Safety and Effectiveness of Apixaban Compared to Warfarin in Secondary Prevention in Patients With NVAF With a History of Stroke or Transient Ischemic Attack - a Nationwide Retrospective Observational Study Using Claims Data in Japan
Conditions: Non-valvular Atrial Fibrillation
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
 
Study information 
Title 
Safety and effectiveness of apixaban compared 
to warfarin in secondary prevention in patients 
with NVAF with a history of stroke or transient 
ischemic attack - a nationwide retrospective 
observational study using claims data in Japan 
Protocol number 
B0661176 
Protocol version identifier 
Ver.1.1 
Date 
24/3/2022 
EU Post Authorization Study (PAS) register 
number 
Not applicable  
Active substance 
B: Blood and blood forming organs 
B01: Antithrombotic agents 
B01A: Antithrombotic agents 
B01AF: Direct factor Xa inhibitors 
B01AF02: Apixaban 
Medicinal product 
Eliquis(Apixaban) 
Research question and objectives 
Japanese population has shown to have higher 
rate of incidence of stroke and stroke mortality is 
also higher1. Patients with a history of ischemic 
stroke are at high risk of recurrence and require 
more rigorous management to prevent 
recurrence2. The same is true for patients with 
non-valvular atrial fibrillation (NVAF) and 
treatment with anticoagulants reduces the risk of 
recurrent embolic stroke. However,some 
patients still suffer from recurrent embolic and/or 
ischemic stroke even if they are on 
anticoagulants for secondary prevention3. In 
addition to the recurrent stroke, risk of bleeding 
is also higher in the patients with a history of 
stroke because they are often chronically treated 
with antiplatelet agents to prevent recurrence 
after cerebral infarction and with an 
anticoagulant after embolic stroke4 5. 
Concomittant use of anticoagulant and anti-
platelet agents is sometimes necessary if 
patients with AF experience cerebral infarction 

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Contents 
2. LIST OF ABBREVIATIONS....................................................................................... 5 
3. RESPONSIBLE PARTIES ......................................................................................... 5 
4. ABSTRACT................................................................................................................. 6 
5. FINAL REPORT APPROVAL.................................................................................. 10 
6. MILESTONES ........................................................................................................... 11 
7. RATIONALE AND BACKGROUND........................................................................ 11 
8. RESEARCH QUESTION AND OBJECTIVES........................................................ 11 
8.1. PRIMARY OBJECTIVE:............................................................................................. 12 
9. RESEARCH METHODS .......................................................................................... 13 
9.1. STUDY DESIGN ...................................................................................................... 13 
9.1.1. Definition 1.................................................................................................... 13 
9.1.1.1. Index date............................................................................................... 13 
9.1.1.2. Ischemic stroke ...................................................................................... 14 
9.1.1.3. Recurrent stroke .................................................................................... 14 
9.1.1.4. Major bleeding ....................................................................................... 14 
9.1.1.5. Baseline period ...................................................................................... 14 
9.1.1.6. Follow up period:.................................................................................... 14 
9.2. SETTING................................................................................................................ 14 
9.2.1. Inclusion criteria ........................................................................................... 14 
9.2.2. Exclusion criteria .......................................................................................... 15 
9.3. VARIABLES ............................................................................................................ 15 
9.4. DATA SOURCES ..................................................................................................... 17 
9.5. STUDY SIZE ........................................................................................................... 18 
9.6. DATA MANAGEMENT .............................................................................................. 18 

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9.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data 
record ...................................................................................................................... 18 
9.6.2. Record retention........................................................................................... 18 
9.7. DATA ANALYSIS ..................................................................................................... 18 
9.8. QUALITY CONTROL ................................................................................................ 19 
9.9. LIMITATIONS OF THE RESEARCH METHODS ............................................................. 20 
9.10. OTHER ASPECTS ................................................................................................. 20 
10. PROTECTION OF HUMAN SUBJECTS .............................................................. 21 
10.1. PATIENT INFORMATION ........................................................................................ 21 
10.2. PATIENT CONSENT............................................................................................... 21 
10.3. PATIENT WITHDRAWAL ......................................................................................... 21 
10.4. INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT ETHICS COMMITTEE (IEC)..... 21 
10.5. ETHICAL CONDUCT OF THE STUDY........................................................................ 21 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ................................................................................................................. 21 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS . 21 
13. REFERENCES ....................................................................................................... 22 
14. LIST OF TABLES................................................................................................... 22 
15. LIST OF FIGURES ................................................................................................. 23 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS ................................................. 23 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS................................ 23 
ANNEX 3. ADDITIONAL INFORMATION .................................................................. 23 
 
 
 
 

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3. ABSTRACT 
Title：  
Safety and effectiveness of apixaban compared to warfarin in secondary prevention in patients with 
NVAF with a history of stroke or transient ischemic attack - a nationwide retrospective observational 
study using claims data in Japan  
Protocol Ver1.1 (24-Mar-2022) 
  
 
Rationale and background： 
Japanese population has shown to have higher rate of incidence of stroke and stroke mortality is 
also higher1. Patients with a history of ischemic stroke are at high risk of recurrence and require 
more rigorous management to prevent recurrence2. The same is true for patients with non-
valvular atrial fibrillation (NVAF) and treatment with anticoagulants reduces the risk of recurrent 
embolic stroke. However, some patients still suffer from recurrent embolic and/or ischemic stroke 
even if they are on anticoagulants for secondary prevention3. In addition to the recurrent stroke, 
risk of bleeding is also higher in the patients with a history of stroke because they are often 
chronically treated with antiplatelet agents to prevent recurrence after cerebral infarction and with 
an anticoagulant after embolic stroke4 5. Concomittant use of anticoagulant and anti-platelet 
agents is sometimes necessary if patients with AF experience cerebral infarction and the risk of 
bleedings largely enhances in these patient6. Thus, patients in secondary prevention are at 
higher risk of both recurrent ischemic stroke and more effective and safter antithrombotic therapy 
should take this into account. 
 
Research question and objectives：  
The pivotal randomized clinical trial, ARISTOTLE study7, and other RWE8-11, in which medical 
and claims data have been retrospectively analyzed, have shown that the risks of incidence of 
stroke + systemic embolism and major bleeding in patients with NVAF treated with apixaban is 
equal to or lessor than those in patinets treated with warfarin. As mentioned above, patients with 
NVAF and with a history of ischemic stroke (that is, in secondary prevention) could be at higher 
risk of recurrence and bleeding. Although neurologists generally use direct oral anticoagulants 
PPD

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(DOAC) for secondary prevention, a significant portion of the patients in secondary prevention 
are still treated with warfarin in Japan. The results of randomized trials have been indicated that 
apixaban is superior to warfarin in reducing the risk of recurrence and/or bleeding with secondary 
prevention of stroke12-14. However, there is no clear evidence in Japanese patients with 
secondary prevention of stroke15. The research question of this study is whether apixaban is 
associated with lower risk of stroke (ischemic andhemorrhagic) and bleeding compared to 
warfarin in higher-risk secondary prevention patients as well.  
The purposes of this study are 1) to characterize the primary and secondary prevention patients, 
2) to calculate incidence rates of stroke/systemic embolism (SE) or major bleeding in each 
cohort and 3) to investigate for Japanese secondary prevention patients as RWE on the 
effectiveness and safety of apixaban compared to warfarin in patients NVAF. 
Study design： 
It is a non-interventional comparative observational study, in which patients who meet the study 
criteria are selected and aggregated from the patients registered in the Medical Data Vision 
(MDV) database. 
Population： 
Patients who are newly diagnosed with NVAF and initiate anticoagulation therapy with warfarin 
or apixaban. Among them, patients with prior diagnosis of stroke (ischemic or hemorrhagic) or 
transient ischemic attack (TIA) are secondary prevention patients and will be included in the 
secondary prevention cohort and those who have not diagnosed with stroke will be included in 
the primary prevention cohort as primary prevention patients. Patient selection and allocation to 
each cohort is shown in Fig.1 below. 

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Fig.1a and 1b: patient selection and summary of planned analyses 
Variables： 
• 
Prior diagnosis of stroke (before diagnosis with NVAF) 

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• 
Clinical and demographic characteristics of patients eligible for this study. 
• 
Incidence of recurrent stroke (ischemic and hemorrhagic) during the follow-up period 
• 
Incidence of any bleeding including intracranial hemorrhage, gastrointestinal bleeding or 
intraocular bleeding dufing the follow-up period  
• 
Anticoagulants (warfarin, apixaban or others) 
• 
Concommittent medicines (baseline or on the index date) 
• 
Comorbid diseases (baseline or on the index date) 
 
Data sources： 
Medical Data Vision database 
De-identified health claim data from 458 acute-care hospitals across Japan (as of Dec.22, 
2021) available from the MDV (Tokyo, Japan, MDV) database. In brief, the MDV database 
comprises administrative data pertaining to approximately 38 million individuals managed in 
the inpatient and outpatient settings. Each patient is associated with a specific ID to which all 
inpatient and outpatient data are linked.  
 
Study size： 
In this study, eligible patients will be aggregated backward.  
• 
The number of estimated patients; 
• 
All registered patients: approximately 38 millions (2008-2021) 
• 
Patients with ischemic stroke: 1.2 millions 
• 
Patients with TIA: 98,887 
• 
Patients with atrial fibrillation: 1.3 millions 
• 
AF patients with a history of ischemic stroke: 226,000 
• 
AF patients on warfarin: 251,000 
• 
AF patients on apixaban: 237,000 
• 
The number of patients who experienced recurrent ischemic stroke on warfarin or 
apixaban: unknown 
 
Data analysis： 
The detailed methodology for data analysis will be described in the Statistical Analysis Plan 
(SAP). Briefly, 

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As a first step, extracted patients will be divided into two cohorts, primary prevention cohort and 
secondary prevention cohort based on the previous diagnosis of stroke. Clinical and demigraphic 
characteristics will be compared with two cohorts at baseline and on the index date (date of the 
initiation of warfarin and apixaban) and incidence rates of stroke/SE and major bleeding per 
1,000 person-years will be calculated during follow-up period. In addition, interaction analysis will 
be conducted to investigate an interaction between OAC (warfarin/apixaban) and presence or 
absence of the previous episode of stroke. 
• 
As a second step, only secondary prevention cohort will be used for further analyses as 
fillows,Crude (before IPTW) patient characteristics will be compared between warfarin and 
apixaban cohorts using appropriate methods (continuous variables: unpaired t-test or Mann-
Whitney U-test, categorical variables: chi-square test) 
• 
A propensity score will be calculated based on multinomial logistic regressions in order to 
account for confounding effects and to ensure that patient characteristics will be balanced 
between the warfarin cohort and apixaban cohort. An inverse probability of treatment 
weighting (IPTW) method using the calculated propensity score will be applied. To avoid 
sample size inflation and to ensure appropriate estimation of variances, s-IPTW (stabilized 
IPTW) will be used here.  
• 
Balanced (after IPTW) patient clinical and demographic characteristics will be shown. 
Covariate balance between apixaban and warfarin cohorts after s-IPTW will be assessed in 
terms of the standardized differences with a threshold of 0.1.  
• 
Kaplan Meier curves of balanced cohorts for each endpoint will be drawn. 
• 
Incidence rates of endpoints will be calculated and shown per 1000 person-year. 
• 
Hazard ratios with 95% confidence intervals will be calculated using a Cox proportional 
hazards regression model that incorporate only the index OACs as independent variables. 
 
Milestones： 
• 
Data extraction start: Apr 15, 2022 
• 
End of data extraction: Jun 30, 2022 
• 
Final report approval: Aug 30, 2022 
4. FINAL REPORT APPROVAL 
Amendment 
number 
Date 
Protocol 
section(s) 
changed 
Summary of amendment(s) 
Reason 

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Ver 1.1 
25/Mar/
2022 
5. 
Milestones 
Change Data 
Extraction Date 
Before: Apr 1, 2022 
After: Apr 15, 2022 
To adjust the project 
schedule 
 
 
 
 
 
 
5. MILESTONES 
Milestone 
Planned date 
<Completion of feasibility assessment> 
October 14, 2021 
Start of data collection  
April 15, 2022 
End of data collection  
Jun 30, 2022 
Final study report 
Aug 30, 2022 
 
6. RATIONALE AND BACKGROUND 
Patients with a history of ischemic stroke, including those with cardiogenic cerebral embolism, are at 
higher risk of recurrence and require more rigorous treatment to prevent recurrence. The same is true 
for patients with non-valvular atrial fibrillation (NVAF), who are at higher risk of recurrence even if they 
are taking anticoagulants to prevent cardiogenic cerebral embolism. On the other hand, NVAF 
patients with previous lacunar infarction are often chronically treated with antiplatelet agents to 
prevent recurrence, and this could result in an increased risk of bleeding. Thus, patients in secondary 
prevention are at higher risk of recurrent stroke (both ischemic stroke andhemorrhagic stroke) and 
bleeding than those in primary prevention, and antithrombotic therapy should take this into account. 
 
7. RESEARCH QUESTION AND OBJECTIVES 
The pivotal randomized clinical trial, ARISTOTLE study, and other RWE,  in which medical and 
claims data have been retrospectively analyzed, have shown that the risks of incidence of stroke 
+ systemic embolism and major bleeding in patients with NVAF treated with apixaban is equal to 
or lessor than those in patinets treated with warfarin. As mentioned above, patients with NVAF 
and with a history of ischemic stroke (that is, in secondary prevention) could be at higher risk of 
recurrence and bleeding. Although neurologists generally use direct oral anticoagulants (DOAC) 
for secondary prevention, a significant portion of the patients in secondary prevention are still 
treated with warfarin in Japan. There is no clear evidence that apixaban is superior to warfarin in 
reducing the risk of recurrence or bleeding in Japanese patients with secondary prevention of 

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stroke. The research question of this study is whether apixaban is associated with lower risk of 
stroke (ischemic stroke and  hemorrhagic stroke) and bleeding compared to warfarin in higher-
risk secondary prevention patients as well.   
7.1. Primary objective: 
The effectiveness of study in secondary prevention cohort will be conducted to elucidate the 
following, 
1. 
Incidence rate (per 1,000 person-years) of a composite of recurrent stroke (ischemic 
stroke and hemorrhage stroke) in NVAF patients treated with warfarin or apixaban. 
2. 
Time course of proportion of a composite of the incidence of recurrent  stroke (ischemic 
stroke and hemorrhage stroke) -free NVAF patients treated with warfarin or apixaban 
(shown as two Kaplan-Meier curves, for warfarin cohort and apixaban cohort, which will 
be statistically compared by a Log-rank test).  
3. 
Risk of a composite of recurrent  “Ischemic stroke” (“cardiogenic cerebral embolism” + 
“cerebral infarction”) and hemorrhagic stroke and SE in patients treated with apixaban 
compared to that in patients treated with warfarin (Hazard ratio and 95% confident 
intervals will be calculated by a COX proportional hazard method) (primary 
effectiveness analysis). 
* TIA is not included in endpoints. 
 
The safety of study will be conducted to elucidate the following, 
1. 
Incidence rate of recurrent bleeding, such as major bleeding, intracranial hemorrhage, 
gastrointestinal tract bleeding or intraocular bleeding in NVAF patients treated with 
warfarin or apixaban  
2. 
Time course of proportion of each bleeding-free in NVAF patients treated with warfarin 
or apixaban (shown as two Kaplan-Meier curves, for warfarin cohort and apixaban 
cohort, which will be statistically compared by a Log-rank test).  
3. 
Risk of each bleeding in NVAF patients treated with apixaban compared to that in 
patients treated with warfarin (Hazard ratio and 95% confident intervals will be 
calculated by a COX proportional hazard method) (primary safety analysis). 
 
In summary, 
• 
Primary effectiveness endpoint : stroke (ischemic stroke and hemorrhage stroke)/SE 

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• 
Secpondary effectiveness endpoints: 
 
Recurrent cardiogenic embolic stroke 
 
Recurrent cerebral infarction 
• 
Primary safety endpoint : major bleeding defined as any bleeding requiring 
hospitalization for treatment 
• 
Secondary safety endpoints: 
 
Intracranial hemorrhage 
 
Gastrointestinal bleeding 
 
Intraocular bleeding 
8. RESEARCH METHODS  
8.1. Study design  
This is a non-interventional, comparative, observational study in which patients registered in the 
MDV database who met the study criteria are retrospectively aggregated. This is a secondary 
collection database study, and no primary data collection will be done. 
 
8.1.1. Definition 1 
8.1.1.1. Index date 
The next day of the day when patients diagnosed NVAF initiate warfarin or apixaban  

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8.1.1.2. stroke 
8.1.1.3. Defined using pre-designated ICD-10 codes (see Statistical Analysis Plan). 
Ischemic and hemorrhagic stroke will be included,stroke 
Stroke is defined using predefined ICD-10 codes and  if hospitalization for the treatment of the 
stroke is necessary, it will be regarded as stroke incident during the followup period. 
(applicable only to the outpatients when recurrent stroke occurs) 
8.1.1.4. Major bleeding 
Major bleeding is defined any bleeding that needs hospitalization for the treatment of 
bleeding. Any bleeding is defined using pre-designated ICD-10 codes (see Statistical Analysis 
Plan). 
8.1.1.5. Other clinical critical bleeding 
Intracranial hemorrhage, gastrointestinal tract bleeding or intraocular bleeging 
8.1.1.6. Baseline period 
Period of 180 days before the index date.  
8.1.1.7. Follow up period:  
The end of observation is the period until the first observation of the earlier of the following 
items. 
1. 
discontinuation of the index OAC (warfarin or apixaban, OAC prescribed on the index 
date); the index treatment is considered to be discontinued if there is a continuous gap of 
45 days or more between the expected refill date and the actual refill date. 
2. 
switch to another OAC; the index treatment is regarded as switched if the index OAC was 
discontinued and another OAC was started within 45 days of the prescription refill date of 
the index OAC. 
3. 
lack of further records in the database; if no further relevant records are added (e.g., no 
further refills or visits), the last date of the patient’s record in the database is considered. 
4. 
occurrence of  stroke or major bleeding (endpoints). 
5. 
elapsing of 2 years from the index date. 
 
 
8.2. Setting 
8.2.1. Inclusion criteria 
Patients must meet all the following selection criteria 

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administrative claims data on approximately 37 million individuals maintained in inpatient and 
outpatient settings. Each patient is associated with a specific ID to which all inpatient and 
outpatient data is linked. 
8.5. Study size 
In this study, eligible patients will be aggregated backward.  
• 
The number of estimated patients; 
• 
All registered patients: approximately 38 millions (2008-2021) 
• 
Patients with ischemic stroke: 1.2 millions 
• 
Patients with atrial fibrillation: 1.3 millions 
• 
AF patients with a history of ischemic stroke: 226,000 
• 
AF patients on warfarin: 251,000 
• 
AF patients on apixaban: 237,000 
• 
The number of patients who experienced recurrent ischemic stroke on warfarin or 
apixaban: unknown 
 
8.6. Data management  
The data will be provided by MDV. All the data is already structured in the database, so there is 
no need for new database development or manual review. The provided data can be used as-is 
for analysis. Therefore, there is no need for data management. 
All analyses will be conducted using SAS software (Version 9.0 or higher, SAS Institute, Cary, 
NC, USA), and findings are presented in charts and tables created in Microsoft Excel.  
8.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data record 
Not applicable 
 
8.6.2. Record retention 
Not applicable 
 
8.7. Data analysis  
The detailed methodology for data analysis will be described in the Statistical Analysis Plan 
(SAP). 

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As a first step, extracted patients will be divided into two cohorts, primary prevention cohort and 
secondary prevention cohort based on the previous diagnosis of stroke. Clinical and 
demographic characteristics will be compared with two cohorts at baseline and on the index date 
(date of the initiation of warfarin and apixaban) and incidence rates of stroke/SE and major 
bleeding per 1,000 person-years will be calculated during follow-up period. In addition, 
interaction analysis will be conducted to investigate an interaction between OAC 
(warfarin/apixaban) and presence or absence of the previous episode of stroke. 
• 
As a second step, only secondary prevention cohort will be used for further analyses as 
follows, Crude (before IPTW) patient characteristics are compared between warfarin and 
apixaban cohorts using appropriate methods (continuous variables: unpaired t-test or Mann-
Whitney U-test, categorical variables: chi-square test) 
• 
A propensity score is calculated based on multinomial logistic regressions in order to 
account for confounding effects and to ensure that patient characteristics are balanced 
between the warfarin cohort and apixaban cohort. An inverse probability of treatment 
weighting (IPTW) method using the calculated propensity score will be applied. To avoid 
sample size inflation and to ensure appropriate estimation of variances, s-IPTW (stabilized 
IPTW) is used here.  
• 
Balanced (after IPTW) patient clinical and demographic characteristics are shown. Covariate 
balance between apixaban and warfarin cohorts after s-IPTW is assessed in terms of the 
standardized differences with a threshold of 0.1  
• 
Kaplan Meier curves of balanced cohorts for each endpoint are drawn. 
• 
Incidence rates of endpoints are calculated and shown per 1000 person-years. 
• 
Hazard ratios with 95% confidence intervals will be calculated using a Cox proportional 
hazards regression model that incorporate only the index OACs as independent variables. 
  
 
8.8. Quality control 
This study is a retrospective analytical study using quality-controlled data in a pre-existing 
database, and primary data collection will not be conducted. As for the data provided, quality of 
the data is guaranteed by MDV Co. Ltd., which has professional teams specialized in the 
maintenance and improvement of data quality. All these processes are consistently managed in-
house. All of operations for data management in MDV Co. Ltd. are conducted in accordance with 
standard operational procedures of MDV Co. Ltd. For quality assurance of analysis, the vendor 

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which deals with the analysis will conduct code review of all modules of program, descriptive 
statistics review of all variables and patients row data examination of all output results in a test 
phase. 
Statistical analysis will be also outsourced to a specialist (a vender specialized to the statistics). 
Validity of analysis programs and the obtained results will be confirmed by the vender according 
to the internal standard of procedures. 
8.9. Limitations of the research methods 
Our study, like most retrospective analyses using claims data, has several intrinsic limitations 
and certain expected biases.  
1. 
The data we will use is obtained from a claims database containing information provided by 
hospitals applying the flat-fee payment system, which are mostly large hospitals responsible 
for acute care. Therefore, a significant proportion of the patients included in the present 
analysis will be likely in poorer health than the average population requiring hospitalization, 
possibly having more comorbidities and higher risk of stroke and bleeding.  
2. 
The claims data we will use here do not include vital signs or laboratory data such as blood 
pressure, international normalized ratio values, and renal function parameters, which is also 
why we could not calculate a HAS-BLED score. These variables will not be considered in 
the calculation of the propensity score, and there is no guarantee that such characteristics 
are fully balanced after s-IPTW. Therefore, although we will compute a propensity score 
based on multiple variables that may affect the risk of stroke and bleeding, the influence of 
unexamined confounding factors will not be fully excluded.  
3. 
We will not provide an estimation of follow-up loss, as we will have no subsequent data on 
patients who visited a different hospital or clinic after being registered with one of the 
hospitals contributing to the MDV database. This could result in an underestimation of the 
incidence of stroke or major bleeding events.  
 
8.10. Other aspects 
Not applicable 

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9. PROTECTION OF HUMAN SUBJECTS 
9.1. Patient information  
This study involves data that exist in anonymized structured format and contain no patient 
personal information.  According to the ethical guidelines for epidemiological studies in Japan, 
informed consent is not always required for studies by unlinkable anonymized data. 
9.2. 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.   
9.3. Patient withdrawal 
Not applicable.  
9.4. Institutional review board (IRB)/Independent ethics committee (IEC) 
Since the MDV database is comprised of unlinkable anonymized data, IRB/IEC approval is not 
required according to the Pfizer’s SOP/Policy and local regulations in Japan. 
9.5. 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 CT24-WI-GL02-RF04 and references to any additional relevant guidance. 
 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS  
Although this study will examine the safety and effectiveness of specific Pfizer’s product 
(apixaban), due to the nature of the database, individuals cannot be identified. Therefore, the 
management and the reporting of adverse events/adverse reactions is not required for this 
study.  
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
All final data will be shared with co-author. It is also anticipated that results from this study will 
generate a manuscript for submission to an local or international peer-reviewed journal.  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 party responsible for collecting data from the 

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participants aware of any new information which might influence the evaluation of the benefits 
and risks of a Pfizer product, Pfizer should be informed immediately.   
12. REFERENCES 
1. Sacco RL, Benjamin EJ, Broderick JP, et al. American Heart Association Prevention Conference. 
IV. Prevention and Rehabilitation of Stroke. Risk factors. Stroke 1997;28(7):1507-17. doi: 
10.1161/01.str.28.7.1507 
2. Hata J, Tanizaki Y, Kiyohara Y, et al. Ten year recurrence after first ever stroke in a Japanese 
community: the Hisayama study. J Neurol Neurosurg Psychiatry 2005;76(3):368-72. doi: 
10.1136/jnnp.2004.038166 
3. D'Anna L, Filippidis FT, Harvey K, et al. Ischemic stroke in oral anticoagulated patients with atrial 
fibrillation. Acta Neurol Scand 2021 doi: 10.1111/ane.13552 
4. Boysen G. Bleeding complications in secondary stroke prevention by antiplatelet therapy: a benefit-
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A Retrospective Chart Review Study. Circ J 2021 doi: 10.1253/circj.CJ-21-0682 
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antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity 
weighted nationwide cohort study. BMJ 2016;353:i3189. doi: 10.1136/bmj.i3189 
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stroke. Best Pract Res Clin Haematol 2013;26(2):131-9. doi: 10.1016/j.beha.2013.07.007 
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10.1080/14656566.2018.1515913 
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ARISTOTLE trial. Lancet Neurol 2012;11(6):503-11. doi: 10.1016/S1474-4422(12)70092-3 
15. Yoshimura S, Koga M, Sato S, et al. Two-Year Outcomes of Anticoagulation for Acute Ischemic 
Stroke With Nonvalvular Atrial Fibrillation- SAMURAI-NVAF Study. Circ J 2018;82(7):1935-
42. doi: 10.1253/circj.CJ-18-0067 
13. LIST OF TABLES  
Table1．Variables 
Table2.   Categories of clinical departments 
 

Apixaban  
< B0661176>NON-INTERVENTIONAL STUDY PROTOCOL 
<version 1.1>,<24 Mar. 2022> 
 
PFIZER CONFIDENTIAL 
 
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14. LIST OF FIGURES 
None 
 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Not applicable 
ANNEX 3. ADDITIONAL INFORMATION 
Not applicable