Comparative Effectiveness and Safety Between Warfarin and Dabigatran Using Real World Claims Data of Japanese Non-valvular Atrial Fibrillation Patients
Conditions: Atrial Fibrillation
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-124_RD-01 (4.0)
TITLE PAGE
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document Number:
C17002710-01
BI Study Number:
1160.0288
BI Investigational
Product(s):
Prazaxa (Dabigatran etexilate)
Title:
Comparative Effectiveness and Safety between Warfarin and 
Dabigatran Using Real World Claims Data of Japanese Non-
valvular Atrial Fibrillation Patients 
Protocol version 
identifier:
version 1.0
Date of last version of 
protocol:
Not Applicable
PASS:
No
EU PAS register 
number:
Not Applicable
Active substance:
Dabigatran and warfarin 
Medicinal product:
Dabigatran and warfarin
Product reference:
Not applicable
Procedure number:
Not Applicable
Joint PASS:
No
Research question and 
objectives:
To compare the effectiveness (stroke/SE) (primary outcome)
and safety (major bleeding) (secondary outcome) in patients 
with atrial fibrillation and newly treated with dabigatran and 
warfarin in the real world Japanese setting using a claims 
database
Country(-ies) of study:
Japan
Author:
Marketing authorisation 
holder(s):

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MAH contact person:
In case of PASS, add:
<EU-QPPV:>
Not Applicable
In case of PASS, add:
<Signature of EU-
QPPV:>
Not Applicable
Date:
6 Jul 2017
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES....................................................................... 9
6.
MILESTONES..................................................................................................... 10
7.
RATIONALE AND BACKGROUND................................................................ 11
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 12
9.
RESEARCH METHODS .................................................................................... 13
9.1
STUDY DESIGN............................................................................................ 13
9.2
SETTING........................................................................................................ 13
9.3
VARIABLES .................................................................................................. 14
9.3.1
Exposures ................................................................................................ 14
9.3.2
Outcomes................................................................................................. 15
9.3.2.1
Primary Outcome ..................................................................................15
9.3.2.2
Secondary Outcome ..............................................................................18
9.3.3
Covariates................................................................................................ 19
9.4
DATA SOURCES........................................................................................... 25
9.5
STUDY SIZE.................................................................................................. 26
9.6
DATA MANAGEMENT................................................................................ 27
9.7
DATA ANALYSIS......................................................................................... 27
9.7.1
Main analysis........................................................................................... 27
9.8
QUALITY CONTROL................................................................................... 27
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 28
9.10
OTHER ASPECTS ......................................................................................... 28
9.11
SUBJECTS...................................................................................................... 28
9.11.1
Cases........................................................................................................ 28
9.11.2
Controls................................................................................................... 28
9.12
BIAS................................................................................................................ 29
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 29

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11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 30
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 31
13.
REFERENCES .................................................................................................... 32
13.1
PUBLISHED REFERENCES......................................................................... 32
13.2
UNPUBLISHED REFERENCES................................................................... 32
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 33
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 34
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 35

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2.
LIST OF ABBREVIATIONS
AF
Atrial Fibrillation
AIC
Akaike Information Criterion
CHADS2
Congestive heart failure, Hypertension, Age, Diabetes, 
Stroke(doubled)
CHA2DS2-
VASc
Cardiac failure or dysfunction, Hypertension, Age 75 (doubled), 
Diabetes, Stroke (doubled) Vascular disease, Age 65-74 and Sex 
category (female) score
CHF
Congestive Heart Failure
CI
Confidence Interval
COPD
Chronic Obstructive Lung Disease
CT
Computed Tomography
DM
Diabetes Mellitus
DPC
Diagnosis Procedure Combination
HR
Hazard Ratio
ICD
International Classification of Diseases
ICH
Intracranial Hemorrhage
MDV
Medical Data Vision
MRI
Magnetic Resonance Imaging
NVAF
Non-Valvular Atrial Fibrillation
OAC
Oral Anticoagulants
PPV
Positive Predictive Value
PS
Propensity Score
PVD
Peripheral Vascular Disease
RR
Relative Risk
SD
Standard Deviation
SE
Systemic Embolism

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3.
RESPONSIBLE PARTIES
Person responsible for trial 
Data manager and analyser
 
Medical writing and claims coding
 
Data Source Provider: 
Medical Data Vision Co., Ltd. (MDV)

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Prazaxa
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
6 Jul  2017
1160.0288
Version 1.0
Not applicable
Title of study:
Comparative Effectiveness and Safety between Warfarin and 
Dabigatran Using Real World Claims data of Japanese Non-valvular 
Atrial Fibrillation Patients
Rationale and 
background:
Real-world data about the characteristics of patients with NVAF initiating 
an oral anticoagulant (OAC) in Japan has been scarce to date. The purpose 
of this study is to compare the effectiveness and safety of dabigatran and 
warfarin using the MDV database.  
Research question 
and objectives:
To compare the effectiveness (stroke/SE)  and safety (major bleeding) 
in patients with atrial fibrillation and newly treated with dabigatran 
and warfarin in the real world Japanese setting using a claims database
Study design:
A non-interventional study based on existing health insurance claims 
data
Population:
Medical Data Vision (MDV) clinical database is used.
OAC-naïve, adult patients with NVAF initiating dabigatran or warfarin 
between 14 March 2011 (considering the launch date of dabigatran) 
and 30 June 2016 will be enrolled. 
Inclusion criteria: patients aged >18 year-old with confirmed diagnosis 
of NVAF (ICD 10 code I48), having a first prescription (index date) of 
either dabigatran or warfarin between 14 March 2011 to 30 June 2016,
having no prescription of any OACs for 12 months prior to the index 
date (this period is defined as the baseline period).
Exclusion criteria: patients having less than 12 months of enrolment 
prior to the index date, being dialysis or kidney transplant recipients in 
baseline period, having either atrial flutter, valvular AF, mechanical 
valve placement, rheumatic AF, and/or mitral valve 
prolapse/regurge/stenosis in baseline period, and having record of deep 
vein thrombosis or pulmonary embolism < 6 months before AF 
diagnosis in baseline period.
Variables:
Baseline characteristics of patients (age, sex, clinical history), year of 
initiating treatment, medical history, type of OAC and its dosage, 
concomitant medications, events related to stroke, systemic embolism, 
major bleeding, TIA, and myocardial infarction.
Data sources:
MDV clinical database. The database is health insurance claims
database. As of end of February 2016, MDV provides commercial 

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Prazaxa
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
6 Jul  2017
1160.0288
Version 1.0
Not applicable
claims for in and out-patients consisting of medical records from more 
than 12.94 million patients from 230 large acute care DPC hospitals.  . 
Observation period is planned from 14 March 2010 to 30 June 2016 
considering the launch date of dabigatran.
Study size:
The previous study 1160.279 was a feasibility study to look into the 
treatment pattern of OACs in Japan and internal validity of MDV 
database including availability of co-variates to conduct 1:1 PS 
matching. For warfarin and dabigatran comparison, the number of AF 
patients meeting inclusion and exclusion criteria after matching was 
4,427 in each cohort. 
Data analysis:
This study plans no formal hypothesis testing. The planned analyses 
are descriptive in nature and results are to be interpreted in an 
exploratory manner. 
1:1 Propensity score matching (PSM) was conducted to to address 
potential channelling bias. Outcomes will be assessed in the PSM 
sample.
Patient characteristics prior to and after propensity score matching will 
be described stratified by treatment group.
Patients will be followed up from treatment initiation (index date) to 
the day of treatment discontinuation (defined as a treatment gap longer 
than 14 days past the number of days of supply of the last 
prescription), the day before a switch to a different anticoagulant, the 
date of disenrollment in MDV, the end of the study period, the 
occurrence of the event of interest, or death of the patient, whichever 
occurs first (as-treated analysis).
Number of observed events, number of patient years, the 
corresponding incidence rates and their 95% confidence intervals (CIs)
will be reported.
Dabigatran and warfarin outcomes will be compared by estimating the 
hazard ratios (HRs) for the outcomes and their CIs using Cox 
regression.
Kaplan-Meier curves for event-free survival will be estimated.
Milestones:
Start of Data Analysis: 1 July 2017
End of Data Analysis: 07 July 2017
Study Report: 18 August 2017

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
None

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6.
MILESTONES
Milestone
Planned Date
Start of data analysis
18 July 2017
End of data analysis
21 July 2017
Final report of study results:
18 Aug 2017

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7.
RATIONALE AND BACKGROUND
Until 2002 in Japan, administrative claims data were not standardized or coded electronically. 
There was limited use for Health Authorities policy decision making or in health research 
(epidemiological, HTA).  Ministry of Health, Labor and Welfare launched the Diagnosis 
Procedure Combination (DPC) system in 2002 linked with the reimbursement system. DPC is 
a Japanese version of the Diagnosis Related Groups system; such system is implemented in 
many countries including UK, US and Germany.
The DPC is a case-mix system, similar to Medicare in the US. It comprises of 18 Major 
Diagnosis Categories, 520 diagnostic groups and 2,658 case-mix groups. In the DPC 
algorithm, the diagnosis, procedure and comorbidities/complications are the 3 key variables 
for classification.
The diagnosis and comorbidities/complications are coded using the International 
Classification of Diseases (ICD) 10 scheme, while the procedures are coded using the 
Japanese Procedure Codes. Not only administrative claims data but also detailed patient data 
are collected for all the inpatients discharged from the participating hospitals.Dabigatran, first 
of the novel oral anticoagulants (OACs) to be approved and launched in Mar 2011 in Japan, 
was supported by the findings from the RE-LY study, which showed dabigatran efficacy in 
stroke reduction compared to warfarin with 150mg (relative risk (RR)=0.65, 95% CI = 0.52-
0.81) and 110mg dose group (RR=0.90, 95% CI 0.74-1.10).1 Major bleeding was also found 
to be reduced in the RE-LY study for both dose groups (110mg RR = 0.80, 95% CI 0.70-
0.93), 150mg RR = 0.93, 95% CI = 0.81-1.07) compared to warfarin.  
Several real world evidence studies have been published recently to compare effectiveness 
and safety of dabigatran, rivaroxaban and apixaban using claims database from the U.S., 
Danish and Taiwan national claims databases.2-5 In addition, several validation studies have 
been reported using DPC hospital claims database.  Yamaguchi et al assessed the positive 
predictive value (PPV) of MDV claims defined event definitions for deep vein thrombosis, 
pulmonary embolism and bleeding events against clinical diagnosis of a panel of experts who 
examined claims codes and reached a consensus.6 Although sample of events were relatively 
small (50 for each event) PPV for thromboembolic events was 75% and bleeding events was 
73.3%. Yamana et al evaluated the DPC data identified Charlson co-morbid conditions from 
4 mid-size acute care hospitals against chart review diagnosis for the validity of claims 
defined diagnosis.7 Specificity was found to be over 96%, although sensitivity was below 
50%.  PPV for cerebrovascular disease diagnosis was reported to be 86.4% with negative 
predictive value of 93.5%. Koretsune et al conducted a validation study on MDV database to 
calculate the PPV for stroke, systemic embolism (SE) and intracranial hemorrhage (ICH) 
utilizing methodology similar to that reported by Yamaguchi et al, and found the PPV of 
stroke, SE events (SEE) and ICH to be 74%, 26.7% and 85.0%.8 Second evaluation of SEE 
after changing claims definition increased the PPV to 86.7%.   
There has been no comparative effectiveness or safety analysis of dabigatran vs. warfarin has 
been published using large scale Japanese claims database thus far.  

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8.
RESEARCH QUESTION AND OBJECTIVES
The primary objective is to compare the effectiveness (incidence of stroke/SE) in Japanese patients 
with atrial fibrillation and newly treated with either dabigatran or warfarin.  
The secondary objective is to compare safety (incidence of major bleeding) in patients with atrial 
fibrillation and newly treated with dabigatran and warfarin in the real world Japanese setting using a 
claims database.
 
 

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
Study design
•
Non-interventional new user cohort study based on existing data (Medical Data Vision
(MDV) database) using propensity score matching
Treatments Considered:
•
Dabigatran and warfarin 
Strength of the study design
•
Channelling bias as well as differences in baseline risk of outcome occurrence between 
treatment groups will be adressed by the use of propensity score (PS) matching 
Outcomes
•
Primary outcome: stroke and systemic embolism 
•
Secondary outcome: major bleeding defined by any bleeding event associated with 
hospitalization claims and/or transfusion claims
•
9.2
SETTING
MDV clinical database is used.
Definition
1. Index date: the date of first oral anticoagulant prescription, namely warfarin or dabigatran
2. Baseline period: 12 months prior to and including the index date
3. Drug exposure period:  period of time from index date to the end of drug treatment 
determined by having continuous record of prescription with less than 14 days of gap in 
prescription (grace period) or by switching to another OAC (end of index treatment is
then consider to occur the day before the prescription of the new OAC)
4. Follow-up period: the day after index date to the earliest of treatment discontinuation, 
day before switch, end of continuous enrolment in the database, end of study period or 
death.  
Inclusion criteria 
1.
>18 year-old with confirmed diagnosis of non-valvular atrial fibrillation (NVAF, ICD 10 
code I48)
2.
New starters of dabigatran or warfarin

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3.
No prescription of other OACs for12 months prior to the index date, defined as the first 
prescription of OACs (the period is defined as baseline period)
4.
Has an index date between 14th of March 2011 to 30 June 2016
Exclusion criteria
1.
Having less than 12 months of enrolment prior to the index date
2.
Dialysis or kidney transplant recipients in baseline period
3.
Having atrial flutter, valvular AF, mechanical valve placement, rheumatic AF, mitral 
valve prolapse/regurge/stenosis in baseline period
4.
Having record of deep vein thrombosis or pulmonary embolism <6 months before AF 
diagnosis in baseline period
The symptoms, diseases, or treatments in these criteria are defined by ICD-10 code, disease 
name, or medical care activity name (see Table 1).
Table 1
Definition of symptoms/diseases/treatment for inclusion/exclusion 
criteria
Symptoms/diseases/treatment
Definition
ICD10 code
Disease name
Medical care activity 
name
Dialysis
-
-
Including “dialysis”
Kidney transplant
T861, Z940
-
-
Atrial flutter
-
Atrial flutter
-
Valvular AF
-
Valvular AF
-
Mechanical valve placement
T820
-
Including “mechanical 
valve placement”
Rheumatic AF
I05-I09
-
-
Mitral valve prolapse
I340
-
-
Mitral valve regurge
I341
-
-
Mitral valve stenosis
I050, I342
-
-
Deep vein thrombosis
I802
-
-
Pulmonary embolism
I269
-
-
9.3
VARIABLES
9.3.1
Exposures
Having at least one prescription of either dabigatran or warfarin defined by ATC code or 
generic name.

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9.3.2
Outcomes
9.3.2.1
Primary Outcome        
•
Outcome name: stroke and systemic embolism
•
Time frame: drug exposure period
•
Safety issue. N/A
•
Definition: definition of stroke and systemic embolism provided in Koretsune et al will 
be used for this study8 as following.

Stroke: all three following conditions must be met:
[1] Imaging (magnetic resonance imaging (MRI) or computed tomography 
(CT)) is performed after a diagnosis code of atrial fibrillation. 
[2] Diagnosis of stroke defined as I60-I64 occurs in the same month as the 
imaging
[3] Either of the following condition is met: 
A) Rehabilitation for cerebrovascular disease within 30 days from the date 
of imaging
B) Death within 30 days from the date of imaging

Systemic embolism events:
1.
Retinal vascular occlusions: three following conditions must be met:
[1] Ophthalmic examination is performed after the date of definitive diagnosis 
of atrial fibrillation or cardioembolic stroke (including the day of the 
diagnosis).
The second or later ophthalmic examination during the same hospitalization 
is excluded.
[2] Diagnosis of retinal vascular occlusion in the month of the date of 
ophthalmic examination.
[3] The following A) and B) are satisfied:
A) Prescription of anticoagulant/antiplatelet agents on the day of 
ophthalmic examination or the next day
B) Non-prescription of anticoagulant/antiplatelet agents within 30 days 
from the date of ophthalmic examination.
2.
Other than retinal vascular occlusions: four following conditions must be met:
[1] Imaging: MRI, CT, roentgenography (using a contrast medium) or vascular 
echo is performed after the date of definitive diagnosis of atrial fibrillation 
or cardioembolic stroke (including the day of the diagnosis).
[2] Systemic embolism (including the name of injury/disease at the time of 
admission) is diagnosed and recorded as the name of the disease during 
hospitalization in the month of the date of imaging.
[3] The date of imaging or the next day: Treatment
Either of the following conditions is satisfied:
A) Treatment with heparin at >5,000 units or thrombectomy on the day of 
imaging or the next day
B) Death within 30 days from the date of imaging 

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[4] Fees for emergency medicine administration or specific intensive care 
management on the day of imaging are calculated.

Intracranial bleeding: all four following conditions must be met:
Condition [1] is applied to the events occurred during the hospitalization after the 
day of definitive diagnosis of atrial fibrillation and is not applied to those during re-
hospitalization.
[1] Medical history (only atrial fibrillation)
The following injury/disease name in ICD 10 does not occur in the month 
prior to the month of the date of definitive diagnosis:
-
Cerebrovascular disease excluding sequelae of subarachnoid 
hemorrhage, sequelae of intracerebral hemorrhage, sequelae of stroke 
not specified as hemorrhage or infarction 
-
Intracranial injury
[2] Imaging (MRI or CT) is performed after the month of the date of definitive
diagnosis of atrial fibrillation or cardioembolic stroke (including the day of 
the diagnosis). 
The second or later imaging during the same hospitalization is excluded.
[3] Disease name
The following disease occurs in the same month as the day of imaging:
-
Cerebrovascular diseases excluding sequelae of subarachnoid 
hemorrhage, sequelae of intracerebral hemorrhage, sequelae of stroke 
not specified as hemorrhage or infarction
-
Intracranial injury
[4] Rehabilitation of stroke
Either of the following conditions is satisfied:
-
Rehabilitation for stroke within 30 days from the date of imaging
-
Death within 30 days from the date of imaging
See below tables for definition of imaging (Table 2) and other symptoms/diseases/treatment
(Table 3).
Table 2
Definition of imaging for primary outcome
Receipt code
Definition
170011810
CT imaging (multi-detector computed tomography)
170020110
MRI imaging (equipment with 1.5+ tesla)
170033410
CT imaging (multi-detector computed tomography)
170033510
MRI imaging (equipment with 3+ tesla)
170000810
Roentgenography (with contrast agent) 
160147110, 160147210
160150050, 160161710
Vascular echo

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Table 3
Definition of symptoms/diseases/treatment for primary outcome
Symptoms/diseases/treatment
Definition
ICD10 code
Receipt code
ATC code
Atrial fibrillation
I48
Stroke
I61-64
Rehabilitation
180027410, 180027510
180027610, 180027710
180030810, 180032410
180032510, 180032610
180033910, 180034010
180034110, 180034210
180034310, 180034410
180043430, 180043530
180043630, 180043730
180043830, 180044310
Cerebrovascular disease
I60-I69
Ophthalmic examination
160081010, 160081130, 
160081450, 160081550, 
160183310, 160199310, 
160199310, 160199410
Cardioembolic stroke
I634
Retinal vascular occlusion
H34
Anticoagulant/antiplatelet 
agents
B01
Systemic embolism
I74
Heparin
B01B
Thrombectomy
I74, I80-I82

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Table 3 (cont'd)
Emergency medicine 
administration/ specific 
intensive care management
113002610, 113010710
113013810, 115003010
160000210, 190100070
190116310, 190116410
190137810, 190138110
190138210, 190138310
190138410, 190138510
190138610, 190138710
190138810, 190138910
190139010, 190139110
190139210, 190139310
190139810, 190139910
190171910, 190172010
190174410, 190174510
190174610, 190174710
190174810
Sequelae of Subarachnoid 
hemorrhage
I690
Sequelae of intracerebral 
hemorrhage
I691
Sequelae of stroke not 
specified as hemorrhage or 
infarction
I694
Intracranial injury
S06
9.3.2.2
Secondary Outcome
•
Outcome name: Major bleeding
•
Time frame: drug exposure period
•
Safety issue. N/A
•
Definition: major bleeding is defined as any bleeding associated with hospitalization 
and/or blood transfusion (defined as MDV procedure code K920 ) claims. Bleeding will 
include the following diagnostic names with ICD 10 codes in the parenthesis, and the list 
is inclusive, not exclusive;

Subarachnoid hemorrhage (I60)

Intracerebral hemorrhage (I61)

Digestive tract hemorrhage (K922, K290)

Hemorrhage, not elsewhere (R58)

Intraocular Hemorrhage (H113, H313, H356, H431)

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
Hematuria (R31, N028, N029)

Excessive Menstruation, Hemorrhage from Uterus (N93)

Hemathrosis (M250)

Hemopericardium (I312)

Hemoptysis, bleeding from airway (R04)

Hematemesis (K920)

Epistaxis (R040)

Acute post-hemorrhagic anemia (D62)
9.3.3
Covariates
Logistic regression model was used to estimate propensity scores based on all covariates 
listed below:

Age

Gender 

Speciality of prescribers of OAC

Time from AF diagnosis to initiation of OAC

History of stroke or transient ischemic attack yes/no

History of myocardial infarction yes/no

History of coronary artery disease yes/no

History of heart failure yes/no

History of diabetes mellitus yes/no

History of dyslipidemia yes/no

History of arterial hypertension yes/no

History of peripheral artery disease yes/no

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
History of peptic ulcer disease yes/no

History of dementia yes/no

History of malignant lymphoma yes/no

History of leukemia yes/no

History of solid tumor cancer yes/no

History of kidney impairment yes/no

History of liver disease yes/no

History of valvular disease yes/no

History of bleeding (gastro-intestinal, etc.) yes/no

History of hospitalization yes/no

CHA2DS2-VASc

HAS-BLED Score

Year of Initiating Treatment 
Index date falling within 12 months starting from 14th of March in 2011 and then 
from 1st of March of each respective year in 2012 to 2016, then to 30 June 2016.  

Concomitant medication (prescription claims within the baseline period)
yes/no for the following:

aspirin

ticlodipine

cilostazole

clopidogrel

angiotensin receptor blockers or angiotensin converting enzyme inhibitors

beta-blocker

amiodarone

procainamide

disopyramide

flecainamide

pilcicainide

procainamide

calcium-channel blocker

digoxin

diuretics

statins

proton-pump inhibitor

H2 receptor antagonist
The disease, condition/disease for AF risk score calculation, AF risk score, and concomitant 
medication are defined as Table 4,Table 5 , Table 6, Table 7, Table 8.

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Table 4
Definition of clinical history
Disease
Definition
ICD10code
prescription
Stroke or transient ischemic 
attack
I60-I64, G45
-
Myocardial infarction
I21-I23
-
Coronary artery disease
I251
-
Heart failure
I110, I130, I132, I420, 
I50
Prescribed furosemide (defined by 
generic name)
Diabetes mellitus
E100, E101, E109, 
E110, E111, E119, E14
Prescribed drugs used in diabetes 
(defined by ATC code as A10)
Dyslipidemia
E78
-
Arterial hypertension
I10-I15
Prescribed 2 or more types of anti-
hypertensive (defined in Table 2b)
Peripheral artery disease
I702-I709, I71, I739
-
Peptic ulcer disease
K22, K25-K28
-
Dementia
F00-F03, G30
-
Malignant lymphoma
C81-C88
-
Leukemia
C90-C96
-
Solid tumor cancer
C00-C80, C97
-
Kidney impairment
N28
-
Liver disease
K70-K77
-
Valvular disease
I059, I089, I358, I38, 
I48
-
Bleeding (gastro-intestinal, 
etc.)
K25-K29, K922
-

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Table 5
Definition of anti-hypertensive
Class/type
ATC code
Calcium channel blockers (CCB)
C08A0
Angiotensin receptor blockers (ARB)
C09C0
Angiotensin converting enzyme inhibitors (ACE)
C09A0
Diuretics
C03A1, C03A2, C03A3, C03A7, C03A9
Thiazide diuretic
C03A3 (Thiazide, plane), C02D0 
(Rauvolfia alkaloids)
Beta blocker
C07A0
Alpha-adrenoreceptor antagonists
C02A2
Potassium-sparing agents
C03A1
Others
C02A1 (Antihypertensives),  C02A3
(Antihypertensives for pulmonary 
arterial hypertension), C09X0 (Other 
agents acting on the renin-angiotensin 
system)
Combination agents
C09D1 (ARB and diuretics), C09D3 
(ARB and CCB)

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Table 6
Definition of condition/disease for AF risk score calculation
Condition/disease
Definition 
ICD10code
prescription
Congestive heart failure or left ventricular 
dysfunction
I110, I130, I132, 
I420, I50
Prescribed furosemide 
(defined by generic name)
Stroke (ischemic stroke, transient ischemic 
disease, or systemic embolism)
I63, I64, G45, I74
Vascular disease (myocardial
infarction, 
peripheral arterial disease, or aortic plaque)
I21-I23, I702-I709, 
I71, I739, I700
Abnormal renal function
I12, I13, N00-N05, 
N07, N11, N14, 
N17-N19, Q61
Abnormal hepatic function
B150, B160, B162, 
B190, K704, K72, 
K766, I85
Stroke (ischemic stroke or transient ischemic 
attack)
I63, I64, G45
Bleeding
I60, I61, I62, D62, 
J942, H113, H356, 
H431, N02, N95, 
R04, R31, R58, 
K250, K260, K270, 
K280, K290, S063, 
S064, S065, S066
Drugs (aspirin, clopidogrel, or non-steroidal 
anti-inflammatory drugs)
Aspirin and clopidogrel: 
defined by general name 
Non-steroidal anti-
inflammatory drugs
defined by ATC code 
(EPHMRA) as M01A
Alcohol intake
F10, G312, G621, 
G721, I426, K292, 
K70, K860, L278, 
O354, T51, Z714, 
Z721

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Table 7
AF risk score calculation
Risk score
Disease/condition
Points if present
CHADS2 (9)
Congestive heart failure or left ventricular dysfunction
1
Hypertension
1
Age ≥75 years
1
Diabetes mellitus
1
Stroke (ischemic stroke, transient ischemic disease, or 
systemic embolism)
2
CHA2DS2VASc 
(10)
Congestive heart failure or left ventricular dysfunction
1
Hypertension
1
Age ≥65 years
1
Age ≥75 years
1
Diabetes mellitus
1
Stroke (ischemic stroke, transient ischemic disease, or 
systemic embolism)
2
Vascular disease (myocardial infarction, peripheral 
arterial disease, or aortic plaque)
1
Female
1
HAS-BLED (10)
Hypertension
1
Abnormal renal function
1
Abnormal hepatic function
1
Stroke (ischemic stroke or transient ischemic attack)
1
Bleeding
1
Labile international normalized ratio*
1
Elderly Age (≥65 years)
1
Drugs (aspirin, clopidogrel, or non-steroidal anti-
inflammatory drugs)
1
Alcohol intake
1
*Not included due to unavailable information

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Table 8
Definition of concomitant medication
Drug
Definition
ATC code
Generic name
Aspirin
-
Aspirin, aspirin dihydroxyaluminum 
aminoacetate magnesium carbonate
Ticlodipine
-
Ticlopidine hydrochloride
Cilostazole
-
Cilostazole
Clopidogrel
-
Clopidogrel sulfate
ARB or ACE
C09A0, C09C0, C09D1
-
Beta blocker
C07A0
-
Amiodarone
-
Amiodarone hydrochloride
Procainamide
-
Procainamide hydrochloride
Disopyramide
-
Disopyramide, disopyramide phosphate
Flecainide
-
Flecainide hydrochloride
Pilsicainide
-
Pilsicainide hydrochloride
CCB
C08A0
-
Digoxin
-
Digoxin, metildigoxin
Diuretics
C03A1, C03A2, C03A3, 
C03A7, C03A9
-
Statins
C10A1
-
Proton pump inhibitor
A02B2
-
H2 receptor antagonist
A02B1
-
9.4
DATA SOURCES
MDV clinical database is health insurance claim database. As of end of February 2016, MDV 
has accumulated commercial claims database for both in and outpatients consisting of 
medical administrative claims records from more than 12.94 million patients from 230 large 
acute care DPC hospitals.  Lab results are also available but number of hospitals providing 
with lab test results are limited.
Study period is from 14 Mar 2010 to 30 June 2016 in MDV database at the time of study 
protocol approval.
The MDV database is broadly representative of the Japanese population with similar 
distribution compared to the Japanese general population  There is research experience using 
the data, 19 publications, 5 conference presentations (as of Aug 2015).

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9.5
STUDY SIZE
This study plans no formal hypothesis testing. The planned analyses are descriptive in nature 
and results of statistical tests are to be interpreted in an exploratory manner. For each 
treatment group, the available sample size is determined by feasibility assessments of the 
previous study 1160.279 according to the pre-specified time window and inclusion/exclusion 
criteria, and not by formal sample size justifications. Therefore, the purpose of the power 
assessments described in this section is to illustrate the precision of the effect estimates that 
can be achieved given the feasible sample size.
The expected sample size of dabigatran new starters meeting inclusion/exclusion criteria after 
matching has been estimated to be 4,427 from the previous study 1160.279.  This expected 
sample size is considered to have sufficient precision, defined as having less than 10% 
chance of the upper bound of 95% confidence interval of hazard ratio (HR) exceeding 1.378, 
which was an FDA recommended non-inferioity margin for effectiveness at the planning 
stage of RE-LY study.  
Hori et al reported that the incidence of stroke and systemic embolism in the Asian subgroup 
of RELY study was 3.06%/year (53 events/926 patient year).11  In the feasibility study 
(CTMS 1160.279), the percentage of patients receiving high dose of dabigatran or 300 mg 
per day was 21% and the rest or 79% was receiving equal to or less than 220mg per day.  
According to the Asian subgroup reported by Hori, the observed hazard ratio of warfarin to 
dabigatran for the endpoint of stroke and systemic embolism was 0.45 and 0.81 for 300mg 
and 220mg daily dose group respectively.  The combined assumed hazard ratio for MDV 
database will therefore be Exp (log(0.45) x 0.21 + log(0.81) x 0.79 )or 0.716.
Table 9
Sample size calculation
follow-up(y)
N per group
Event Rate
(/y)
NI Margin
Power
(non-inferioirty)
0.40487
4421
0.025
1.378
0.987
0.40487
4421
0.025
1.378
0.944
0.40487
4421
0.025
1.378
0.846
0.40487
4421
0.025
1.378
0.692
0.40487
4421
0.025
1.378
0.507
0.40487
4421
0.03
1.378
0.996
0.40487
4421
0.03
1.378
0.974
0.40487
4421
0.03
1.378
0.905
0.40487
4421
0.03
1.378
0.770
0.40487
4421
0.03
1.378
0.583
0.40487
4421
0.035
1.378
0.999
0.40487
4421
0.035
1.378
0.988
0.40487
4421
0.035
1.378
0.943
0.40487
4421
0.035
1.378
0.832
0.40487
4421
0.035
1.378
0.650
Assuming stroke/SE event rate of 0.03/PY and HR of 0.716, the probability of the upper 
bound of 95% CI exceeding 1.378 is considered to be less than 10%.  Lower event rate or
narrower margin will reduce power.  

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9.6
DATA MANAGEMENT
Data are provided as electrical data formatted csv by MDV and stored and managed in 
Milliman Inc.
SAS and Microsoft Excel are used for statistics.
9.7
DATA ANALYSIS
9.7.1
Main analysis
Propensity Score Matching 
To reduce channelling bias, dabigatran and warfarin study groups will be established using 
PS matching method, on a 1:1 fixed ratio.  The nearest neighbour method of propensity score 
matching within a caliper of 0.10 of the standard deviation of the estimated logit will be used 
to select the matched samples.  All pre-defined variables has been evaluated in CTMS 
1160.279 for inclusion into the model.  Covariates with less than 10 patients present in the 
data was eliminated as well as CHADs which showed high co-linearity with CHADsVASc 
which was eliminated from the model.  Otherwise, all pre-defined variables will be used.    
For further detail of the methodology of PS matching, please see the study protocol CTMS 
1160.279.  
For the primary outcome
Incidence rates of each treatment cohort (warfarin and dabigatran) will be provided, and all 
analysis will be conducted on the PS matched sample.    The hazard ratio (HR) of 
stroke/systemic embolism for the dabigatran cohort as compared to the warfarin cohort and 
its 95% confidence interval (CI) will be estimated from the PS matched cohort using a Cox 
regression model with treatment group as the dependent variable. No additional covariates 
are considered in the Cox model as no residual imbalance was identified after PS matching 
(1160.276 study report, c15432368)” There will be no formal hypothesis testing.  Kaplan 
Meier analysis with the number of patients at risk during the follow-up period after the index 
date and the number of events for ischemic stroke and major bleeding will be provided.  
For the secondary outcome
Same analysis method will be utilized to calculate HR for the outcome of major bleeding.   
  
9.8
QUALITY CONTROL
Milliman will conduct a quality check as below:
Calculation check: both of program codes for calculation and the data codes used the 
calculation will be checked by different person from that who calculated. 

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Pre-release peer review: comprehensive check on methodology, calculation process, and 
consistency of results will be performed by a qualified peer-reviewer.
Post-release peer review: comprehensive check on the project will be conducted by qualified 
peer-reviewer belonging to another office.
9.9
LIMITATIONS OF THE RESEARCH METHODS
•
•
Unobservable factors or factors not captured in the database such as laboratory data not 
equally distributed in the treatment groups that may also influence the outcomes could 
lead to unobserved confounding.
•
The anticipated sample size might be limited which might lead to imprecise results. 
Therefore the study can only be considered to be exploratory. Based on the expected 
small sample size there is also the risk of pure chance findings. No hypothesis testing is 
planned,
•
All information of each patient is from consent giving DPC hospitals. If patients have 
visits to other non-DPC medical institutions, these data are not included in the MDV 
data.
9.10
OTHER ASPECTS
None
9.11
SUBJECTS
The source population is Japanese patients who have claims data in MDV commercial 
database.  In order to have claims in the database, the patients must have received some 
medical intervention, out or in-patient hospital visit, or pharmacy prescription from the DPC 
hospitals in Japan.  DPC hospitals are large hospitals, often associated with medical schools 
or government funding, providing both acute and chronic medical care in Japan. Compared to 
non-DPC hospitals, they tend to provide more specialized, intensive medical care in addition 
to outpatient primary care tending to chronic disease requiring non-urgent care.  MDV 
database has contractual agreement to receive claims data from approximately 12% of all 
DPC hospitals in Japan, and the selection is based on the willingness on the side of DPC 
hospitals to receive either financial compensation or data services from MDV.  The inclusion
and exclusion criteria are intended to select those Japanese atrial fibrillation patients who 
have non-valvular etiology and have newly initiated oral anti-coagulants for stroke 
prevention.  The data cut-off of 14 Mar 2011 to 30 June 2016 is to select those claims that 
have occurred after the launch of dabigatran and to the most recent available data cut from 
MDV at the time of protocol writing.  
9.11.1
Cases
Not Applicable
9.11.2
Controls
Not Applicable

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9.12
BIAS
Unobservable factors or factors not captured in the database such as laboratory data not 
equally distributed in the treatment groups that may also influence the outcomes could lead to 
unobserved confounding..  In order to minimize bias, this study will include only new users 
(treatment-naïve initiators) of warfarin and dabigatran and use propensity score matching.
10.
PROTECTION OF HUMAN SUBJECTS
As this is a study based on databases using anonymous and personally unidentifiable data; 
therefore protection of human subjects is not applicable for this study.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
The outcomes of the study are the baseline characteristics (pre-treatment) and medication 
prescriptions..  This is a non-interventional study based on existing data, in which all patient 
data will be de-identified and analyzed in aggregate. Individual patient safety related 
information will not be captured during this study. Thus, individual safety reporting is not 
applicable for this study.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
A manuscript describing this work will be submitted for publication in a peer-reviewed 
journal.  
Target of final study report (publication submission): Sep 2017

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
Reference: 
1. Connoly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. NEJM 
2009; 361: 1139-51 
2. Graham DJ, et al. Stroke, bleeding and mortality risks in elderly medicare beneficiaries 
treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern 
Med 2016; 176: 1662-1671
3. Larsen TB, et al. Comparative effectiveness and safety of non-vitamin K antagonist oral 
anticoagulants and warfarin in patients with atrial fibrillation; propensity weighted 
nationwide cohort study. BMJ 2016;353: i3189
4. Gorst-Rasmussen A, et al. Rivaroxaban versus warfarin and dabigatran in atrial 
fibrillation; comparative effectiveness and safety in Danish routine care. 
Pharmacoepidemiology and Drug Safety 2016; 25: 1236-1244
5. ChanYH, et al. Thromboembolic, Bleeding, and mrtality risks of rivaroxaban and 
dabigatran in Asians with nonvalvular atrial fibrillation. J Am Coll Cardiol 2016; 68: 
1389-1401
6. Yamaguchi T, et al. The epidemiological study of venous thromboembolism and bleeding 
events using a Japanese healthcare database –validation study-.  Jpn J Drug Inform 2015; 
17: 87-93
7. Yamana H, et al. Validity of diagnoses, procedures, and laboratory data in Japanese 
administrative data. J Epidemiol 2017; pii: S0917-5040(17)30003-5.
8. Koretsune Y, et al. Usefulness of a healthcare database for epidemiological research in 
atrial fibrillation,  J Cardiol 2016; pii: S0914-5087(16)30289-1.
9. Shannon W, et al. Validation of clinical classification schemes for predicting stroke: 
results from the National Registry of Atrial Fibrillation. JAMA. 2001; 285(22): 2864-70.
10. Larsen TB, et al. Comparative effectiveness and safety of non-vitamin K antagonist oral 
anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted 
nationwide cohort study. BMJ. 2016; 353: i3189.
11. Hori M, et al. Efficacy and safety of dabigatran vs. warfarin in patients with atrial 
fibrillation-sub-analysis in Japanese population in RE-LY trial. Circ J 2011; 75: 800-805
13.2
UNPUBLISHED REFERENCES

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
None

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ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS
None

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ANNEX 3. ADDITIONAL INFORMATION
None

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17002710
1.0
non-interventional-study-protocol-1160-0288
Comparative Effectiveness and Safety between Warfarin and Dabigatran Using Real
World Claims Data of Japanese Non-valvular Atrial Fibrillation Patients
Approval-
 Medical Affairs
11 Jul 2017 10:54 CEST
Approval-
 Medicine
11 Jul 2017 12:24 CEST
Author-Trial Clinical Monitor
13 Jul 2017 03:49 CEST

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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17002710
1.0