Treatment Patterns and Clinical Outcomes Among Venous Thromboembolism Patients Treated With Anticoagulants After the Entry of Non-vitamin K Antagonist Oral Anticoagulants in Korea
Conditions: Venous Thromboembolism
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
Study information 
Title 
Treatment patterns and clinical outcomes 
among venous thromboembolism patients 
treated with anticoagulants after the entry of 
non-vitamin K antagonist oral anticoagulants 
in Korea 
Protocol number 
X9001305 
Protocol version identifier 
2.0 
Date 
27 April 2022 
Active substance 
B01AB01 (heparin) 
B01AB04 (dalteparin) 
B01AB05 (enoxaparin) 
B01AB06 (nadroparin) 
B01AB12 (bemiparin) 
B01AA03 (warfarin) 
B01AE07 (dabigatran) 
B01AF01 (rivaroxaban) 
B01AF02 (apixaban) 
B01AF03 (edoxaban) 
Medicinal product 
Eliquis® (apixaban) 
Research question and objectives 
• 
To describe the sociodemographic and 
clinical characteristics of patients with 
venous thromboembolism (VTE), 
overall and according to their index 
VTE treatment (parenteral 
anticoagulants [PAC] only, warfarin-
based, non-vitamin K antagonist oral 
anticoagulants [NOAC]-based) 
• 
To describe index anticoagulant 
treatment patterns by investigating the 

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1. TABLE OF CONTENTS 
 
1. TABLE OF CONTENTS .......................................................................................................3 
2. LIST OF ABBREVIATIONS ................................................................................................5 
3. RESPONSIBLE PARTIES ....................................................................................................8 
4. ABSTRACT ...........................................................................................................................9 
5. AMENDMENTS AND UPDATES .....................................................................................18 
6. MILESTONES .....................................................................................................................19 
7. RATIONALE AND BACKGROUND ................................................................................19 
8. RESEARCH QUESTION AND OBJECTIVES .................................................................21 
9. RESEARCH METHODS ....................................................................................................22 
9.1. Study design ............................................................................................................22 
9.2. Setting ......................................................................................................................25 
9.2.1. Inclusion criteria .........................................................................................25 
9.2.2. Exclusion criteria ........................................................................................25 
9.3. Variables ..................................................................................................................27 
9.4. Data sources ............................................................................................................32 
9.5. Study size ................................................................................................................33 
9.6. Data management ....................................................................................................36 
9.7. Data analysis ...........................................................................................................36 
9.8. Quality control .........................................................................................................40 
9.9. Limitations of the research methods .......................................................................40 
9.10. Other aspects .........................................................................................................41 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................41 
10.1. Patient information ................................................................................................41 
10.2. Patient consent .......................................................................................................41 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) ................41 
10.4. Ethical conduct of the study ..................................................................................42 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................42 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........42 
13. REFERENCES ..................................................................................................................44 

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14. LIST OF TABLES .............................................................................................................45 
15. LIST OF FIGURES ...........................................................................................................45 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................46 
ANNEX 2. ADDITIONAL INFORMATION .........................................................................46 
 

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2. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse Event 
ARB 
Angiotensin II receptor blockers 
ATC 
Anatomical Therapeutic Chemical Classification 
System 
CCI 
Charlson Comorbidity Index 
CI 
Confidence Intervals 
CIOMS 
Council for International Organizations of Medical 
Sciences 
COPD 
Chronic Obstructive Pulmonary Disease 
DOAC 
Direct Oral Anticoagulants 
DVT 
Deep Vein Thrombosis 
EMA 
European Medicines Agency 
ENCePP 
European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance 
GEP 
Good Epidemiological Practice 
GPP 
Guidelines for Good Pharmacoepidemiology 
Practices 
GI 
Gastrointestinal 
HAS-BLED 
Hypertension, Abnormal renal and liver function, 
Stroke, Bleeding history or predisposition, Labile 
international normalized ratio (INR), Elderly (> 65 
years), Drugs or alcohol concomitantly 
HIRA 
Health Insurance Review and Assessment Service 

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HIRA-NPS 
Health Insurance Review and Assessment Service-
National Patient Sample 
HR 
Hazard Ratios 
ICD-10 
International Classification of Diseases, 10th 
Revision 
IQR 
Interquartile Range 
IEA 
International Epidemiological Association  
IRB 
Institutional Review Board 
ISPE 
International Society for Pharmacoepidemiology 
ISPOR 
International Society for Pharmacoeconomics and 
Outcomes Research 
LMWH 
Low Molecular Weight Heparin 
NDC 
National Drug Code 
NOAC 
Non-vitamin K Antagonist Oral Anticoagulants 
NSAIDs 
Nonsteroidal Anti-inflammatory Drugs 
NVAF 
Non-Valvular Atrial Fibrillation 
OAC 
Oral Anticoagulant 
PAC 
Parenteral Anticoagulants 
PASS 
Post-Authorisation Safety Study 
PE 
Pulmonary Embolism 
PPV 
Positive Predictive Value 
PS 
Propensity Score 
RCT 
Randomized Controlled Trial 
SD 
Standardized Difference 

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SSRI 
Selective serotonin reuptake inhibitors 
STD 
Standard Deviation 
UFH 
Unfractionated Heparin 
VKA 
Vitamin K Antagonist 
VTE 
Venous Thromboembolism 
 

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4. ABSTRACT 
• Protocol title 
Treatment patterns and clinical outcomes among venous thromboembolism patients 
treated with anticoagulants after the entry of non-vitamin K antagonist oral 
anticoagulants in Korea 
• Protocol version and date 
2.0, 27 Apr 2022 
 
• Rationale and background 
Venous Thromboembolism (VTE), which includes deep vein thrombosis (DVT) and 
pulmonary embolism (PE), is a major cause of morbidity, mortality and healthcare 
expenditure. Although the occurrence of VTE in the Asian population has been lower 
than that in Western populations, its incidence has been reported to have increased 
rapidly in recent years. 
For pharmacologic treatment of patients with VTE without cancer, the American College 
of Chest Physicians (CHEST) guidelines recommend the use of Non-Vitamin K 
antagonist oral anticoagulants (NOACs) over Vitamin K Antagonists (VKAs), with 
supporting evidences suggesting that each NOAC (e.g., apixaban) is effective at 
preventing recurrent VTE. In more recent treatment guidelines for the management of 
VTE released by the American Society of Hematology (ASH), NOACs are still 
recommended over VKAs for the initial management of VTE. NOACs are classified as a 
new generation of anticoagulants with approved indications of the risk reduction of stroke 
and embolism in nonvalvular atrial fibrillation (NVAF) as well as prophylaxis and 
treatment of DVT and PE. 
All NOACs became available as the first-line treatment of acute VTE in Korea after 
reimbursement expansion in May 2015. However, despite the increasing use of NOACs 
among VTE patients, there are still limited real-world evidence that assess treatment 
patterns as well as effectiveness and safety of the different anticoagulants especially 
among Asian population.  
• Research question and objectives 
Research question 
- 
What is the real-world evidence of anticoagulant treatment for patients with VTE that 
can be found in the nationwide claims database in Korea? 
The current study will take place in two phases: 

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Phase I involves a descriptive assessment of VTE patient characteristics and treatment 
patterns in Korea as well as detailed power calculations for comparative analyses. 
Phase II involves analyses of comparative safety between each NOAC and warfarin. 
These analyses will be implemented if there is sufficient power to enable scientifically 
valid inferences. 
Primary objectives of Phase I of the study 
- 
To describe the sociodemographic and clinical characteristics of patients with VTE, 
overall and according to ther index VTE treatment (parenteral anticoagulants [PAC] 
only, warfarin-based, NOAC-based)To describe index anticoagulant treatment 
patterns by investigating the utilization of different anticoagulants, treatment 
interruption, switches, discontinuations, and overall treatment duration 
Primary objective of Phase II of the study 
- 
To describe and compare the risk of clinical outcome (major bleeding) according to 
the specific type of OAC 
[NOTE] Comparative analyses, especially NOAC vs NOAC direct comparisons, will be 
performed contingent on a feasibility assessment based on the descriptive analyses and 
the agreed opinion on scope after discussion with Eliquis Alliance Real World Data 
Review Committee. 
Secondary objective of Phase I of the study 
- 
To explore the relevant clinical events preceding treatment change from index 
anticoagulant 
• Study design 
- 
Retrospective, observational, nationwide population-based cohort study 
• Population 
Study period 
- 
1 Mar 2012 to 31 Dec 2019 
Inclusion criteria 
- 
Incident VTE diagnosis in an inpatient or outpatient setting (International 
Classification of Diseases 10th Revision [ICD-10]: I26.0, I26.9, I80.2, I80.3) between 
1 Mar 2013 and 30 Jun 2019. 

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- 
Received anticoagulation therapy (all medication codes for anticoagulants approved 
for VTE in Korea; unfractionated heparin [UFH], low molecular weight heparin 
[LMWH], warfarin, and NOACs) within 30 days of their VTE diagnosis (the index 
date will be defined as the date of treatment initiation with anticoagulants) 
- 
Aged ≥18 years at index date 
Exclusion criteria 
- 
A record of VTE diagnosis within the 12-month period prior to the index VTE 
encounter 
- 
Diagnosed with atrial fibrillation, atrial flutter, mechanical heart valve replacement or 
mitral stenosis anytime prior to index date 
- 
Had a record of Inferior Vena Cava filter anytime prior to index date 
- 
Received anticoagulation therapy within the 12-month period prior to index VTE 
encounter to restrict to new users of anticoagulation therapy 
- 
Prescribed two different anticoagulants on the same index date to prevent exposure 
misclassification 
- 
Had a record of pregnancy within the 9-month period prior to index date 
Additional exclusion criteria for comparative analyses 
- 
Had a record of active cancer, defined as first diagnosis of cancer with V code (a 
special code applied to patients with confirmed diagnosis of cancer by Korean 
Ministry of Health and Welfare for reimbursement for 5 years or longer if 
recurrent/metastatic) within the past 6 months of period prior to index date; or 
receiving anti-cancer treatment (chemotherapy, radiation therapy, or cancer-related 
surgery) under cancer diagnosis with V code within the past 6 months period prior to 
index date 
Follow-up 
- 
Phase I of the study: Patients will be followed-up from the index date until the 
earliest of in-hospital death or end of the study period (31 Dec 2019). 
- 
Phase II of the study: Patients will be followed-up from the index date until the 
earliest of outcome occurrence (bleeding event), treatment discontinuation, switch to 
another anticoagulant, in-hospital death, or end of the study period (31 Dec 2019), 
where patients will be considered to have discontinued treatment when new 
prescription is absent within the 30-day grace period after the end of the former 
prescription. 

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• Variables 
Exposure(s) 
- 
Anticoagulant therapy (PAC [LMWH, UFH, others], NOACs [apixaban, dabigatran, 
rivaroxaban, edoxaban], warfarin). 
Outcome(s) 
- 
Phase I of the study: sociodemographic and clinical characteristics of patients with 
VTE, utilization of index anticoagulant treatment, treatment patterns (including 
treatment interruption, switching, complete discontinuation), overall treatment 
duration, and clinical events preceding first treatment change 
- 
Phase II of the study: Primary or secondary diagnosis with major bleeding (by site: 
intracranial, gastrointestinal [GI], and other sites) after the index date 
Covariate(s) 
- 
Sociodemographics (age, sex) will be assessed on the index date. Clinical 
characteristics including comorbidities, previous use of medications, and the number 
of outpatient visits will be assessed within the 6-month period prior to the index date 
• Data sources 
- 
South Korea’s Health Insurance and Review Assessment Service (HIRA) database 
• Study size 
- 
The estimated number of incident patients with VTE and no history of active cancer 
from the 2018 HIRA-National Patient Sample (HIRA-NPS) database is 1,465, where 
the HIRA-NPS database is a 3% random sample of the entire Korean population of 
50 million. Based on this estimation, the projected number of patients with VTE from 
the entire Korean population (HIRA database) of 2018 is 48,828 (1,465 * 33.33). 
 Excluding period for patients with previous OAC treatment,VTE history or a 
history of active cancer was set to prior 3 months because HIRA NPS database 
used in sample size estimation was constituted of one-year data only.   
1) Apixaban vs. warfarin 
- 
Among the above-mentioned number of incident patients with VTE and no history of 
active cancer, those who newly initiated apixaban or warfarin was estimated to be 
211 patients (14.4%; 211/1,465), where patients had no prescription for OACs and no 
history of VTE within the 3-month period prior to VTE diagnosis. From these 211 
patients, there were 83 (39.3%) apixaban users and 128 (60.7%) warfarin users 

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(based on 2018 HIRA-NPS data). Hence, the projected number of patients with VTE 
who newly initiated OACs to be present in the HIRA database in a single year is 
7,032 patients (apixaban 2,766; warfarin 4,266). As this study aims to utilize data 
from 2013 to 2019 (7 years), the final projected number of patients with VTE who 
newly initiated apixaban or warfarin from the HIRA database is 49,224 patients 
(apixaban 19,362; warfarin 29,862). 
- 
Considering a 95% for a two-sided CI level (α-error=0.05) and 80% power, the 
sample size for the comparative safety study for major bleeding events was 
calculated based on the following components:  
 HR for major bleeding events from previous literature: 0.31-0.75 
 Overall probability of major bleeding events from previous literature: 1.19% 
 Proportion of apixaban users among patients with VTE from the 2018 HIRA-
NPS database: 39.3% (83 apixaban users; 128 warfarin users). 
 2,013 patients with VTE treated with apixaban or warfarin are required to detect 
at 5% α-error, and 80% statistical power, and HR of 0.31 by sample size 
calculations for survival analysis; alternatively (more conservative estimate), 
33,340 patients with VTE treated with apixaban or warfarin are required to 
detect at 5% α-error, and 80% statistical power, and HR of 0.75 by sample size 
calculations for survival analysis. 
 As this study is expected to include 49,224 patients with VTE, with 19,362 
patients treated with apixaban from the nationwide HIRA database, this study 
will have enough statistical power to test the hypothesis of the association 
between apixaban use and risk of bleeding events among patients with VTE. 
2) Rivaroxaban vs. warfarin 
- 
Among the above-mentioned number of incident patients with VTE and no history of 
active cancer, those who newly initiated rivaroxaban or warfarin was estimated to be 
382 patients (26.1%; 382/1,465), where patients had no prescription for OACs and no 
history of VTE within the 3-month period prior to VTE diagnosis. From these 382 
patients, there were 264 (69.1%) rivaroxaban users and 118 (30.9%) warfarin users 
(based on 2018 HIRA-NPS data). Hence, the projected number of patients with VTE 
who newly initiated OACs to be present in the HIRA database in a single year is 
12,732 patients (rivaroxaban 8,799; warfarin 3,933). As this study aims to utilize data 
from 2013 to 2019 (7 years), the final projected number of patients with VTE who 
newly initiated rivaroxaban or warfarin from the HIRA database is 89,124 patients 
(rivaroxaban 61,593; warfarin 27,531). 

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- 
Considering a 95% for a two-sided CI level (α-error=0.05) and 80% power, the 
sample size for the comparative safety study for major bleeding events was 
calculated based on the following components:  
 HR for major bleeding events from previous literature: 0.77-1.19 
 Overall probability of major bleeding events from previous literature: 8.1% 
 Proportion of rivaroxaban users among patients with VTE from the 2018 HIRA-
NPS database: 69.1% (264 rivaroxaban users; 118 warfarin users). 
 6,630 patients with VTE treated with rivaroxaban or warfarin are required to 
detect at 5% α-error, and 80% statistical power, and HR of 0.77 by sample size 
calculations for survival analysis; alternatively (more conservative estimate), 
14,967 patients with VTE treated with rivaroxaban or warfarin are required to 
detect at 5% α-error, and 80% statistical power, and HR of 1.19 by sample size 
calculations for survival analysis. 
 As this study is expected to include 89,124 patients with VTE, with 61,593 
patients treated with rivaroxaban from the nationwide HIRA database, this study 
will have enough statistical power to test the hypothesis of the association 
between rivaroxaban use and risk of bleeding events among patients with VTE. 
3) Edoxaban vs. warfarin 
- 
Among the above-mentioned number of incident patients with VTE and no history of 
active cancer, those who newly initiated edoxaban or warfarin was estimated to be 
184 patients (12.6%; 184/1,465), where patients had no prescription for OACs and no 
history of VTE within the 3-month period prior to VTE diagnosis. From these 184 
patients, there were 57 (31.0%) edoxaban users and 127 (69.0%) warfarin users 
(based on 2018 HIRA-NPS data). Hence, the projected number of patients with VTE 
who newly initiated OACs to be present in the HIRA database in a single year is 
6,132 patients (edoxaban 1,900; warfarin 4,232). As this study aims to utilize data 
from 2013 to 2019 (7 years), the final projected number of patients with VTE who 
newly initiated edoxaban or warfarin from the HIRA database is 42,924 patients 
(edoxaban 13,300; warfarin 29,624). 
- 
Considering a 95% for a two-sided CI level (α-error=0.05) and 80% power, the 
sample size for the comparative safety study for major bleeding events was 
calculated based on the following components:  
 HR for major bleeding events from previous literature: 0.56-0.81 
 Overall probability of major bleeding events from previous literature: 8.5% 

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 Proportion of edoxaban users among patients with VTE from the 2018 HIRA-
NPS database: 31.0% (57 edoxaban users; 127 warfarin users). 
 1,282 patients with VTE treated with edoxaban or warfarin are required to detect 
at 5% α-error, and 80% statistical power, and HR of 0.56 by sample size 
calculations for survival analysis; alternatively (more conservative estimate), 
9,703 patients with VTE treated with edoxaban or warfarin are required to detect 
at 5% α-error, and 80% statistical power, and HR of 0.81 by sample size 
calculations for survival analysis. 
 As this study is expected to include 42,924 patients with VTE, with 13,300 
patients treated with edoxaban from the nationwide HIRA database, this study 
will have enough statistical power to test the hypothesis of the association 
between edoxaban use and risk of bleeding events among patients with VTE. 
4) Dabigatran vs. warfarin 
- 
Among the above-mentioned number of incident patients with VTE and no history of 
active cancer, those who newly initiated dabigatran or warfarin was estimated to be 
155 patients (10.6%; 155/1,465), where patients had no prescription for OACs and no 
history of VTE within the 3-month period prior to VTE diagnosis. From these 155 
patients, there were 26 (16.8%) dabigatran users and 129 (83.2%) warfarin users 
(based on 2018 HIRA-NPS data). Hence, the projected number of patients with VTE 
who newly initiated OACs to be present in the HIRA database in a single year is 
5,166 patients (dabigatran 866; warfarin 4,299). As this study aims to utilize data 
from 2013 to 2019 (7 years), the final projected number of patients with VTE who 
newly initiated dabigatran or warfarin from the HIRA database is 36,162 patients 
(dabigatran 6,062; warfarin 30,093). 
- 
Considering a 95% for a two-sided CI level (α-error=0.05) and 80% power, the 
sample size for the comparative safety study for major bleeding events was 
calculated based on the following components:  
 HR for major bleeding events from previous literature: 0.52-0.69 
 Overall probability of major bleeding events from previous literature: 1.4% 
 Proportion of dabigatran users among patients with VTE from the 2018 HIRA-
NPS database: 16.8% (26 dabigatran users; 129 warfarin users). 
 9,361 patients with VTE treated with dabigatran or warfarin are required to 
detect at 5% α-error, and 80% statistical power, and HR of 0.52 by sample size 
calculations for survival analysis; alternatively (more conservative estimate), 
29,071 patients with VTE treated with edoxaban or warfarin are required to 

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detect at 5% α-error, and 80% statistical power, and HR of 0.69 by sample size 
calculations for survival analysis. 
 As this study is expected to include 36,162 patients with VTE, with 6,062 
patients treated with dabigatran from the nationwide HIRA database, this study 
will have enough statistical power to test the hypothesis of the association 
between dabigatran use and risk of bleeding events among patients with VTE. 
• Data analysis 
- 
Descriptive analysis will be conducted separately in two cohorts of non-cancer VTE 
and cancer VTE patients according to co-presence of active cancer. 
- 
We will use descriptive statistics to describe the baseline sociodemographic and 
clinical characteristics of patients with VTE and present them as mean and standard 
deviation (STD) for continuous variables or counts with proportions for categorical 
variables. Significance test will be conducted between the three treatment groups of 
interest using analysis of variance for continuous variables and chi-square test for 
categorical variables. 
- 
We will describe the utilization pattern of anticoagulant treatments among patients 
with VTE as counts with proportions. We will also estimate the treatment patterns 
(including treatment interruption, switches, discontinuation) and the overall treatment 
duration as median (interquartile range [IQR]) or mean (STD) by each index 
anticoagulant treatment. To identify potential reasons for treatment change, clinical 
events preceding the first treatment change will be measured within 30 days prior to 
the first date of treatment change. 
- 
We will calculate the incidence of major bleeding overall and by  site per 1,000 
person-years based on the Poisson distribution. We will estimate propensity scores 
(PS) using multivariable logistic regression models for the likelihood of receiving 
each NOAC or warfarin, conditioned on baseline sociodemographic and clinical 
characteristics. We will use multivariable Cox proportional hazard regression models 
to estimate HRs with 95% CIs for the risk of major bleeding associated with each 
OAC use, as compared with other OAC, with the PS applied as inverse probability of 
treatment weights to minimize residual confounding bias and increase comparability 
between treatment groups. 
- 
All analyses will be conducted using SAS Enterprise Guide 7.1 (SAS Institute Inc, 
Cary, NC), provided by HIRA through a virtual access machine. 
• Milestones 

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- 
The results of this study are anticipated in Q2 2022. The expected completion date of 
preliminary analyis is Q3 2021 and the final report in Q3 2022. The milestones are 
dependent on receipt of requested dataset from HIRA. 

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5. AMENDMENTS AND UPDATES 
Amendment 
number 
Date 
Protocol 
section(s) 
changed 
Summary of amendment(s) 
Reason 
Amendment 
1 (V.2.0) 
28Mar20
22 
Study 
information 
Changed index treatment grouping to 
PAC only, warfarin-based, and 
NOAC-based therapy. 
Amendment following Protocol 
Administrative Change Letter in Oct 
22, 2021 
Updated author information 
Revised due to author’s title change 
4. Abstract 
Changed index treatment grouping to 
PAC only, warfarin-based, and 
NOAC-based therapy. 
Amendment following Protocol 
Administrative Change Letter in Oct 
22, 2021 
Added secondary objective of Phase I 
Revised according to additional 
analysis in Phase I 
Added outcome for secondary 
objective of Phase I 
Revised data analysis for additional 
analyses  
6. Milestones 
Updated planned dates to study 
milestones  
Revised due to change in study 
schedule 
8. Research 
question and 
objectives 
Added secondary objective of Phase I  
 
Revised according to additional 
analysis in Phase I 
9.1 Study design 
Updated Figure 1 and Figure 2 
Amendment following Protocol 
Administrative Change Letter in Oct 
22, 2021 
9.3 Variables 
Revised the sentence regarding 
heparin bridging period 
Amendment following Protocol 
Administrative Change Letter in Oct 
22, 2021 (acute heparin therapy to be 
considered in all OACs) 
Added outcome definition for 
secondary objective of Phase I 
Added according to additional 
analysis in Phase I 
Revised evaluation period of 
comorbidies (APS, history of cancer) 
Amendment following Protocol 
Administrative Change Letter in Oct 
22, 2021 and detailed explanation 
Added antiplatelet agents and azole 
antifungal agents 
9.7 Data analysis 
Added data analysis for secondary 
objective of Phase I 
Revised according to additional 
analysis in Phase I 
 

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6. MILESTONES 
Milestone† 
Planned date 
Institutional Review Board (IRB) approval 
1Q 2021 
HIRA data application 
1Q 2021 
Study protocol development 
1Q 2021 
Study protocol finalization and approval 
2Q 2021 
HIRA data extraction and access 
2Q 2021 
Data analysis 
3Q 2021 
Preliminary results 
3Q 2021 
Data analysis for final 
2Q 2022 
Manuscript draft 
2Q 2022 
Final study report 
3Q 2022 
Manuscript finalization and approval 
3Q 2022 
†Note that milestones are dependent on timely delivery of data provided by HIRA 
 
7. RATIONALE AND BACKGROUND 
Venous thromboembolism (VTE)  is a disorder that includes deep vein thrombosis (DVT) 
and pulmonary embolism (PE). Of VTE, DVT occurs when a blood clot forms in a deep 
vein, usually in the lower leg, thigh, or pelvis and PE occurs when a clot breaks loose and 
travels through the bloodstream to the lungs to eventually block an artery in the lung. Blood 
clots can develop in veins when damaged by surgery or trauma, or because of an 
inflammation in response to an infection or injury. Other risk factors for VTE include a 
history of a previous VTE event, comorbidities such as cancer or spinal cord injury, 
pregnancy, paralysis or long periods of immobilization, specific genes, and certain 
circumstances related to age, race, and sex. As a previous VTE event is a strong risk factor 
for the onset of VTE, recurrence of VTE is common, with a previous study reporting that 
approximately 30% of patients who experienced VTE will develop recurrent VTE within 10 
years of their initial event [1]. With high rates of recurrence and mortality, as well as 
increased long‐term morbidity and functional disability, VTE remains a major public health 
concern with a substantial disease burden [2] [3]. 
For pharmacologic treatment of patients with VTE without cancer, the American College of 
Chest Physicians (CHEST) guidelines recommend the use of non-vitamin K antagonist oral 

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anticoagulants (NOACs) over Vitamin K Antagonists (VKAs), with supporting evidence 
suggesting that each NOAC (e.g., apixaban) is effective at preventing recurrent VTE [4]. 
More recently, in the treatment guidelines for management of VTE released by the American 
Society of Hematology (ASH), NOACs are still recommended over VKAs for the initial 
management of VTE [5]. 
NOACs, or also known as direct oral anticoagulants (DOACs), are a relatively new 
generation of anticoagulants approved by the US FDA; dabigatran, rivaroxaban, apixaban, 
and edoxaban were approved in October 2010, July 2011, December 2012, and January 
2015, respectively, for treatment indication of risk reduction of stroke and embolism in 
nonvalvular atrial fibrillation (NVAF) [6]. These NOACs have also been approved for 
prophylaxis and treatment of DVT and PE, which comprise VTE [7, 8]. Compared with 
VKAs, NOACs have fewer drug interactions, food interactions, and adverse effects and 
therefore, do not require frequent laboratory monitoring or dosage adjustments [4, 9]. Among 
NOACs, apixaban and rivaroxaban were approved as a single-drug approach for the 
treatment of VTE and do not require initial parenteral treatment with low molecular weight 
heparin (LMWH) or unfractionated heparin (UFH) [10, 11]. In actual real-world clinical 
practice, the two aforementioned NOACs are the most widely used and preferred treatments 
for VTE and preventing its recurrence [12-14]. Although NOACs demonstrated better safety 
profile than VKAs, concerns regarding their risk of adverse bleeding events remain due to 
their mechanism of action [15]. 
With both conventional and new anticoagulant therapies being used in real-world clinical 
practice, it is necessary to identify the utilization characteristics of individual anticoagulant 
treatments through the analysis of nationwide claims database. It is important to examine the 
treatment pattern and assess whether Korean patients are being treated appropriately based on 
the current treatment guidelines. 
Several previous studies evaluated comparative effectiveness and safety of apixaban versus 
warfarin in patients with VTE. According to the AMPLIFY trial, the use of apixaban was 
non-inferior to conventional therapy for the treatment of VTE (relative risk [RR] 0.84, 95% 
confidence interval [CI] 0.60-1.18) and was superior to the bleeding event (RR 0.44, 95% CI 
0.36-0.55) [10]. In the same manner as the results of the clinical trial, 
pharmacoepidemiologic studies reflecting real-world practice showed consistent results [16, 
17]. However, those studies were focused on the western population, and the evidence on the 
effectiveness and safety of warfarin and apixaban from real-world clinical practice among the 
Asian population with venous thromboembolism is still limited. Of the NOACs, both 
apixaban and rivaroxaban are known to have low rates of major bleeding events[18, 19]. One 
US population-based retrospective cohort study compared the risk of major bleeding events 
between apixaban and rivaroxaban in patients with VTE [20]. According to the study’s 
findings, the use of apixaban was associated with a reduced risk of major bleeding events 
when compared to rivaroxaban use (hazard ratio [HR] 0.54, 95% confidence interval [CI] 
0.37-0.82). Although findings suggest a significant protective effect on major bleeding events 
associated with apixaban, more studies are needed to provide evidence on the different risk 
of major bleeding events between apixaban and other OACs in various ethnic populations. 

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Therefore, through this retrospective study utilizing Korean national claims database, we aim 
to 1) describe the clinical characteristics and anticoagulant treatment pattern of Korean VTE 
patients and 2) evaluate the safety outcome of current anticoagulant therapy regarding 
bleeding. 
 
8. RESEARCH QUESTION AND OBJECTIVES 
Research Question 
What is the real-world evidence of anticoagulant treatment for patients with VTE that can be 
found in the nationwide claims database in Korea? The current study will take place in two 
phases: 
Phase I involves a descriptive assessment of patient characteristics and treatment patterns in 
Korea as well as detailed power calculations for comparative study. 
Phase II involves analyses of comparative safety between each NOAC and warfarin. These 
analyses will be implemented if there is sufficient power to enable scientifically valid 
inferences. 
Primary Objectives of Phase I of the study 
- 
To describe the sociodemographic and clinical characteristics of patietns with VTE, 
overall and according to ther index VTE treatment (PAC only, warfarin-based, 
NOAC-based) 
- 
To describe index anticoagulant treatment patterns by investigating the utilization of 
different anticoagulants, treatment interruption, switches, discontinuations, and 
overall treatment duration 
Primary Objective of Phase II of the study 
- 
To describe and compare the risk of clinical outcome (major bleeding) according to 
the specific type of OAC 
[NOTE] Comparative analyses, especially NOAC vs NOAC direct comparisons, will be 
performed contingent on a feasibility assessment based on the descriptive analyses and 
agreed opinion on scope after discussion with Eliquis Alliance Real World Data Review 
Committee. 
Secondary objective of Phase I of the study 
- 
To explore the relevant clinical events preceding treatment change from index 
anticoagulant 

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9. RESEARCH METHODS  
9.1. Study design  
A retrospective, observational, nationwide population-based cohort study will be conducted 
to describe the treatment patterns of anticoagulation therapies prescribed to patients with 
VTE in South Korea, and assess the risk of major bleeding associated with apixaban and 
other NOACs use, as compared with warfarin, by using the Health Insurance Review and 
Assessment Service (HIRA) database from 1 Mar 2012 to 31 Dec 2019 (Figure 1). 
 
Figure 1. Study participants inclusion and exclusion criteria 
Note: HIRA, Health Insurance and Review Assessment service; LMWH, low molecular 
weight heparin; NOAC, non-vitamin K antagonist; PAC, parenteral anticoagulants; VTE, 
venous thromboembolism 

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†Record of active cancer is defined as first diagnosis of cancer with V code within the past 6 
months of period prior to index date; or receiving anti-cancer treatment under cancer 
diagnosis with V code within the past 6-month period prior to index date. 
‡Warfarin-based and NOAC-based include either PAC with warfarin/NOAC or 
warfarin/NOAC only. 
The study cohort will be defined as patients diagnosed with VTE between 1 Mar 2013 
and 30 Jun 2019. The cohort entry will be defined as the date of incident VTE diagnosis. The 
index date will be defined as the date of first prescription for anticoagulants within 30 days 
after the index VTE event. The length of the exclusion assessment window will vary 
depending on the condition, from 12-months at minimum to anytime prior to index date. The 
following patients will be excluded: A record of VTE diagnosis within the 12-month period 
prior to the index VTE encounter, diagnosed with atrial fibrillation, atrial flutter, mechanical 
heart valve replacement or mitral stenosis anytime prior to index date, had a record of 
Inferior Vena Cava filter anytime prior to index date, received anticoagulatory therapy within 
the 12-month period prior to index VTE encounter to restrict to new users of anticoagulatory 
therapy, prescribed two different anticoagulants on the same index date to prevent exposure 
misclassification, had a record of pregnancy within the 9-month period prior to index date, 
and for the Phase II of the study only, had a record of active cancer within six months period 
prior to index date. 
Baseline sociodemographic characteristics (e.g., age, sex) will be assessed on the index date, 
whereas clinical characteristics (comorbidities, previous use of medications, Charlson 
comorbidity index [CCI], HAS-BLED scores, initial presentation of VTE, number of 
outpatient visits) will be assessed in the 6-month period prior to the index date except when 
otherwise specfied in section 9.3 Variables (Figure 2). 

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Figure 2. Overall study schematic 
a. Baseline conditions included: Charlson comorbidity index, HAS-BLED scores, 
comorbidities (antiphospholipid syndrome, asthma, cancer, chronic obstructive 
pulmonary disease, chronic kidney disease, chronic liver disease, diabetes mellitus, 
fracture, heart failure, hyperlipidemia, hypertension, ischemic heart disease, 
myocardial infarction, stroke, trauma), previous use of medications (corticosteroids, 
nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, 

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angiotensin II receptor blockers, antiplatelet agents, azole antifungal agents, β-
blockers, calcium-channel blockers, selective serotonin reuptake inhibitors, proton 
pump inhibitors, diuretics, thiazides, vasodilators, estrogens, cyclooxygenase-2 
inhibitors), initial presentation of VTE (DVT, PE, both DVT and PE), number of 
outpatient visits 
b. Earliest of: outcome of interest (major bleeding event), treatment discontinuation, 
switch to another anticoagulant, in-hospital death, end of the study period (31 Dec 
2019) 
Note: Dx, diagnosis; NOAC, non-vitamin K antagonist oral anticoagulant; Rx, prescription; 
VTE, venous thromboembolism; PE, pulmonary embolism 
 
Within this study cohort, we will describe the treatment patterns of anticoagulants 
prescribed for VTE treatment throughout the period of follow-up, defined as the period from 
the index date to the end of the study period. Moreover, if feasible, we will also examine the 
risk of major bleeding overall and by site, associated with each NOAC use, as compared with 
warfarin. 
 
9.2. Setting 
9.2.1. Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
1. Incident VTE diagnosis in an inpatient or outpatient setting (International Classification 
of Diseases 10th Revision [ICD-10]: I26.0, I26.9, I80.2, I80.3) between 1 Mar 2013 and 
30 Jun 2019 
2. Received anticoagulation therapy (all medication codes for anticoagulants approved for 
VTE in Korea; UFH, LMWH, warfarin, and NOACs) within 30 days of their VTE 
diagnosis (the index date will be defined as the date of treatment initiation with 
anticoagulants) 
3. Aged ≥18 years at index date 
9.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
1. Had a record of VTE diagnosis (ICD-10: I26.0, I26.9, I80.2, I80.3) within the 12-month 
period prior to the index VTE encounter. 
2. Diagnosed with atrial fibrillation/flutter (ICD-10: I48), mechanical heart valve 
replacement (National Procedure Code: Z952, M6531, M6532, M6533, O1781, O1782, 

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Q2651, QA671-QA673, QA679, Q1261, Q1262,  Q2671-
Q2673, Q2679, Q2761, Q2762, Q2791-Q2794, Q2796-
Q2798, Q2890-Q2893, Q2901, Q0292, Q2921-Q2924, 
Q2927, Q2928, QA921-QA924, QA928, Q2925, Q2926, 
QA925, QA926, R3271, R3273, R3274, R3275, R3290, 
R3305, R3307, R3299, R3300, R3309, R3310, R3432, 
R3433, R3451, R3470, R3481, R3482, R3541-R3543, 
R3530, R3590, R3755, R3756, R3791, R3792, R3801, 
R3802, R3851, R3853, R3861, R3862, R3891, R3901, 
R3902, R3950, RZ512, R3960, R3975, R4003, R4004, 
R4067, R4068, R4071-R4074, R4140, R4143, R4144, 
R4147-R4149, R0141, R0142, R4154, R4155, R4156, 
R4250, R4331, R4332, R4423-R4428, P4543, P4551-
P4554, P4561, P4571, P4572, S4616, S4634-S4639, 
S6691-6696, S4694-S4696, S4707-S4709, S4743, S4756-
S4758, S4780, S4801-S4803, S4880, S4900, S4950, 
S5200, S5220, S5231, S5232, S5246, S5592, S5745, 
M6774, M6870, M6880, M6775, QZ841, M6890, M6900, 
M6991, M6910, Q0841, Q0842, N7136-N7139, N7140-
N7153, Q7221-Q7225, Q7230, Q7280-Q7285, Q7342, 
Q7380, Q7410, Q7561-Q7567, Q7571, Q7572, Q7651-
Q7654, Q7701-Q7703, QX706, Q7751, Q7752, Q7761-
Q7763,Q7766, Q7771, Q7772, Q7775, Q7788, Q7789, 
U4811, U4812, U4881-U4883 
Others 
X5131-X5137 (hemopoietic cell transplantation) 
 
9.3. Variables 
Exposure 
- 
Phase I of the study: PAC (UFH [Anatomical Therapeutic Chemical [ATC] code: 
B01AB01], LMWH [B01AB04, B01AB05, B01AB06, B01AB12]), VKA (warfarin 
[B01AA03]), NOACs (apixaban [B01AF02], rivaroxaban [B01AF01], edoxaban 
[B01AF03], dabigatran [B01AE07]) 
- 
Phase II of the study: Apixaban (B01AF02), Rivaroxaban (B01AF01), Edoxaban 
(B01AF03), Dabigatran (B01AE07), Warfarin (B01AA03) 
Outcome(s) 
- 
Phase I of the study 

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 Sociodemographic and clinical characteristics of patients with VTE who 
initiated anticoagulants. 
 Utilization of different anticoagulants at treatment initiation. Patients will be 
classified based on their index anticoagulant treatment received within 30 days 
after being diagnosed with VTE. 
 Treatment interruption from the index anticoagulant treatment, which will be 
defined as when a patient has a gap with no new treatment within 30 days of the 
estimated end of supply, but subsequently restarts the index treatment after this 
period.[21] The time to treatment interruption will be defined as the period from 
the index date to the date of treatment interruption. 
 Treatment switching will be defined as a prescription of another anticoagulant 
therapy that is started after the treatment initiation of the index anticoagulant 
treatment and within 30 days after the estimated end of supply of the index 
anticoagulant drug (exposure to the new anticoagulant treatment must last for at 
least 30 days to be considered as a treatment switch). The time to treatment 
switch will be defined as the period from the index date to the date of treatment 
switch. 
Exemption: As heparin can be initiated at acute stage of DVT/PE before clinical 
decision to use OAC, a switch from initial heparin treatment to an OAC within 2 
weeks after heparin treatment initiation will not be considered a treatment 
switch.  
 Treatment discontinuation (complete discontinuation; no reinitiation) will be 
defined as when a patient who ended their first continuous treatment episode 
with the index anticoagulant treatment without switching, and subsequently have 
no further prescriptions for that respective anticoagulant treatment during all 
available follow-up time. The time to treatment discontinuation will be defined 
as the period from the index date to the date of treatment discontinuation. 
 Overall anticoagulant treatment duration will be defined as the time period from 
the index date to the earliest of treatment interruption, switch, or discontinuation. 
 If a patient has evidence of a repeat prescription within 30 days of the end of 
their prescription and does not experience any of the above events (treatment 
interruption, switch, or discontinuation), they will be assumed to be persistent on 
treatment.[21] 
 Clinical event preceding first treatment change will be defined as occurrence of 
any event listed below within 30 days before treatment interruption, switch, or 
discontinuation. A new clinical event will be considered ‘new’ when it occurs 
for the first time within a 6-month period for acute conditions (arterial 

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MRI: HE101, HE102, 
HE135, HE201, HE202, 
HE235, HE301, HE302, 
HE401, HE402, HE501, 
HE502, HE535 
GI 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 
Diagnosis code + 
admission code 
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 
Diagnosis code + 
admission code 
- 
The earliest date of diagnosis of the major bleeding event after the index date will be 
defined as the outcome occurrence date. 
- 
Patients will be followed up from the index date to the occurrence of an outcome, 
treatment discontinuation (30-day grace period), switch to another anticoagulants, in-
hospital death, or end of the study period (31 Dec 2019) whichever comes first. 
Potential Confounder(s) 
- 
Sociodemographic characteristics such as age, sex, and index year will be assessed at 
the index date. 
- 
CCI [23] and HAS-BLED [24] scores will be measured within the 6-month period 
prior to the index date. 
- 
Initial presentation of VTE 
 DVT (I80.2, I80.3) 
 PE (I26.0, I26.9) 
 Both DVT and PE 
- 
Comorbidities (ICD-10 diagnostic code) will be measured within the 6-month period 
prior to the index date. 

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 Antiphospholipid syndrome (D68.6, I82.9): As diagnosis of antiphospholipid 
syndrome is usually made after VTE diagnosis with subsequent diagnostic 
procedures, its presence will be evaulated within the 6-month period after the 
index date. 
 Asthma (J45) 
 Cancer (C00-C97): History of cancer (non-active) will be evaluated within a 
lifetime prior to the index date. 
 Chronic obstructive pulmonary disease (COPD; J40-J44) 
 Chronic kidney disease (N18, N19) 
 Chronic liver disease (B18, B19, K70-K77) 
 Diabetes mellitus (E10-E14) 
 Fracture (S22, S32, S42, S52, S62, S72, S82, S92, T10, T12) 
 Heart failure (I50) 
 Hyperlipidemia (E78) 
 Hypertension (I10-I15) 
 Ischemic heart disease (I24, I25) 
 Myocardial infarction (I21) 
 Stroke (I60-I64, I69, G45) 
 Trauma (T79, T98, V01–V99, W11–W17, W50–W52, W64, X34–X39, Y01–
Y04, Y30–Y32) 
- 
Previous use of medications (WHO-ATC code) will be measured within the 6-month 
period prior to the index date. 
 Corticosteroids (H02) 
 Nonsteroidal anti-inflammatory drugs (NSAIDs; M01A) 
 Angiotensin-converting enzyme (ACE) inhibitors (C09A, C09B) 
 Angiotensin II receptor blockers (ARBs; C09C, C09D) 

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 Antiplatelet agents (aspirin [N02BA01], aspirin/dipyridamole [B01AC30], 
abciximab [B01AC13], beraprost [B01AC19], cilostazol [B01AC23], 
clopidogrel [B01AC04], iloprost [B01AC11], indobufen [B01AC10], limaprost 
[C04AX], ozagrel [R03DX], prasugrel [B01AC22], sarpogrelate [B01AC], 
ticagrelor [B01AC24], ticlopidine [B01AC05], tirofiban [B01AC17], 
Treprostinil [B01AC21], triflusal [B01AC18]) 
 Azole antifungal agents (fluconazole [J02AC01], itraconazole [J02AC02], 
voriconazole [J02AC03], posaconazole [J02AC04]) 
 β-blockers (C07) 
 Calcium-channel blockers (C08) 
 Selective serotonin reuptake inhibitors (SSRIs; N06AB) 
 Proton pump inhibitors (PPIs; A02BC) 
 Diuretics (C03) 
 Thiazides (C03A) 
 Vasodilators (C01D, C04A) 
 Estrogens (G03C) 
 Cyclooxygenase (COX)-2 inhibitors (M01AH) 
- 
Number of outpatient visits within the 6-month period prior to the index date. 
 
9.4. Data sources  
We will use the nationwide HIRA database of South Korea between 1 Mar 2012 and 31 Dec 
2019 to identify all variables (exposure, outcome, covariates) needed to conduct this study. 
The HIRA database includes healthcare utilization information of residents of South Korea, 
with patient identifiers anonymized. Information on age, sex, diagnosis (ICD-10 diagnostic 
code, date of diagnosis, setting of diagnosis [inpatient, outpatient, emergency department], 
and others), medications dispensed/prescribed (national drug chemical code based on the 
active ingredient, date of prescription, days’ supply, dose, route of administration, and 
others). Previous validation study that compared diagnosis codes recorded in the HIRA to 
those of recorded in electronic medical records found an overall positive predictive value 
(PPV) of 82.3%. 
 

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9.5. Study size 
Phase I of the study (descriptive) 
Not applicable as there are no specified a priori hypotheses 
Phase II of the study (comparative) 
- 
The estimated number of incident patients with VTE and no history of active cancer 
from the 2018 HIRA-National Patient Sample (HIRA-NPS) database is 1,465, where 
the HIRA-NPS database is a 3% random sample of the entire Korean population of 
50 million. Based on this estimation, the projected number of patients with VTE from 
the entire Korean population (HIRA database) of 2018 is 48,828 (1,465 * 33.33). 
 Excluding period for patients with previous OAC treatment,VTE history or a 
history of active cancer was set to prior 3 months because HIRA NPS database 
used in sample size estimation was constituted of one-year data only.   
1) Apixaban vs. warfarin 
- 
Among the above-mentioned number of incident patients with VTE and no history of 
active cancer, those who newly initiated apixaban or warfarin was estimated to be 
211 patients (14.4%; 211/1,465), where patients had no prescription for OACs and no 
history of VTE within the 3-month period prior to VTE diagnosis. From these 211 
patients, there were 83 (39.3%) apixaban users and 128 (60.7%) warfarin users 
(based on 2018 HIRA-NPS data). Hence, the projected number of patients with VTE 
who newly initiated OACs to be present in the HIRA database in a single year is 
7,032 patients (apixaban 2,766; warfarin 4,266). As this study aims to utilize data 
from 2013 to 2019 (7 years), the final projected number of patients with VTE who 
newly initiated apixaban or warfarin from the HIRA database is 49,224 patients 
(apixaban 19,362; warfarin 29,862). 
- 
Considering a 95% for a two-sided CI level (α-error=0.05) and 80% power, the 
sample size for the comparative safety study for major bleeding events was 
calculated based on the following components:  
 HR for major bleeding events from previous literature: 0.31-0.75 
 Overall probability of major bleeding events from previous literature: 1.19% 
 Proportion of apixaban users among patients with VTE from the 2018 HIRA-
NPS database: 39.3% (83 apixaban users; 128 warfarin users). 
 2,013 patients with VTE treated with apixaban or warfarin are required to detect 
at 5% α-error, and 80% statistical power, and HR of 0.31 by sample size 
calculations for survival analysis; alternatively (more conservative estimate), 

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33,340 patients with VTE treated with apixaban or warfarin are required to 
detect at 5% α-error, and 80% statistical power, and HR of 0.75 by sample size 
calculations for survival analysis. 
 As this study is expected to include 49,224 patients with VTE, with 19,362 
patients treated with apixaban from the nationwide HIRA database, this study 
will have enough statistical power to test the hypothesis of the association 
between apixaban use and risk of bleeding events among patients with VTE. 
2) Rivaroxaban vs. warfarin 
- 
Among the above-mentioned number of incident patients with VTE and no history of 
active cancer, those who newly initiated rivaroxaban or warfarin was estimated to be 
382 patients (26.1%; 382/1,465), where patients had no prescription for OACs and no 
history of VTE within the 3-month period prior to VTE diagnosis. From these 382 
patients, there were 264 (69.1%) rivaroxaban users and 118 (30.9%) warfarin users 
(based on 2018 HIRA-NPS data). Hence, the projected number of patients with VTE 
who newly initiated OACs to be present in the HIRA database in a single year is 
12,732 patients (rivaroxaban 8,799; warfarin 3,933). As this study aims to utilize data 
from 2013 to 2019 (7 years), the final projected number of patients with VTE who 
newly initiated rivaroxaban or warfarin from the HIRA database is 89,124 patients 
(rivaroxaban 61,593; warfarin 27,531). 
- 
Considering a 95% for a two-sided CI level (α-error=0.05) and 80% power, the 
sample size for the comparative safety study for major bleeding events was 
calculated based on the following components:  
 HR for major bleeding events from previous literature: 0.77-1.19 
 Overall probability of major bleeding events from previous literature: 8.1% 
 Proportion of rivaroxaban users among patients with VTE from the 2018 HIRA-
NPS database: 69.1% (264 rivaroxaban users; 118 warfarin users). 
 6,630 patients with VTE treated with rivaroxaban or warfarin are required to 
detect at 5% α-error, and 80% statistical power, and HR of 0.77 by sample size 
calculations for survival analysis; alternatively (more conservative estimate), 
14,967 patients with VTE treated with rivaroxaban or warfarin are required to 
detect at 5% α-error, and 80% statistical power, and HR of 1.19 by sample size 
calculations for survival analysis. 
 As this study is expected to include 89,124 patients with VTE, with 61,593 
patients treated with rivaroxaban from the nationwide HIRA database, this study 
will have enough statistical power to test the hypothesis of the association 
between rivaroxaban use and risk of bleeding events among patients with VTE. 

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3) Edoxaban vs. warfarin 
- 
Among the above-mentioned number of incident patients with VTE and no history of 
active cancer, those who newly initiated edoxaban or warfarin was estimated to be 
184 patients (12.6%; 184/1,465), where patients had no prescription for OACs and no 
history of VTE within the 3-month period prior to VTE diagnosis. From these 184 
patients, there were 57 (31.0%) edoxaban users and 127 (69.0%) warfarin users 
(based on 2018 HIRA-NPS data). Hence, the projected number of patients with VTE 
who newly initiated OACs to be present in the HIRA database in a single year is 
6,132 patients (edoxaban 1,900; warfarin 4,232). As this study aims to utilize data 
from 2013 to 2019 (7 years), the final projected number of patients with VTE who 
newly initiated edoxaban or warfarin from the HIRA database is 42,924 patients 
(edoxaban 13,300; warfarin 29,624). 
- 
Considering a 95% for a two-sided CI level (α-error=0.05) and 80% power, the 
sample size for the comparative safety study for major bleeding events was 
calculated based on the following components:  
 HR for major bleeding events from previous literature: 0.56-0.81 
 Overall probability of major bleeding events from previous literature: 8.5% 
 Proportion of edoxaban users among patients with VTE from the 2018 HIRA-
NPS database: 31.0% (57 edoxaban users; 127 warfarin users). 
 1,282 patients with VTE treated with edoxaban or warfarin are required to detect 
at 5% α-error, and 80% statistical power, and HR of 0.56 by sample size 
calculations for survival analysis; alternatively (more conservative estimate), 
9,703 patients with VTE treated with edoxaban or warfarin are required to detect 
at 5% α-error, and 80% statistical power, and HR of 0.81 by sample size 
calculations for survival analysis. 
 As this study is expected to include 42,924 patients with VTE, with 13,300 
patients treated with edoxaban from the nationwide HIRA database, this study 
will have enough statistical power to test the hypothesis of the association 
between edoxaban use and risk of bleeding events among patients with VTE. 
4) Dabigatran vs. warfarin 
- 
Among the above-mentioned number of incident patients with VTE and no history of 
active cancer, those who newly initiated dabigatran or warfarin was estimated to be 
155 patients (10.6%; 155/1,465), where patients had no prescription for OACs and no 
history of VTE within the 3-month period prior to VTE diagnosis. From these 155 
patients, there were 26 (16.8%) dabigatran users and 129 (83.2%) warfarin users 
(based on 2018 HIRA-NPS data). Hence, the projected number of patients with VTE 

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who newly initiated OACs to be present in the HIRA database in a single year is 
5,166 patients (dabigatran 866; warfarin 4,299). As this study aims to utilize data 
from 2013 to 2019 (7 years), the final projected number of patients with VTE who 
newly initiated dabigatran or warfarin from the HIRA database is 36,162 patients 
(dabigatran 6,062; warfarin 30,093). 
- 
Considering a 95% for a two-sided CI level (α-error=0.05) and 80% power, the 
sample size for the comparative safety study for major bleeding events was 
calculated based on the following components:  
 HR for major bleeding events from previous literature: 0.52-0.69 
 Overall probability of major bleeding events from previous literature: 1.4% 
 Proportion of dabigatran users among patients with VTE from the 2018 HIRA-
NPS database: 16.8% (26 dabigatran users; 129 warfarin users). 
 9,361 patients with VTE treated with dabigatran or warfarin are required to 
detect at 5% α-error, and 80% statistical power, and HR of 0.52 by sample size 
calculations for survival analysis; alternatively (more conservative estimate), 
29,071 patients with VTE treated with edoxaban or warfarin are required to 
detect at 5% α-error, and 80% statistical power, and HR of 0.69 by sample size 
calculations for survival analysis. 
 As this study is expected to include 36,162 patients with VTE, with 6,062 
patients treated with dabigatran from the nationwide HIRA database, this study 
will have enough statistical power to test the hypothesis of the association 
between dabigatran use and risk of bleeding events among patients with VTE. 
 
9.6. Data management  
Data management (data programming and analysis) will be conducted on secure servers with 
regular backup provided by HIRA. All statistical analyses will be performed using SAS 
Enterprise Guide 7.1 (SAS Institute Inc., Cary, NC, USA), provided by HIRA through a 
virtual access machine. 
 
9.7. Data analysis  
Phase I of the study (descriptive) 
Main Analysis 

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- 
Descriptive analysis will be conducted separately in two cohorts of non-cancer VTE 
and cancer VTE patients according to co-presence of active cancer. 
- 
Sociodemographic and clinical characteristics will be summarized with means 
(standard deviations [STD]) or median (interquartile range [IQR]) for continuous 
variables and with count (proportions) for categorical variables for the three 
treatment groups of interest: PAC only (UFH, LMWH, UFH+LMWH), warfarin-
based (warfarin, PAC/warfarin) group, NOAC-based (NOAC, PAC/NOAC) group. 
Analysis of variance, and chi-square test will be conducted for continuous variables, 
and categorical variables, respectively.  
 In order to distinguish between PAC bridging therapy and PAC treatment, we 
will apply a time restriction of 2 weeks to PAC bridging therapy. 
- 
Temporal trend in anticoagulation therapy for VTE will be presented between 1 Mar 
2013 and 30 Jun 2019. Proportions of the index OACs will be estimated according to 
calendar year and quarter. 
- 
The number and percentage of patients who discontinue treatment completely, 
experience treatment interruption and treatment switch during their follow-up will be 
described by the index anticoagulant treatment received. Results will be limited to 
the first of each of these events for each patient. For patients experiencing a treatment 
switch, the new treatment will be described at the time of their first switcher per 
individual drug.  
- 
The duration of the index treatment by the index anticoagulant treatment received 
will also be summarized in terms of days using descriptive statistics (mean [STD], 
median [IQR]). 
- 
The Kaplan-Meier method will be applied to derive the empirical distribution of time 
to each of the treatment endpoints of interest (e.g., treatment discontinuation or 
switch); these analyses will be performed per index anticoagulant treatment received 
and no comparisons will be made. Log-rank test will be conducted at the 3-, and 6 
months after treatment initiation to assess statistical significance between the survival 
curves among three treatment groups of interest. Persistent rate will also be 
calculated at the same time point. 
- 
In the NOAC-based group, all analyses will be repeated stratified by each individual 
NOAC class (e.g, apixaban, dabigatran, rivaroxaban, edoxaban) to identify the 
difference in baseline characteristics and treatment patterns between each NOAC 
class. 
- 
To identify potential reasons for treatment change, clinical events preceding the first 
treatment change (major bleeding, thromboembolism diagnosis, complications of 
VTE, major surgery, active cancer, a new diagnosis of CKD or AKI, a new diagnosis 

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of liver disease or abnormal liver function) will be measured within 30 days prior to 
the first date of treatment change. Patients can contribute with multiple events.  
- 
All analyses of treatment patterns will be presented stratified according to the index 
anticoagulant treatment, and not overall or per drug class. 
Phase II of the study (comparative) 
Propensity score analysis 
- 
To balance and adjust for any potential differences in baseline sociodemographic and 
clinical characteristics between treatment groups, propensity score (PS) methods will 
be implemented. 
 A logistic regression model will be used to estimate the predicted probability 
(propensity) of initiating each NOAC compared with warfarin given baseline 
covariates mentioned above. By using the estimated PS, we will apply the PS 
based on the inverse probability of treatment weights (IPTW), where the 
treatment group of interest will be given a weight of 1/PS, and the comparator 
group will be given a weight of 1/(1-PS) [25, 26]. The most extreme 1% of PS 
values (IPTW with trimming) will be excluded to improve comparability 
between exposure groups. 
Main Analysis 
- 
Sociodemographic and clinical characteristics will be summarized with means (STD) 
or median (IQR) for continuous variables and with count (proportions) for 
categorical variables for the two treatment comparisons of: apixaban vs warfarin,  
rivaroxaban vs warfarin, edoxaban vs. warfarin and dabigatran vs. warfarin (and 
NOAC vs. NOAC, if scientifically feasible). 
 Differences in baseline covariates between users of different OACs will be 
assessed using the SD where the absolute SD <0.1 will be considered as well 
balanced. 
- 
The incidence rate of major bleeding overall and by site will be presented as the total 
number of events per 1,000 person-years, with its 95% CIs estimated using the 
Poisson distribution. 
- 
The risk of major bleeding according to the treatment of interest will be investigated 
in time-to-event analyses using standard Kaplan-Meier methods. 
- 
Cox proportional hazards model will be used to compare the safety outcome between 
users of different OACs, weighted on the estimated PS according to the IPTW 
approach. 

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 Proportionality assumption will be tested by use of Schoenfeld residuals. 
Subgroup Analysis 
- 
The potential heterogeneity of treatment effects in selected subgroups of patients 
with VTE will be examined for the major bleeding as follows: 
 Aged <65 years vs. aged ≥65 years 
 Females vs. males 
 Setting of VTE diagnosis (inpatient vs. outpatient) 
 Type of VTE (DVT without PE vs. PE with or without DVT) 
 Major orthopedic surgery-provoked VTE 
 Major orthopedic surgery-provoked VTE is defined as an event preceded by 
knee arthroplasty, hip arthroplasty, or hip fracture surgery (National 
Procedure Codes: N0305, N0601, N0611, N0641, N0711, N2070, N0715, 
N2710, N0731, N0981, N0991, N1711, N3710, N1721, N3720, 
N1715,N4710, N1725, N4720,  N2072, N2077, N2712, N2717, N3712, 
N3717, N3722, N3727, N4712, N4717, N4722 or N4727) within 3 months 
period prior to index date 
 With vs. without CKD stage 3 or 4 (N18.3, N18.4) 
- 
P-for-interaction value <0.05 will be used to denote a significant difference between 
the two groups. 
Sensitivity Analysis 
- 
Vary the definition of treatment interruption/discontinuation to 15 and 60 days 
(allowing for varying non-adherence) to assess the effect this had on study outcomes. 
- 
Four other approaches involving PS will be applied to determine the robustness of 
our study findings. First, we will vary the extreme value of PS in trimming process 
(most extreme 5%, and 10% will be excluded). Second, we will include the estimated 
PS, in addition to other covariates, into our multivariable Cox proportional hazards 
regression model. Third, we will stratify on the estimated PS in deciles. Lastly, we 
will apply another weighting approach, standardized mortality ratio weights, with the 
weights given as follows: 1 for the treatment group of interest and PS/(1 − PS) for the 
comparator group.[25] 

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- 
Exclude patients with a history of bleeding during the 6-month pre-index-date period 
in Phase II comparative analysis to evaluate the robustness of findings with respect to 
changes in underlying risk of patients  
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. 
 
9.8. Quality control 
All data will be checked for completeness and outlying values by research group with 
requisite background and experiences in pharmacoepidemiology. We will archive all data 
files and data management and statistical programs for quality control. 
 
9.9. Limitations of the research methods 
Information bias 
- 
Outcome misclassification is possible as the records of diagnoses reported in the 
HIRA database may be different from their actual diagnoses recorded in the 
hospital’s electronic medical records. 
- 
To minimize any bias arising from exposure misclassification, analyses will be 
repeated by using a 15 and 60-day grace period definition for non-overlapping 
successive prescriptions. 
Selection bias 
- 
By using the nationwide HIRA database that encompasses the entire Korean 
population of 50 million, this study is unlikely to miss out any patients with VTE in 
South Korea. 
Confounding bias 
- 
Owing to the nature of observational studies, residual confounding from unmeasured 
or unaccounted confounders may be present. 
- 
Nevertheless, to minimize confounding bias, we will apply various PS approaches, 
with the IPTW approach applied as our main analysis. 
External validity of study design 

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- 
Our study results will achieve generalizability by using the nationwide HIRA 
database. 
Analysis limitations 
- 
Potential incompleteness of information on potential confounders such as laboratory 
data are unavailable for assessment due to inherent limitations of the HIRA database 
as its primary purpose is for administrative means. 
- 
Sensitivity analysis using the E-value will be conducted to quantify the impact of 
residual confounding from unmeasured or unaccounted confounders on the risk 
estimates for the association between apixaban use and risk of VTE recurrence and 
bleeding events. 
Limitations due to missing and/or incomplete data 
- 
HIRA data are released for research only after thorough internal review, this would 
not be applicable to HIRA data. 
 
9.10. Other aspects 
Not applicable. 
 
10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient information  
This study involves data that exist in anonymized structured format and contain no patient 
personal information.  
 
10.2. Patient consent 
As this study involves anonymized structured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required. 
   
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) 
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (e.g., informed consent forms if applicable) from the relevant IRBs/IECs.  
All correspondence with the IRB/IEC must be retained.  Copies of IRB/IEC approvals must 
be forwarded to Pfizer.  

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We will obtain a customized HIRA database between 1 Mar 2012 and 31 Dec 2019. This 
study was approved by the Sungkyunkwan University’s Institutional Review Board (SKKU-
IRB-2020-12-010), which waived the requirement for informed consent. 
 
10.4. 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) and the European Medicines Agency (EMA) European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological 
Standards in Pharmacoepidemiology. 
 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
This study involved data that exist as structured data by the time of study start. 
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (e.g., identify a potential association between) a particular product and 
medical event for any individual. Thus, the minimum criteria for reporting an adverse event 
(AE) (e.g., identifiable patient, identifiable reporter, a suspect product, and event) cannot be 
met. 
 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
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.   
Results of this study will be submitted for publication in an academic journal within one year 
after the end of the study. The target academic journals with their impact factors (as of 2019) 
are as below: 
 European Heart Journal-Cardiovascular Pharmacotherapy (Impact Factor: 6.696) 

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 BMC Medicine (Impact Factor: 6.782) 
 JAMA Network Open (Impact Factor: 5.032) 
 Journal of Thrombosis and Haemostasis (Impact Factor: 4.157) 
 Frontiers in Cardiovascular Medicine (Impact Factor: 3.915) 
 
 

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13. REFERENCES 
1. 
WRITING GROUP MEMBERS, et al., Heart Disease and Stroke Statistics—2010 
Update. Circulation, 2010. 121(7): p. e46-e215. 
2. 
Raskob, G., et al., Thrombosis: A Major Contributor to Global Disease Burden. 
Arteriosclerosis, Thrombosis, and Vascular Biology, 2014. 34(11): p. 2363-2371. 
3. 
Chuang, L., et al., Health-related quality of life and mortality in patients with 
pulmonary embolism: a prospective cohort study in seven European countries. 
Quality of Life Research, 2019. 28: p. 2111-2124. 
4. 
Kearon, C., et al., Antithrombotic Therapy for VTE Disease: CHEST Guideline and 
Expert Panel Report. Chest, 2016. 149(2): p. 315-352. 
5. 
Ortel, T., et al., American Society of Hematology 2020 guidelines for management of 
venous thromboembolism: treatment of deep vein thrombosis and pulmonary 
embolism. Blood Advances, 2020. 4(19): p. 4693-4738. 
6. 
Food and Drug Administration (FDA). Eliquis (apixaban) drug label.  November 9, 
2020]; Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202155s012lbl.pdf. 
7. 
Food and Drug Administration (FDA). Savaysa (edoxaban) drug label.  November 9, 
2020]; Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf. 
8. 
Food and Drug Administration (FDA). Xarelto (rivaroxaban) drug label.  November 
9, 2020]; Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202439s031,022406s035
lbl.pdf. 
9. 
Heidbuchel, H., et al., European Heart Rhythm Association Practical Guide on the 
use of new oral anticoagulants in patients with non-valvular atrial fibrillation. EP 
Europace, 2013. 15(5): p. 625-651. 
10. 
Agnelli, G., et al., Oral Apixaban for the Treatment of Acute Venous 
Thromboembolism. N Engl J Med, 2013. 369: p. 799-808. 
11. 
The EINSTEIN Investigators, Oral Rivaroxaban for Symptomatic Venous 
Thromboembolism. N Engl J Med, 2010. 363: p. 2499-2510. 
12. 
Loo, S., et al., Trends in the prescription of novel oral anticoagulants in UK primary 
care. British Journal of Clinical Pharmacology, 2017. 83(9): p. 2096-2106. 
13. 
Sindet-Pederson, C., et al., Temporal trends in initiation of VKA, rivaroxaban, 
apixaban and dabigatran for the treatment of venous thromboembolism - A Danish 
nationwide cohort study. Scientific Reports, 2017. 7: p. 3347. 
14. 
Stevens, H., H. Tran, and H. Gibbs, Venous thromboembolism: current management. 
Australian Prescriber, 2019. 42(4): p. 123-126. 
15. 
van der Hulle, T., et al., Effectiveness and safety of novel oral anticoagulants as 
compared with vitamin K antagonists in the treatment of acute symptomatic venous 
thromboembolism: a systematic review and meta-analysis. J Thromb Haemost, 2014. 
12(3): p. 320-8. 
16. 
Weycker, D., et al., Effectiveness and Safety of Apixaban versus Warfarin as 
Outpatient Treatment of Venous Thromboembolism in U.S. Clinical Practice. Thromb 
Haemost, 2018. 118(11): p. 1951-1961. 

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17. 
Guo, J.D., et al., Comparative Clinical and Economic Outcomes Associated with 
Warfarin Versus Apixaban in the Treatment of Patients with Venous 
Thromboembolism in a Large U.S. Commercial Claims Database. J Manag Care Spec 
Pharm, 2020. 26(8): p. 1017-1026. 
18. 
Agnelli, G., et al., Apixaban for Extended Treatment of Venous Thromboembolism. N 
Engl J Med, 2013. 368: p. 699-708. 
19. 
Weitz, J., et al., Rivaroxaban or Aspirin for Extended Treatment of Venous 
Thromboembolism. N Engl J Med, 2017. 376: p. 1211-1222. 
20. 
Dawwas, G., et al., Effectiveness and safety of apixaban versus rivaroxaban for 
prevention of recurrent venous thromboembolism and adverse bleeding events in 
patients with venous thromboembolism: a retrospective population-based cohort 
analysis. The Lancet Haematology, 2019. 6(1): p. e20-e28. 
21. 
Yao, X., et al., Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban 
Versus Warfarin in Nonvalvular Atrial Fibrillation. J Am Heart Assoc, 2016. 5(6): p. 
e003725. 
22. 
Choi, E.K., Cardiovascular Research Using the Korean National Health Information 
Database. Korean Circ J, 2020. 50(9): p. 754-772. 
23. 
Quan, H., et al., Updating and validating the Charlson comorbidity index and score 
for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J 
Epidemiol, 2011. 173(6): p. 676-82. 
24. 
Rief, P., et al., Calculation of HAS-BLED Score Is Useful for Early Identification of 
Venous Thromboembolism Patients at High Risk for Major Bleeding Events: A 
Prospective Outpatients Cohort Study. Semin Thromb Hemost, 2018. 44(4): p. 348-
352. 
25. 
Desai, R. and J. Franklin, Alternative approaches for confounding adjustment in 
observational studies using weighting based on the propensity score: a primer for 
practitioners. BMJ, 2019. 367: p. l5657. 
26. 
Austin, P. and E. Stuart, Moving towards best practice when using inverse probability 
of treatment weighting (IPTW) using the propensity score to estimate causal 
treatment effects in observational studies. Stat Med, 2015. 34(28): p. 3661-79. 
 
14. LIST OF TABLES  
Table 1. WHO-ATC codes and National Procedure Codes for anti-cancer treatment 
Table 2. Definition of major bleeding by site 
 
15. LIST OF FIGURES 
Figure 1. Study participants inclusion and exclusion criteria 
Figure 2. Overall study schematic 
 

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ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None.  
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable.