Non-interventional Study Describing Direct Costs Related to Anticoagulation Treatment in Patients With Nonvalvular Atrial Fibrillation (NVAF) in Secondary Stroke Prevention Prescribed Apixaban or Warfarin Treatment
Conditions: Atrial Fibrillation
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
Non-interventional study describing 
direct costs related to anticoagulation 
treatment in patients with nonvalvular 
atrial fibrillation (NVAF) in secondary 
stroke prevention prescribed apixaban or 
warfarin treatment
Protocol number
B0661121
Protocol version identifier
1.2
Date 
5. November 2018
Active substance
B01AF02 apixaban
Medicinal product
Eliquis 
Research question and objectives
To describe the direct costs related to 
warfarin/apixaban treatment during the first 
6 months of the secondary stroke prevention 
in NVAF patients. 
Author
MUDr.
Ph.D.
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
PPD
PPD

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TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
1. LIST OF ABBREVIATIONS................................................................................................4
2. RESPONSIBLE PARTIES....................................................................................................5
3. ABSTRACT...........................................................................................................................5
4. AMENDMENTS AND UPDATES.......................................................................................5
5. MILESTONES.......................................................................................................................5
6. RATIONALE AND BACKGROUND..................................................................................6
7. RESEARCH QUESTION AND OBJECTIVES ...................................................................8
8. RESEARCH METHODS ......................................................................................................8
8.1. Study design ..............................................................................................................8
8.2. Setting........................................................................................................................9
8.2.1. Inclusion criteria ...........................................................................................9
8.2.2. Exclusion criteria..........................................................................................9
8.3. Variables..................................................................................................................10
8.4. Data sources ............................................................................................................11
8.5. Study size ................................................................................................................11
8.6. Data management....................................................................................................11
8.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic Data 
Record........................................................................................................................11
8.6.2. Record Retention..................................................................................................12
8.7. Data analysis ...........................................................................................................12
8.8. Quality control.........................................................................................................14
8.9. Strengths and limitations of the research methods..................................................14
8.10. Other aspects .........................................................................................................14
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................14
9.1. Patient Information..................................................................................................14
9.2. Patient Consent........................................................................................................15
9.3. Patient Withdrawal..................................................................................................15
9.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............15

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9.5. Ethical Conduct of the Study ..................................................................................15
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................15
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........16
12. REFERENCES ..................................................................................................................16
13. LIST OF TABLES.............................................................................................................19
14. LIST OF FIGURES ...........................................................................................................19
15. ANNEX 1. LIST OF STAND ALONE DOCUMENTS ...................................................19
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................19
ANNEX 3. ADDITIONAL INFORMATION.........................................................................19

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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse events 
AEM
adverse event monitoring 
AF
atrial fibrillation
BMI
body-mass index
e-CRF
electronic case report form
EDP
exposure during pregnancy
FXa
coagulation factor Xa
IEC
Independent Ethics Committee
INR
international normalized ratios 
IRB
Institutional Review Board 
LSLV
last subject last visit
NIS
non-interventional study
NOAC
non-vitamin K antagonist oral anticoagulant
NVAF
non-valvular atrial fibrillation
SAE
serious adverse events 
TIA
transient ischemic attack
VKA
vitamin K antagonists 

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2. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Title
Affiliation
Address
MUDr. 
 Ph.D., 
FESO 
Principal 
Investigator
Department of 
Neurology 
MUDr. 
NI Study Lead
Medical advisor 
MUDr. 
 Ph.D. 
3. ABSTRACT
None.
4. AMENDMENTS AND UPDATES
None.
5. MILESTONES
Milestone
Planned date
Completion of feasibility assessment
September 2018
Start of data collection 
July 2020
End of data collection
September 2020
Final study report
November 2020
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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6. RATIONALE AND BACKGROUND
Patients with atrial fibrillation (AF) are at increased risk for stroke. AF is associated with a 
four to fivefold increase in risk of stroke and thromboembolic events, resulting in significant 
morbidity, mortality, and costs.1.2 Stroke is the second most common cause of death and 
major cause of disability worldwide.3 About 30% of strokes occur in individuals with a 
previous transient ischemic attack (TIA) or stroke4, and more than 50% occur in individuals 
with previous vascular events of any kind.5
Warfarin is a highly effective treatment, reducing the risk of stroke by about two thirds, but 
its effectiveness in clinical practice is challenged by its variable dose response, drug-food and 
drug-drug interactions, need for frequent monitoring of international normalized ratios (INR), 
and associated risk of hemorrhage.6 Bleeding complications are relatively frequent, and 
a high proportion of patients discontinues or receives suboptimal therapy in clinical practice.7
In recent, carefully monitored trials, patients treated with warfarin spent only 63–68% of the 
time in the therapeutic INR range.8 Warfarin is associated with bleeding and drug related 
hospitalizations relate to a narrow therapeutic window and difficulties in adjusting the dose. 
Among elderly patients (65 years and older) warfarin was the most common drug leading to 
drug related hospitalizations followed by insulins, oral antiplatelet agents, and oral 
hypoglycemic agents.9
Bleeding among patients on anticoagulant therapy often leads to cessation of anticoagulant 
treatment, which may increase the risk of subsequent thrombotic events. Termination of 
warfarin after a gastrointestinal bleed was shown in one study to increase the risk of death 
and thrombotic events.10 In a real-world registry, patients who experienced serious bleeding 
had a threefold increase in the risk of thrombotic events even though the majority of patients 
did not permanently stop oral anticoagulation.11
Non-vitamin K antagonist oral anticoagulants (NOACs) that have emerged in recent years as 
alternatives to warfarin are proven to reduce these events, similar to or more than warfarin, 
with a similar or lower risk of hemorrhage.14,15,16,17 Additionally NOACs have predictable 
effect without need for routine monitoring, and fewer food and drug interactions compared 
with vitamin K antagonists (VKA). Apixaban is a direct oral factor Xa inhibitor with rapid 
absorption, a 12-hour half-life, and 27% renal excretion.19 In patients with AF and at least 
one additional risk factor for stroke, the use of apixaban, as compared with warfarin, 
significantly reduced the risk of stroke or systemic embolism by 21%, major bleeding by 
31%, and death by 11%.18 In the patients with AF who were not candidates for VKA
treatment, apixaban was compared to aspirin (ASA) and showed significant reduction in rate 
of stroke and systemic embolism by 55% without increasing the risk of major bleeding.15
Real-world clinical observations are justifying that improved clinical profile of NOACs is 
translated to hard end-points in clinical practice. Favorable effectiveness and safety together 
with easiness of monitoring and improved adherence are generating important savings in cost 
of healthcare services. According to Laliberté et al. the NOACs´ (rivaroxaban) users have 

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significantly less AF-related hospitalization days than those patients who use warfarin.20
Apixaban was found to be a cost-effective alternative to warfarin for stroke prevention in 
patients with AF in Sweden, Portugal as well as in the USA21,22,24 and also (compared to 
warfarin) apixaban is a cost-saving medicine with significantly lower rates of stroke and
major bleeding in a real-world nonvalvular atrial fibrillation (NVAF) population in the 
USA.23,24 In the group of NOACs apixaban seems to be the most cost-effective alternative in 
comparison to rivaroxaban and dabigatran.25,26
NOACs are indicated for prevention of stroke and systemic embolism in patients with 
nonvalvular atrial fibrillation 28. When oral anticoagulation is initiated in a patient with AF 
who is eligible for a NOAC (apixaban, dabigatran, edoxaban, or rivaroxaban), a NOAC is 
recommended in preference to a VKA as stated in guidelines of European Society of 
Cardiology (endorsed by Czech Society of Cardiology) 28.
Nonetheless NOACs were categorized as a second line treatment due to the restriction of 
SUKL (local regulatory authority) in Czech Republic and therefore Czech patients are 
primarily treated with warfarin (including patient post stroke/TIA) and NOACs treatment can 
be initiated only in case of defined contraindication. Czech Cardiology Society, Society of 
Ambulatory Specialist together with main Czech Public Insurance House (VZP) defined 
number of conditions where safe and efficacious anticoagulation therapy by VKA cannot be 
adequately ensured29. Prescription of NOACs as first line therapy is allowed in these defined
situations 29. One of the situations is described as higher sensitivity to warfarin. There are 
two variants of two genes, CYP2C9 and VKORC1, account for 30-50% of the variability in 
dosing of warfarin.12 The prevalence of CYP2C9 (allele *1, *2 and *3) and VKORC1 (-1639
G and A alleles), and their combinations in Czech population was analyzed and about 30% of 
the Czech healthy subjects have genetically determined higher sensitivity to warfarin.13
Individuals with higher sensitivity to warfarin are eligible for first line NOACs treatment in 
secondary prevention of stroke. 
Additionally there is no healthcare resource use (hospitalization days, outpatient visits, and 
clinical events) comparison of apixaban to warfarin available in the Czech Republic. The 
most intensive resource use is expected in the first 6 months after stroke, especially because 
of a high risk of the event recurrence. Considering that there are less outpatient visits, less 
monitoring needed and lower risk of the complications and adverse events expected with 
apixaban. Real-world data about the impact of different treatment strategies on healthcare 
resource use and costs are essential arguments for establishing the clinical value of new 
therapies.  
In the light of this situation we have designed this study to compare the healthcare resource 
use in patients who use warfarin or apixaban in secondary stroke prevention as a first line 
therapy.

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7. RESEARCH QUESTION AND OBJECTIVES
The primary objective of the study is:

Description of direct costs related to warfarin/apixaban treatment during the first 
6 months of the secondary stroke prevention in NVAF patients. 
The secondary objectives of this study are:

Comparison of direct costs related to warfarin/apixaban treatment during the first 
6 months of the secondary stroke prevention in NVAF patients;

Number of hospitalization days in the first 6 months of the treatment;

Number of ischemic/hemorrhagic strokes in the first 6 months of the treatment;

Number of ischemic events in the first 6 months of the treatment;

Number of major/minor hemorrhagic events in the first 6 months of the treatment;

Mortality rates in both cohorts;

Number and costs of medical procedures directly related to the treatment in the first 
6 months (visits, hospitalizations, labs, diagnostics, etc.);

Overall safety (adverse events) of the treatment.
8. RESEARCH METHODS 
8.1. Study design
This is a double arm, non-interventional, single-center retrospective study according to 
Czech legal definitions (Law 378/2007 Sb.). For the description of the direct costs related to 
warfarin/apixaban treatment, retrospective data will be used for both, the warfarin treatment 
arm and the apixaban treatment arm.
The study follows two cohorts of NVAF patients, who used either warfarin or apixaban as 
a secondary stroke/TIA prevention. 
The data to be collected retrospectively:

Consecutive data of the 6 months after the first prescription of warfarin/apixaban
(indicated as a secondary stroke/TIA prevention).
Considering the retrospective design of data collection, the non-interventional study will not 
impose any additional procedures, assessments or changes to the routine management of 
subjects. Data for the study will be obtained from clinical practice records and transcribed to 
an anonymous electronic case report form (e-CRF).

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8.2. Setting
In total, this non-interventional study follows the population of 240 patients with nonvalvular 
atrial fibrillation. From 240 NVAF patients, 120 patients are treated with warfarin and 120 
patients are treated with apixaban. 
The study will follow the period of 6 months after the prescription of warfarin or apixaban 
for the secondary stroke/TIA prevention. 
The data will be collected retrospectively from clinical practice hospital records. 
It´s expected that the data will be collected within 3 months from the start of the study – the 
data collection will be closed as soon as there are 120 patients enrolled in each study arm. If 
there are not 120 patients enrolled in each study arm after 3 months of the data collection, the 
period can be prolonged up to 6 months from the start of the study. 
Requirements for the center´s eligibility are as followed: center able to genetically determine 
patients´ higher sensitivity to warfarin; neurologists, who work in cerebrovascular center in a 
hospital; satisfactory experience in the care of patients with NVAF and treatment with 
warfarin and NOAC; sufficient number of patients with NVAF diagnosis fulfilling eligibility 
criteria.  
8.2.1. Inclusion criteria
The data will be collected for patients who have met all of the following inclusion criteria:
1. Diagnosis of non-valvular atrial fibrillation (NVAF);
2. New initiation of anticoagulation therapy (apixaban or warfarin) due to the ischemic 
event (stroke/TIA) meaning patients previously not anticoagulated due to diagnosis of
NVAF;
3. Indication to anticoagulation therapy as a secondary stroke prevention within 7 to 
30 days after the stroke/TIA event;
4. Apixaban arm: genetically determined higher sensitivity to warfarin;
5. Patients whose status allowed oral treatment with apixaban/warfarin;
6. Age ≥ 18;
7. Access to patient´s records of the first 6 months of the warfarin/apixaban treatment.
8.2.2. Exclusion criteria
Patients meeting any of the following criteria will not be included in the study:
8. Diagnosis of valvular disease;
9. Treatment with other anticoagulants in previous 6 months due to other the NVAF 
indication;
10. Treatment or prophylaxis of deep vein thrombosis or pulmonary embolism;
11. Contraindications according SmPC of Eliquis.

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8.3. Variables
Table 1: Table of variables
Variable
Role
Data source(s)
Operational 
definition
Age, Sex, BMI, 
date of index event 
(stroke/TIA
diagnosis), date of 
indication to 
warfarin/apixaban 
treatment (index 
date)
Demographic data
Medical records
Specified in e-CRF
CHA2-DS2-Vasc 
score, 
HAS-BLED score
Outcome
Medical records
Specified in e-CRF
Therapy after index 
event, prior to 
warfarin/apixaban 
treatment
Exposure
Medical records
Specified in e-CRF
Warfarin/apixaban 
therapy information 
(dosage; number of 
INR measurements
in warfarin arm)
Exposure
Medical records
Specified in e-CRF
Number and type of 
resource use during 
the first 6 months of 
warfarin/apixaban 
treatment (outpatient 
visits, diagnostic 
procedures, labs, 
medication, hospital 
admissions)
Outcome
Medical records
Specified in e-CRF
Amount, type, 
severity and cost of 
ischemic events
Outcome
Medical records
Specified in e-CRF

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Amount, type, 
severity and cost of 
major/minor 
hemorrhagic events
Outcome
Medical records
Specified in e-CRF
Adverse events
Outcome
Medical records
Specified in e-CRF
Index date = The index date will be the first date of OAC prescription indicated for secondary stroke/TIA 
prevention.
Index event = The index event will be the first stroke/TIA event based on which the OAC treatment will be 
initiated.
Index event date = The index event date will be the date of first stroke/TIA event based on which the OAC 
treatment will be initiated
Therapy after index event, prior to warfarin/apixaban treatment (Aspirin, clopidigrel, Trombolytics (rhu-tPA -
alteplase, urokinase), Anticoagulans (heparin, heparinoids), other)
8.4. Data sources
The data will be obtained retrospectively from hospital medical records, this study will not 
impose any additional procedures, assessments or changes to the routine management of 
subjects. The data will be transcribed to an anonymous e-CRF.
8.5. Study size
The study will be descriptive in nature. No sample size was statistically determined. Based 
on experience of experts on anticoagulant treatment the data from 120 patients per study arm 
can be collected.
8.6. Data management 
The data will be transcribed by the physician to an anonymous electronic Case Report Form 
from the patient´s medical records. The data will be obtained retrospectively and no patient 
data identification will be possible.
8.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties.

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The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document. 
8.6.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, e.g., CRFs and hospital records), all safety reporting 
forms, source documents, detailed records of treatment disposition, and adequate 
documentation of relevant correspondence (e.g., letters, meeting minutes, and telephone call 
reports).  The records should be retained by the investigator according to local regulations or
as specified in the clinical study agreement (CSA), whichever is longer.  The investigator 
must ensure that the records continue to be stored securely for so long as they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
8.7. Data analysis 
The statistical analyses will be descriptive and exploratory. Given the nature of the study, 
which is exploratory, it is not designed to confirm or reject predetermined hypotheses. 

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Categorical outcomes will be summarized by the number and percentage in each category. 
Continuous outcomes will be summarized by mean, standard deviation, median, minimum 
and maximum values. 
All analyses will be based on the full analysis set, comprising all subjects enrolled into the 
study.
The paired tests will be applied in the detailed analyses. Relevant endpoints will be compared 
using the differences in mean / median or proportion. Statistical significance will be assessed 
at a significance level of 0.05. All statistical analyses will be conducted using STATA 
version 13.1. 
Table 2: Table of descriptive analyses
Variable
Categorical outcome
Continuous outcome
Age
X
Sex
X
Body height, weight, BMI
X
Period between stroke/TIA and start of 
secondary stroke prevention (duration in days)
X
Period between stroke/TIA and start of 
secondary stroke prevention (medication)
X
CHA2-DS2-VASc Score
X
Stratification: (0, 1, 2-9)
X
HAS-BLED Score
X
Stratification: (0-2, 3-9)
X
Warfarin/apixaban dosage
X
INR measurements
X
Number and type of
outpatient visits, diagnostic procedures, labs, 
hospital admissions
X
Cost of
outpatient visits, diagnostic procedures, labs, 
medication, hospital admissions
X
Amount, type and severity of ischemic events
X
Cost of ischemic events
X
Amount, type, severity of major/minor 
hemorrhagic events 
X

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Cost of major/minor hemorrhagic events
X
Adverse events
X
8.8. Quality control
Data entry into eCRF and Electronic Data Record will be accomplished by qualified subjects 
only. Entered data will be reviewed by CRO for consistency and logic via implemented 
quality checks and by manual reviews, as well.
8.9. Strengths and limitations of the research methods
The study design is considered to be the main strength of this study. It brings a unique 
opportunity to compare the outcomes of two cohorts of patients fulfilling the same inclusion 
criteria. Another strength of the design is data collection in real-world setting without any 
patient's selection according subgroups characteristics.  The main limitation of the research 
may be a random distribution of patients on warfarin/apixaban treatment.
8.10. Other aspects
Not applicable.
9. PROTECTION OF HUMAN SUBJECTS
9.1. Patient Information 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff has access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code.
The investigator site will maintain a confidential list of patients who participated in the study, 

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linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the Clinical Study Agreement and applicable privacy laws.
9.2. Patient Consent
As this study involves anonymized structured or unstructured 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)
The study will be reviewed by Independent Ethics Committee of the study site.   
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 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), European Medicines Agency (EMA) European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological 
Standards 
in 
Pharmacoepidemiology, 
and 
FDA 
Guidance 
for 
Industry: 
Good 
Pharmacovigilance and Pharmacoepidemiologic Assessment, FDA Guidance for Industry 
and FDA Staff: Best Practices for Conducting and Reporting of Pharmacoepidemiologic 
Safety Studies Using Electronic Healthcare Data Sets, Guidance for Industry: Patient-
Reported Outcome Measures: Use in Medical Product Development to Support Labeling
Claims and/or equivalent.
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database.  The investigator is obligated to report adverse 
events (AE) with explicit attribution to any Pfizer drug that appear in the reviewed 

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information (defined per the patient population and study period specified in the protocol).  
Explicit attribution is not inferred by a temporal relationship between drug administration 
and an AE, but must be based on a definite statement of causality by a healthcare provider 
linking drug administration to the AE.
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows:

All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the the e-CRF and reported, 
within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form

Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form.
For these safety events with an explicit attribution to or associated with use of, respectively, a 
Pfizer product, the data captured in the medical record will constitute all clinical information
known regarding these AEs.  No follow-up on related AEs will be conducted.
All research staff members will complete the Pfizer requirements regarding training on the 
following: “Your Reporting Responsibilities: Monitoring the Safety, Performance and 
Quality of Pfizer Products (Multiple Languages)” and any relevant Your Reporting 
Responsibilities supplemental training.  This training must be completed by research staff 
members prior to the start of data collection.  All trainings include a “Confirmation of
Training Certificate” (for signature by the trainee) as a record of completion of the training, 
which must be kept in a retrievable format.  Copies of all signed training certificates must be 
provided to Pfizer. 
11. 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.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NI study protocol that the investigator becomes aware of.
12. REFERENCES
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mortality associated with suboptimal anticoagulation in atrial fibrillation patients. 
Thromb Haemost 2011;106:968–977.
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ischaemic stroke and transient ischaemic attack to prevent recurrent major vascular 
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Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, 
Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. 
Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 
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Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, 
Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 
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2013 Nov 28;369(22):2093-104.
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versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 
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Borges M, Gouveia M. Custo‐efetividade dos novos anticoagulantes orais na fibrilhação 
auricular em Portugal. Revista Portuguesa de Cardiologia 2015; 34(12), 723-737.
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Edition) [online]. 2015; 68(6), 537-539.
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29. https://media.vzpstatic.cz/media/Default/dokumenty/ostatni/shrnujici_zapis.pdf

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13. LIST OF TABLES 
Table 1. Table of variables
Table 2. Table of descriptive analyses
14. LIST OF FIGURES
None.
15. ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.
ANNEX 3. ADDITIONAL INFORMATION
Not applicable.