Comparative Safety and Effectiveness of Warfarin, Dabigatran, and Rivaroxaban Among Japanese Patients With Non-valvular Atrial Fibrillation (NVAF) and Concomitant Coronary Artery Disease (CAD)
Conditions: Coronary Artery Disease, Atrial Fibrillation
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020 
 
Non-Interventional Study (NIS) Protocol 
 
 
Document Number: 
c37044336-01 
BI Study Number: 
1160-0308 
BI Investigational 
Product(s): 
Pradaxa 
Title: 
Comparative safety and effectiveness of warfarin, dabigatran, and 
rivaroxaban among Japanese patients with non-valvular atrial 
fibrillation (NVAF) and concomitant coronary artery disease 
(CAD) 
Brief lay title: 
A study based on Japanese medical records that looks at bleeding 
events in people with atrial fibrillation and coronary artery disease 
who start taking either dabigatran, rivaroxaban, or warfarin 
Protocol version 
identifier: 
1.0 
Date of last version of 
protocol: 
Not applicable 
PASS: 
Yes 
EU PAS register 
number: 
EUPAS41345 
Active substance: 
Dabigatran, warfarin, rivaroxaban 
Medicinal product: 
Pradaxa, Xarelto 
Product reference: 
1160 
Procedure number: 
Not applicable 
Marketing authorisation 
holder(s): 
 
Joint PASS: 
No 
Research question and 
objectives: 
The study aims to evaluate the safety and effectiveness 
comparisons between warfarin, dabigatran, and rivaroxaban in 
routine clinical practice among Japanese NVAF patients with 
concomitant CAD.  
Primary objective: 

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To compare the risk of major bleeding between dabigatran and 
warfarin, and between rivaroxaban and warfarin, among Japanese 
NVAF patients with concomitant CAD. 
Secondary objective: 
To compare the net clinical benefits of dabigatran vs. warfarin, and 
rivaroxaban vs. warfarin, among Japanese NVAF patients with 
concomitant CAD. 
Further objective: 
If the required sample size can be fulfilled and the baseline 
characteristics are balanced between dabigatran and rivaroxaban 
groups after IPTW adjustment, to compare the safety and net 
clinical benefits of dabigatran vs rivaroxaban among Japanese 
NVAF patients with concomitant CAD. 
Country(-ies) of study: 
Japan 
Author: 
 
Observational Study Specialist,  
Marketing authorisation 
holder(s): 
Phone : 
 
Fax : 
 
In case of PASS, add: 
MAH contact person: 
 
In case of PASS, add: 
<EU-QPPV:> 
Phone: 
 
Fax: 
24-hour phone contact: 

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In case of PASS, add: 
<Signature of EU-
QPPV:> 
Date: 
15 Nov 2021 
Page 1 of 46 
Proprietary confidential information 
© 2021 Boehringer Ingelheim Group of 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 

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1.
TABLE OF CONTENTS
TITLE PAGE .................................................................................................................. 1 
1.
TABLE OF CONTENTS ....................................................................................... 4 
2.
LIST OF ABBREVIATIONS ................................................................................ 6 
3.
RESPONSIBLE PARTIES .................................................................................... 8 
4.
ABSTRACT ........................................................................................................... 9 
5.
AMENDMENTS AND UPDATES ..................................................................... 17 
6.
MILESTONES ..................................................................................................... 18 
7.
RATIONALE AND BACKGROUND ................................................................ 18 
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 19 
9.
RESEARCH METHODS .................................................................................... 19 
9.1 
STUDY DESIGN ............................................................................................ 19 
9.2 
SETTING ........................................................................................................ 20 
9.2.1 
Study Sites ............................................................................................... 20 
9.2.2 
Study population ..................................................................................... 21 
9.2.3 
Study visits .............................................................................................. 21 
9.2.4 
Study discontinuation .............................................................................. 21 
9.3 
VARIABLES .................................................................................................. 21 
9.3.1 
Exposures ................................................................................................ 21 
9.3.2 
Outcomes ................................................................................................. 22 
9.3.2.1 
Primary outcomes ............................................................................. 22 
9.3.2.2 
Secondary outcomes ......................................................................... 22 
 
 
9.3.3 
Covariates ................................................................................................ 22 
9.4 
DATA SOURCES ........................................................................................... 23 
9.5 
STUDY SIZE .................................................................................................. 24 
9.6 
DATA MANAGEMENT ................................................................................ 25 
9.7 
DATA ANALYSIS ......................................................................................... 25 
9.7.1 
Main analysis ........................................................................................... 25 
 
 
9.7.3 
Safety Analysis ........................................................................................ 26 
9.8 
QUALITY CONTROL ................................................................................... 26 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 27 
9.10 
OTHER ASPECTS ......................................................................................... 27 

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9.10.1 
Data quality assurance ............................................................................. 27 
9.10.2 
Study records ........................................................................................... 27 
9.10.2.1 
Source documents ............................................................................ 27 
9.10.2.2 
Direct access to source data and documents .................................... 27 
9.10.3 
Protocol deviations .................................................................................. 28 
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 28 
10.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 28 
10.2 
STATEMENT OF CONFIDENTIALITY ...................................................... 28 
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE
REACTIONS ....................................................................................................... 28 
11.1 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 29 
11.2 
REPORTING TO HEALTH AUTHORITIES................................................ 29 
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
 ............................................................................................................................. 29 
13.
REFERENCES .................................................................................................... 29 
13.1 
PUBLISHED REFERENCES ......................................................................... 29 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 32 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 32 
ANNEX 3. TABLE SHELLS ....................................................................................... 38 
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES ................................... 45 

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2.
LIST OF ABBREVIATIONS
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
ASD 
Absolute Standardized Difference 
CA 
Competent Authority 
CAD 
Coronary Artery Disease 
CCDS 
Company Core Data Sheet 
CHA2DS2-
VASc 
Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes 
mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category 
(female) 
CI 
Confidence Interval 
CML 
Local Clinical Monitor  
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTP 
Clinical Trial Protocol 
DMRP 
Data Management and Review Plan 
eCRF 
Electronic Case Report Form 
ENCePP 
EMA 
ESC 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance  
European Medicines Agency 
European Society of Cardiology 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEP 
Good Epidemiological Practice 
GI 
Gastrointestinal 
GPP 
Good Pharmacoepidemiology Practice 
GVP 
Good Pharmacovigilance Practices 
HAS-BLED 
Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or 
predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol 
concomitantly  
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
ICD-10 
The 10th Revision of the International Classification of Diseases 
ICH 
Intracranial Hemorrhage 
ID 
Identification Number 
IEC 
Independent Ethics Committee 
IPTW 
Inverse Probability of Treatment Weighting 
IRB 
Institutional Review Board 
MAH 
Marketing Authorization Holder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
NIS 
NOAC 
NVAF 
OAC 
Non-Interventional Study 
Non-vitamin K Oral Anticoagulant 
Non-valvular Atrial Fibrillation  
Oral Anticoagulation 

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PASS 
Post-Authorization Safety Study 
RE-LY 
Randomized Evaluation of Long-term Anticoagulant Therapy 
ROCKET-AF 
The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared 
with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial 
in Atrial Fibrillation 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SEAP 
Statistical and Epidemiological Analysis Plan 
SE 
Systemic Embolism 
s-IPTW
Stabilized Inverse Probability of Treatment Weighting 
TIA
Transient Ischemic Attack 

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3.
RESPONSIBLE PARTIES
BI NIS 
 

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4.
ABSTRACT
Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Pradaxa, Xarelto 
Name of active ingredient: 
Dabigatran, warfarin, rivaroxaban 
Study 
number: 
Version/Revision: 
Version/Revision date: 
Protocol date: 
Nov. 15th, 2021 
1160-0308 
1.0 
NA 
Title of study: 
Comparative safety and effectiveness of warfarin, dabigatran, and 
rivaroxaban among Japanese patients with non-valvular atrial 
fibrillation (NVAF) and concomitant coronary artery disease (CAD) 
Rationale and 
background: 
Atrial fibrillation (AF) is a common cardiac arrhythmia and is 
associated with 15-20% of all strokes [R96-0267], [R96-0252]. Among 
AF patients, the prevalence of concomitant coronary artery disease 
(CAD) is estimated to range from 17% to 46.5% [P17-09543], which 
can increase the risks of major bleeding, stroke, and mortality 
[R21-3491]. The management of AF is complicated by the presence of 
concomitant CAD when co-prescription of oral anticoagulation (OAC) 
with antiplatelet therapy is needed. Therefore, careful considerations 
are necessary in choosing antithrombotic therapies to balance the 
bleeding risk, stroke risk, and other thrombosis risks. 
Non-valvular atrial fibrillation (NVAF) is a subtype of AF. The 2020 
European Society of Cardiology (ESC) Guidelines recommends non-
vitamin K oral anticoagulant (NOAC) treatments over warfarin for 
eligible oral anticoagulant-naïve NVAF patients [P21-09613]. 
Dabigatran and rivaroxaban are the first two NOACs approved for 
thromboprophylaxis of AF, which are also the two widely used NOACs 
in Asia. According to RE-LY and ROCKET-AF, both dabigatran and 
rivaroxaban have shown at least equal efficacy compared to warfarin in 
the prevention of stroke/systemic embolism (SE), and dabigatran 110 
mg bid demonstrates superiority over warfarin in major bleeding among 
NVAF patients [P09-11669], [R11-4223]. Further, post hoc or subgroup 
analyses of the two pivotal trials indicate consistent superiority in the 
safety profiles of NOACs versus warfarin among NVAF patients with 
concomitant CAD [P12-00109].  However, the current literature lacks 
comparative assessment of clinical outcomes among Asian NVAF 
patients with CAD who are managed with warfarin, dabigatran, or 
rivaroxaban in routine clinical practice. Given the increased risks of 
major bleeding and recurrent coronary events associated with CAD, it is 
necessary to evaluate the safety outcomes and net clinical benefits 
among Asian NVAF patients with concomitant CAD. 

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Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Pradaxa, Xarelto 
Name of active ingredient: 
Dabigatran, warfarin, rivaroxaban 
Study 
number: 
Version/Revision: 
Version/Revision date: 
Protocol 
date: 
Nov. 15th, 2021 
1160-0308 
1.0 
NA 
Research 
question and 
objectives: 
The study aims to make safety and effectiveness comparisons between 
warfarin, dabigatran, and rivaroxaban in routine clinical practice among 
Japanese NVAF patients with concomitant CAD.  
Primary objective: 
To compare the risk of major bleeding between dabigatran and 
warfarin, and between rivaroxaban and warfarin, among Japanese 
NVAF patients with concomitant CAD. 
Secondary objective: 
To compare the net clinical benefits of dabigatran vs. warfarin, and 
rivaroxaban vs. warfarin, among Japanese NVAF patients with 
concomitant CAD. 
Further objective: 
If the required sample size can be fulfilled and the baseline 
characteristics are balanced between dabigatran and rivaroxaban groups 
after IPTW adjustment, to compare the safety and net clinical benefits 
of dabigatran vs rivaroxaban among Japanese NVAF patients with 
concomitant CAD. 
Study design: 
This study will be a non-interventional study based on existing data. 
Patients meeting the in/exclusion criteria will be selected and will be 
defined as 3 patient groups:  
Group 1: new users of warfarin 
Group 2: new users of dabigatran 
Group 3: new users of rivaroxaban 
Comparative analyses of the study will follow a two-step approach. In 
the first step, the primary and secondary outcomes, as well as baseline 
characteristics, will be compared between Group 1&2 and Group 1&3, 

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Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Pradaxa, Xarelto 
Name of active ingredient: 
Dabigatran, warfarin, rivaroxaban 
Study 
number: 
Version/Revision: 
Version/Revision date: 
Protocol date: 
Nov. 15th, 2021 
1160-0308 
1.0 
NA 
5.
Prescribed with more than 2 anti-platelet drugs per prescription
(triple or quadruple anti-platelet use), or prescribed with any anti-
platelet injection
6.
Patients with missing or ambiguous age or sex information
Variables: 
Exposure:  
Initiation of dabigatran, rivaroxaban, or warfarin during the study 
period (dosage and duration not restricted) 
Primary outcome: 

Fatal or non-fatal major bleeding (defined as any blood transfusion
and/or any hospitalization with associated bleeding) in all three
patient groups
Secondary outcome: 

Composite outcome of stroke/systemic embolism (SE)/myocardial
infarction (MI)/all-cause mortality (inpatient)/major bleeding/major
gastrointestinal 
(GI) 
bleeding 
(hospitalization 
due 
to 
GI
bleeding)/intracranial hemorrhage (ICH) in all three patient groups
(the first occurrence of any of the component events counts as an
event; this outcome indicates the net clinical benefit)
Further outcomes: 

Individual component of the composite outcome in all three patient
groups
Covariates (collected at baseline): 
Demographic characteristics 

Age

Gender (male/female/other)
Ischemic and hematologic characteristics (if available) 

CHA2DS2-VASc score

HAS-BLED score

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Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Pradaxa, Xarelto 
Name of active ingredient: 
Dabigatran, warfarin, rivaroxaban 
Study 
number: 
Version/Revision: 
Version/Revision date: 
Protocol 
date: 
Nov. 15th, 2021 
1160-0308 
1.0 
NA 
Comorbidities (has at least 1 diagnosis before or on the index date 
during the look-back period) 

Heart failure (yes/no)

Peripheral arterial disorder (yes/no)

Hypertension (yes/no)

Diabetes (yes/no)

Prior stroke/transient ischemic attack (TIA)/SE (yes/no)

Cerebrovascular disease (yes/no)

Myocardial infarction (yes/no)

Acute Coronary Syndrome (yes/no)

Unstable angina (yes/no)

Bleeding history (yes/no)

Renal dysfunction (yes/no)

Hepatic dysfunction (yes/no)

Cancers (yes/no)

Peptic ulcer disease (yes/no)

Obesity (yes/no)
Baseline co-medication (had used the drug before or on the index date 
during the look-back period) 

Anti-platelet drugs (include aspirin, clopidogrel, ticagrelor,
prasugrel) (yes/no)

The number of anti-platelet drugs per prescription (single
antiplatelet, dual antiplatelet, none)

Antiplatelet use duration (single antiplatelet use: 6 months to 1
year, single antiplatelet use: 1 month to 6 months, single
antiplatelet use: <1 month, dual antiplatelet use: 6 months to 1
year, dual antiplatelet use: 1 month to 6 months, dual
antiplatelet use: <1 month, none; measured from the first
antiplatelet prescription to baseline)

Nonsteroidal anti-inflammatory drugs (yes/no)

Gastric secretion inhibitors (yes/no)

Statins (yes/no)

Heparins (yes/no)

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Name of company: 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Pradaxa, Xarelto 
Name of active ingredient: 
Dabigatran, warfarin, rivaroxaban 
Study 
number: 
Version/Revision: 
Version/Revision date: 
Protocol date: 
Nov. 15th, 2021 
1160-0308 
1.0 
NA 
primary and secondary outcomes will be conducted between treatment 
groups.  
The comparative analysis will follow a two-step approach. The first step 
will compare the baseline characteristics and clinical outcomes of 
individual NOAC (Dabigatran, Rivaroxaban) - versus warfarin-treated 
groups. To minimize potential confounding bias, the baseline 
characteristics of the individual NOAC groups will be balanced with the 
warfarin group using Stabilized Inverse Probability of Treatment 
Weighting (s-IPTW). Absolute standardized difference (ASD) will be 
used to measure balance of patient characteristics.  
A Cox proportional hazard regression model with the time since NOAC 
drug index date as the underlying timescale will be used to compute 
adjusted hazard ratios (aHRs) with 95% CIs. If substantial covariate 
imbalance between treatment group is noted, as assessed by a 
standardized difference >0.1, then outcome models will be further 
adjusted by covariates that are out of balance using multivariable Cox 
proportional hazards models. 
The second step will determine whether the patient characteristics are 
comparable between dabigatran and rivaroxaban treatment groups and 
whether there is the required sample size for comparisons between 
dabigatran- and rivaroxaban-treated groups. If the database can fulfil the 
sample size requirement, analysis will move forward for comparative 
analysis between the two NOAC groups.  
For each component outcome of all 3 groups, the event-free survival 
will be plotted with Kaplan-Meier curves after s-IPTW adjustments. 
A sensitivity analysis will be conducted for primary and secondary 
outcomes by using a conventional 1:1 propensity score matching 
method to assess the robustness of the s-IPTW model. 
Milestones: 
Protocol finalization: Sep. 2021 
DMRP completion: Nov. 2021 
Final report of study results: Dec. 2021 

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5.
AMENDMENTS AND UPDATES
Number 
Date 
Section of 
study 
protocol 
Amendment or 
update 
Reason 
1 
2 

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6.
MILESTONES
Milestone 
Planned Date 
Protocol finalization 
Sep. 2021 
DMRP 
Oct. 2021 
Final report of study results: 
Dec. 2021 
7. 
RATIONALE AND BACKGROUND
Atrial fibrillation (AF) is a common cardiac arrhythmia and is associated with 15-20% of all 
strokes [R96-0267], [R96-0252]. Among AF patients, the prevalence of concomitant 
coronary artery disease (CAD) is estimated to range from 17% to 46.5% [P17-09543], which 
can increase the risks of major bleeding, stroke, and mortality [R21-3491]. The management 
of AF is complicated by the presence of concomitant CAD when co-prescription of oral 
anticoagulation (OAC) with antiplatelet therapy is needed. Therefore, careful considerations 
are necessary in choosing antithrombotic therapies to balance the bleeding risk, stroke risk, 
and other thrombosis risks. 
Non-valvular atrial fibrillation (NVAF) is a subtype of AF. The 2020 European Society of 
Cardiology (ESC) Guidelines recommends non-vitamin K oral anticoagulant (NOAC) 
treatments over warfarin for eligible oral anticoagulant-naïve NVAF patients [P21-09613]. 
Dabigatran and rivaroxaban are the first two NOACs approved for thromboprophylaxis of 
AF, which are also the two widely used NOACs in Asia. According to RE-LY and 
ROCKET-AF, both dabigatran and rivaroxaban have shown at least equal efficacy compared 
to warfarin in the prevention of stroke/systemic embolism (SE), and dabigatran 110 mg bid 
demonstrates superiority over warfarin in major bleeding among NVAF patients 
[P09-11669], [R11-4223]. Further, post hoc or subgroup analyses of the two pivotal trials 
indicate consistent superiority in the safety profiles of NOACs versus warfarin among NVAF 
patients with concomitant CAD [P12-00109]. However, the current literature lacks 
comparative assessment of clinical outcomes among Asian NVAF patients with CAD who 
are managed with warfarin, dabigatran, or rivaroxaban in routine clinical practice. Given the 
increased risks of major bleeding and recurrent coronary events associated with CAD, it is 
necessary to evaluate the safety outcomes and net clinical benefits among Asian NVAF 
patients with concomitant CAD. 

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8. 
RESEARCH QUESTION AND OBJECTIVES 
The study aims to make safety and effectiveness comparisons between warfarin, dabigatran, 
and rivaroxaban in routine clinical practice among Japanese NVAF patients with 
concomitant CAD.  
 
Primary objective:  
To compare the risk of major bleeding between dabigatran and warfarin, and between 
rivaroxaban and warfarin, among Japanese NVAF patients with concomitant CAD 
 
Secondary objective: 
To compare the net clinical benefits of dabigatran vs. warfarin, and rivaroxaban vs. warfarin, 
among Japanese NVAF patients with concomitant CAD. Specifically, the composite 
outcome will be used to indicate net clinical benefits. 
 
Further objective: 
If the required sample size can be fulfilled and the baseline characteristics are balanced 
between dabigatran and rivaroxaban groups after IPTW adjustment, to compare the safety 
and net clinical benefits of dabigatran vs rivaroxaban among Japanese NVAF patients with 
concomitant CAD. 
 
9. 
RESEARCH METHODS 
9.1 
STUDY DESIGN 
This study will be a non-interventional cohort study based on existing data. Patients meeting 
the in/exclusion criteria will be selected and will be defined as 3 patient groups:  
 
Group 1: new users of warfarin 
Group 2: new users of dabigatran 
Group 3: new users of rivaroxaban  
 
Comparative analyses of the study will follow a two-step approach. In the first step, the 
primary and secondary outcomes, as well as baseline characteristics, will be compared 
between Group 1&2 and Group 1&3, respectively.  
 
The second step will utilize the estimated results from step one, which are HRs of major 
bleeding events between Group 1&2 and between Group 1&3 among NVAF patients with 
concomitant CAD, to carry out a more accurate sample size calculation to compare 
dabigatran versus rivaroxaban. If feasible, comparisons will be made on the same outcomes 
as in step one. 
 

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9.2 
SETTING 
Study Period: the entire time period that includes the look-back period, the cohort entry date 
(drug index date), and follow-up period for the study population. The study period will be 
from April 18th, 2011 (start of data collection) to December 31st, 2020 (end of data 
collection). 
Patient Selection Period: the time period for which patients are eligible to enter the cohort, 
which is from April 18th, 2012 to December 31st, 2020.  
Cohort Entry Date:  The drug index date, defined as the first date of prescription for 
dabigatran, rivaroxaban, or warfarin during the patient selection period. 
Look-back Period: the 365-day period that ends 1 day prior to the cohort entry date. The 
earliest start date of the look-back period is April 18th, 2011. 
Loss of follow-up: the last data point available in the database during the study period. 
Follow-Up Period: the period starting from the cohort entry date (first prescription of the drug 
of interest) and ending at the earliest occurrence of the following: 

Discontinuation of the index OAC, defined as a continuous gap of 45 days or more
between the expected refill date and the actual refill date (discontinuation date defined as
45 days after the expected refill date)

Switching to another OAC, if the index OAC is discontinued and another OAC is started
within 45 days of the expected refill date of the index OAC

Loss of follow-up

Occurrence of outcomes of interest (for primary outcome: major bleeding; for secondary
outcome: the onset of the first occurring component event; for further outcomes: the
respective onset of component events)

Death (except for analyses for the composite outcome and all-cause mortality as a
component outcome)

End of study period
The notion of enrollment is not defined in 
 Therefore, a proxy enrolment criterion 
defined as start of enrolment = date of first inpatient/outpatient encounter; end of enrolment = 
date of last inpatient/outpatient encounter will be used. “Enrolment” herein will refer to this 
proxy enrolment measure. For entry into the study population, patients will be required to have 
had at least 365 days of enrollment prior to the cohort entry date.  
9.2.1 
Study Sites 
The study will be based on existing data from the 
 database, which covers all insurance 
types and a large population size (9.4). Thus, selection bias can be minimized. 

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9.2.2 
Study population 
The target population of the study are Japanese NVAF patients with concomitant CAD, who 
are prescribed with dabigatran, rivaroxaban, or warfarin. The source population of the study 
are Japanese patients in the Japan 
) database during the 
study period, which is from April 18th, 2011 to December 31st, 2020. The study population 
will be selected based on the following in/exclusion criteria: 
 
Inclusion Criteria 
1. ≥18 years of age 
2. Has one year of look-back period prior to the index date (defined as the first date of 
prescription for dabigatran, rivaroxaban, or warfarin during the study period) 
3. New users of warfarin, dabigatran, and rivaroxaban, defined as patients without historic 
use of any oral anticoagulants during the look-back period 
4. Has at least 1 diagnosis of NVAF during the look-back period prior to or on the index date 
5. Has at least 1 diagnosis of CAD during the look-back period prior to or on the index date 
 
Exclusion Criteria 
1. Diagnosed with end-stage renal disease, or undergo hemodialysis, or experience 
pregnancy during the study period 
2. Initiate warfarin, dabigatran, rivaroxaban due to valvular AF, AF associated with 
mechanical valve malfunction or mechanical complication of heart valve prosthesis, or 
rheumatic AF 
3. Underwent joint replacement procedures or diagnosed with venous thromboembolism 
during the look-back period prior to or on the index date 
4. Prescribed with more than 1 OAC on the index date 
5. Prescribed with more than 2 anti-platelet drugs per prescription (triple or quadruple anti-
platelet use), or prescribed with any anti-platelet injection 
6. Patients with missing or ambiguous age or sex information 
 
9.2.3 
Study visits 
This is a non-interventional study based on existing data, hence not applicable. 
9.2.4 
Study discontinuation 
This is a non-interventional study based on existing data, hence not applicable.  
 
9.3 
VARIABLES 
9.3.1 
Exposures 
Exposure:  
Respectively for Group 1, 2, and 3, the initiation of warfarin, dabigatran, or rivaroxaban 
during the study period (dosage and duration are not restricted).  

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The exposure is measured through drug prescription records, which is recorded as 
 
Receipt Code. In the 
 database, information pertinent to exposure records include the 
date of dispensing, drug quantity, dose, number of days of prescription supply, and 
prescriber. 
 
9.3.2 
Outcomes 
Outcomes are recorded with the 10th Revision of the International Classification of Diseases 
(ICD-10) codes. In the 
 database, information related to outcomes include the date of 
occurrence, the number of events, and the severity. All outcomes are incident events after the 
index date. 
9.3.2.1 
Primary outcomes 
Primary outcome: 
 
Fatal or non-fatal major bleeding (defined as any blood transfusion and/or any 
hospitalization with associated bleeding) in all three patient groups 
 
9.3.2.2 
Secondary outcomes 
Secondary outcome: 
 
Composite outcome of stroke/SE/MI/all-cause mortality (inpatient) /major bleeding/major 
GI bleeding (hospitalization due to GI bleeding)/ICH in all three patient groups (the first 
occurrence of any of the component events counts as an event; this outcome indicates the 
net clinical benefit) 
 
9.3.3 
Covariates 
Covariates are recorded with the 10th Revision of the International Classification of Diseases 
(ICD-10) codes for disease diagnosis and 
 Receipt Code for medications. 
Covariates (collected at baseline): 
Demographic characteristics 
 
Age 
 
Gender (male/female/other)  
Ischemic and hematologic characteristics (if available) 
 
CHA2DS2-VASc score 
 
HAS-BLED score 

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Comorbidities (has at least 1 diagnosis before or on the index date during the look-back 
period) 
 
Heart failure (yes/no) 
 
Peripheral arterial disorder (yes/no) 
 
Hypertension (yes/no) 
 
Diabetes (yes/no) 
 
Prior stroke/transient ischemic attack (TIA)/SE (yes/no) 
 
Cerebrovascular disease (yes/no) 
 
Myocardial infarction (yes/no) 
 
Acute Coronary Syndrome (yes/no) 
 
Unstable angina (yes/no) 
 
Bleeding history (yes/no) 
 
Renal dysfunction (yes/no) 
 
Hepatic dysfunction (yes/no) 
 
Cancers (yes/no) 
 
Peptic ulcer disease (yes/no) 
 
Obesity (yes/no) 
Baseline co-medication (had used the drug before or on the index date during the look-back 
period) 
 
Anti-platelet drugs (include aspirin, clopidogrel, ticagrelor, prasugrel) (yes/no) 
 
The number of anti-platelet drugs per prescription (single antiplatelet, dual 
antiplatelet, none) 
 
Antiplatelet use duration (single antiplatelet use: 6 months to 1 year, single 
antiplatelet use: 1 month to 6 months, single antiplatelet use: <1 month, dual 
antiplatelet use: 6 months to 1 year, dual antiplatelet use: 1 month to 6 months, dual 
antiplatelet use: <1 month, none; measured from the first antiplatelet prescription to 
baseline) 
 
Nonsteroidal anti-inflammatory drugs (yes/no) 
 
Gastric secretion inhibitors (yes/no) 
 
Statins (yes/no) 
 
Heparins (yes/no) 
 
Proton pump inhibitor (yes/no) 
 
Antihypertensive drugs (yes/no) 
Baseline medical procedures (underwent the procedure before or on the index date during the 
look-back period) 
 
Cardioversion procedures (yes/no) 
 
Ablation procedures (yes/no) 
 
Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting (yes/no) 
9.4 
DATA SOURCES 
The 
) database is one of the largest 
databases in Japan, collecting data from over 400 acute care hospitals which account for 25% 
of emergency hospitals in Japan. The database contains comprehensive medical record data, 

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blood test result data, insurance claims data, and pharmacy claims data, covering more than 
35 million patients, 34% of whom are ≥ 65 years old. Each patient is assigned a specific 
identification number (ID) to which all inpatient and outpatient data are linked. The diagnosis 
is coded according to the 10th Revision of the International Classification of Diseases (ICD-
10) codes or local disease codes.  
The distribution of demographic characteristics, including age and sex, of patients registered 
in the 
 database is very similar to the distribution of these characteristics of patients 
visiting hospitals in Japan.  
9.5 
STUDY SIZE 
During the period from April 2011 to December 2020, there are roughly 17000, 11000, and 
4000 NVAF adult patients with a medical history of CAD being respectively treated with 
either warfarin, rivaroxaban or dabigatran as the first OAC (defined as no history of OAC 
usage during the 12-month look-back period) within the 
 database.  
 
According to a published paper based on the 
 database, the mean (standard deviation, 
SD) treatment duration of different drugs among new user groups ranged from 265 (263.8) to 
868 (725) days, with the dabigatran group exposed to the treatment the longest [P20-03503]. 
According to the same article, the major bleeding rate for AF patients is 1.5 per 100 patient-
years. In comparison, AF patients with concomitant CAD are more likely to fall under high 
or medium/high risk categories of the HAS-BLED score, a predictor of bleeding 
complications among AF patients, thus increasing the event rate for major bleeding about 2-3 
times [P09-11669], [R11-4223]. Therefore, the major bleeding rate is assumed to be rather 3-
4.5 per 100 patient-years among Japanese AF+CAD patients in the 
 database. 
Furthermore, previous analysis concluded substantial superiority of dabigatran (HR=0.66, 
95% CI 0.529-0.825) and rivaroxaban (HR=0.74, 95% CI 0.618-0.879) over warfarin in 
major bleeding among AF patients [P09-11669], [R11-4223]. The comparative rates of major 
bleeding between individual NOAC- and warfarin- treated patients should follow a similar 
trend among NVAF patients with concomitant CAD. 
 
For dabigatran vs. warfarin, if the HR is assumed to be 0.66 and the average exposure time to 
be 1 year per patient, an event rate of 3 per 100 patient-years with 80% power will require a 
total sample size of 6050 patients and 3025 patients for each arm; an event rate of 4.5 per 100 
patient-years will require a total sample size of 4040 patients and 2020 patients for each arm. 
To be conservative, the lower bound is selected and therefore each arm needs around 3025 
patients.  
 
Similarly, assuming the HR of rivaroxaban vs. warfarin is 0.74 and the average exposure time 
to be 1 year per patient, the lower-bound event rate of 3 per 100 patient-years with 80% 
power will require a total sample size of 9690 patients and 4845 patients for each arm.  
 
Additionally, to balance the baseline characteristics between groups, truncated Inverse 
Probability of Treatment Weighting (IPTW) will be applied and therefore sample loss is 
expected. In NOAC vs. warfarin comparisons,  if the sample loss due to IPTW truncation is 
assumed to be 20%, the sample sizes for dabigatran and rivaroxaban groups need to be 
greater than 3781 and 6056 respectively, which can be satisfied by the database. 

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9.6 
DATA MANAGEMENT 
The data management plan is summarized below. Full details of the data management plan 
are documented in a separate NIS-Data Management and Review Plan (NIS-DMRP). 
The data will be managed by BI. Source code of data management and data analyses will be 
kept for inspection at least for five years after publication of the results.  
9.7 
DATA ANALYSIS 
For the purpose of this study, analyses will be conducted using 
 
 from 
 and SAS statistical software (version 9.3 or higher).  
 
Descriptive analysis will be performed for describing patient demographic and clinical 
characteristics. For categorical variables, the frequency (n) and percentage (%) of patients 
under each category will be calculated. For continuous variables, the mean, median, standard 
deviations, interquartile range and minimum and maximum will be summarized. 
In comparative analysis, the number of patients, number of events, number of person-years, 
incidence rate, and incidence proportion will be reported for all outcomes. Incidence rate of 
each outcome for each treatment group will be reported as the number of events (counts the 
first event per patient) divided by the total number of person-years at risk during follow-up. In 
addition, the incidence proportion of each outcome for each treatment group will be reported 
as the number of events (counts the first event per patient) divided by the total number of 
patients at risk.  
Incidence rate of each outcome for each treatment group will be reported as the main 
descriptive statistics. 
 
Table shells are attached as Annex 3. 
 
9.7.1 
Main analysis 
Comparative analysis for primary and secondary outcomes will be conducted between 
treatment groups. The comparative analysis will follow a two-step approach. The first step will 
compare the baseline characteristics and clinical outcomes of individual NOAC (Dabigatran, 
Rivaroxaban) -versus warfarin-treated groups.   
 
During the first step of the comparative analysis, the baseline characteristics of the individual 
NOAC groups will be balanced with the warfarin group to account for potential confounding 
effects. Propensity scores will be calculated based on multinomial logistic regressions, with all 
covariates being incorporated. Next, an inverse probability of treatment weighting (IPTW) 
method will be applied using the calculated propensity score to avoid sample size inflation and 
to ensure appropriate estimation of variances. Yet, the IPTW estimates can be heavily 
influenced by large weights, thus destabilizing the results. To increase the robustness of the 
model, weight truncation will be applied once the distribution of propensity score is available. 
The distribution of propensity scores will be described, based on which the cut-off points of 
weight estimates will be chosen. Lastly, the calculated stabilized IPTW (s-IPTW) estimates 
will be applied to obtain two comparative pairs of individual NOAC vs. warfarin groups, for 
which the baseline demographics, risk factors, and clinical characteristics will be compared 

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using the absolute standardized difference (ASD) pre- and post- IPTW to assess the balance 
and model robustness. A covariate (baseline demographics, risk factors, clinical characteristics) 
will be considered well balanced if the ASD is below 0.1.  
A Cox proportional hazard regression model with the time since NOAC drug index date as the 
underlying timescale will be used to compute adjusted hazard ratios (aHRs) with 95% CIs. If 
substantial covariate imbalance between treatment group is noted assessed by a standardized 
difference >0.1, then outcome models will be further adjusted by covariates that are out of 
balance using multivariable Cox proportional hazards models. 
The second step will determine whether the patient characteristics are comparable between 
dabigatran and rivaroxaban treatment groups and whether there is the required sample size for 
comparisons between dabigatran- and rivaroxaban-treated groups. If the database can fulfil the 
sample size requirement, analysis will move forward for comparative analysis between the two 
NOAC groups. 
For each component outcome of all 3 groups, the event-free survival will be plotted with 
Kaplan-Meier curves after s-IPTW adjustments.  
9.7.3 
Safety Analysis 
Please refer to the other analysis sections. 
9.8 
QUALITY CONTROL 
The quality control, review, and monitoring plan are summarized below. Greater details are 
documented in the NIS-DMRP. 
The study will strictly follow BI NIS SOP, PASS SOP and any other relevant SOPs. In 
addition, this study will follow key elements of the Guideline for Good 
Pharmacoepidemiology Practices (GPP) and Good Pharmacovigilance Practice (GVP). The 
statistical analytic approach will be reviewed/repeated by a second analyst. The study report 
will be reviewed, approved and archived per BI SOP. 
Whenever possible, validated algorithm will be used for variables, including exposure, 
outcomes, and covariates, to minimize misclassification and information bias. 
One Analyst from 
 
 will build measures (variables) for cohort inclusion, exposures, 
outcomes and covariates. All measures created, cohorts developed, statistical analyses 
implemented, and tables output will undergo quality control review performed by at least 1 
additional Analyst from 
 
.  

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Quality controls include checks for the validity and logical content of codes and checks for 
missing values and variables.  
The Analyst from BI assigned to the study will perform a cross-review of the different tables 
of results. 
  
In order to control for potential inconsistencies and errors, all variables will be tabulated. The 
distribution of each variable will be examined. Extreme observations with values larger than ± 
3 standard deviations (SD) will be examined as potential outliers and consequently excluded 
from the dataset. 
 
9.9 
LIMITATIONS OF THE RESEARCH METHODS 
This is a non-interventional study based on existing data. The data do not include vital signs 
or laboratory test results (e.g. blood pressure, international normalized ratio values, renal 
function parameters). Therefore, the study may be subject to potential residual confounding 
due to the absence of certain key data.  
Further, the 
 database contains around 23% of emergency care hospitals in Japan, which 
does not form a fully closed healthcare system and therefore could lead to information bias.  
Additionally, the mortality is only known for hospitalized patients during hospitalization, 
thus resulting in inaccurate estimates of the mortality rate. 
Due to the above reasons, the study results might not be generalizable to the entire AF patient 
population in Japan.  
 
9.10 
OTHER ASPECTS 
Not Applicable. 
9.10.1 
Data quality assurance 
The quality assurance auditor will have access to the investigator’s study-related files and 
correspondence of this study. 
9.10.2 
Study records 
9.10.2.1 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at BI. 
 
9.10.2.2 
Direct access to source data and documents 
All source documents must be available at all times for review by BI, IRB/IEC, auditor and 
inspection by health authorities.  
 
 

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9.10.3 
Protocol deviations 
The investigators or sub-investigators will not develop or implement any deviation or change 
to the protocol without prior review by BI. 
 
10. 
PROTECTION OF HUMAN SUBJECTS 
 
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, Guidelines for Good Pharmacoepidemiology Practice (GPP), and the 
relevant BI Standard Operating Procedures (SOPs).  
 
 
10.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
This NIS will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and Competent Authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments. 
 
10.2 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers. 
 
Only anonymized data will be used in the study. Data generated as a result of the study need 
to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities. 
 
11. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 

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11.1 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING 
Collection of AEs 
This study is a non-interventional study based on secondary data without involving review or 
analysis of any individual patient level data. The data is extracted and analyzed in an 
aggregate manner. Therefore, from safety information collecting perspective, no AE/ADR 
collection & reporting of individual case safety reports is required. . 
11.2 
REPORTING TO HEALTH AUTHORITIES 
Based on current guidelines from the International Society for Pharmacoepidemiology  
[R11-4318] and the European Medicines Agency (EMA) [R16-4913], non-interventional 
studies conducted using health care records do not require expedited reporting of suspected 
adverse events/reactions. Specifically, as stated in section VI.C.1.2.1 of GVP, Module VI – 
Management and Reporting of Adverse Reactions to Medicinal Products, for non-
interventional study designs, which are based on use of secondary data, reporting of adverse 
reactions is not required. 
This study is a non-interventional study based on secondary data, which will not involve 
individual medical record review. Therefore, no AE/ADR collection of this study will be 
performed and reported to Chinese regulatory authorities. 
This study is classified as a PASS, and the study report will be reported to health authorities 
according to local regulations. The study results will also be reflected in the PSURs. 
12.
PLANS FOR DISSEMINATING AND COMMUNICATING
STUDY RESULTS
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report.  
BI intends to use data from this study to prepare peer-reviewed publications and other scientific 
communications such as abstracts, posters, and podiums presentations. 
The final report of the study result is planned in December 2021. Results of this PASS will 
be disclosed on encepp.eu and ClinicalTrials.gov. 
13.
REFERENCES
13.1 
PUBLISHED REFERENCES 
[R96-0267] Wolf, P. A. (1987). Atrial fibrillation: A major contributor to stroke in the 
elderly. The Framingham Study. Archives of Internal Medicine, 147(9), 1561–1564. 
https://doi.org/10.1001/archinte.147.9.1561 

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[R96-0252] Wolf, P. A., Abbott, R. D., & Kannel, W. B. (1991). Atrial fibrillation as an 
independent risk factor for stroke: The Framingham Study. Stroke, 22(8), 983–988. 
https://doi.org/10.1161/01.str.22.8.983  
[P17-09543] Michniewicz E, Mlodawska E, Lopatowska P, Tomaszuk-Kazberuk A, 
Malyszko J. Patients with atrial fibrillation and coronary artery disease - Double trouble. 
Adv Med Sci. 2018 Mar;63(1):30-35. doi: 10.1016/j.advms.2017.06.005. Epub 2017 Aug 
14. PMID: 28818746. 
[R21-3491] Kralev S, Schneider K, Lang S, Süselbeck T, Borggrefe M. Incidence and 
severity of coronary artery disease in patients with atrial fibrillation undergoing first-time 
coronary angiography. Plos one. 2011 ;6(9):e24964. DOI: 10.1371/journal.pone.0024964. 
PMID: 21957469; PMCID: PMC3177852. 
[P21-09613] Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, 
Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La 
Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, 
Van Gelder IC, Van Putte BP, Watkins CL; ESC Scientific Document Group. 2020 ESC 
Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration 
with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for 
the diagnosis and management of atrial fibrillation of the European Society of Cardiology 
(ESC) Developed with the special contribution of the European Heart Rhythm Association 
(EHRA) of the ESC. Eur Heart J. 2021 Feb 1;42(5):373-498. doi: 
10.1093/eurheartj/ehaa612. Erratum in: Eur Heart J. 2021 Feb 1;42(5):507. Erratum in: Eur 
Heart J. 2021 Feb 1;42(5):546-547. Erratum in: Eur Heart J. 2021 Sep 14;: PMID: 
32860505. 
[P09-11669] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, 
Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, 
Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and 
Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 
2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30. Erratum 
in: N Engl J Med. 2010 Nov 4;363(19):1877. PMID: 19717844. 
[R11-4223] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, 
Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox 
KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular 
atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 
10.1056/NEJMoa1009638. Epub 2011 Aug 10. PMID: 21830957. 
[P12-00109] Hohnloser SH, Oldgren J, Yang S, Wallentin L, Ezekowitz M, Reilly P, 
Eikelboom J, Brueckmann M, Yusuf S, Connolly SJ. Myocardial ischemic events in patients 
with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized 
Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation. 2012 Feb 
7;125(5):669-76. doi: 10.1161/CIRCULATIONAHA.111.055970. Epub 2012 Jan 3. PMID: 
22215856. 
[P20-03503] Kohsaka S, Katada J, Saito K, et al. Safety and effectiveness of non-vitamin K 
oral anticoagulants versus warfarin in real-world patients with non-valvular atrial 
fibrillation: a retrospective analysis of contemporary Japanese administrative claims data. 
Open Heart 2020;7:e001232. doi: 10.1136/openhrt-2019-001232 

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[R11-4318] ISPE. (April 2007). Guidelines for good pharmacoepidemiology practices 
(GPP).International Society for Pharmacoepidemiology. 
http://www.pharmacoepi.org/resources/guidelines_08027.cfm (access date: 9 October 2021) 
[R16-4913] European Medicines Agency (EMA). (8 September 2014). Guideline on good 
pharmacovigilance practices (GVP): module VI - management and reporting of adverse 
reactions to medicinal products (rev 1). European Medicines Agency (EMA). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/0 
9/WC500172402.pdf (access date: 9 October 2021) 
 
 
 

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
 
Number 
Document 
Reference Number 
Date 
Title 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Doc.Ref. EMA/540136/2009  
 
 
ENCePP Checklist for Study Protocols (Revision 4) 
Adopted by the ENCePP Steering Group on 15/10/2018 
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) 
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to promote 
the quality of such studies, not their uniformity. The user is also referred to the ENCePP Guide on 
Methodological Standards in Pharmacoepidemiology, which reviews and gives direct electronic 
access to guidance for research in pharmacoepidemiology and pharmacovigilance. 
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the section number of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply to 
a particular study (for example, in the case of an innovative study design). In this case, the answer 
‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section should be 
used to explain why. The “Comments” field can also be used to elaborate on a “No” answer.  
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory authority 
(see the Guidance on the format and content of the protocol of non-interventional post-authorisation 
safety studies). The Checklist is a supporting document and does not replace the format of the 
protocol for PASS presented in the Guidance and Module VIII of the Good pharmacovigilance 
practices (GVP). 
 
Study title: 
Comparative safety and effectiveness of warfarin, dabigatran, and rivaroxaban among 
Japanese patients with non-valvular atrial fibrillation (NVAF) and concomitant 
coronary artery disease (CAD) 
 
EU PAS Register® number: EUPAS41345 

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Study reference number (if applicable): 1160-0308 
 
Section 1: Milestones 
Yes 
No 
N/A 
Section 
Number 
1.1 
Does the protocol specify timelines for  
 
 
 
 
1.1.1 Start of data collection1 
 
 
 
6.0 
1.1.2 End of data collection2 
 
 
 
6.0 
1.1.3 Progress report(s) 
 
 
 
 
1.1.4 Interim report(s) 
 
 
 
6.0 
1.1.5 Registration in the EU PAS Register® 
 
 
 
 
1.1.6 Final report of study results. 
 
 
 
6.0 
Comments: 
 
 
Section 2: Research question 
Yes 
No 
N/
A 
Section 
Number 
2.1 
Does the formulation of the research question 
and objectives clearly explain:  
 
 
 
 
2.1.1 Why the study is conducted? (e.g. to 
address an important public health concern, a risk 
identified in the risk management plan, an emerging 
safety issue) 
 
 
 
7.0 
2.1.2 The objective(s) of the study? 
 
 
 
8.0 
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised) 
 
 
 
9.2.2 
2.1.4 Which hypothesis(-es) is (are) to be 
tested? 
 
 
 
8.0 
2.1.5 If applicable, that there is no a priori 
hypothesis? 
 
 
 
8.0 
Comments: 
 
 
Section 3: Study design 
Yes 
No 
N/
A 
Section 
Number 
3.1 
Is the study design described? (e.g. cohort, case-
control, cross-sectional, other design)  
 
 
 
9.1 
3.2 
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection? 
 
 
 
9.1 
3.3 
Does the protocol specify measures of 
occurrence? (e.g., rate, risk, prevalence) 
 
 
 
9.3.2 
 
1 Date from which information on the first study is first recorded in the study dataset or, in the case of secondary use of data, the date from 
which data extraction starts. 
2 Date from which the analytical dataset is completely available. 

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Section 3: Study design 
Yes 
No 
N/
A 
Section 
Number 
3.4 
Does the protocol specify measure(s) of 
association? (e.g. risk, odds ratio, excess risk, rate 
ratio, hazard ratio, risk/rate difference, number needed to 
harm (NNH)) 
 
 
 
9.7 
3.5 
Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection) 
 
 
 
11.0 
Comments: 
 
 
Section 4: Source and study populations 
Yes 
No 
N/
A 
Section 
Number 
4.1 
Is the source population described? 
 
 
 
9.4 
4.2 
Is the planned study population defined in 
terms of: 
 
 
 
 
4.2.1 Study time period 
 
 
 
9.2.2 
4.2.2 Age and sex 
 
 
 
9.2.2 
4.2.3 Country of origin 
 
 
 
9.2.2 
4.2.4 Disease/indication 
 
 
 
9.2.2 
4.2.5 Duration of follow-up 
 
 
 
9.2.2 
4.3 
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria) 
 
 
 
9.2.2 
Comments: 
 
 
Section 5: Exposure definition and 
measurement 
Yes 
No 
N/
A 
Section 
Number 
5.1 
Does the protocol describe how the study 
exposure is defined and measured? 
(e.g. operational details for defining and categorising 
exposure, measurement of dose and duration of drug 
exposure) 
 
 
 
9.3.1 
5.2 
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, 
use of validation sub-study) 
 
 
 
 
5.3 
Is exposure categorised according to time 
windows?  
 
 
 
 
5.4 
Is intensity of exposure addressed?  
(e.g. dose, duration) 
 
 
 
9.3.1 
5.5 
Is exposure categorised based on biological 
mechanism of action and taking into account 
the pharmacokinetics and pharmacodynamics 
of the drug? 
 
 
 
 

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Section 5: Exposure definition and 
measurement 
Yes 
No 
N/
A 
Section 
Number 
5.6 
Is (are) (an) appropriate comparator(s) 
identified? 
 
 
 
9.1 
Comments: 
 
 
Section 6: Outcome definition and 
measurement 
Yes 
No 
N/
A 
Section 
Number 
6.1 
Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated? 
 
 
 
9.3.2 
6.2 
Does the protocol describe how the outcomes 
are defined and measured?  
 
 
 
9.3.2 
6.3 
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, use of 
validation sub-study) 
 
 
 
 
6.4 
Does the protocol describe specific outcomes 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services 
utilisation, burden of disease or treatment, compliance, 
disease management) 
 
 
 
 
Comments: 
 
 
Section 7: Bias 
Yes 
No 
N/
A 
Section 
Number 
7.1 
Does the protocol address ways to measure 
confounding? (e.g. confounding by indication) 
 
 
 
9.7.1 
7.2 
Does the protocol address selection bias? (e.g. 
healthy user/adherer bias) 
 
 
 
 
7.3 
Does the protocol address information bias? 
(e.g. misclassification of exposure and outcomes, time-
related bias) 
 
 
 
9.8 
Comments: 
 
 
Section 8: Effect measure modification 
Yes 
No 
N/A 
Section 
Number 
8.1 
Does the protocol address effect modifiers? 
(e.g. collection of data on known effect modifiers, sub-
group analyses, anticipated direction of effect)  
 
 
 
9.7.2 
Comments: 
 
 

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Section 9: Data sources 
Yes 
No 
N/
A 
Section 
Number 
9.1 
Does the protocol describe the data source(s) 
used in the study for the ascertainment of: 
 
 
 
 
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-
face interview) 
 
 
 
9.4 
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics) 
 
 
 
9.4 
9.1.3 Covariates and other characteristics? 
 
 
 
9.4 
9.2 
Does the protocol describe the information 
available from the data source(s) on: 
 
 
 
 
9.2.1 Exposure? (e.g. date of dispensing, drug 
quantity, dose, number of days of supply prescription, 
daily dosage,  prescriber) 
 
 
 
9.3.1 
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event) 
 
 
 
9.3.2 
9.2.3 Covariates and other characteristics? 
(e.g. age, sex, clinical and drug use history, co-
morbidity, co-medications, lifestyle) 
 
 
 
9.3.3 
9.3 
Is a coding system described for:  
 
 
 
 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, 
Anatomical Therapeutic Chemical (ATC) Classification 
System)  
 
 
 
9.3.1 
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD), Medical Dictionary for Regulatory 
Activities (MedDRA)) 
 
 
 
9.3.2 
9.3.3 Covariates and other characteristics? 
 
 
 
9.3.3 
9.4 
Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)  
 
 
 
9.4 
Comments: 
 
 
Section 10: Analysis plan 
Yes 
No 
N/
A 
Section 
Number 
10.1 Are the statistical methods and the reason for 
their choice described?  
 
 
 
9.7 
10.2 Is study size and/or statistical precision 
estimated? 
 
 
 
9.5 
10.3 Are descriptive analyses included? 
 
 
 
9.7 
10.4 Are stratified analyses included? 
 
 
 
 
10.5 Does the plan describe methods for analytic 
control of confounding? 
 
 
 
9.7 
10.6 Does the plan describe methods for analytic 
control of outcome misclassification? 
 
 
 
 

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Section 10: Analysis plan 
Yes 
No 
N/
A 
Section 
Number 
10.7 Does the plan describe methods for handling 
missing data? 
 
 
 
 
10.8 Are relevant sensitivity analyses described? 
 
 
 
9.7.2 
Comments: 
 
 
Section 11: Data management and quality 
control 
Yes 
No 
N/
A 
Section 
Number 
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving) 
 
 
 
9.6 
11.2 Are methods of quality assurance described? 
 
 
 
9.10.1 
11.3 Is there a system in place for independent 
review of study results?  
 
 
 
 
Comments: 
 
 
Section 12: Limitations 
Yes 
No 
N/
A 
Section  
Number 
12.1 Does the protocol discuss the impact on the 
study results of: 
 
 
 
 
12.1.1 Selection bias? 
 
 
 
9.9 
12.1.2 Information bias? 
 
 
 
9.9 
12.1.3 Residual/unmeasured confounding? 
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods). 
 
 
 
9.9 
12.2 Does the protocol discuss study feasibility? 
(e.g. study size, anticipated exposure uptake, duration of 
follow-up in a cohort study, patient recruitment, precision 
of the estimates) 
 
 
 
9.5 
Comments: 
 
 
Section 13: Ethical/data protection issues 
Yes 
No 
N/
A 
Section  
Number 
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described? 
 
 
 
10.1 
13.2 Has any outcome of an ethical review 
procedure been addressed? 
 
 
 
 
13.3 Have data protection requirements been 
described? 
 
 
 
10.2 

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Patients older than 18 year old at drug index date 
  
  
Have 1y look-back prior drug index date 
  
  
New user of Dabigatran or Rivaroxaban or Warfarin 
  
  
Have at least 1 diagnosis of NVAF during the look-back period prior to 
or on the index date 
  
  
Have at least 1 diagnosis of CAD during the look-back period prior to or 
on the index date 
  
  
Excluded because of Diagnosis of end-stage renal disease, or undergo 
hemodialysis, or experience pregnancy during the study period 
  
  
Excluded because of Initiation of warfarin, dabigatran, rivaroxaban due 
to valvular AF, AF associated with mechanical valve malfunction or 
mechanical complication of heart valve prosthesis, or rheumatic AF 
  
  
Excluded because of Prescription with more than 1 OAC on the index 
date 
  
  
Final cohort 
- 
  
Warfarin  
- 
  
Dabigatran  
- 
  
Rivaroxaban 
- 
  
 
Table 2a. Baseline Characteristics Comparisons – Dabigatran vs. Warfarin 
  
Overall 
s-IPTWAdjusted 
PS-matched 
Variable 
Da
big
atr
an 
Warfari
n 
Abs.
Std.
Dif 
Dabigatra
n 
Wa
rfar
in 
Abs.St
d.Dif 
Dabig
atran 
Warf
arin 
Abs.St
d.Dif 
Age 
  
  
  
  
  
  
  
  
  
...mean (sd) 
  
  
  
  
  
  
  
  
  
...median 
[IQR] 
  
  
  
  
  
  
  
  
  
…Min-Max 
 
 
 
 
 
 
 
 
 
Gender 
  
  
  
  
  
  
  
  
  
...1 - Male; n 
(%) 
  
  
  
  
  
  
  
  
  
...2 - Female; 
n (%) 
  
  
  
  
  
  
  
  
  

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CHA2DS2-
VASc  score  
  
  
  
  
  
  
  
  
  
...mean (sd) 
  
  
  
  
  
  
  
  
  
...median 
[IQR] 
  
  
  
  
  
  
  
  
  
…Min-Max 
 
 
 
 
 
 
 
 
 
HAS-BLED 
score 
 
 
 
 
 
 
 
 
 
…mean(sd) 
 
 
 
 
 
 
 
 
 
…median[IQR
] 
 
 
 
 
 
 
 
 
 
…Min-Max 
 
 
 
 
 
 
 
 
 
Heart failure; 
n (%) 
  
  
  
  
  
  
  
  
  
Peripheral 
arterial 
disorder; n 
(%) 
  
  
  
  
  
  
  
  
  
Hypertension; 
n (%) 
  
  
  
  
  
  
  
  
  
Diabetes; n 
(%) 
  
  
  
  
  
  
  
  
  
Prior 
stroke/transie
nt ischemic 
attack 
(TIA)/SE; n 
(%) 
  
  
  
  
  
  
  
  
  
Myocardial 
infarction; n 
(%) 
  
  
  
  
  
  
  
  
  
Acute 
Coronary 
Syndrome; n 
(%) 
 
 
 
 
 
 
 
 
 
Unstable 
angina; n (%) 
  
  
  
  
  
  
  
  
  
Bleeding 
history; n (%) 
  
  
  
  
  
  
  
  
  

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Renal 
dysfunction; n 
(%) 
  
  
  
  
  
  
  
  
  
Hepatic 
dysfunction; n 
(%) 
  
  
  
  
  
  
  
  
  
Cancers; n (%) 
  
  
  
  
  
  
  
  
  
Peptic ulcer 
disease; n (%) 
  
  
  
  
  
  
  
  
  
Cerebrovascul
ar disease; n 
(%) 
  
  
  
  
  
  
  
  
  
Obesity; n (%) 
  
  
  
  
  
  
  
  
  
Anti-platelet 
drugs 
(include 
aspirin, 
clopidogrel, 
ticagrelor, 
prasugrel); n 
(%) 
  
  
  
  
  
  
  
  
  
The number 
of anti-
platelet 
drugs per 
prescription 
(single 
antiplatelet, 
dual 
antiplatelet, 
none) 
 
 
 
 
 
 
 
 
 
   single 
antiplatelet; 
n (%) 
 
 
 
 
 
 
 
 
 
   dual 
antiplatelet; 
n (%) 
 
 
 
 
 
 
 
 
 
   none; n (%) 
 
 
 
 
 
 
 
 
 
Antiplatelet 
use duration 
 
 
 
 
 
 
 
 
 

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   Single 
antiplatelet 
use: 6 
months to 1 
year; n (%) 
 
 
 
 
 
 
 
 
 
   Single 
antiplatelet 
use: 1 month 
to 6 months; 
n (%) 
 
 
 
 
 
 
 
 
 
   Single 
antiplatelet 
use: <1 
month; n (%) 
 
 
 
 
 
 
 
 
 
   Dual 
antiplatelet 
use: 6 
months to 1 
year; n (%) 
 
 
 
 
 
 
 
 
 
   Dual 
antiplatelet 
use: 1 month 
to 6 months; 
n (%) 
 
 
 
 
 
 
 
 
 
   Dual 
antiplatelet 
use: <1 
month; n (%) 
 
 
 
 
 
 
 
 
 
None; n 
(%) 
 
 
 
 
 
 
 
 
 
Nonsteroidal 
anti-
inflammator
y drugs; n (%) 
  
  
  
  
  
  
  
  
  
Gastric 
secretion 
inhibitors; n 
(%) 
  
  
  
  
  
  
  
  
  
Statins; n (%) 
  
  
  
  
  
  
  
  
  

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Heparins; n 
(%) 
  
  
  
  
  
  
  
  
  
Proton 
pump 
inhibitor; n 
(%) 
  
  
  
  
  
  
  
  
  
Antihyperten
sive drugs; n 
(%) 
  
  
  
  
  
  
  
  
  
Cardioversio
n 
procedures; 
n (%) 
  
  
  
  
  
  
  
  
  
Ablation 
procedures; 
n (%) 
  
  
  
  
  
  
  
  
  
Percutaneou
s Coronary 
Intervention 
or Coronary 
Artery 
Bypass 
Grafting; n 
(%) 
 
 
 
 
 
 
 
 
 
 
Table 3. Rates and Risks of Fatal/Non-fatal Major Bleeding 
  
Comparison 1 
Comparison 2 
Comparison 3* 
  
Dabig
atran 
Warfa
rin 
Rivaro
xaban 
Warfa
rin 
Dabig
atran 
Rivaroxab
an 
Rate 
 
 
 
 
 
 
Overall 
 
 
 
 
 
 
Number of patients  
  
  
  
  
  
  
Number of events 
  
  
  
  
  
  
Number of person-years  
  
  
  
  
  
  
Incidence Rate per 1,000 person-
years (95% CI) 
  
  
  
  
  
  
Incidence Proportion (n (%)) 
 
 
 
 
 
 
s-IPTW adjusted 
 
 
 
 
 
 

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Number of patients 
 
 
 
 
 
 
Number of events 
 
 
 
 
 
 
Number of person-years 
 
 
 
 
 
 
Incidence Rate per 1,000 person-
years (95% CI) 
 
 
 
 
 
 
Incidence Proportion (n (%)) 
 
 
 
 
 
 
PS-matched 
 
 
 
 
 
 
Number of patients 
 
 
 
 
 
 
Number of events 
 
 
 
 
 
 
Number of person-years 
 
 
 
 
 
 
Incidence Rate per 1,000 person-
years (95% CI) 
 
 
 
 
 
 
Incidence Proportion (n (%)) 
 
 
 
 
 
 
Hazard ratios 
  
  
  
  
  
  
s-IPTWAdjusted Hazard Ratio (95% 
CI) 
  
  
  
  
  
  
PS Matched Hazard Ratio (95% CI) 
  
  
  
  
  
  
 
 
 
 
 
 
 
*Note: comparison 3 will be 
conducted if sample size is sufficient 
(see section 9.5 of protocol) 
 
 
 
 
 
 
 

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I herewith certify that I agree to the content of the study protocol and to all documents 
referenced in the study protocol. 
 
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