hypertension diagnosis
in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses  for
hyper tension ICD-10 or disease codes during the baseline 
period.  
Diabetes mellitus
diagnosis in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses  for
diabetes mellitus ICD-10 or disease codes during the baseline 
period.  
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Cancer diagnosis in 
baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 diagnoses for
diabetes mellitus ICD-10 or disease codes during the 
baseline period.  
Treated with antiplatelet 
drug in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 prescriptions of 
antiplatelet drug ATC or receipt codes during the baseline 
period.  
Treated with NSAIDs in 
baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 prescriptions of 
NSAIDs ATC or receipt codes during the baseline period.  
Treated with gastric 
secretion inhibitor in 
baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 prescriptions
of  gastric secretion inhibitor drug ATC or receipt codes during 
the baseline period.  
Treated with statin-based
drug in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 prescriptions of 
statin-based drug ATC or receipt codes during the baseline 
period.  
Treated with anti-
hypertensives in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 prescriptions of 
anti-hypertensive ATC or receipt codes during the baseline 
period.  
Treated with anti-
arrhythmics in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 prescriptions of 
anti-arrythmics ATC or receipt codes during the baseline 
period.  
Treated with beta-
blockers in baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 prescriptions of 
beta-blockers ATC or receipt codes during the baseline period.  
Treated with heparins in 
baseline
Baseline period
Dichotomous variable equals 1 if there are ≥1 prescriptions of 
heparins ATC or receipt codes during the baseline period.  
Cardioversion in baseline
Baseline period
Dichotomous variable equals 1 if there is ≥1 operation of 
cardioversion receipt codes during the baseline period.  
Major bleeding in follow-
up
Follow-up 
period
Dichotomous variable equals 1 if there are ≥1 diagnoses for 
major bleeding ICD-10 or disease codes during the follow-up
period.  
Any bleeding in follow-up
Follow-up 
period
Dichotomous variable equals 1 if there are ≥1 diagnoses for 
any bleeding ICD-10 or disease codes during the follow-up
period.  
Stroke/SE in follow-up
Follow-up 
period
Dichotomous variable equals 1 if there are ≥1 diagnoses for
stroke or SE ICD-10 or disease codes during the follow-up
period.  
7.4. 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 45%). The database provides claims data from 314 hospitals (as of June 2017) 
using the DPC system for medical service claims (21% of general hospitals but 55% of general beds 
in Japan is under the DPC system) including approximately 14 million patient data.
7.5. Study size
All eligible patients are extracted from the database and used for the analysis. In the previous study 
(CER2; conducted based on the data from March 1st, 2011 to December 31st, 2017 for apixaban, 
edoxaban and warfarin), 14,830 patients on warfarin, 16,176 patients on apixaban and 4,438 patients 
on edoxaban 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 Statistical Analysis Plan 
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(SAP).
7.6. Data management 
Data will be securely provided by MDV Co. Ltd. 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.
7.7. Data analysis 
Baseline patient demographic information will be compared among the warfarin and NOACs cohorts 
by appropriate tests (e.g., t-test, Mann Whitney-U test, chi-square test) based on the distribution of 
the measures. A PSM method will be used to balance patient characteristics between compared 
cohorts (apixaban versus warfarin, dabigatran versus warfarin, edoxaban versus warfarin or 
rivaroxaban versus warfarin). In addition to the simple PSM (that is, without “weighting”), a stabilized 
inverse probability treatment weighting (IPTW) method will be also used to balance patient 
characteristics between groups11 (see also Statistical Analysis Plan). Cox proportional hazards 
models (OAC treatment as a single variable) will be used to calculate the hazard ratios with 95% 
confident intervals. Anticoagulant type (apixaban or warfarin, dabigatran or warfarin, edoxaban or 
warfarin or rivaroxaban or warfarin) was included and no other covariates were included in the COX 
model because two cohorts were balanced after propensity score matching.
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.
7.8. 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 Crecon Medical Assessment Inc. (Tokyo, Japan). The final results 
will be quality checked internally by Crecon Medical Assessment 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.
7.9. Limitations of the research methods
1) Identification of NVAF, bleeding, stroke, TIA and SE events will be based on insurance claims 
data, and there is no medical record review to adjudicate these diagnosis, which may subject the 
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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. 
7.10. Other aspects
Not applicable.
8. PROTECTION OF HUMAN SUBJECTS
8.1. Patient Information and Consent
The MDV database is comprised of unlinkable anonymized data. According to the ethical guidelines 
for epidemiological studies in Japan, informed consent is not always required for studies by 
unlinkable anonymized data.
8.2. Patient withdrawal
Not Applicable.
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
Since the MDV database is comprised of unlinkable anonymized data, IRB/IEC approval is not 
required.
8.4. Ethical Conduct of the Study
Not Applicable.
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study only includes data that already exist as structured data in an electronic database. In the 
data sources (MDV Co. Ltd.), 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 (i.e., identifiable patient, identifiable reporter, a suspect product, and event) are not 
available and unprojected adverse events are not reportable as individual adverse event reports.
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10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
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 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
11. COMMUNICATION OF ISSUES
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 investigator 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.  
12. 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.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus 
warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.
6.
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.
7.
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban 
versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-2104.
8.
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.
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 guidelines for 
the management of patients with atrial fibrillation: a report of the American College of 
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Cardiology Foundation/American Heart Association Task Force on practice guidelines. 
Circulation 2011;123:e269-367.
10.
Shen AY, Yao JF, Brar SS, Jorgensen MB, Wang X, Chen W. Racial/Ethnic differences in 
ischemic stroke rates and the efficacy of warfarin among patients with atrial fibrillation. Stroke
2008;39:2736-2743.
11.
Austin PC, Stuart EA. Moving towards best practice when using inverse probability of 
treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in 
observational studies. Stat Med 2015;34:3661-3679.
13. LIST OF TABLES 
Table 1.  Demographic and clinical information of patients
14. LIST OF FIGURES
None.
15. ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
16. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
None
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