Medical Need of Oral Anti-coagulant Reversal in Japan: Epidemiological Assessment of Head Trauma, Fracture, and Emergency Surgery Using Large Scale Claims Database (Please Note That This Study Contains no Patients Treated With Idarucizumab Although the Study Number Begins With 1321; the Study Contains Only Patients Treated With OACs, Namely Warfarin, Dabigatran, Edoxaban, Apixaban, Rivaroxaban, Edoxaban)
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:
c18071759-01
BI Study Number:
1321-0022
BI Investigational
Product(s):
Prazaxa (Dabigatran etexilate)
Title:
Medical Need of Non-vitamin K Oral Anti-coagulant Reversal in 
Japan: Epidemiological Assessment of Emergency Surgery,
Major Bleeding due to Trauma and Fracture, using Large Scale 
Claims Database
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, warfarin, apixaban, rivaroxaban, edoxaban 
Medicinal product:
Dabigatran, warfarin, apixaban, rivaroxaban, edoxaban 
Product reference:
Not applicable
Procedure number:
Not Applicable
Joint PASS:
No
Research question and 
objectives:
The primary objective of this study is to assess, for adult patients 
initiating an oral anticoagulant for non-valvular atrial fibrillation, 
the incidence rates of emergency surgery, major bleeding due to 
fracture, and major bleeding due to trauma, overlall and stratified 
by age (<64, 65-74, >75).  The secondary objective of the study
is to assess the incidence rates of cardiac tamponade or
pericardiocentesis, overall and stratified by age (<64, 65-74, 
>75).  .
 
Country(-ies) of study:
Japan

Boehringer Ingelheim
Page 2 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Author:
Marketing authorisation 
holder(s):
MAH contact person:
In case of PASS, add:
<EU-QPPV:>
Not Applicable
In case of PASS, add:
<Signature of EU-
QPPV:>
Not Applicable
Date:
18 July 2017
Page 1 of 29
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

Boehringer Ingelheim
Page 3 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
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..................................................................... 10
6.
MILESTONES..................................................................................................... 11
7.
RATIONALE AND BACKGROUND................................................................ 12
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 13
9.
RESEARCH METHODS .................................................................................... 14
9.1
STUDY DESIGN............................................................................................ 14
9.2
SETTING........................................................................................................ 14
9.3
VARIABLES .................................................................................................. 15
9.3.1
Exposures ................................................................................................ 15
9.3.2
Outcomes................................................................................................. 15
9.3.2.1
Primary outcomes..................................................................................15
9.3.2.2
Secondary outcomes..............................................................................15
16
9.3.3
Covariates................................................................................................ 16
9.4
DATA SOURCES........................................................................................... 19
9.5
STUDY SIZE.................................................................................................. 19
9.6
DATA MANAGEMENT................................................................................ 20
9.7
DATA ANALYSIS......................................................................................... 20
9.7.1
Main analysis........................................................................................... 20
20
9.8
QUALITY CONTROL................................................................................... 20
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 21
9.10
OTHER ASPECTS ......................................................................................... 21
9.11
SUBJECTS...................................................................................................... 21
9.11.1
Cases........................................................................................................ 21
9.11.2
Controls................................................................................................... 22
9.12
BIAS................................................................................................................ 22
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 23

Boehringer Ingelheim
Page 4 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 24
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 25
13.
REFERENCES .................................................................................................... 26
13.1
PUBLISHED REFERENCES......................................................................... 26
13.2
UNPUBLISHED REFERENCES................................................................... 26
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 27
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 28
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 29

Boehringer Ingelheim
Page 5 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
2.
LIST OF ABBREVIATIONS
ACE
Angiotensin Converting Enzyme inhibitors
AF
Atrial Fibrillation
ARB
Angiotensin Receptor Blockers
ATC
Anatomical Therapeutic Chemical
CCB
Calcium-Channel Blocker
DPC
Diagnosis Procedure Combination
ICD
International Classification of Diseases
MDV
Medical Data Vision
NOAC
Non-warfarin Oral Anti Coagulants
NVAF
Non-Valvular Atrial Fibrillation
OAC
Oral Anticoagulants

Boehringer Ingelheim
Page 6 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
3.
RESPONSIBLE PARTIES
Person responsible for trial 
, 
Biostatistics
Data 
 and analyser
Milliman Inc.  
 
Medical writing and claims coding
Milliman Inc.  
Data Source Provider: 
Medical Data Vision Co., Ltd. (MDV)

Boehringer Ingelheim
Page 7 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
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:
18 July 2017
1321-0022
1.0
Not applicable
Title of study:
Medical Need of Non-vitamin K Oral Anti-coagulant Reversal in 
Japan: Epidemiological Assessment of Emergency Surgery, Major 
Bleeding due to Trauma and Fracture, using Large Scale Claims 
Database
Rationale and 
background:
There has been no epidemiological assessment to investigate the medical need 
of reversal in patients undergoing emergency surgery or major bleeding from 
trauma or fracture receiving oral anticoagulant in Japan.  The objective of this 
study is to assess the incidence of emergency surgery and major bleeding 
associated with fracture and head trauma in Japanese patients prescribed with 
oral anti-coagulants such as warfarin, dabigatran, apixaban, rivaroxaban and 
edoxaban
Research question 
and objectives:
The primary objective is to assess, for adult patients initiating an oral 
anticoagulant for non-valvular atrial fibrillation (NVAF), the
incidence rates of emergency surgery, major bleeding due to trauma, 
and major bleeding due to fracture, overall and stratified by age (<64, 
65-74, >75).  The secondary objective is to estimate the overall and 
age stratified incidence of cardiac tamponade and pericardiocentesis.  
.    
Study design:
Non-interventional study based on existing health insurance claims 
data
Population:
Medical Data Vision (MDV) clinical database is used
Oral anticoagulants (OAC) naïve, adult patients with NVAF initiating 
dabigatran, warfarin, apixaban, rivaroxaban or edoxaban between 
March 1, 2011 and June 30, 2016
Inclusion criteria: patients aged >18 year-old with confirmed diagnosis 
of NVAF (International Classification of Diseases (ICD) 10 I48), 
having a first prescription (index date) of any one of OACs 
(dabigatran, warfarin, rivaroxaban, apixaban or edoxaban) having no 
prescription of OACs for 6 months prior to the index date (this period 
is defined as the baseline period).
Exclusion criteria: patients having less than 6 months of enrolment 
prior to the index date, being dialysis or kidney transplant recipients in 
baseline period, having either atrial flutter, valvular atrial fibrillation
(AF), mechanical valve placement, rheumatic AF, and/or mitral valve 
prolapse/regurge/stenosis in baseline period, and having record of deep 

Boehringer Ingelheim
Page 8 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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:
18 July 2017
1321-0022
1.0
Not applicable
vein thrombosis or pulmonary embolism < 6months before AF 
diagnosis in baseline period.  
Variables:
Outcomes of interest are emergency surgeries, major bleeding due to 
fracture, major bleeding due to trauma, cardiac tamponade and 
pericardial effusion.  Co-variates are baseline characteristics of patients 
(age, sex, clinical history), medical history, type of OAC, concomitant 
medications, events related to bleeding, trauma and fracture
Data sources:
MDV clinical database.  The database is health insurance claims 
database.  As of end of February 2016, MDV has accumulated claims 
records from 12.94 million patients, both in and out-patients, from 
more than 230 large acute, sub-acute and outpatient care DPC 
hospitals.  
Study size:
The previous study 1160.279 has identified the patients with confirmed 
6 months of baseline period and no OAC treatment (defining 
“treatment naïve” new starter population). The total of these patients 
was 62,888.  The breakdown by OAC initiated was 7,441 for 
dabigatran, 23,412 for warfarin, 16,026 for apixaban, 12,779 for 
rivaroxaban and 3,230 for edoxaban. The mean on-treatment follow-up 
duration for all OACs new starters combined in patients with one year 
of baseline period was calculated as 121 days.  The mean on-treatment 
follow-up duration for all OACs new starters combined with 6 months 
of baseline period is unknown.  
Data analysis:
Baseline characteristics of patients overall and stratified by age will be 
provided in a tabulated format.
The main analysis will be on OAC-naïve initiators and will consider 
outcomes until the complete discontinuation of any OAC (i.e. 
including the periods during which patients switched from an OAC to 
another OAC in less than 14 days)     
 
 
  
For the primary objective

Boehringer Ingelheim
Page 9 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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:
18 July 2017
1321-0022
1.0
Not applicable
Incidence rate (overall and age stratified) of emergency surgery, and
major bleeding due to fracture, and major bleeding due to trauma will 
be described with number of patients presenting the event, patient-
years and 95% confidence interval overall and stratified by age.  
For the secondary objective
1.
Incidence rates (overall and age stratified) of cardiac tamponade 
or peri-cardiocentesis, along with number of events, patient year of 
follow-up and 95% confidence interval.  
 
Milestones:
Start of Data Analysis: 1 Aug 2017
End of Data Analysis: 19 Sep 2017
Study Report: 30 Nov 2017

Boehringer Ingelheim
Page 10 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
None

Boehringer Ingelheim
Page 11 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
6.
MILESTONES
Milestone
Planned Date
Start of data collection
1 Aug 2017
End of epidemiology analysis
19 Sep 2017
Final report of study results:
30 Nov 2017

Boehringer Ingelheim
Page 12 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
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.
MDV provides commercial claims database consisting of medical records from more than 
12.94 million in and out-patients (>80% outpatient claims) from 230 large DPC hospitals as 
of February 2016. 
Dabigatran was the first of the non-warfarin oral anti coagulants (NOACs) to be approved 
and launched in March 2011 in Japan, then three additional NOACs have been launched for 
an indication of stroke prevention in patients with non-valvular atrial fibrillation (NVAF).  
Idarucizumab, a specific reversal agent of dabigatran’s coagulation effect, has been launched 
in November of 2016, and is indicated in dabigatran treated patients who undergo emergency 
operation or experience life threatening bleeding. 
 
 
Buchelle et al analysed the German claims database system to calculate the incidence of 
traumatic brain injury in 65 years or older population, and concluded that 4.8 hospital 
admissions in 1000 patient year of follow-up, and was found to be higher in nursing home 
resident with higher morbidity and mortality [1]. Curtis et al reported that fracture annual 
incidence was 155.3 per 10,000 patient-year in men aged 18-24.  For age above 90, the 
incidence was 224.8 per 10,000 patient-year[2].
There has been no epidemiological assessment to investigate the medical need of reversal in 
patients undergoing emergency surgery or major bleeding from trauma or fracture receiving 
NOACs in Japan.  The objective of this study is to assess the incidence of emergency surgery 
and major bleeding associated with fracture and head trauma in Japanese patients prescribed 
with oral anti-coagulants such as warfarin, dabigatran, apixaban, rivaroxaban and edoxaban.

Boehringer Ingelheim
Page 13 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
8.
RESEARCH QUESTION AND OBJECTIVES
The primary objective of this study is to assess the incidence rate (overall and age stratified)
of emergency surgery and major bleeding associated with fracture and trauma among patients 
to characterize the incidence of relatively homogeneous population who undergo oral 
anticoagulants (OAC) therapy.  
The secondary objective is to estimate the incidence rate (overall and age stratified) of 
cardiac tamponade or pericardiocentesis occurring during or within one day after conducting 
a PCI or cardiac ablation procedure.   

Boehringer Ingelheim
Page 14 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.
RESEARCH METHODS
9.1
STUDY DESIGN
Study design
•
Non-interventional study based on existing health insurance claims data
Treatments Considered: 
•
Dabigatran, rivaroxaban, apixaban, edoxaban, and warfarin
Strength of the study design
•
Up-to-date epidemiological information can be obtained using large-scale real-world 
database.
9.2
SETTING
MDV clinical database is used.
Inclusion criteria 
1. >18 year old non-valvular atrial fibrillation (NVAF) patients
2. Prescribed dabigatran, rivaroxaban, apixaban, edoxaban or warfarin 
3.
Patients with confirmed date of initiation of OACs
4. Patients with a minimum of 6 months of enrolment data prior to index date
5. Has an index date between 14th of March 2011 to 30 June, 2016
Exclusion criteria
1. Patients receiving two or more oral anti-coagulants at the same time at index date
2. Patients with prescriptions of index treatment in the 6 months prior to index date
3. Patients without enrolment period of at least six month in the database
Definition of terminology
1.
Index date: the date of first oral anticoagulant prescription, namely dabigatran, apixaban, 
rivaroxaban, edoxaban and warfarin
2.
Follow-up period: the day after index date to the earliest of treatment discontinuation, , 
end of continuous enrolment in the database, end of study period, first occurrence of the 
event of interest, or death. 
3.
Any OAC treatment discontinuation: treatment gap of any one of OACs for more than 14 
days including the time after switch from one OAC to another OAC (primary analysis)
 
 

Boehringer Ingelheim
Page 15 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.3
VARIABLES
9.3.1
Exposures
Patients prescribed with NOACS (dabigatran, rivaroxaban, apixaban, edoxaban) or warfarin 
will be grouped as a single exposure group and analysed as a whole.  
On treatment duration will be expressed in patient year for the follow-up duration to calculate 
the incidence of various clinical events during the on-treatment duration.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
•
Outcome name: A combined endpoint of three outcomes; 1) emergency surgery, (2)
major bleeding due to fracture (3) major bleeding due to trauma
•
Definition: each events will be defined as following:
(1) Emergency Surgery defined as any surgical procedure(International Classification of 
Diseases (ICD) 10 code K000-879) performed on the same day as hospital admission 
with additional claims associated with urgent fee MDV codes (114701370, 
160000210, 180709110)
(2) Major bleeding due to fracture 
Any bleeding associated with hospitalization or blood transfusion (ICD10 code 
E83.111) accompanied by any fracture (M484, M80, S021, S12, S22, S32, S42, S52, 
S62, S72, S82, S92, T02, T08, T10, T12, T142) listed as the primary diagnosis 
requiring most medical resource
       (3). Major Bleeding due to trauma
Any bleeding associated with hospitalization or blood transfusion (ICD10 code 
E83.111) accompanied by any trauma (S00-S09, I620, M125, M164, M165, M172, 
M173, M191, M483, M872, S065, S066, S081, S089, S130, S18, S230, S480, S481, S532, 
S533, S580, S581, S589, S633, S634, S680, S681, S684, S688, S689, S780, S789, S889, 
S980, S981, S982, T050, T053, T058, T059, T116, T136, T147, T794, T795, T796, T797, 
S271, S272, S330, S334, S382, S480, S481, S532, S580, S581, S589, S633, S634, S680, 
S681) listed as the primary diagnosis requiring most medical resource
9.3.2.2
Secondary outcomes
Outcome name:  cardiac tamponade and pericardiocentisis
Event Definition: 
(1). Cardiac tamponade diagnosis (ICD 10 code 4200001) on the same or next day as catheter 
ablation or PCI (MDV procedure codes 150153910, 150267810, 150263310, 150284310, 
150303310, 150345710, 150374910, 150375010, 150375210, 150375310, 150375410)  
(2). Pericardiocentisis (MDV procedure code 140010510) on the same or next day as catheter 
ablation or PCI (MDV procedure codes as above) 

Boehringer Ingelheim
Page 16 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.3.3
Covariates
These covariates will be used as patient characteristics for the overall population 
 
 with the primary outcome events.  
1.
History of stroke or transient ischemic attack yes/no
2.
History of myocardial infarction yes/no
3.
History of heart failure yes/no
4.
History of diabetes mellitus yes/no
5.
History of dyslipidemia
6.
History of arterial hypertension yes/no
7.
History of peripheral artery disease
8.
History of kidney impairment
9.
History of valvular disease
10. History of liver disease
11. History of dementia
12. History of trauma
13. History of fracture 
14. Nursing home resident
15. History of bleeding
16. Charlson co-morbidity index [3]
17. Concomitant medication yes/no for the following:
a. aspirin
b. clopidogrel
c. angiotensin receptor blockers (ARB) or angiotensin converting enzyme inhibitors
(ACE)
d. beta-blocker
e. amiodarone
f. calcium-channel blocker (CCB)
g. diuretics
h. statins
i. proton-pump inhibitor
j. H2 receptor antagonist
The disease, Charlson co-morbidity index and concomitant medication are defined as Table 
1-Table 4. Nursing home resident is defined as MDV codes 113011710, 113016010, 
114020910. 

Boehringer Ingelheim
Page 17 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Table 1
Definition of clinical history
Disease
Definition
ICD10code
prescription
Stroke or transient ischemic 
attack
I60-I64, G45
-
Myocardial infarction
I21-I23
-
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 Anatomical 
Therapeutic Chemical (ATC)
code as A10)
Dyslipidemia
E78
-
Arterial hypertension
I10-I15
Prescribed 2 or more types of 
anti-hypertensive (defined in 
Table 2)
Peripheral artery disease
I702-I709, I71, I739
-
Kidney impairment
N28
-
Valvular disease
I059, I089, I358, I38, I48
-
Liver disease
K70-K77
-
Dementia
F00-F03, G30
-
Trauma
S00-S09, I620, M125, M164, 
M165, M172, M173, M191, 
M483, M872, S065, S066, 
S081, S089, S130, S18, S230, 
S480, S481, S532, S533, S580, 
S581, S589, S633, S634, S680, 
S681, S684, S688, S689, S780, 
S789, S889, S980, S981, S982, 
T050, T053, T058, T059, 
T116, T136, T147, T794, 
T795, T796, T797, S271, 
S272, S330, S334, S382, S480, 
S481, S532, S580, S581, S589, 
S633, S634, S680, S681
Fracture
M484, M80, S02, S12, S22, 
S32, S42, S52, S62, S72, S82, 
S92, T02, T08, T10, T12, T142
Bleeding (gastro-intestinal, 
etc.)
K25-K29, K922, R04, R31, 
R58, K250, K260, K270, 
K280, K290, S063, S064, 
S065, S066
-

Boehringer Ingelheim
Page 18 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Table 2
Definition of anti-hypertensive
Class/type
ATC code
CCB
C08A0
ARB
C09C0
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)
Table 3
Definition of disease/conditions and weighted index for Charlson co-
morbidity score
Score
Desease/conditions
Definition (ICD-10 code)
1
Myocardial infarct
See Table 1
1
Congestive heart failure 
I110, I130, I132, I500
1
Peripheral vascular disease
I70-I74, I77
1
Cerebrovascular disease
I60-69
1
Dementia
See Table 1
1
Chronic pulmonary disease
J40-J47, J60-J67, J684, J701, J703, J841, J920, J961,
J982, J983
1
Connective tissue disease
M05, M06, M08, M09, M30-M36, D86
1
Ulcer disease
  K221, K25-K28
1
Mild liver disease
B18, K700-K703, K709, K71, K73, K74, K760
1
Diabetes mellitus
See Table 1
2
Hemiplegia
G81, G82
2
Moderate/severe renal disease
I12, I13, N00-N05, N07, N11, N14, N17-N19, Q61
2
Diabetes mellitus with chronic 
complications
E102-E018, E112-E118
2
Any tumor
C00-C75
2
Leukemia
C90-C96
2
Lymphoma
C81-C85, C88, C90, C96

Boehringer Ingelheim
Page 19 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Table 3 (cont'd)
Score
Desease/conditions
Definition (ICD-10 code)
3
Moderate/severe liver disease
B150, B160, B162, B190, K704, K72, K766, I85
6
Metastatic solid tumor
C76-C80
6
AIDS
B21-B24
Table 4
Definition of concomitant medication
Drug
Definition
ATC code
Generic name
Aspirin
-
Aspirin, aspirin dihydroxyaluminum 
aminoacetate magnesium carbonate
Clopidogrel
-
Clopidogrel sulfate
ARB or ACE
C09A0, C09C0, C09D1
-
Beta blocker
C07A0
-
Amiodarone
-
Amiodarone hydrochloride
CCB
C08A0
-
Diuretics
C03A1, C03A2, C03A3, 
C03A7, C03A9
-
Statins
C10A1
-
Proton pump inhibitor
A02B2
-
H2 receptor antagonist
A02B1
-
9.4
DATA SOURCES
MDV commercial claims database will be used.  
Observation period for the primary objective is planned from March 2011 to June 2016 
considering the launch date of dabigatran.  The observation period for the secondary 
objective is from March 2008 to June 2016. 
9.5
STUDY SIZE
This study plans no formal hypothesis testing.  
The previous study 1160.279 has identified the patients with confirmed 6 months of baseline 
period and no OAC treatment (defining “treatment naïve” new starter population).  The total 
of these patients was 62,888.  The breakdown by OAC initiated was 7,441 for dabigatran, 
23,412 for warfarin, 16,026 for apixaban, 12,779 for rivaroxaban and 3,230 for edoxaban.
The average on-treatment follow-up period for pooled OAC in patients with at least one year 
of baseline period prior to index date excluding the time after switching from one OAC to 
another was approximately 0.3 year.  The average on-treatment follow-up period for pooled 

Boehringer Ingelheim
Page 20 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
OAC including the time afer switching with 6 months of baseline period is unknown, but
should be longer than 0.3 year.  
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
For the primary outcome
Incidence rate of emergency surgery and major bleeding due to fracture/trauma will be 
described with each number of patients with event, patient-year and 95% confidence interval 
overall and stratified by age (age <64, 65-74 and >75).  Baseline characteristics of patients 
overall and stratified by age will be provided in a tabulated format.  
For the secondary outcome
2.
Incidence rates of cardiac tamponade and peri-cardiocentesis, along with number of 
events, patient year of follow-up not including time after switch, and 95% confidence 
interval.  
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. 
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.

Boehringer Ingelheim
Page 21 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.9
LIMITATIONS OF THE RESEARCH METHODS
•
The sensitivity and specificity of the definitions used in this study, particularly the use of 
urgent fee, trauma, fracture MDV codes, is unknown.  Additionally, there have been no 
published studies validating the codes to identify emergency surgery, trauma, fracture, 
cardiac tamponade or pericardiocentesis.  
•
The findings from this study may not be generalizable to other Japanese population 
outside of DPC hospitals
•
All information of each patient is from consent giving DPC hospitals. If patients have 
visits to other 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 exclusion criteria also include patients on dialysis or kidney 
transplant and having records of deep vein thrombosis or pulmonary embolism to exclude 
those patients who are presumed to have high risk of bleeding and those receiving OAC for 
indications other than atrial fibrillation.  
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.  
The availability of co-variates for matching was evaluated in the feasibility analysis of CTMS 
1160.279.  External validity was assessed by comparing the incidence of claims defined 
incidence of stroke, intracraniala haemorrhage and systemic embolism in MDV database 
against previously reported prospective atrial fibrillation registry conducted in Japan by 
Koretsune et al [4]
9.11.1
Cases
Not Applicable

Boehringer Ingelheim
Page 22 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
9.11.2
Controls
Not Applicable
9.12
BIAS
.
1. Selection bias: the database is derived from claims arising from DPC hospitals which
tend to treat patients with acute and severe disease, and thus may not reflect the 
general NVAF population of Japan.  
2. Misclassification bias: outcomes of emergency surgery and bleeding due to 
fracture/trauma are not validated.  

Boehringer Ingelheim
Page 23 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
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.

Boehringer Ingelheim
Page 24 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
No safety reporting is needed as this is a retrospective study using anonymized, existing 
database.  

Boehringer Ingelheim
Page 25 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
A manuscript describing this work will be submitted for publication in a peer-reviewed 
journal (Japanese medical journal).  

Boehringer Ingelheim
Page 26 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1] Büchele G, Rapp K, König HH, Jaensch A, Rothenbacher D, Becker C, Benzinger P. 
The Risk of Hospital Admission Due to Traumatic Brain Injury Is Increased in Older 
Persons With Severe Functional Limitations. J Am Med Dir Assoc. 2016;17(7):609-12.
[2] Curtis EM, van der Velde R, Moon RJ, van den Bergh JP, Geusens P, de Vries F, van 
Staa TP, Cooper C, Harvey NC. Epidemiology of fractures in the United Kingdom 1988-
2012: Variation with age, sex, geography, ethnicity and socioeconomic status. Bone. 
2016 Jun;87:19-26.
[3] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying 
prognostic comorbidity in longitudinal studies: development and validation. J Chronic 
Dis. 1987;40(5):373-83.
[4] Koretsune Y, Yamashita T, Yasaka M, Oda E, Matsubayashi D, Ota K, Kobayashi M, 
Matsushita Y, Kaburagi J, Ibusuki K, Takita A, Iwashita M, Yamaguchi T. Usefulness of 
a healthcare database for epidemiological research in atrial fibrillation. J Cardiol. 2016:
S0914-5087(16)30289-1.
13.2
UNPUBLISHED REFERENCES
None

Boehringer Ingelheim
Page 27 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
None

Boehringer Ingelheim
Page 28 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS
Not applicable

Boehringer Ingelheim
Page 29 of 29
Protocol for non-interventional studies based on existing data
BI Study Number 1321-0022
c18071759-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c18071759
1.0
non-intervention-study-protocol-1321-0022
Medical Need of Non-vitamin K Oral Anti-coagulant Reversal in Japan:
Epidemiological Assessment of Emergency Surgery, Major Bleeding due to Trauma
and Fracture, using Large Scale Claims Database
Approval–Clinical Monitor
20 Jul 2017 04:09 CEST
Approval-
 Medical Affairs
20 Jul 2017 07:01 CEST
Approval-
 Medicine
20 Jul 2017 13:30 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c18071759
1.0