THE REAL WORLD EVIDENCE ON TREATMENT PATTERNS, EFFECTIVENESS, AND SAFETY OF DRUGS FOR STROKE PREVENTION IN NONVALVULAR ATRIAL FIBRILLATION PATIENTS IN KOREA
Conditions: Atrial Fibrillation
Sponsor: Pfizer

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Study information 
Title 
The real world evidence on treatment 
patterns, effectiveness, and safety of drugs 
for stroke prevention in nonvalvular atrial 
fibrillation patients in Korea 
Protocol number 
X9001134 
Protocol version identifier 
V.3.0 
Date of last version of protocol 
03 May 2018 
Active substance 
Apixaban ((PF-04652577/BMS-562247) 
(617001ATB, 617002ATB) 
Medicinal product 
ELIQUIS® 
Research question and objectives 
This study seeks to address the following 
objectives: 
z To explore baseline characteristics and 
drug utilization patterns in patients with 
nonvalvular atrial fibrillation (NVAF) 
newly prescribed with anti-thrombotic 
therapies.  
z To compare the effectiveness of anti-
thrombotic therapies in patients with 
NVAF 
z To compare the safety of anti-
thrombotic therapies.in patients with 
NVAF 
Country(-ies) of study 
South Korea 
Author 
 PharmD 
 
, Pfizer Korea 
PPD
PPD
PPD
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, MPharm, MA, PhD 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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TABLES OF CONTENTS 
 
TABLES OF CONTENTS ........................................................................................................3 
1. LIST OF ABBREVIATIONS ...............................................................................................5 
2. RESPONSIBLE PARTIES ...................................................................................................7 
4. AMENDMENTS AND UPDATES ....................................................................................11 
5. MILESTONES ....................................................................................................................13 
6. RATIONALE AND BACKGROUND ...............................................................................14 
7. RESEARCH QUESTION AND OBJECTIVES .................................................................14 
8. RESEARCH METHODS ...................................................................................................15 
8.1 Study design .............................................................................................................15 
8.2 Setting .......................................................................................................................17 
8.2.1 Inclusion criteria ..........................................................................................17 
8.2.2 Exclusion criteria .........................................................................................17 
8.3 Variables ...................................................................................................................18 
8.4. Data sources ............................................................................................................23 
8.5. Study size ................................................................................................................23 
8.6. Data management ....................................................................................................23 
8.7. Data analysis ...........................................................................................................24 
8.8. Quality control .........................................................................................................24 
8.9. Limitations of the research methods .......................................................................25 
8.9.1. Measurement Error(s)/Misclassification(s) ................................................25 
8.9.2. Information Bias .........................................................................................25 
8.9.3. Selection Bias .............................................................................................25 
8.9.4. Analysis Limitations ...................................................................................26 
8.9.5. Missing and/or Incomplete Data .................................................................26 
8.10. Other aspects .........................................................................................................26 
9. PROTECTION OF HUMAN SUBJECTS .........................................................................26 
9.1. Patient Information and Consent .............................................................................26 
9.2. Patient withdrawal ...................................................................................................26 
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............26 
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9.4. Ethical Conduct of the Study ..................................................................................26 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................26 
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........27 
12. REFERENCES ..................................................................................................................27 
1. LIST OF TABLES ...............................................................................................................28 
2. LIST OF FIGURES .............................................................................................................28 
3. ANNEX 1. LIST OF STAND ALONE DOCUMENTS .....................................................28 
4. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .....................................28 
5. ANNEX 3. ADDITIONAL INFORMATION .....................................................................29 
 
 
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1. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AIDS 
Acquired immune deficiency syndrome 
CABG 
Coronary Artery Bypass Graft surgery 
CHA2DS2-VASc 
Clinical stroke risk prediction tool based on comorbidities of 
congestive heart failure, hypertension, elderly age, diabetes 
mellitus, prior stroke or thromboembolism, vascular disease, 
and gender. 
HAS-BLED 
Clinical major bleeding risk score based on comorbidities of 
hypertension, abnormal renal and liver function, prior stroke, 
bleeding history, labile international normalized ratio values of 
anticoagulation level, elderly age, and concomitant drug or 
alcohol use. 
HIRA 
Health Insurance Review & Assessment Service 
HIV 
Human immunodeficiency virus 
ICD-10 
International Classification of Diseases 10th revision 
ICJME 
International Committee of Medical Journal Editors 
KCD-6 
Korean Standard Classification of Diseases 6th revision 
KCD-7 
Korean Standard Classification of Diseases 7th revision 
MI 
Myocardial infarction 
MPR 
Medication possession ratio 
NOAC 
Non vitamin K antagonist oral anticoagulants 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
NVAF 
Nonvalvular atrial fibrillation 
OAC 
Oral anticoagulants 
PCI 
Percutaneous coronary intervention 
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Abbreviation 
Definition 
PPI 
Proton pump inhibitor 
TE 
Thromboembolism 
TIA 
Transient ischemic attack 
 
 
 
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2. RESPONSIBLE PARTIES 
  
Principal Investigator(s) of the Protocol 
Name, degree(s) 
Title 
Affiliation 
Address 
, 
PharmD 
 
 
Pfizer 
Pharmaceuticals 
Korea Ltd. 
Seoul, Korea 
, 
MPharm, MA, PhD 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
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3.  ABSTRACT 
Study title: Real world evidence on treatment patterns, effectiveness, and safety of drugs for 
stroke prevention in nonvalvular atrial fibrillation patients in Korea (Version 2.0, 10 Oct 
2017) 
Rationale and Background:  
There have been far fewer real world studies on effectiveness and safety outcomes of 
antiplatelet therapy, warfarin and Non vitamin K antagonist oral anticoagulants (NOACs) in 
Asian populations. The nationwide claims database in Korea can provide an opportunity to 
study comparative effectiveness and safety outcomes of therapies to prevent thromboembolic 
events in patients with nonvalvular atrial fibrillation.  
Research question and objectives: 
Research question: What is the real world data on antiplatelet therapy, warfarin and NOACs 
that can be found in the nationwide claims database in Korea? 
Primary objectives 
1. To explore baseline characteristics and drug utilization patterns in patients with 
nonvalvular atrial fibrillation (NVAF) who newly initiated NOACs, warfarin, or used 
aspirin 
2. To compare effectiveness including hemorrhagic stroke, ischemic stroke and systemic 
embolism of antithrombotic therapies in patients with NVAF with the following 
antithrombotic therapies: NOACs, warfarin, and aspirin 
3. To compare safety including major bleeding of antithrombotic therapies in patients 
with NVAF with the following antithrombotic therapies: NOACs, warfarin, and 
aspirin 
[NOTE] Comparative analyses will be performed contingent on a feasibility assessment 
based on the descriptive analyses 
Secondary objectives 
1. To explore and understand more detailed drug utilization patterns 
o Standard doses versus reduced doses of NOACs 
PPD
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o Patterns of usage (i.e., switching, discontinuation) and clinical events preceding 
the pattern 
o Compliance (i.e., medication possession ratio) 
2. To compare effectiveness and safety of antithrombotic therapies versus not using 
therapies among low risk patients (low score of CHA2DS2-VASc) 
 
Study design: Retrospective cohort study 
Population: Subjects with atrial fibrillation diagnosed (from January 1, 2007 up to and 
including the index date*) who newly initiated antithrombotic therapies (NOACs (not 
including edoxaban), warfarin, or used aspirin) between July 1, 2015 and November 30, 2016 
in the Korean Health Insurance Review & Assessment Service (HIRA) database  
*Index date is the first prescription date of study drugs, including NOACs, warfarin, and 
aspirin during the intake period (from July 1, 2015 to November 30, 2016). 
Variables:  
Exposure: The exposure to the following will be considered: 
1. Aspirin 
2. Aspirin-clopidogrel combination* 
3. Clopidogrel* 
4. Warfarin 
5. NOACs 
- Apixaban, Rivaroxaban, Dabigtran  
*[Note] Clopidogrel, Aspirin-clopidogrel will be included in descriptive analysis.  
Outcome variables: The following outcomes will be assessed:  
1. Effectiveness outcomes 
o Primary outcome: Composite of hemorrhagic stroke, ischemic stroke, and 
systemic embolism 
o Secondary outcomes: Individual outcome of hemorrhagic stroke, ischemic stroke, 
and systemic embolism  
2. Safety outcomes 
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o Primary safety outcome: Major bleeding including gastrointestinal bleeding or 
intracranial bleeding and other bleeding 
o Secondary safety outcomes: Individual outcome of major bleeding 
Key-Covariates: Variables, including, but not limited to, will be age, sex, types of health 
insurance, CHA2DS2-VASc score, HAS-BLED score, Charlson Comorbidity Index score, 
etc. 
Data sources: The Korean Health Insurance Review & Assessment Service (HIRA) database 
from January 1, 2007 to November 30, 2016 will be used for the analysis. The HIRA 
database contains the data of universal health insurance system in Korea. The database 
contains patients’ demographic information, their use of inpatient and outpatient services, 
and pharmacy dispensing claims. 
Study size: Based on HIRA disease statistics, the number of patients with atrial fibrillation 
(KCD code: I48) were 148,130 and 169,259 in 2015 and 2016, respectively. Thus, the 
anticipated number of patients will be approximately 150,000 since we plan to include 
patients who already had atrial fibrillation and were prescribed with aspirin, warfarin, or 
NOACs from July 1, 2015 to November 30, 2016. However, the study size might change 
after applying inclusion and exclusion criteria. 
Data analysis: Patients will be matched on demographic and clinical characteristics. All 
outcome variables will be summarized descriptively through the tabular and graphical 
display of mean values, medians, ranges, and standard deviations of continuous variables of 
interest and frequency distributions for categorical variables. Effectiveness and safety 
outcomes of treatments will be estimated from time-to-event models. The 95% confidence 
intervals for the estimates will be calculated and p < 0.05 will be considered significant. All 
analyses will be carried out using SAS version 9.4. Analysis and reporting will be compliant 
with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 
recommendations. 
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4. AMENDMENTS AND UPDATES 
Amendment 
number 
Date 
Substantial or 
administrative 
amendment 
Protocol 
section(s) 
changed  
Summary of amendment(s) 
Reason 
Amendment
01 (V.2.0) 
31Jan2018 
Administrative 
amendment 
Author 
 
 
 
NI Study lead change 
Substantial 
amendment 
Effectiveness 
Endpoints 
- Add ‘Hemorrhagic stroke’  
Meet to Harmonized Protocol 
Substantial 
amendment 
Safety Endpoints 
-Change to ‘Major bleeding’ 
- Delete the ‘Clinically relevant non-
major bleeing’  
Meet to Harmonized Protocol 
Administrative 
amendment 
3. ABSTRACT 
- Add the information of version, 
date of protocol, name and affilation 
of main author 
- Add the variables of Exposure 
- Correct the milestone 
Required SOP  
Administrative 
amendment 
5.MILESTONES 
Change the milestones which meet 
SOP required 
Required SOP 
Administrative 
amendment 
3. ABSTRACT 
7.RESEARCH 
QUESTION 
AND 
OBJECTIVES 
Add research questions 
Add research questions 
Administrative 
amendment 
8.1 Study design 
Add the endpoints  
Required SOP 
Substantial 
amendment 
8.2.2 
Exclusion 
criteria 
Delete the explains unnecessary 
Add the exclusion criteria 
Delete the explains unnecessary 
Meet to Harmonized Protocol 
Administrative 
amendment 
8.7. 
Data 
Analysis 
Add the SOP recommendation words 
Required SOP 
Administrative 
amendment 
9.3. Institutional 
Review 
Board 
(IRB)/Independe
nt 
Ethics 
Committee 
(IEC ) 
9.4.Ethical 
Conduct of the 
Study 
Change the SOP required words 
Required SOP 
Amendment
02 (V.3.0) 
03May 
2018 
Administrative 
amendment 
3. Abstract 
Change the phrases of Research 
question and objectives 
Amend protocol phrases consistently 
with SAP. 
Administrative 
7. Research 
question and 
Change the phrases of Research 
Amend protocol phrases consistently 
PPD
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Amendment 
number 
Date 
Substantial or 
administrative 
amendment 
Protocol 
section(s) 
changed  
Summary of amendment(s) 
Reason 
amendment 
objectives 
8.1 Study design 
8.2 Setting 
question and objectives 
with SAP. 
Administrative 
amendment 
8.2.2 Exclusion 
criteria 
Delete ‘Hip or knee replacement’ 
from #5. 
Duplicate from exclusion criteria #1. 
Substantial 
amendment 
8.3 Variables 
Change the operational definitions  
Redefinition of hemorrhagic stroke, 
ischemic stroke and systemic embolism 
Delete the variable of ‘myocardial 
infarction’ from effectiveness 
outcome. 
Redefinition of effectiveness outcome 
Add variable of ‘Individual outcome 
of major bleeding’ 
Redefinition of each major bleeding 
events 
Delete variables of ‘Dose’, ‘Medical 
history’ and ‘Study drugs’ 
Delete unnecessary sections. 
Add codes on operational definitions 
of ‘Valvular AF/ Prosthetic heart 
valves’ and ‘Hip or knee 
replacement’ 
Add procedure codes. 
Substantial 
amendment 
8.7  
Additional sensitivity analysis  
Perform IPTW using the propensity 
score derived from multinomial model  
 
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5. MILESTONES 
 
Milestone 
Planned date 
Completion of feasibility assessment 
10 Apr 2017 
Start of data collection  
01 Feb 2018 
End of data collection  
31 Nov 2018 
Interim report 1  
30 Jun 2018 
Interim report 2 
31 Dec 2018 
Final study report 
28 Feb 2019 
 
 
 
 
 
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6. RATIONALE AND BACKGROUND 
Atrial fibrillation (AF) is the most common persistent arrhythmia, and its prevalence has 
been estimated to be 1-2% of the general population, with a progressive increase 
thromboembolic events and death (1). AF increases the risk of ischemic stroke by five-fold 
and is associated with 15% of stroke for all age groups and 30% in patients aged 80 years and 
older (2). Patients with AF-related ischemic stroke have higher recurrent risk, morbidity, and 
mortality as compared to patients with other types of stroke (3). Thus, current clinical 
guidelines for AF emphasize stroke prevention in patients with AF, in the presence of stroke 
risk factors (4). Effective stroke prevention essentially requires oral anticoagulants (OAC) 
therapy. Vitamin K antagonists (i.e., warfarin) effectively decrease the risk for 
thromboembolic events in patients with AF (5). However, vitamin K antagonists have several 
limitations, including need for regular blood monitoring and possibility for food or drug 
interactions. This had led to the quest for new OACs that would be more safe and effective 
than warfarin (6). In randomized controlled trials, NOACs demonstrated noninferior or 
superior reduction in stroke and systemic embolism when compared to warfarin (7-10).  
Physicians now have a choice between the available NOACs but have relatively little 
evidence to guide their decision-making because of no head-to-head trials of these drugs. In 
addition, there have been few studies on efficacy and safety outcomes of NOACs. The 
nationwide claims database in Korea can provide an opportunity to study comparative 
effectiveness and safety outcomes of NOACs in patients with atrial fibrillation in Korea.  
 
7. RESEARCH QUESTION AND OBJECTIVES 
Research question: What is the real world data on antiplatelet therapy, warfarin and NOACs 
that can be found in the nationwide claims database in Korea? 
Primary objectives 
1. To explore baseline characteristics and drug utilization patterns in patients with 
nonvalvular atrial fibrillation (NVAF) who newly initiated NOACs, warfarin, or used 
aspirin 
2. To compare effectiveness including hemorrhagic stroke, ischemic stroke, and 
systemic embolism of antithrombotic therapies in patients with NVAF with the 
following antithrombotic therapies: NOACs, warfarin, and aspirin 
3. To compare safety including major bleeding of antithrombotic therapies in patients 
with NVAF with the following antithrombotic therapies: NOACs, warfarin, and 
aspirin 
[NOTE] Comparative analyses will be performed contingent on a feasibility assessment 
based on the descriptive analyses 
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Secondary objectives 
1. To explore and understand more detailed drug utilization patterns 
o Standard doses versus low dose of NOACs 
o Patterns of usage (i.e., switching, discontinuation) and clinical events preceding 
the pattern 
o Compliance (i.e., medication possession ratio) 
2. To compare effectiveness and safety of antithrombotic therapies versus not using 
therapies among low risk patients (low score of CHA2DS2-VASc) 
 
8. RESEARCH METHODS  
8.1  Study design  
This study will use a retrospective cohort design in which the treatment effectiveness and 
safety outcomes of new use of NOACs compared to other NOACs, new use of warfarin, and 
aspirin will be evaluated in patients with atrial fibrillation using the Korean Health Insurance 
Review & Assessment Service (HIRA) database. Comparative analyses will be performed 
contingent on a feasibility assessment based on the descriptive analyses. Propensity score 
method and Cox proportional hazards models will be used to account for selection bias, 
differences in follow-up time, and right data censoring. This will allow us to minimize 
selection bias and confounding bias and provide outcome data amenable to rapid clinical 
interpretation (i.e., time-to-event analysis, hazard ratios). Furthermore, HIRA database will 
allow us to preserve the population-based longitudinal data collection advantages. The 
overall study design is described in Figure 1.
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Figure 1. Study design scheme
1) Discontinuation 
2) Switching to other study drugs 
3) Death  
Outcomes 
No event 
Pre-index period  
(from 1 year prior to the day 
 before index date) 
Follow-up period (Index date – Nov 30, 2016) 
Index date 
(1st prescription of study drugs, including warfarin, NOACs, aspirin) 
Intake period (Jul 1, 2015 – Nov 30, 2016) 
Reference period  
for AF Diagnosis 
(1 Jan 2007 – Index date) 
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8.2 Setting 
8.2.1 Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
1. Patients aged 18 years or older on the index date 
2. Patients had ≥1 medical claim for AF (refer to Table 1) before or on the index date 
with at least one hospitalization or at least two outpatient visits: 
Table 1. Diagnosis codes for inclusion criteria. 
KCD-61) 
KCD-72) 
I48 (Atrial fibrillation and flutter) 
I48 (Atrial fibrillation and flutter) 
I480 (Atrial fibrillation) 
I480 (Paroxysmal atrial fibrillation) 
I481 (Atrial flutter) 
I481 (Persistent atrial fibrillation) 
 
I482 (Chronic atrial fibrillation) 
I483 (Typical atrial flutter) 
I484 (Atypical atrial flutter) 
 
I489 (Atrial fibrillation and atrial flutter, 
unspecified) 
KCD-6, Korean version of ICD-10 (6th revision); KCD-7, Korean version of ICD-10 (7th revision) 
1) KCD-6 diagnosis codes will be used from 1 July 2015 to 31 December 2015. 
2) KCD-7 diagnosis codes will be used from 1 January 2016 to 30 November 2016.  
[NOTE] KCD code is based on ICD-10 and almost similar, but KCD code is slightly different from ICD-
10 (e.g., ICD-10 is more subdivided  and extensive than KCD code).   
 
3. Patients prescribed aspirin, warfarin, or NOACs during intake period (from July 1, 
2015 to November 30, 2016)  
[Note] NOACs include apixaban, dabigatran, and rivaroxaban. 
8.2.2 Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study. 
1. Medical claims indicating diagnosis or procedure for hip/knee replacement surgery 
within 6 weeks prior to index date  
2. Medical claims indicating a diagnosis code indicative of rheumatic mitral valvular 
heart disease, mitral valve stenosis during the 12-month baseline period  
(Valvular AF / Prosthetic heart valves) 
3. Medical claims indicating a diagnosis code of VTE (Venous thromboembolism) 
during the 12-month baseline period 
4. Medical claims indicating a diagnosis or procedure code of transient AF, or cardiac 
surgery during the 12-month baseline period  
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(Thyrotoxicosis, Hypertrophic cardiomyopathy, Elective defibrillation, 
radiofrequency ablation, or left atrial appendage occlusion) 
5.  Medical claims indicating a diagnosis code of other conditions during the 12-month 
baseline period  
(End-stage chronic kidney disease / Kidney transplant / Dialysis / Pericarditis) 
6.  For the comparison of “NOAC versus NOAC”, and “NOAC versus warfarin”, 
patients with any OACs (apixaban, dabigatran, rivaroxaban, or warfarin) in the pre-
index period (from 1 year prior to the day before index date)  
o [NOTE] Patients prescribed antiplatelets in the pre-index period will not be 
excluded. 
7. For the comparison of “NOAC versus aspirin”, patients with following medications in 
the pre-index period (from 1 year prior to the day before index date) 
o NOAC user: OACs (apixaban, dabigatran, rivaroxaban, warfarin) 
o Aspirin user: none 
o [NOTE] NOAC user is defined as OAC naïve user and aspirin user is allowed to 
have OACs or antiplatelets in the pre-index period. 
 
8.3 
 Variables 
Variable 
Role 
Data source(s) 
Operational definition 
Composite of hemorrhagic 
stroke, ischemic stroke and 
systemic embolism 
Primary effectiveness 
outcome 
HIRA database 
Claims with the following KCD codes in all 
diagnosis codes (main and sub-diagnosis 
codes) whichever came first (i.e., the first 
occurred event will be used): 
1. Ischemic stroke: G459, I63, I693 
2. Systemic embolism: I74 
3. Hemorrhagic stroke: I60, I61, I62, I690, 
I691, I692 
[NOTE] Hospitalization and CT or MRI 
codes (brain CT or MRI for ischemic stroke 
and hemorrhagic stroke; any CT or MRI for 
systemic embolism) were also required for 
identification. 
*Brain CT or MRI: 
CT: HA441, HA451, HA461, HA471, HA851  
MRI: HE101, HE102, HE135, HE201, 
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Variable 
Role 
Data source(s) 
Operational definition 
HE202, HE235, HE301, HE302, HE401, 
HE402, HE501, HE502, HE535 
**Any CT or MRI:  
CT: HA401, HA402, HA403, HA404, HA405, 
HA406, HA407, HA408, HA409, HA410, 
HA411, HA412, HA413, HA414, HA415, 
HA416, HA424, HA425, HA434, HA435, 
HA443, HA444, HA445, HA446, HA447, 
HA448, HA449, HA453, HA456, HA457, 
HA458, HA459, HA463, HA464, HA465, 
HA466, HA467, HA468, HA469, HA473, 
HA474, HA475, HA476, HA477, HA478, 
HA479, HA496, HA497, HA801, HA805, 
HA809, HA813, HA834, HA835, HA853, 
HA856, HA857, HA858, HA859, S4852 
MRI: HE103, HE104, HE105, HE106, 
HE107, HE108, HE109, HE110, HE111, 
HE112, HE113, HE114, HE115, HE116, 
HE117, HE118, HE119, HE120, HE121, 
HE122, HE123, HE124, HE125, HE126, 
HE127, HE128, HE129, HE130, HE131, 
HE132, HE133, HE134, HE136, HE137, 
HE138, HE139, HE140, HE141, HE142, 
HE203, HE204, HE205, HE206, HE207, 
HE208, HE209, HE210, HE211, HE212, 
HE213, HE214, HE215, HE216, HE217, 
HE218, HE219, HE220, HE221, HE222, 
HE223, HE224, HE225, HE226, HE227, 
HE228, HE229, HE230, HE231, HE232, 
HE233, HE234, HE236, HE237, HE238, 
HE239, HE240, HE241, HE303, HE304, 
HE305, HE306, HE307, HE308, HE309, 
HE310, HE311, HE312, HE313, HE314, 
HE315, HE316, HE317, HE318, HE319, 
HE320, HE321, HE322, HE323, HE324, 
HE325, HE326, HE327, HE328, HE329, 
HE330, HE331, HE332, HE333, HE334, 
HE403, HE404, HE405 ,HE406, HE407, 
HE408, HE409, HE410, HE411, HE412, 
HE413, HE414, HE415, HE416, HE417, 
HE418, HE419, HE420, HE421, HE422, 
HE423, HE424, HE425, HE426, HE427, 
HE428, HE429, HE430, HE431, HE432, 
HE433, HE434, HE503, HE504, HE505, 
HE506, HE507, HE508, HE509, HE510, 
HE511, HE512, HE513, HE514, HE515, 
HE516, HE517, HE518, HE519, HE520, 
HE521, HE522, HE523, HE524, HE525, 
HE526, HE527, HE528, HE529, HE530, 
HE531, HE532, HE533, HE534, HE536, 
HE537, HE538, HE539, HE540, HE541, 
HF101, HF102, HF104, HF105, HF106, 
HF107, HF201, HF202, HF305, HF306 
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Variable 
Role 
Data source(s) 
Operational definition 
Individual outcome of 
primary outcome 
Secondary 
effectiveness outcome 
HIRA database 
Claims with the following KCDcodes in all 
diagnosis codes (main and sub-diagnosis 
codes) whichever came first (i.e., the first 
occurred event will be used): 
1. 
Ischemic stroke: G459, I63, I693 
2. 
Systemic embolism: I74 
3. 
Hemorrhagic stroke: I60, I61, I62, I690, 
I691, I692 
[NOTE] Hospitalization and CT or MRI 
codes (brain CT or MRI for ischemic stroke 
and hemorrhagic stroke; any CT or MRI for 
systemic embolism) were also required for 
identification. For CT or MRI codes, please 
see above. 
Major bleeding 
Primary safety 
outcome 
HIRA database 
Bleeding requiring hospitalization will be 
identified using hospital claims which had a 
bleeding diagnosis code as the first occurred 
KCD code and it will be consisted of 
intracranial hemorrhage (ICH) and 
gastrointestinal (GI) bleeding, and other 
bleeding. All KCD diagnosis codes (main 
and sub-diagnosis codes) will be used. 
Especially, hospitalization and brain CT or 
MRI codes will be needed to identify ICH. 
- Intracranial (I60, I61, I62, I690, I691, 
I692, S064, S065, S066, S068) 
- Gastrointestinal bleeding (I850, I983, 
K2211, K226, K228, K250, K252, 
K254, K256, K260, K262, K264, K266, 
K270, K272, K274, K276, K280, K282, 
K284, K286, K290, K3181, K5521, 
K625, K920, K921, K922) 
- Other bleeding (D62, H448, H3572, 
H356, H313, H210, H113, H052, H470, 
H431, I312, N020-N029, N421, N831, 
N857, N920, N923, N930, N938, N939, 
M250, R233, R040, R041, R042, R048, 
R049, T792, T810, N950, R310, R311, 
R318, R58, T455, Y442, D683)  
Individual outcome of 
major bleeding 
Secondary safety 
outcome 
HIRA database 
Individual outcome of ICH (diagnosis codes 
in all main and sub-diagnosis codes + 
hospitalization + brain CT or MRI), 
gastrointestinal bleeding (diagnosis codes in 
all main and sub-diagnosis codes + 
hospitalization), and other bleeding 
(diagnosis codes in all main and sub-
diagnosis codes + hospitalization).  
 
For codes, please see above. 
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Variable 
Role 
Data source(s) 
Operational definition 
Types of health insurance 
Covariates 
HIRA database 
Types of health insurance divided as the 
following: 
1. 
National Health Insurance 
2. 
Medical aid 
CHA2DS2-VASc 
Covariates 
HIRA database 
CHA2DS2-VASc as continuous data or 
dichotomous data. The score will be 
calculated using the following KCD codes 
(refer to SAP-Appendix 2, Table 9): 
1. Congestive heart failure 
2. Hypertension 
3. Diabetes mellitus 
4. Stroke/TIA/TE 
5. Vascular disease 
6. Age ≥ 75 
7. Age 65-74 
8. Sex (female) 
HAS-BLED 
Covariates 
HIRA database 
HAS-BLED as continuous data or 
dichotomous data. The score will be 
calculated using the following KCD codes 
(refer to SAP-Appendix 2, Table 10): 
1. Hypertension 
2. Abnormal renal function 
3. Abnormal liver function 
4. Stroke 
5. Bleeding history or predisposition 
6. Age > 65 
7. Antiplatelet or NSAID use 
8. Alcoholism 
Charlson Comorbidity 
Index 
Covariates 
HIRA database 
Charlson Comorbidity Index as continuous 
data or dichotomous data. The index will be 
calculated using the following KCD codes 
(Refer to SAP-Appendix 2, Table 11): 
1. Myocardial infarction 
2. Congestive heart failure 
3. Peripheral vascular disease 
4. Cerebrovascular disease 
5. Dementia 
6. Chronic pulmonary disease 
7. Rheumatic disease 
8. Peptic ulcer disease 
9. Mild liver disease 
10. Diabetes without chronic complication 
11. Diabetes with chronic complication 
12. Hemiplegia or paraplegia 
13. Renal disease 
14. Any malignancy, including lymphoma 
and leukemia, except malignant neoplasm of 
skin 
15. Moderate or severe liver disease 
16. Metastatic solid tumor 
17. AIDS/HIV 
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Variable 
Role 
Data source(s) 
Operational definition 
Medication use 
Covariates 
HIRA database 
It will be consisted of the following: 
1. 
History of NSAIDs 
2. 
History of antiplatelet  
3. 
History of PPI 
4. 
History of H2-receptor antagonists 
5. 
History of antiarrhythmics 
6. 
History of digoxin 
7. 
History of statins  
Exclusion criteria 
Exclusion criteria 
HIRA database 
Claims with the following KCD codes or 
procedure codes: 
1. 
Valvular AF/ Prosthetic heart valves: 
I05, I08, I09, I34, Q23, T820, T826, 
Z952, Z953, Z954 
- Korean procedure codes: M6580, 
M6581, M6582, O1791, O1792, O1793, 
O1794, O1795, O1796, O1797, O1798, 
O1799, M6531, M6532, M6533, O1690, 
O1730, 1740, O1750, O1760, O1770, 
O1781, O1782, O1783, O1810, O1826 
2. 
End-stage of chronic kidney 
disease/dialysis: N185, T824, Y602, 
Y612, Y622, Y841, Z49, Z992, E1022, 
E1122, E1222, E1322, E1422 
3. 
Kidney transplant: Z940 
4. 
Venous thromboembolism: I636, I676, 
I801, I802, I803, I808, I809, I81, I822, 
I823, I829, I26 
5. 
Hip or knee replacement  
- Korean procedure codes: N0711, 
N0715, N1711, N1715, N1721, N1725, 
N2070, N2072, N2077, N2710, N2712, 
N2717, N3710, N3712, N3717, N3720, 
N3722, N3727, N4710, N4712, N4717, 
N4720, N4722, N4727 
6. 
Thyrotoxicosis: E05 
7. 
Pericarditis: I30, I31, I32 
8. 
Hypertrophic cardiomyopathy: I422 
9. 
Elective defibrillation, radiofrequency 
ablation, or left atrial appendage 
occlusion 
- Korean procedure codes: M5880, 
M6540, M6542, M6545, M6547, 
M6511 
Follow-up period 
Follow-up period 
HIRA database 
From the index date until the first occurrence 
of the following whichever came first:  
1. 
Discontinuation: maximum of a 30-day 
gap after the calculated time to finishing 
the pack based on pack size and number 
of tablets per day. Switching: switch to 
any other study drugs 
2. 
Outcome occurrence 
3. 
Study ends: November 30, 2016 
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8.4 Data sources  
South Korea has a universal health coverage system that the National Health Insurance 
covers approximately 97% of the overall South Korean population. The claims data of Health 
Insurance Review & Assessment Service (HIRA) contains 46 million patients per year that 
account for 90% of the total population in Korea and include claims from almost 80,000 
healthcare service providers across South Korea as of 2011. 
The claims data of HIRA includes patients’ diagnosis, treatment, procedures, surgical history, 
and prescription drugs which provide a valuable resource for healthcare service research. 
Data elements captured in the HIRA database include patient-level demographic and plan 
enrollment information (e.g., start and stop dates of health plan enrollment), date-stamped 
(month and year) inpatient and outpatient medical claims (e.g., diagnosis codes, procedure 
codes, provider specialty), and pharmacy claims (e.g., prescription fill/refill dates, drug 
name/code, dosage). While procedure codes that identify patient receipt of laboratory tests 
are available, actual laboratory values and test results are not available. 
The HIRA database has unique attributes that make it a useful data source for this study. The 
key advantage of the HIRA database relative to other potential data sources (e.g., medical 
chart review) is that it is a population level data including most of Korean population and it 
will provide a large analytic sample and provide accurate claim-level treatments pattern and 
health care utilization across all provider settings (e.g., inpatient, outpatient, pharmacy) in 
patients’ spectrum of care. 
One key limitation of the HIRA database is that it does not include clinical variables such as 
laboratory values and clinical markers. To overcome this limitation, the Charlson 
comorbidity index and overall healthcare utilization observed during the pre-index period 
will be used as proxy measures to incorporate the overall health status of the individual 
patients. 
8.5 Study size 
Based on the 2015-2016 HIRA disease statistics, there are 148,130 – 169,259 patients with 
atrial fibrillation (KCD code: I48). Thus, we anticipate getting the number of patients with 
approximately 150,000 since we plan to include patients who already had atrial fibrillation 
and were prescribed aspirin, warfarin, or NOACs from July 1, 2015 to November 30, 2016. 
However, the study size might change after applying inclusion and exclusion criteria. 
8.6 Data management  
Obtaining data files 
Pusan National University team will submit the data request form to HIRA. After the HIRA 
committee review, the data will be uploaded in the server. The study team will access the 
data through the remote access using IP address. All medical or pharmacy claims and 
demographic information from January 1, 2007 to November 30, 2016 of patients with atrial 
fibrillation (KCD code: I48) from July 1, 2015 to November 30, 2016 will be accessed. 
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8.7 Data analysis  
 All outcome variables will be summarized descriptively through the tabular and 
graphical display of mean values, medians, ranges, and standard deviations of 
continuous variables of interest and frequency distributions for categorical variables. 
 Patients with aspirin, warfarin, and NOACs will be matched via propensity-score 
method. Patients will be matched on patient demographics (i.e., age, sex) and clinical 
(i.e., CHA2DS2-VASc score, Charlson Comorbidity Index score, etc) variables. 
Other propensity score method (i.e., covariate adjustment, inverse probability of 
treatment weighting (IPTW)) will also be used. A Cox proportional hazards model, 
to account for differences in follow-up time and right data censoring, will be used to 
compare effectiveness and safety outcomes between treatment groups. 
 Comparative analyses will be performed contingent on a feasibility assessment based 
on the descriptive analyses 
 All analyses will be carried out using SAS version 9.4. The 95% confidence intervals 
for the estimates will be calculated and p < 0.05 considered significant. 
 Sensitivity analysis of performing IPTW using the propensity score derived from 
multinomial model will be conducted. 
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be dated, filed and 
maintained by the sponsor. The SAP may modify the plans outlined in the protocol; any 
major modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment. 
 
8.8 Quality control 
The HIRA data files are large and complex. The study analysts will thoroughly evaluate and 
assess the data quality—including review of data for accuracy, consistency, and 
completeness—by generating descriptive summaries of variables to be used for study 
analysis. To ensure the integrity and quality of data and study results, the study team will 
implement several practice standards for statistical programming, database management, and 
documentation for all projects involving database analyses. The following three steps will be 
undertaken to achieve this high level of quality: 
o Documentation of SAS programming 
• 
To ensure smooth transition of analytic methods and work among programmers, 
reviewers, and other project personnel, documentation of the following 
information will be created for each SAS program: Project name; Program 
name; Program purpose; Program author; Date the program was completed; 
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Descriptions of subsequent changes and/or enhancements, with name of 
programmer and date for each. 
o Validation of SAS programs 
• 
We will conduct following programming validation methods: Log review; 
Review of data listings and tables of summary statistics. 
o Database storage and retention 
• 
The HIRA data is not allowed to be possessed by individual researcher. The data 
will be stored in the server owned by HIRA and will be only accessed through 
the remote access. Thus, the study team will not be able to store and possess the 
data. Two researchers will be allowed to access the data at once since only two 
IP addresses will be provided by HIRA. To ensure the integrity of the original 
data files, the data will be stored on a Linux server in a designated folder that 
cannot be overwritten. Data sets derived from the original files during the 
analysis process will be stored in a separate folder. 
8.9 Limitations of the research methods 
8.9.1  Measurement Error(s)/Misclassification(s) 
In general, all study measures will be defined by information available in the claims data in 
the form of diagnosis codes, procedure codes, drug codes, and dates of service. Patients were 
identified for study inclusion on the prescription claims, which (as with all claims-based 
studies) are subject to coding error. Patient charts were not available to validate the accuracy 
of case identification. 
8.9.2  Information Bias  
Information bias is less likely to occur since the HIRA data is a population level data which 
covers the whole population in Korea which has a universal health insurance system. 
8.9.3  Selection Bias 
This study will include only those patients who filled a prescription through their insurance 
for aspirin, warfarin, or NOACs. Patients who did not fill a prescription through their insurer 
(i.e., patients who received free samples or paid for the medication out of pocket) cannot be 
evaluated in an administrative claims database.  
Since the HIRA database does not include eligibility data and the complete mortality data for 
beneficiaries, the continuous health plan enrollment cannot be ensured and the deceased 
could be included in the analysis. 
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8.9.4  Analysis Limitations 
The results of this study can be generalizable only to patients included in the HIRA 
population which is the entire Korean population. Results should not be generalized to other 
patient populations or healthcare systems outside Korea. 
8.9.5  Missing and/or Incomplete Data 
This study does not account for unobserved confounders. No information is provided in the 
database as to why patients may discontinue treatment. Further, no information is available 
regarding medications the patients may have received as over-the-counter treatment or as 
samples from the physician, as well as medications paid for out of pocket. 
8.10 
Other aspects 
Not applicable. 
9. PROTECTION OF HUMAN SUBJECTS 
9.1. Patient Information and Consent  
Informed consent is not required for this study, because this study is secondary data 
collection study using fully anonymized data. 
9.2. Patient withdrawal 
Not Applicable. 
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)  
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents, (e.g., 
recruitment advertisements), if applicable, from the IRB/IEC. All correspondence with the 
IRB/IEC should be retained in the Investigator File. Copies of IRB/IEC approvals should be 
forwarded to Pfizer. 
9.4. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practice 
(GEP) guidelines issued by the International Epidemiological Association (IEA), Good 
Practices for Outcomes Research issued by the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR), International Ethical Guidelines for Epidemiological 
Research issued by the Council for International Organizations of Medical Sciences 
(CIOMS), management and REPORTING of adverse events/adverse reactions  
This study includes unstructured data (e.g., narrative fields in the database) that will be 
converted to structured (i.e., coded) data solely by a computer using automated/algorithmic 
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methods and/or data that already exist as structured data in an electronic database. In these 
data sources, it is not possible to link (i.e., identify a potential association between) a 
particular product and medical event for any individual. Thus, the minimum criteria for 
reporting an adverse event (AE) (i.e., identifiable patient, identifiable reporter, a suspect 
product, and event) are not available and AEs are not reportable as individual AE reports.  
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
The results of this research will be submitted for publication in a peer-reviewed journal and 
will be submitted for presentation in either poster or oral format at a medical or outcomes 
based research conference. 
Authorship of any publications resulting from this study will be determined on the basis of 
the International Committee of Medical Journal Editors (ICJME) Recommendations for the 
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
states: 
o  Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of 
the version to be published and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved. Authors should meet conditions 1, 
2, 3 and 4. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) based on 
this study must be submitted to Pfizer for corporate review. The vendor agreement will detail 
the procedures for, and timing of, Pfizer’s review of publications. 
COMMUNICATION OF ISSUES 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer product, 
Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NI study protocol that the investigator becomes aware of. 
11. REFERENCES 
1. 
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart 
disease and stroke statistics--2015 update: a report from the American Heart Association. 
Circulation. 2015;131(4):e29-322. 
2. 
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in 
the elderly. The Framingham Study. Arch Intern Med. 1987;147(9):1561-4. 
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3. 
Savelieva I, Bajpai A, Camm AJ. Stroke in atrial fibrillation: update on 
pathophysiology, new antithrombotic therapies, and evolution of procedures and devices. 
Ann Med. 2007;39(5):371-91. 
4. 
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., et al. 
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a 
report of the American College of Cardiology/American Heart Association Task Force on 
Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):e1-76. 
5. 
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent 
stroke in patients who have nonvalvular atrial fibrillation. Annals of internal medicine. 
2007;146(12):857-67. 
6. 
Banerjee A, Marín F, Lip GY. A New Landscape for Stroke Prevention in Atrial 
Fibrillation. Stroke. 2011:STROKEAHA. 111.617886. 
7. 
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. 
Dabigatran versus warfarin in patients with atrial fibrillation. N Engl j Med. 
2009;2009(361):1139-51. 
8. 
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban 
versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine. 
2011;365(10):883-91. 
9. 
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. 
Apixaban versus warfarin in patients with atrial fibrillation. New England Journal of 
Medicine. 2011;365(11):981-92. 
10. 
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. 
Edoxaban versus warfarin in patients with atrial fibrillation. New England Journal of 
Medicine. 2013;369(22):2093-104. 
 
1. LIST OF TABLES  
Table 1. Diagnosis codes for inclusion criteria. .......................................................................17 
 
2. LIST OF FIGURES 
Figure 1. Study design scheme ................................................................................................16 
 
3. ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None. 
4. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Not applicable. 
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5. ANNEX 3. ADDITIONAL INFORMATION 
Not applicable. 
 
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