Patient Characteristics, Treatment Patterns and Incidence of Events (Discontinuation, Persistence, Key Primary Clinical Outcomes) in NVAF Patients Initiating OAC Therapy in Colombia
Conditions: Atrial Fibrillation
Sponsor: Pfizer

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Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 2 of 53 
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. 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 3 of 53 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................ 5 
1. RESPONSIBLE PARTIES................................................................................................................................. 7
2. ABSTRACT ....................................................................................................................................................... 8
3. AMENDMENTS AND UPDATES ................................................................................................................. 11
4. MILESTONES ................................................................................................................................................. 12
5. RATIONALE AND BACKGROUND............................................................................................................. 13
6. RESEARCH QUESTION AND OBJECTIVES .............................................................................................. 14
7. RESEARCH METHODS ................................................................................................................................. 15
7.1. Study Design ...................................................................................................................................... 15 
7.2. Setting ................................................................................................................................................ 16 
Inclusion Criteria ........................................................................................................................... 17 
Exclusion Criteria .......................................................................................................................... 17 
7.2.3. Cohorts ................................................................................................................................ 17 
7.3. Variables ............................................................................................................................................ 18 
Definition of outcome variables .................................................................................................... 23 
7.4. Data Sources ...................................................................................................................................... 44 
7.4.1. 
Claim Database ....................................................................................................... 44 
7.4.2. 
Medical Record ....................................................................................................... 44 
7.5. Study Size .......................................................................................................................................... 44 
7.6. Data Management .............................................................................................................................. 44 
7.6.1 Electronic Case Report (ECR) .............................................................................................. 44 
7.6.2 
Record Retention .................................................................................................... 45 
7.6.3 
Patient Identification ............................................................................................... 46 
7.6.4 
Collection of Information ....................................................................................... 46 
7.6.5 
Database Retention ................................................................................................. 46 
7.7 Data Analysis ...................................................................................................................................... 46 
7.7.1 
Missing Data Management ..................................................................................... 47 
7.8 Quality Control .................................................................................................................................... 47 
7.9 Limitations of the research methods.................................................................................................... 47 
7.10 
Other aspects ............................................................................................................................ 48 
8 PROTECTION OF STUDY SUBJECTS ....................................................................................................... 48 
8.1 Patient Information .............................................................................................................................. 48 
8.2 Patient Consent .................................................................................................................................... 48 
8.3 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ........................................... 49 
8.4 Ethical Conduct of the Study............................................................................................................... 49 
9 MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS ...................... 50 
10 PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ..................................... 51 
11. REFERENCES ............................................................................................................................................... 52
12. LIST OF TABLES ......................................................................................................................................... 53
13. LIST OF FIGURES ........................................................................................................................................ 53
ANNEX 1. LIST OF STAND ALONE DOCUMENTS ...................................................................................... 53 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ...................................................................... 53 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 4 of 53 
ANNEX 3. ADDITIONAL INFORMATION...................................................................................................... 53 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 5 of 53 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ARB 
Angiotensin II receptor blockers 
ACE 
Angiotensin-converting-enzyme inhibitor 
AE 
Adverse event 
AEM 
Adverse event monitoring 
AIDS 
Acquired Immune Deficiency Syndrome 
AF 
Atrial fibrillation 
ANOVA 
Analysis of variance 
ATC 
Anatomical Therapeutic Chemical 
CHA2DS2-VASc 
C:  Congestive heart failure 
H:  Hypertension 
A:  Age ≥75 years 
D: Diabetes mellitus 
S2:  Prior Stroke or transient ischemic attack or Thromboembolism 
V:   Vascular disease ( peripheral artery disease, myocardial infarction, aortic 
plaque) 
A: Age 65–74 years 
Sc: Sex category ( female sex) 
CHADS2 
C:  Congestive heart failure 
H:  Hypertension 
A:  Age ≥75 years 
D: Diabetes mellitus 
S2:  Prior Stroke or transient ischemic attack or Thromboembolism 
COPD 
Chronic obstructive pulmonary disease 
ECR 
Electronic Case Report 
GEP 
Good Epidemiological Practice 
GPP 
Good Pharmacoepidemiology Practices 
HAS-BLED 
H: Hypertension 
A:  Abnormal renal and liver function 
S: Stroke 
B: Bleeding 
L: Labile INR 
E: Elderly 
D: Drugs or alcohol 
HMO 
Health Maintenance Organizations 
ICD-10 
10th revision of the International classification of diseases 
IEA 
International Epidemiological Association 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISPE 
International Society for Pharmacoepidemiology 
ISPOR 
International Society for Pharmacoeconomics and Outcomes Research 
MANOVA 
Multivariate analysis of variance 
NI 
Non- interventional 
NIS 
Non-interventional study 
NOAC 
New oral anticoagulant 
NSAID 
Non-steroidal anti-inflammatory drugs 
NVAF 
Non-valvular atrial fibrillation 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 6 of 53 
Abbreviation 
Definition 
OAC 
Oral anticoagulant 
SAMe-TT2R2 
S: Sex (female) 
A:  Age (<60 years) 
Me: Medical history 
T:  Treatment 
T:  Tobacco use (within 2 years) 
R: Race (non-Caucasian) 
SPSS 
Statistical Package for the Social Sciences 
TIA 
Transient ischaemic attack 
VKA 
Vitamin K Antagonist 
VTE 
Venous thromboembolism 

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Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 8 of 53 
2. ABSTRACT
Study title: Patient characteristics, treatment patterns and incidence of events (discontinuation, persistence, 
key primary clinical outcomes) in NVAF patients initiating OAC therapy in Colombia   
Protocol number 
B0661148 
Phase 
4 
Type 
Observational 
Condition/Disease 
Non-valvular atrial fibrillation (NVAF) 
Number of patients 
The total population of 
patients treated with OAC 
between January 1, 2013 and 
June 30, 2018 was analyzed in 
the claim dabtabase. For the 
purpose of the study, it 
contains the information of 
7,500 patients, once they were 
verified that they met the 
inclusion criteria of the study. 
Duration of 
the patients 
in the study 
Follow-up will be performed 
until the patient presents a 
switch, discontinuation, death, 
event of stroke / systemic 
embolism or major bleeding, 
or until June 30, 2019. 
Country participants 
Colombia 
Duration of 
the study 
8 months 
Rational and background: 
Non-valvular atrial fibrillation (NVAF) is an acute or chronic heart disorder that is associated with an increase 
in the mortality rate, strokes and other thromboembolic events (1). This is further increased by individual 
conditions of patients, such as hypertension, abnormal renal or hepatic function, stroke, history of or 
predisposition to bleeding, people over 65, among others. (2) 
One of the standard treatments for management of these patients is usually vitamin K antagonists (VKA, for 
example, warfarin); in the analysis of net clinical benefits of this therapy it is suggested that the effect of 
VKA is even more positive in patients with a high score on the HAS-BLED (hypertension, abnormal 
renal/liver function, stroke, bleeding history or predisposition, labile International Normalized Ratio, elderly, 
drugs/alcohol concomitantly) scale. (3) Another therapeutic alternative is the new oral anticoagulants 
(NOACs) ─ dabigatran, rivaroxaban and apixaban ─, which according to evidence have advantages in 
efficacy and safety compared to warfarin (4) and even when the risk of bleeding and stroke are high, the net 
clinical benefit appears to be greater when compared to warfarin. (5) Likewise, there is a lower prevalence of 
intracranial hemorrhage and its different subtypes of patients being treated with new oral anticoagulants when 
compared to warfarin. (6)  
While it is true there are several studies that seek to understand the characteristics of patients who were 
diagnosed with NVAF under different treatment options, and even subpopulation analyses, the evidence at the 
national level is limited, both in demographic and clinical characteristics and in treatment patterns of this 
population. In a retrospective descriptive study of an emergency department in a third level care center in the 
city of Bogota, it was observed that the main comorbidities of patients with atrial fibrillation (AF) were 
arterial hypertension and heart failure where most patients do not receive anticoagulation. (7) In turn, for the 
overall population it is estimated that the prevalence of AF in Colombia (4.8%) seems to be higher than that 
reported in developed countries (0.03% to 1.25%) (8), according to a study conducted in a university hospital 
in the country (9). 
Taking into account the limited knowledge on the use of oral anticoagulants in patients diagnosed with NVAF 
in the country and, even more in the differences in the response to these therapies in different patient 
subpopulations. The purpose of this study is to assess the demographic and clinical charateristics, treatment 
patterns and incidence of events (discontinuation, persistence, key primary clinical outcomes) in NVAF 
patients that initiated OACs in study period.  
Primary Objectives 
•
To assess demographic and clinical characteristics of NVAF patients treated with oral anticoagulants
(OACs) in Colombia.
•
To describe treatment patterns (eg OAC usage,dose, concomitant medications, persistence)

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Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL  
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 11 of 53 
3. AMENDMENTS AND UPDATES 
None 
 
 
 

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Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 13 of 53 
5. RATIONALE AND BACKGROUND
Non-valvular atrial fibrillation (NVAF) is an acute or chronic heart disorder that is associated 
with an increase in the mortality rate, strokes and other thromboembolic events (1). This is 
further increased by individual conditions of patients, such as hypertension, abnormal renal or 
hepatic function, stroke, history of or predisposition to bleeding, people over 65, among others. 
(2) 
One of the standard treatments for management of these patients is usually vitamin K 
antagonists (VKA, for example, warfarin); in the analysis of net clinical benefits of this therapy 
it is suggested that the effect of VKA is even more positive in patients with a high score on the 
HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or 
predisposition, labile International Normalized Ratio, elderly, drugs/alcohol concomitantly) 
scale. (3) Another therapeutic alternative is the new oral anticoagulants (NOAC) ─ dabigatran, 
rivaroxaban and apixaban ─, which according to evidence have advantages in efficacy and 
safety compared to warfarin (4) and even when the risk of bleeding and stroke are high, the net 
clinical benefit appears to be greater when compared to warfarin. (5) Likewise, there is a lower 
prevalence of intracranial hemorrhage and its different subtypes of patients being treated with 
new oral anticoagulants when compared to warfarin. (6)  
While it is true there are several studies that seek to understand the characteristics of patients 
who were diagnosed with NVAF under different treatment options, and even subpopulation 
analyses, the evidence at the national level is limited, both in demographic and clinical 
characteristics and in treatment patterns of this population. In a retrospective descriptive study 
of an emergency department in a third level care center in the city of Bogota, it was observed 
that the main comorbidities of patients with atrial fibrillation (AF) were arterial hypertension 
and heart failure where most patients do not receive anticoagulation. (7) In turn, for the overall 
population it is estimated that the prevalence of AF in Colombia (4.8%) seems to be higher 
than that reported in developed countries (0.03% to 1.25%) (8), according to a study conducted 
in a university hospital in the country (9). 
Taking into account the limited knowledge on the use of oral anticoagulants in patients 
diagnosed with NVAF in the country and, even more in the differences in the response to these 
therapies in different patient subpopulations. The purpose of this study is to assess the 
demographic and clinical charateristics, treatment patterns and incidence of events 
(discontinuation, persistence, key primary clinical outcomes) in NVAF patients that initiated 
OACs in study period. 

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Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 15 of 53 
7. RESEARCH METHODS
7.1. Study Design 
Observational, descriptive study of a retrospective cohort of adult patients diagnosed with 
NVAF in selected Health Maintenance Organization (HMO) of Colombia. These patients will 
be identified from the drug claim database, whose index date of the study will be the first 
prescription with any of the oral anticoagulants, that is, they are patients with NVAF for the 
first time starting a therapy with any of the NOACs between January 1, 2013 and June 30, 
2018 and follow up period will be among January 2013 to July 2019, to ensure that the last 
patients can provide follow-up for one year. Patients will be required to have an NVAF 
diagnosis before or on the index date and health plan for 6 months pre-index date (baseline 
period). 
Following, it will be verified that the patients meet the inclusion and exclusion criteria of the 
study. Once patients are selected and with the index date of each patient, they will be followed-
up until discontinuation, switch of treatment, death or first event of stroke/ systemic embolism, 
major bleeding event, death or end of follow-up. Patients who are lost to follow-up, change of 
HMO and do not have access to the medical record will be considered as missing (Figure 1).  
Figure 1. Study Design 
The information will be analyzed in two moments: (i) the period of the index date, where the 
baseline information of patients will be collected; (ii) and the follow-up period, during this 
period the clinical results will be evaluated as well as the continuation of the treatment in the 
study population and for specific subpopulations.  
Those patients who initiated treatment with any oral anticoagulant between January 2013 and 
June 30, 2018 will be included. This means that patients who start warfarin and NOACs would 
Index Date  
Prescription  
oral anticoagulant 
Follow-up until the patient has: 
•
Major bleeding event
•
Death or first stroke/systemic
embolism
•
Discontinuation
•
Switch of treatement
•
End of follow-up
Follow-up Period 
Baseline period 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 16 of 53 
be included within this period. Patients who initiate NOACs within the established period and 
who have been exposed to warfarin before 2013 will also be included. 
Only the exposure period will be considered with the initial treatment, even in those patients 
who were on warfarin treatment before 2013, in the latter, the follow-up will be the treatment 
initiation with a NOAC in case of change after 2013. Follow-up will be carried out until the 
patient has a switch of treatment, discontinuation, death, first stroke/ systemic embolism, or 
major bleeding, or until end of follow-up, June 30, 2019 (Figure 2).  
Figure 2. Inclusion of Patients 
7.2. Setting 
The study will be conducted with the Audifarma patient cohort that meets the inclusion and 
exclusion criteria between the periods from January 2013 to June 30, 2018. The follow up 
period will be among January 2013 to July 2019, to ensure that the last patients can provide 
follow-up for one year.  
This study will include the entire population in which medical records can be accessed. This 
will depend on the authorization of the HMOs for review of medical records. Participating 
patients will be followed-up until the patient has a stroke/systemic embolism, major bleeding, 
discontinuation, change of treatment or until the data collection period is completed.  
Warfarina
2013
2019
X
NOAC 
X
Warfarina 
X 
NOAC 
Warfarina 
X
NOAC 
Follow-up time 
NOAC1 
X
NOAC2 
Follow-up time 
Follow-up time 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 17 of 53 
7.2.1. Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:  
a)
Patients with a diagnosis of AF considered according to the following diagnoses as per
the ICD I48 codes at some point before or on the index date, without recorded valvular
disease;
b)
Patients who have started treatment with apixaban, dabigatran, rivaroxaban and
warfarin for the first time during the identification period, understanding as start of
drug delivery by insurer, and after the diagnosis of AF between January 1, 2013 to
June 30, 2018;
c)
Patients starting apixaban, dabigatran, rivaroxaban from January 1, 2013 to June 30,
2018 in patients previously exposed to warfarin;
d)
Patient had continuous health plan for 6 months pre-index date (baseline period);
e)
Patients older than 18 years old on the index date;
f)
NVAF diagnosis before or on the index date
7.2.2. Exclusion Criteria  
Patients meeting any of the following criteria will not be included in the study: 
e)
Patients with any of the following diagnoses prior to the use of the treatments of
interest or index date:
•
Valvular heart disease or valve replacement – ICD-10 codes: I05, I06, I07, I08,
I09, I22, I34, I35, I36, I37, I38, I39, I700, I702-I709; Q22, Q23, Q25, T82,Z95.
•
Pregnancy during the study period. ICD-10 O00-O9A
•
Diagnosis of venous thromboembolism (VTE) – ICD-10 codes: I26, I80 - I82;
f)
Individuals with a transitory diagnosis of NVAF prior to the use of the treatments of
interest or index date;
g)
Exposure to more than one OAC on or after the index date, during the follow-up
period.
h)
NOAC doses different from those recommended by the manufacturing laboratories.
7.2.3. Cohorts 
After applying the inclusion and exclusion criteria, eligible patients will be assigned to the 
following four cohorts based on the OAC received on the index date.  
1. Apixaban

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 18 of 53 
2. Dabigatran
3. Rivaroxaban
4. Warfarin
Depending on the dosage of the NOAC prescribed on the index date, and in comparison to 
the standard conventions of total daily doses, patients may be classified into 3 different 
groups:  
•
High doses: apixaban 10 mg/day - rivaroxaban: 20 mg/day - dabigatran: 300 mg/day;
•
Low doses: apixaban 5 mg/day - rivaroxaban: 15 mg/day - dabigatran: 220 mg/day
•
Other doses: to be excluded, doses not recommended by the manufacturing laboratories.
7.3. Variables 
The described variables are classified into two variable groups according to the role, the 
clinical outcome and baseline (demographic, clinical, treatment variables). The latter include 
the possible subgroups to consider. These analyses are initially exploratory to the extent that 
the specific analyses may be performed according to the sample collected.  
Table 1. Table of Variables 
Variable 
Role 
Data source (s) 
Operational 
definition 
Age 
Demographic 
characteristic 
Medical record 
Birthday 
Gender 
Demographic 
characteristic 
Medical record 
Male, female, other 
Race 
Demographic 
characteristic 
Medical record 
White, half-breed, 
indigenous, black, 
others 
Weight 
Demographic 
characteristic 
Medical record 
Kg 
Height 
Demographic 
characteristic 
Medical record 
Mt (meters) 
Body mass index 
Demographic 
characteristic 
Medical record 
Kg/mt2 
City of residence 
Demographic 
characteristic 
Medical record 
Cities of Colombia 
Time to diagnosis to 
NVAF 
Clinical 
characteristic 
Medical record 
Date (dd/mm/yy) 
High alcohol intake at 
OAC prescription date 
Clinical 
characteristic 
Medical record 
Yes, No 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 19 of 53 
Variable 
Role 
Data source (s) 
Operational 
definition 
Diabetes 
Clinical 
characteristic 
Medical record 
No, without chronic 
complication, with 
end-organ damage 
Liver disease 
Clinical 
characteristic 
Medical record 
No, mild, 
moderade, severe 
Hypertension 
Clinical 
characteristic 
Medical record 
Diagnosis of 
hypertension (Yes, 
No) 
Uncontrolled 
hypertension at OAC 
prescription date 
Clinical 
characteristic 
Medical record 
Yes, No 
Rheumatic disease 
Clinical 
characteristic 
Medical record 
Yes, No 
Acquired Immune 
Deficiency Syndrome 
(AIDS) 
Clinical 
characteristic 
Medical record 
Yes, No 
Severe renal disease 
(dialysis, organ 
transplant) 
Clinical 
characteristic 
Medical record 
Yes, No 
Moderade renal 
disease (creatinine > 
3 mg/dL) 
Clinical 
characteristic 
Medical record 
Yes, No 
Chronic heart failure 
Clinical 
characteristic 
Medical record 
Yes, No 
Myocardial infarction 
Clinical 
characteristic 
Medical record 
Yes, No 
Chronic obstructive 
pulmonary disease 
(COPD) 
Clinical 
characteristic 
Medical record 
Yes, No 
Peripheral vascular 
disease 
Clinical 
characteristic 
Medical record 
Yes, No 
Stroke or transient 
ischemic attack (TIA) 
Clinical 
characteristic 
Medical record 
Yes, No 
Dementia 
Clinical 
characteristic 
Medical record 
Yes, No 
Hemiplegia 
Clinical 
characteristic 
Medical record 
Yes, No 
Connective tissue 
disease 
Clinical 
characteristic 
Medical record 
Yes, No 
Leukemia 
Clinical 
characteristic 
Medical record 
Yes, No 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 20 of 53 
Variable 
Role 
Data source (s) 
Operational 
definition 
Malignant lymphoma 
Clinical 
characteristic 
Medical record 
Yes, No 
Peptic ulcer disease 
Clinical 
characteristic 
Medical record 
Yes, No 
Metastatic solid 
tumor 
Clinical 
characteristic 
Medical record 
Yes, No 
History of ischemic 
or hemorrhagic 
stroke 
Clinical 
characteristic 
Medical record 
Yes, No 
History of TIA 
Clinical 
characteristic 
Medical record 
Yes, No 
History of de 
tromboembolismo 
Clinical 
characteristic 
Medical record 
Yes, No 
Enfermedad 
coronaria 
Clinical 
characteristic 
Medical record 
Yes, No 
History of de 
hemorragia 
gastrointestinal 
Clinical 
characteristic 
Medical record 
Yes, No 
History of 
Intracranial bleeding 
Clinical 
characteristic 
Medical record 
Yes, No 
History of Other 
bleeding 
Clinical 
characteristic 
Medical record 
Yes, No 
Bleeding history or 
predisposition at start 
OAC treatment 
Clinical 
characteristic 
Medical record 
Yes, No 
INR > 60% at start 
OAC treatment 
Clinical 
characteristic 
Medical record 
Yes, No 
Use of aspirin at start 
OAC treatment 
Clinical 
characteristic 
Medical record 
Yes, No 
Use of clopidogrel at 
start OAC treatment 
Clinical 
characteristic 
Medical record 
Yes, No 
Use of NSAIDs at 
start OAC treatment 
Clinical 
characteristic 
Medical record 
Yes, No 
HASBLED at start 
OAC treatment 
Clinical 
characteristic 
Medical record 
Score – number 
higher than 0 
CHA2DS2-VASc at 
start OAC treatment 
Clinical 
characteristic 
Medical record 
Score – number 
higher than 0 
Anaemia at start 
OAC treatment 
Clinical 
characteristic 
Medical record 
Yes, No 
Stroke 
Clinical outcome 
Medical record 
Yes, No 
Time to stroke 
Clinical outcome 
Medical record 
Date of event 
dd/mm/yy 

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Apixaban  
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Final, 10 October 2019 
PFIZER CONFIDENTIAL  
Page 24 of 53 
ICD-10 
Description 
K252 
Acute with both haemorrhage and perforation 
K254 
Chronic or unspecified with haemorrhage 
K256 
Chronic or unspecified with both haemorrhage and perforation 
K260 
Acute with haemorrhage 
K262 
Acute with both haemorrhage and perforation 
K264 
Chronic or unspecified with haemorrhage 
K266 
Chronic or unspecified with both haemorrhage and perforation 
K270 
Acute with haemorrhage 
K272 
Acute with both haemorrhage and perforation 
K274 
Chronic or unspecified with haemorrhage 
K276 
Chronic or unspecified with both haemorrhage and perforation 
K280 
Acute with haemorrhage 
K282 
Acute with both haemorrhage and perforation 
K284 
Chronic or unspecified with haemorrhage 
K286 
Chronic or unspecified with both haemorrhage and perforation 
K290 
Acute haemorrhagic gastritis 
K625 
Haemorrhage of anus and rectum 
K920 
Haematemesis 
K921 
Melaena 
K922 
Gastro-intestinal haemorrhage, unspecified 
D62 
Acute posthaemorrhagic anaemia 
H356 
Retinal haemorrhage 
H431 
Vitreous haemorrhage 
H450 
Vitreous haemorrhage in diseases classified elsewhere 
H922 
Otorrhagia 
I312 
Haemopericardium, not elsewhere classified 
J942 
Haemothorax 
R04 
Haemorrhage from respiratory passages 
K661 
Haemoperitoneum 
M250 
Haemarthrosis 
N02 
Recurrent and persistent haematuria 
N938 
Other specified abnormal uterine and vaginal bleeding 
N939 
Abnormal uterine and vaginal bleeding, unspecified 
N950 
Postmenopausal bleeding 
R31 
Unspecified haematuria 
R58 
Haemorrhage, not elsewhere classified 
T792 
Traumatic secondary and recurrent haemorrhage 
•
Ischemic stroke: Patients who report the following diagnoses in the medical history
during the follow-up period:
ICD-10 
Description 
I63 
Cerebral infarction 
I64 
Stroke, not specified as haemorrhage or infarction 
Except I63.6  Cerebral infarction due to thrombosis of cerebral veins, non-pyogenic 
•
Hemorrhagic stroke: Patients presenting the following diagnosis in the medical record:

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
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PFIZER CONFIDENTIAL  
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ICD-10 
Description 
I60 
Subarachnoid haemorrhage 
I61 
Intracerebral haemorrhage 
I62 
Other nontraumatic intracranial haemorrhage 
•
Systemic embolism: Patients who report any of the following diagnoses:
ICD-10 
Description 
I74 
Arterial embolism and thrombosis 
Definition of covariates 
•
Age: Categorical variable, continues in years. It will be defined from the index date and
will be used to assign patients to the following age categories:
18 - 49 
50 - 59 
60 - 69 
70 - 79 
≥ 80 years old. 
•
Charlson Index: Charlson comorbidity index will be created during the reference
period taking into account the following score: 
1 point each: 

Myocardial infarction
ICD-10 
Description 
I21 
Acute myocardial infarction 
I22 
Subsequent myocardial infarction 
I252 
Old myocardial infarction 

Congestive heart failure
ICD-10 
Description 
I110 
Hypertensive heart disease with (congestive) heart failure 
I130 
Hypertensive heart and renal disease with (congestive) heart failure 
I132 
Hypertensive heart and renal disease with both (congestive) heart failure and renal failure 
I110 
Hypertensive heart disease with (congestive) heart failure 

Peripheral vascular disease
ICD-10 
Description 
I70 
Atherosclerosis 
I71 
Aortic aneurysm and dissection 
I731 
Thromboangiitis obliterans [Buerger] 
I738 
Other specified peripheral vascular diseases 
I739 
Peripheral vascular disease, unspecified 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
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PFIZER CONFIDENTIAL  
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ICD-10 
Description 
I771 
Stricture of artery 
I790 
Aneurysm of aorta in diseases classified elsewhere 
I792 
Peripheral angiopathy in diseases classified elsewhere 
K551 
Chronic vascular disorders of intestine 
K558 
Other vascular disorders of intestine 
K559 
Vascular disorder of intestine, unspecified 
Z958 
Presence of other cardiac and vascular implants and grafts 
Z959 
Presence of cardiac and vascular implant and graft, unspecified 

Dementia
ICD-10 
Description 
F00 
Dementia in Alzheimer's disease 
F01 
Vascular dementia 
F02 
Dementia in other diseases classified elsewhere 
F03 
Unspecified dementia 
G30 
Alzheimer's disease 
F051 
Delirium superimposed on dementia 
G311 
Senile degeneration of brain, not elsewhere classified 

Cerebrovascular disease
ICD-10 
Description 
G45 
Transient cerebral ischaemic attacks and related syndromes 
G46 
Vascular syndromes of brain in cerebrovascular diseases 
I60 
Subarachnoid haemorrhage 
I61 
Intracerebral haemorrhage 
I62 
Other nontraumatic intracranial haemorrhage 
I63 
Cerebral infarction 
I64 
Stroke, not specified as haemorrhage or infarction 
I65 
Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction 
I66 
Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction 
I67 
Other cerebrovascular diseases 
I68 
Cerebrovascular disorders in diseases classified elsewhere 
I69 
Sequelae of cerebrovascular disease 
H340 
Transient retinal artery occlusion 

Chronic pulmonary disease
ICD-10 
Description 
J40 
Bronchitis, not specified as acute or chronic 
J41 
Simple and mucopurulent chronic bronchitis 
J42 
Unspecified chronic bronchitis 
J43 
Emphysema 
J44 
Other chronic obstructive pulmonary disease 
J45 
Asthma 
J46 
Status asthmaticus 
J47 
Bronchiectasis 
J60 
Coalworker's pneumoconiosis 
J61 
Pneumoconiosis due to asbestos and other mineral fibres 
J62 
Pneumoconiosis due to dust containing silica 

Apixaban  
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ICD-10 
Description 
J63 
Pneumoconiosis due to other inorganic dusts 
J64 
Unspecified pneumoconiosis 
J65 
Pneumoconiosis associated with tuberculosis 
J66 
Airway disease due to specific organic dust 
J67 
Hypersensitivity pneumonitis due to organic dust 
I278 
Other specified pulmonary heart diseases 
I279 
Pulmonary heart disease, unspecified 
J684 
Chronic respiratory conditions due to chemicals, gases, fumes and vapours 
J701 
Chronic and other pulmonary manifestations due to radiation 
J703 
Chronic drug-induced interstitial lung disorders 

Apixaban  
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
Connective tissue disease
ICD-10 
Description 
M05 
Seropositive rheumatoid arthritis 
M06 
Other rheumatoid arthritis 
M32 
Systemic lupus erythematosus 
M33 
Dermatopolymyositis 
M34 
Systemic sclerosis 
M315 
Giant cell arteritis with polymyalgia rheumatica 
M351 
Other overlap syndromes 
M353 
Polymyalgia rheumatica 
M360 
Dermato(poly)myositis in neoplastic disease 

Ulcer disease
ICD-10 
Description 
K25 
Gastric ulcer 
K26 
Duodenal ulcer 
K27 
Peptic ulcer, site unspecified 
K28 
Gastrojejunal ulcer 

Mild liver disease
ICD-10 
Description 
B18 
Chronic viral hepatitis 
K73 
Chronic hepatitis, not elsewhere classified 
K74 
Fibrosis and cirrhosis of liver 
K700 
Alcoholic fatty liver 
K701 
Alcoholic hepatitis 
K702 
Alcoholic fibrosis and sclerosis of liver 
K703 
Alcoholic cirrhosis of liver 
K709 
Alcoholic liver disease, unspecified 
K717 
Toxic liver disease with fibrosis and cirrhosis of liver 
K713 
Toxic liver disease with chronic persistent hepatitis 
K714 
Toxic liver disease with chronic lobular hepatitis 
K715 
Toxic liver disease with chronic active hepatitis 
K760 
Fatty (change of) liver, not elsewhere classified 
K762 
Central haemorrhagic necrosis of liver 
K763 
Infarction of liver 
K764 
Peliosis hepatis 
K768 
Other specified diseases of liver 
K769 
Liver disease, unspecified 
Z944 
Liver transplant status 
B18 
Chronic viral hepatitis 
K73 
Chronic hepatitis, not elsewhere classified 
K74 
Fibrosis and cirrhosis of liver 
K700 
Alcoholic fatty liver 
K701 
Alcoholic hepatitis 
K702 
Alcoholic fibrosis and sclerosis of liver 
K703 
Alcoholic cirrhosis of liver 
K709 
Alcoholic liver disease, unspecified 
K717 
Toxic liver disease with fibrosis and cirrhosis of liver 
K713 
Toxic liver disease with chronic persistent hepatitis 
K714 
Toxic liver disease with chronic lobular hepatitis 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
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PFIZER CONFIDENTIAL  
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ICD-10 
Description 
K715 
Toxic liver disease with chronic active hepatitis 
K760 
Fatty (change of) liver, not elsewhere classified 
K762 
Central haemorrhagic necrosis of liver 
K763 
Infarction of liver 
K764 
Peliosis hepatis 
K768 
Other specified diseases of liver 
K769 
Liver disease, unspecified 
Z944 
Liver transplant status 

Diabetes without chronic complication
ICD-10 
Description 
E100 
Insulin-dependent diabetes mellitus with coma 
E101 
Insulin-dependent diabetes mellitus with ketoacidosis 
E106 
Insulin-dependent diabetes mellitus with other specified complications 
E108 
Insulin-dependent diabetes mellitus with unspecified complications 
E109 
Insulin-dependent diabetes mellitus without complications 
E110 
Non-insulin-dependent diabetes mellitus with coma 
E111 
Non-insulin-dependent diabetes mellitus with ketoacidosis 
E116 
Non-insulin-dependent diabetes mellitus with other specified complications 
E118 
Non-insulin-dependent diabetes mellitus with unspecified complications 
E119 
Non-insulin-dependent diabetes mellitus without complications 
E120 
Malnutrition-related diabetes mellitus with coma 
E121 
Malnutrition-related diabetes mellitus with ketoacidosis 
E126 
Malnutrition-related diabetes mellitus with other specified complications 
E128 
Malnutrition-related diabetes mellitus with unspecified complications 
E129 
Malnutrition-related diabetes mellitus without complications 
E130 
Other specified diabetes mellitus with coma 
E131 
Other specified diabetes mellitus with ketoacidosis 
E136 
Other specified diabetes mellitus with other specified complications 
E138 
Other specified diabetes mellitus with unspecified complications 
E139 
Other specified diabetes mellitus without complications 
E140 
Unspecified diabetes mellitus with coma 
E141 
Unspecified diabetes mellitus with ketoacidosis 
E146 
Unspecified diabetes mellitus with other specified complications 
E148 
Unspecified diabetes mellitus with unspecified complications 
E149 
Unspecified diabetes mellitus without complications 
E100 
Insulin-dependent diabetes mellitus with coma 
E101 
Insulin-dependent diabetes mellitus with ketoacidosis 
E106 
Insulin-dependent diabetes mellitus with other specified complications 
E108 
Insulin-dependent diabetes mellitus with unspecified complications 
E109 
Insulin-dependent diabetes mellitus without complications 
E110 
Non-insulin-dependent diabetes mellitus with coma 
E111 
Non-insulin-dependent diabetes mellitus with ketoacidosis 
E116 
Non-insulin-dependent diabetes mellitus with other specified complications 
E118 
Non-insulin-dependent diabetes mellitus with unspecified complications 
E119 
Non-insulin-dependent diabetes mellitus without complications 
E120 
Malnutrition-related diabetes mellitus with coma 
E121 
Malnutrition-related diabetes mellitus with ketoacidosis 
E126 
Malnutrition-related diabetes mellitus with other specified complications 
E128 
Malnutrition-related diabetes mellitus with unspecified complications 
E129 
Malnutrition-related diabetes mellitus without complications 

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ICD-10 
Description 
E130 
Other specified diabetes mellitus with coma 
E131 
Other specified diabetes mellitus with ketoacidosis 
E136 
Other specified diabetes mellitus with other specified complications 
E138 
Other specified diabetes mellitus with unspecified complications 
E139 
Other specified diabetes mellitus without complications 
E140 
Unspecified diabetes mellitus with coma 
E141 
Unspecified diabetes mellitus with ketoacidosis 
E146 
Unspecified diabetes mellitus with other specified complications 
E148 
Unspecified diabetes mellitus with unspecified complications 
E149 
Unspecified diabetes mellitus without complications 
2 point each: 

Hemiplegia or paraplegia
ICD-10 
Description 
G81 
Hemiplegia 
G82 
Paraplegia and tetraplegia 
G041 
Tropical spastic paraplegia 
G114 
Hereditary spastic paraplegia 
G801 
Spastic diplegia 
G802 
Infantile hemiplegia 
G830 
Diplegia of upper limbs 
G831 
Monoplegia of lower limb 
G832 
Monoplegia of upper limb 
G833 
Monoplegia, unspecified 
G834 
Cauda equina syndrome 
G839 
Paralytic syndrome, unspecified 
G81 
Hemiplegia 
G82 
Paraplegia and tetraplegia 
G041 
Tropical spastic paraplegia 
G114 
Hereditary spastic paraplegia 
G801 
Spastic diplegia 
G802 
Infantile hemiplegia 
G830 
Diplegia of upper limbs 
G831 
Monoplegia of lower limb 
G832 
Monoplegia of upper limb 
G833 
Monoplegia, unspecified 
G834 
Cauda equina syndrome 
G839 
Paralytic syndrome, unspecified 

Moderate or severe renal disease
ICD-10 
Description 
N18 
Chronic renal failure 
N19 
Unspecified renal failure 
N052 
Diffuse membranous glomerulonephritis 
N053 
Diffuse mesangial proliferative glomerulonephritis 
N054 
Diffuse endocapillary proliferative glomerulonephritis 
N055 
Diffuse mesangiocapillary glomerulonephritis 
N056 
Dense deposit disease 
N057 
Diffuse crescentic glomerulonephritis 

Apixaban  
B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 10 October 2019 
PFIZER CONFIDENTIAL  
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ICD-10 
Description 
N250 
Renal osteodystrophy 
I120 
Hypertensive renal disease with renal failure 
I131 
Hypertensive heart and renal disease with renal failure 
N032 
Diffuse membranous glomerulonephritis 
N033 
Diffuse mesangial proliferative glomerulonephritis 
N034 
Diffuse endocapillary proliferative glomerulonephritis 
N035 
Diffuse mesangiocapillary glomerulonephritis 
N036 
Dense deposit disease 
N037 
Diffuse crescentic glomerulonephritis 
Z490 
Preparatory care for dialysis 
Z491 
Extracorporeal dialysis 
Z492 
Other dialysis 
Z940 
Kidney transplant status 
Z992 
Dependence on renal dialysis 

Diabetes with end-organ damage
ICD-10 
Description 
E102 
Insulin-dependent diabetes mellitus with renal complications 
E103 
Insulin-dependent diabetes mellitus with ophthalmic complications 
E104 
Insulin-dependent diabetes mellitus with neurological complications 
E105 
Insulin-dependent diabetes mellitus with peripheral circulatory complications 
E107 
Insulin-dependent diabetes mellitus with multiple complications 
E112 
Non-insulin-dependent diabetes mellitus with renal complications 
E113 
Non-insulin-dependent diabetes mellitus with ophthalmic complications 
E114 
Non-insulin-dependent diabetes mellitus with neurological complications 
E115 
Non-insulin-dependent diabetes mellitus with peripheral circulatory complications 
E117 
Non-insulin-dependent diabetes mellitus with multiple complications 
E122 
Malnutrition-related diabetes mellitus with renal complications 
E123 
Malnutrition-related diabetes mellitus with ophthalmic complications 
E124 
Malnutrition-related diabetes mellitus with neurological complications 
E125 
Malnutrition-related diabetes mellitus with peripheral circulatory complications 
E127 
Malnutrition-related diabetes mellitus with multiple complications 
E132 
Other specified diabetes mellitus with renal complications 
E133 
Other specified diabetes mellitus with ophthalmic complications 
E134 
Other specified diabetes mellitus with neurological complications 
E135 
Other specified diabetes mellitus with peripheral circulatory complications 
E137 
Other specified diabetes mellitus with multiple complications 
E142 
Unspecified diabetes mellitus with renal complications 
E143 
Unspecified diabetes mellitus with ophthalmic complications 
E144 
Unspecified diabetes mellitus with neurological complications 
E145 
Unspecified diabetes mellitus with peripheral circulatory complications 
E147 
Unspecified diabetes mellitus with multiple complications 
E102 
Insulin-dependent diabetes mellitus with renal complications 
E103 
Insulin-dependent diabetes mellitus with ophthalmic complications 
E104 
Insulin-dependent diabetes mellitus with neurological complications 
E105 
Insulin-dependent diabetes mellitus with peripheral circulatory complications 
E107 
Insulin-dependent diabetes mellitus with multiple complications 
E112 
Non-insulin-dependent diabetes mellitus with renal complications 
E113 
Non-insulin-dependent diabetes mellitus with ophthalmic complications 
E114 
Non-insulin-dependent diabetes mellitus with neurological complications 
E115 
Non-insulin-dependent diabetes mellitus with peripheral circulatory complications 

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B0661148- NON-INTERVENTIONAL STUDY PROTOCOL 
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PFIZER CONFIDENTIAL  
Page 32 of 53 
ICD-10 
Description 
E117 
Non-insulin-dependent diabetes mellitus with multiple complications 
E122 
Malnutrition-related diabetes mellitus with renal complications 
E123 
Malnutrition-related diabetes mellitus with ophthalmic complications 
E124 
Malnutrition-related diabetes mellitus with neurological complications 
E125 
Malnutrition-related diabetes mellitus with peripheral circulatory complications 
E127 
Malnutrition-related diabetes mellitus with multiple complications 
E132 
Other specified diabetes mellitus with renal complications 
E133 
Other specified diabetes mellitus with ophthalmic complications 
E134 
Other specified diabetes mellitus with neurological complications 
E135 
Other specified diabetes mellitus with peripheral circulatory complications 
E137 
Other specified diabetes mellitus with multiple complications 
E142 
Unspecified diabetes mellitus with renal complications 
E143 
Unspecified diabetes mellitus with ophthalmic complications 
E144 
Unspecified diabetes mellitus with neurological complications 
E145 
Unspecified diabetes mellitus with peripheral circulatory complications 
E147 
Unspecified diabetes mellitus with multiple complications 

Apixaban  
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PFIZER CONFIDENTIAL  
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
Any tumor (including lymphoma and leukemia except malignant neoplasms of
skin)
ICD-
10 
Description 
C00 
Malignant neoplasm of lip 
C01 
Malignant neoplasm of base of tongue 
C02 
Malignant neoplasm of other and unspecified parts of tongue 
C03 
Malignant neoplasm of gum 
C04 
Malignant neoplasm of floor of mouth 
C05 
Malignant neoplasm of palate 
C06 
Malignant neoplasm of other and unspecified parts of mouth 
C07 
Malignant neoplasm of parotid gland 
C08 
Malignant neoplasm of other and unspecified major salivary glands 
C09 
Malignant neoplasm of tonsil 
C10 
Malignant neoplasm of oropharynx 
C11 
Malignant neoplasm of nasopharynx 
C12 
Malignant neoplasm of pyriform sinus 
C13 
Malignant neoplasm of hypopharynx 
C14 
Malignant neoplasm of other and ill-defined sites in the lip, oral cavity and pharynx 
C15 
Malignant neoplasm of oesophagus 
C16 
Malignant neoplasm of stomach 
C17 
Malignant neoplasm of small intestine 
C18 
Malignant neoplasm of colon 
C19 
Malignant neoplasm of rectosigmoid junction 
C20 
Malignant neoplasm of rectum 
C21 
Malignant neoplasm of anus and anal canal 
C22 
Malignant neoplasm of liver and intrahepatic bile ducts 
C23 
Malignant neoplasm of gallbladder 
C24 
Malignant neoplasm of other and unspecified parts of biliary tract 
C25 
Malignant neoplasm of pancreas 
C26 
Malignant neoplasm of other and ill-defined digestive organs 
C30 
Malignant neoplasm of nasal cavity and middle ear 
C31 
Malignant neoplasm of accessory sinuses 
C32 
Malignant neoplasm of larynx 
C33 
Malignant neoplasm of trachea 
C34 
Malignant neoplasm of bronchus and lung 
C37 
Malignant neoplasm of thymus 
C38 
Malignant neoplasm of heart, mediastinum and pleura 
C39 
Malignant neoplasm of other and ill-defined sites in the respiratory system and intrathoracic 
organs 
C40 
Malignant neoplasm of bone and articular cartilage of limbs 
C41 
Malignant neoplasm of bone and articular cartilage of other and unspecified sites 
C43 
Malignant melanoma of skin 
C45 
Mesothelioma 
C46 
Kaposi's sarcoma 
C47 
Malignant neoplasm of peripheral nerves and autonomic nervous system 
C48 
Malignant neoplasm of retroperitoneum and peritoneum 
C49 
Malignant neoplasm of other connective and soft tissue 
C50 
Malignant neoplasm of breast 
C51 
Malignant neoplasm of vulva 
C52 
Malignant neoplasm of vagina 
C53 
Malignant neoplasm of cervix uteri 

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ICD-
10 
Description 
C54 
Malignant neoplasm of corpus uteri 
C55 
Malignant neoplasm of uterus, part unspecified 
C56 
Malignant neoplasm of ovary 
C57 
Malignant neoplasm of other and unspecified female genital organs 
C58 
Malignant neoplasm of placenta 
C60 
Malignant neoplasm of penis 
C61 
Malignant neoplasm of prostate 
C62 
Malignant neoplasm of testis 
C63 
Malignant neoplasm of other and unspecified male genital organs 
C64 
Malignant neoplasm of kidney, except renal pelvis 
C65 
Malignant neoplasm of renal pelvis 
C66 
Malignant neoplasm of ureter 
C67 
Malignant neoplasm of bladder 
C68 
Malignant neoplasm of other and unspecified urinary organs 
C69 
Malignant neoplasm of eye and adnexa 
C70 
Malignant neoplasm of meninges 
C71 
Malignant neoplasm of brain 
C72 
Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system 
C73 
Malignant neoplasm of thyroid gland 
C74 
Malignant neoplasm of adrenal gland 
C75 
Malignant neoplasm of other endocrine glands and related structures 
C76 
Malignant neoplasm of other and ill-defined sites 
C81 
Hodgkin's disease 
C82 
Follicular [nodular] non-Hodgkin's lymphoma 
C83 
Diffuse non-Hodgkin's lymphoma 
C84 
Peripheral and cutaneous T-cell lymphomas 
C85 
Other and unspecified types of non-Hodgkin's lymphoma 
C88 
Malignant immunoproliferative diseases 
C90 
Multiple myeloma and malignant plasma cell neoplasms 
C91 
Lymphoid leukaemia 
C92 
Myeloid leukaemia 
C93 
Monocytic leukaemia 
C94 
Other leukaemias of specified cell type 
C95 
Leukaemia of unspecified cell type 
C96 
Other and unspecified malignant neoplasms of lymphoid, haematopoietic and related tissue 
C97 
Malignant neoplasms of independent (primary) multiple sites 

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3 points each: 

Moderate or severe liver disease
ICD-10 
Description 
K704 
Alcoholic hepatic failure 
K711 
Toxic liver disease with hepatic necrosis 
K721 
Chronic hepatic failure 
K729 
Hepatic failure, unspecified 
K765 
Hepatic veno-occlusive disease 
K766 
Portal hypertension 
K767 
Hepatorenal syndrome 
I850 
Oesophageal varices with bleeding 
I859 
Oesophageal varices without bleeding 
I864 
Gastric varices 
I982 
Oesophageal varices in diseases classified elsewhere 
6 points each: 

Metastatic solid tumor
ICD-10 
Description 
C77 
Secondary and unspecified malignant neoplasm of lymph nodes 
C78 
Secondary malignant neoplasm of respiratory and digestive organs 
C79 
Secondary malignant neoplasm of other sites 
C80 
Malignant neoplasm without specification of site 

Human immunodeficiency virus (HIV)-AIDS
ICD-10 
Description 
B20 
Human immunodeficiency virus [HIV] disease resulting in infectious and parasitic diseases 
B21 
Human immunodeficiency virus [HIV] disease resulting in malignant neoplasms 
B22 
Human immunodeficiency virus [HIV] disease resulting in other specified diseases 
B24 
Unspecified human immunodeficiency virus [HIV] disease 
Z21 
Asymptomatic human immunodeficiency virus [HIV] infection status 
One point was added to the total score of the Charlson index for each decade after the age of 
50 years: 
 50 to 59: 1 point, 
60 to 69: 2 points, 
70 to 79: 3 points, 
80 to 89: 4 points, 
>90: 5 points. 
•
CHA2DS2-VACs score: The CHA2DS2-VASc score will be used to analyze the effect of
stratification of the risk of stroke. CHA2DS2-VASc scores range from 0 to 9. ICD-10
diagnostic codes for each component of the index when applicable:
•  
C: I11.0, I13.0, I13.2, I50 
Score 1 point  

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ICD-10 
Description 
I110 
Hypertensive heart disease with (congestive) heart failure 
I130 
Hypertensive heart and renal disease with (congestive) heart failure 
I132 
Hypertensive heart and renal disease with both (congestive) heart failure and renal failure 
I50 
Heart failure 
H: I10, I11, I12, I13, I15 
Score 1 point 
ICD-10 
Description 
I10 
Essential (primary) hypertension 
I11 
Hypertensive heart disease 
I12 
Hypertensive renal disease 
I13 
Hypertensive heart and renal disease 
I15 
Secondary hypertension 
A: Age ≥75 years 
Score 2 points  
D: E10 a E14 
Score 1 point  
ICD-10 
Description 
E10 
Insulin-dependent diabetes mellitus 
E11 
Non-insulin-dependent diabetes mellitus 
E12 
Malnutrition-related diabetes mellitus 
E13 
Other specified diabetes mellitus 
E14 
Unspecified diabetes mellitus 
S2: G45.0, G45.1, G45.2, G45.3, G45.8, G45.9 
Score 2 points  
ICD-10 
Description 
G450 
Vertebro-basilar artery syndrome 
G451 
Carotid artery syndrome (hemispheric) 
G452 
Multiple and bilateral precerebral artery syndromes 
G453 
Amaurosis fugax 
G458 
Other transient cerebral ischaemic attacks and related syndromes 

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V: I26, I82, I21- I25, I65, I70- I72, I73.1, I73.8, I73.9, I79.0, I79.2, K55.1, K55.8, K55.9, 
Z95.8, Z95.9 
Score 1 point  
ICD-10 
Description 
I26 
Pulmonary embolism 
I82 
Other venous embolism and thrombosis 
I21 
Acute myocardial infarction 
I22 
Subsequent myocardial infarction 
I23 
Certain current complications following acute myocardial infarction 
I24 
Other acute ischaemic heart diseases 
I25 
Chronic ischaemic heart disease 
I65 
Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction 
I70 
Atherosclerosis 
I71 
Aortic aneurysm and dissection 
I72 
Other aneurysm 
I731 
Thromboangiitis obliterans [Buerger] 
I738 
Other specified peripheral vascular diseases 
I739 
Peripheral vascular disease, unspecified 
I790 
Aneurysm of aorta in diseases classified elsewhere 
I792 
Peripheral angiopathy in diseases classified elsewhere 
K551 
Chronic vascular disorders of intestine 
K558 
Other vascular disorders of intestine 
A: Age 64-74 years 
Score 1 point  
Sc: Sex category (female ) 
Score 1 
•
HASBLED score: The HAS-BLED score will be used to analyze the risk of bleeding. The
modified HAS-BLED score ranges from 0 to 8. ICD-10 diagnostic codes for each
component of the index when applicable:
•  
H: I10, I11, I12, I13, I15 
Score 1 point  
ICD-10 
Description 
I10 
Essential (primary) hypertension 
I11 
Hypertensive heart disease 
I12 
Hypertensive renal disease 
I13 
Hypertensive heart and renal disease 
I15 
Secondary hypertension 

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A: N03.2, N03.3, N03.4, N03.5, N03.6, N03.7, N05.2, N05.3, N05.4, N05.5, N05.6, N057, 
N18- N19, N25.0, Z49.0, Z49.2, Z94.0, Z99.2 
Score 1 point  
ICD-10 
Description 
N032 
Diffuse membranous glomerulonephritis 
N033 
Diffuse mesangial proliferative glomerulonephritis 
N034 
Diffuse endocapillary proliferative glomerulonephritis 
N035 
Diffuse mesangiocapillary glomerulonephritis 
N036 
Dense deposit disease 
N037 
Diffuse crescentic glomerulonephritis 
N052 
Diffuse membranous glomerulonephritis 
N053 
Diffuse mesangial proliferative glomerulonephritis 
N054 
Diffuse endocapillary proliferative glomerulonephritis 
N055 
Diffuse mesangiocapillary glomerulonephritis 
N056 
Dense deposit disease 
N057 
Diffuse crescentic glomerulonephritis 
N18 
Chronic renal failure 
N19 
Unspecified renal failure 
N250 
Renal osteodystrophy 
Z490 
Preparatory care for dialysis 
Z492 
Other dialysis 
Z940 
Kidney transplant status 
Z992 
Dependence on renal dialysis 
A: B18, I85, I86.4, I98.2, K70, K71.1,K71.3, K71.4, K71.5, K71.7, K72.1, K72.9, K73, K74, 
K76.0, K76.2, K76.3, K76.4, K76.5, K76.6, K76.7, K76.8, K76.9, Z94.4 
Score 1 point 
ICD-10 
Description 
B18 
Chronic viral hepatitis 
I85 
Oesophageal varices 
I864 
Gastric varices 
I982 
Oesophageal varices in diseases classified elsewhere 
K70 
Alcoholic liver disease 
K711 
Toxic liver disease with hepatic necrosis 
K713 
Toxic liver disease with chronic persistent hepatitis 
K714 
Toxic liver disease with chronic lobular hepatitis 
K715 
Toxic liver disease with chronic active hepatitis 
K717 
Toxic liver disease with fibrosis and cirrhosis of liver 
K721 
Chronic hepatic failure 
K729 
Hepatic failure, unspecified 
K73 
Chronic hepatitis, not elsewhere classified 
K74 
Fibrosis and cirrhosis of liver 
K760 
Fatty (change of) liver, not elsewhere classified 
K762 
Central haemorrhagic necrosis of liver 
K763 
Infarction of liver 
K764 
Peliosis hepatis 
K765 
Hepatic veno-occlusive disease 
K766 
Portal hypertension 
Z944 
Liver transplant status 
S: I64, I69.3, D62, D68.3, D69.8, D69.9, H31.3, H35.6, H43.1, H45.0, H92.2, I23.0, I31.2 
Score 1 point 

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ICD-10 
Description 
I64 
Stroke, not specified as haemorrhage or infarction 
I693 
Sequelae of cerebral infarction 
D62 
Acute posthaemorrhagic anaemia 
D683 
Haemorrhagic disorder due to circulating anticoagulants 
D698 
Other specified haemorrhagic conditions 
D699 
Haemorrhagic condition, unspecified 
H313 
Choroidal haemorrhage and rupture 
H356 
Retinal haemorrhage 
H431 
Vitreous haemorrhage 
H450 
Vitreous haemorrhage in diseases classified elsewhere 
H922 
Otorrhagia 
I230 
Haemopericardium as current complication following acute myocardial infarction 
I312 
Haemopericardium, not elsewhere classified 
B: I60, I61, I62, I85.0, I98.3, J94.2, K22.6, K25.0, K25.2, K25.4, K25.6, K26.0, K26.2, 
K26.4, K26.6, K27.0, K27.2, K27.4, K27.6, K28.0, K28.2, K28.4, K28.6, K29.0, K62.5, 
K66.1, K76.2, K92.0, K92.1, K92.2 
Score 1 point 
ICD-10 
Description 
I60 
Subarachnoid haemorrhage 
I61 
Intracerebral haemorrhage 
I62 
Other nontraumatic intracranial haemorrhage 
I850 
Oesophageal varices with bleeding 
I983 
Oesophageal varices with bleeding, , not elsewhere classified 
J942 
Haemothorax 
K226 
Gastro-oesophageal laceration-haemorrhage syndrome 
K250 
Acute with haemorrhage 
K252 
Acute with both haemorrhage and perforation 
K254 
Chronic or unspecified with haemorrhage 
K256 
Chronic or unspecified with both haemorrhage and perforation 
K260 
Acute with haemorrhage 
K262 
Acute with both haemorrhage and perforation 
K264 
Chronic or unspecified with haemorrhage 
K266 
Chronic or unspecified with both haemorrhage and perforation 
K270 
Acute with haemorrhage 
K272 
Acute with both haemorrhage and perforation 
K274 
Chronic or unspecified with haemorrhage 
K276 
Chronic or unspecified with both haemorrhage and perforation 
K280 
Acute with haemorrhage 
K282 
Acute with both haemorrhage and perforation 
K284 
Chronic or unspecified with haemorrhage 
K286 
Chronic or unspecified with both haemorrhage and perforation 
K290 
Acute haemorrhagic gastritis 
K625 
Haemorrhage of anus and rectum 
K661 
Haemoperitoneum 
K762 
Central haemorrhagic necrosis of liver 
K920 
Haematemesis 
K921 
Melaena 
K922 
Gastro-intestinal haemorrhage, unspecified 

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L: INR 
Score 1 point 
E: Elderly ≥ 65 years 
Score 1 point  
D: E24.4, F10, G31.2, G62.1, G72.1, I42.6, K29.2, K85.2, K86.0, T51, Y90.4, Y90.5, Y90.6, 
Y90.7, Y90.8, Y91.2, Y91.3, Z50.2, Z71.4, Z72.1 
1 or 2 point each  
ICD-10 
Description 
E244 
Alcohol-induced pseudo-Cushing's syndrome 
F10 
Mental and behavioural disorders due to use of alcohol 
G312 
Degeneration of nervous system due to alcohol 
G621 
Alcoholic polyneuropathy 
G721 
Alcoholic myopathy 
I426 
Alcoholic cardiomyopathy 
K292 
Alcoholic gastritis 
K852 
Alcohol-induced acute pancreatitis 
K860 
Alcohol-induced chronic pancreatitis 
T51 
Toxic effect of alcohol 
Y904 
Blood alcohol level of 80-99 mg/100 ml 
Y905 
Blood alcohol level of 100-119 mg/100 ml 
Y906 
Blood alcohol level of 120-199 mg/100 ml 
Y907 
Blood alcohol level of 200-239 mg/100 ml 
Y908 
Blood alcohol level of 240 mg/100 ml or more 
Y912 
Severe alcohol intoxication 
Y913 
Very severe alcohol intoxication 
Z502 
Alcohol rehabilitation 
Z714 
Alcohol abuse counselling and surveillance 
Z721 
Alcohol use 
Codes Anatomical Therapeutic Chemical (ATC): B01AC, M01A 
•
SMAe-TT2R2 score: The estimation of SAMe-TT2R2 will be performed by adding the
following variables:
Sex (female) 
Score 1 point
Age (<60 years) Score 1 point
Medical history (history of more than two of the following: hypertension, diabetes,
coronaty artery disease or myocardial infactions, peripheral artery disease, heart failure,
stroke; pulmonary, hepatic, or renal disease) 
Score 1 point
Treatment (interacting medications , amiodarone ATC- C01BD01) 
Score 1 point
Tobacco use (within 2 years) 
Score 2 points

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Race (non-Caucasian) 
Score 2 points 
Table 2. Baseline variables or possible confounders 
Variable 
Operacional definition ICD-10 
Diabetes 
E10 
Insulin-dependent diabetes mellitus 
E11 
Non-insulin-dependent diabetes mellitus 
E12 
Malnutrition-related diabetes mellitus 
E13 
Other specified diabetes mellitus  
E14 
Unspecified diabetes mellitus 
Hypertension 
I10 
Essential (primary) hypertension 
I11 
Hypertensive heart disease 
I12 
Hypertensive renal disease 
I13 
Hypertensive heart and renal disease 
I15 
Secondary hypertension 
Ischaemic stroke 
I63 
Cerebral infarction 
Excepto I636 
Cerebral infarction due to cerebral venous thrombosis, nonpyogenic 
I64 
Stroke, not specified as haemorrhage or infarctionz 
Haemorrhagic stroke 
I60 
Subarachnoid haemorrhage 
I61 
Intracerebral haemorrhage 
I62 
Other nontraumatic intracranial haemorrhage 
Bleeding 
(gastrointestinal 
intracranial, other) 
I60 
Subarachnoid haemorrhage 
I61 
Intracerebral haemorrhage 
I62 
Other nontraumatic intracranial haemorrhage 
S064 
Epidural haemorrhage 
S065 
Traumatic subdural haemorrhage 
S066 
Traumatic subarachnoid haemorrhage 
I850 
Oesophageal varices with bleeding 
K250 
Acute with haemorrhage 
K252 
Acute with both haemorrhage and perforation 
K254 
Chronic or unspecified with haemorrhage 
K256 
Chronic or unspecified with both haemorrhage and perforation 
K260 
Acute with haemorrhage 
K262 
Acute with both haemorrhage and perforation 
K264 
Chronic or unspecified with haemorrhage 
K266 
Chronic or unspecified with both haemorrhage and perforation 
K270 
Acute with haemorrhage 
K272 
Acute with both haemorrhage and perforation 
K274 
Chronic or unspecified with haemorrhage 
K276 
Chronic or unspecified with both haemorrhage and perforation 
K280 
Acute with haemorrhage 
K282 
Acute with both haemorrhage and perforation 
K284 
Chronic or unspecified with haemorrhage 
K286 
Chronic or unspecified with both haemorrhage and perforation 
K290 
Acute haemorrhagic gastritis 
K625 
Haemorrhage of anus and rectum 
K920 
Haematemesis 
K921 
Melaena 
K922 
Gastro-intestinal haemorrhage, unspecified 
D62 
Acute posthaemorrhagic anaemia 
H356 
Retinal haemorrhage 
H431 
Vitreous haemorrhage 
H450 
Vitreous haemorrhage in diseases classified elsewhere 
H922 
Otorrhagia 

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Variable 
Operacional definition ICD-10 
I312 
Haemopericardium, not elsewhere classified 
J942 
Haemothorax 
R04 
Haemorrhage from respiratory passages 
K661 
Haemoperitoneum 
M250 
Haemarthrosis 
N02 
Recurrent and persistent haematuria 
N938 
Other specified abnormal uterine and vaginal bleeding 
N939 
Abnormal uterine and vaginal bleeding, unspecified 
N950 
Postmenopausal bleeding 
R31 
Unspecified haematuria 
R58 
Haemorrhage, not elsewhere classified 
T792 
Traumatic secondary and recurrent haemorrhage 
Systemic embolism 
I74 
Arterial embolism and thrombosis 
Alcohol consumption 
E244 
Alcohol-induced pseudo-Cushing's syndrome 
E52 
Niacin deficiency [pellagra] 
G312 
Degeneration of nervous system due to alcohol 
G621 
Alcoholic polyneuropathy 
G721 
Alcoholic myopathy 
I426 
Alcoholic cardiomyopathy 
K292 
Alcoholic gastritis 
K70 
Alcoholic liver disease 
K860 
Alcohol-induced chronic pancreatitis 
O354 
Maternal care for (suspected) damage to foetus from alcohol 
T51 
Toxic effect of alcohol 
Z714 
Alcohol abuse counselling and surveillance 
Z721 
Alcohol use 
Peripheral 
artery disease 
I702 
Atherosclerosis of arteries of the extremities 
I708 
Atherosclerosis of other arteries 
I709 
Generalised and unspecified atherosclerosis 
Anaemia 
D50 
Iron deficiency anaemia 
D51 
Vitamin B12 deficiency anaemia 
D52 
Folate deficiency anaemia 
D53 
Other nutritional anaemias 
D55 
Anaemia due to enzyme disorders 
D56 
Thalassaemia 
D57 
Sickle-cell disorders 
D58 
Other hereditary haemolytic anaemias 
D59 
Acquired haemolytic anaemia 
Congestive 
heart 
failure 
I110 
Hypertensive heart disease with (congestive) heart failure 
I130 
Hypertensive heart and renal disease with (congestive) heart failure 
I132 
Hypertensive heart and renal disease with both (congestive) heart failure and 
renal failure 
Renal disease 
B15 
Acute hepatitis A 
B16 
Acute hepatitis B 
B17 
Other acute viral hepatitis 
B18 
Chronic viral hepatitis 
B19 
Unspecified viral hepatitis 
C22 
Malignant neoplasm of liver and intrahepatic bile ducts 
K70 
Alcoholic liver disease 
K71 
Toxic liver disease 
K72 
Hepatic failure, not elsewhere classified 
K73 
Chronic hepatitis, not elsewhere classified 
K74 
Fibrosis and cirrhosis of liver 

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Variable 
Operacional definition ICD-10 
K75 
Other inflammatory liver diseases 
K76 
Other diseases of liver 
K77 
Liver disorders in diseases classified elsewhere 
Z944 
Liver transplant status 
Myocardial 
infarction 
I21 
Acute myocardial infarction 
I22 
Subsequent myocardial infarction 
I252 
Old myocardial infarction 
Peripheral vascular 
disease 
I70 
Atherosclerosis 
I71 
Aortic aneurysm and dissection 
I731 
Thromboangiitis obliterans [Buerger] 
I738 
Other specified peripheral vascular diseases 
I739 
Peripheral vascular disease, unspecified 
I771 
Stricture of artery 
I790 
Aneurysm of aorta in diseases classified elsewhere 
I792 
Peripheral angiopathy in diseases classified elsewhere 
K551 
Chronic vascular disorders of intestine 
K558 
Other vascular disorders of intestine 
K559 
Vascular disorder of intestine, unspecified 
Z958 
Presence of other cardiac and vascular implants and grafts 
Z959 
Presence of cardiac and vascular implant and graft, unspecified 
TIA 
G450 
Vertebro-basilar artery syndrome 
G458 
Other transient cerebral ischaemic attacks and related syndromes 
G451 
Carotid artery syndrome (hemispheric) 
G459 
Transient cerebral ischaemic attack, unspecified 
Coronary 
artery 
disease 
I20 
Angina pectoris 
I21 
Acute myocardial infarction 

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7.4. Data Sources 
The information that will be used in the study comes exclusively from secondary sources. Two 
databases will be used to extract the information:  
7.4.1. Claim Database 
Claim databasee contains all prescriptions of all patients' medications chronologically. From 
this database, the index date will be established and the diagnosis of NVAF of the patient will 
be extracted. Similarly, this base will be used to assess the persistence on therapy and treatment 
patterns (duration of treatment, changes, persistence), pharmacy claim information, 
demographic information, diagnosis and insurance data.   
7.4.2. Medical Record 
Of the patients identified from the claim database, information will be extracted from the 
second database, the medical record, it will serve to characterize patients based on their 
baseline demographic and clinical characteristics, that is, on the index date. In turn, it contains 
the main control variables and the information related to the outcomes of interest, stroke and 
bleeding events.  
7.5. Study Size 
The total population of patients treated with OAC between January 1, 2013 and June 30, 2018 
was analyzed in the claim dabtabase. For the purpose of the study, it contains the information 
of 7,500 patients, once they were verified that they met the inclusion criteria of the study. This 
means that patients who start warfarin and NOACs would be included within this period. 
Patients who initiate NOACs within the established period and who have been exposed to 
warfarin before 2013 will also be included. 
7.6. Data Management 
The data sources are databases owned by the investigator, he will execute the data management 
for this study.  
7.6.1 Electronic Case Report (ECR) 
As used in this protocol, the term ECR 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. 
ECR is required and should be completed for each included patient. The completed original 
ECRs 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 party performing medical record review shall 
ensure that the ECRs 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 party performing medical records review has ultimate responsibility for the abstraction of 
all clinical, safety, and laboratory data entered on the ECRs and any other data collection forms 
(source documents).  
In order to ensure the accurate, complete, consistent, timely enduring of the data, Pfizer and 
the third party will design and validate the ECR from review of 30 medical records to guarantee 
the operationalization adequate of the variables, idenfifying alternative coding data available 
(abbreviatures, synonyms, symbols, units, etc) and setting of the variables following this 
protocol. From the results of the validation and the standard operating procedures of Pfizer, 
data magement plan, data review plan, ECR completion instruction and data entry guidelines 
will be builted to ensure the consistency and accurate of data. and distribuited to different 
physicians who participate in the abstraction of the data.  
The personal responsible to abstract the data will be physicians who will be trained in the 
abstraction process, use of manuals and ECR. These grupo will be blinded of the objective of 
the study in order to avoid the reviewer bias. The party will responsible to conduct and record 
this activity. 
Likewise, the party execute monitoring of tha data which will be follow the guidelines 
described in the data review plan and data quality control plan as required by the Pfizer policy. 
Finally, the concordance of the abstracters, the intrarater and interrater reliability, will be 
measure for cohens kappa and interclass correlation, respectively.  
7.6.2 Record Retention 
To enable evaluations or inspections/audits from regulatory authorities or Pfizer, third party 
responsible for performing medical record review agrees to keep all study-related records, 
including the identity of all participating patients (sufficient information to link records, e.g., 
ECRs and medical records), ECR file, 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 third 
party responsible for performing medical record review according to local regulations or as 
specified in the vendor contract, whichever is longer. Third party responsible for performing 
medical record review must ensure that the records continue to be stored securely for so long 
as they are retained.  
If third party responsible for performing medical record review becomes unable for any reason 
to continue to retain study records for the required period, Pfizer should be prospectively 
notified. The study records must be transferred to a designee acceptable to Pfizer. 
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless third party responsible for performing medical record review and Pfizer have 
expressly agreed to a different period of retention via a separate written agreement. Record 
must be retained for longer than 15 years if required by applicable local regulations.  
The third party responsible for performing medical record review obtain Pfizer's written 
permission before disposing of any records, even if retention requirements have been met. 

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7.6.3 Patient Identification 
The Investigators will identify patients from the claim database, initially, in this database the 
type of therapy with any of the OACs will be verified, and then that they meet the inclusion 
criteria of the study.  
7.6.4 Collection of Information 
For the analysis of the data, the statistical package Statistical Package for the Social Sciences 
(SPSS) Statistics, version 26.0 (IBM, US) for Windows will be used.  
Data collection will be performed by healthcare providers following a data collection template 
developed in Microsoft Excel. For the purpose of unifying criteria and concepts, the template 
will be parametrized according to the possible responses or options for each variable, which 
will be defined by the medical expertise, information availability and published clinical 
studies. The template will be then validated according to a pilot testing of 20 randomly selected 
clinical charts. 
Data collection will be performed after verifying the inclusion and exclusion criteria by the 
investigation staff. Firstly, the data regarding demographic data and delivery of the 
medications of interest to the patients meeting the criteria will be reviewed and collected. 
Subsequently, the electronic medical chart will be reviewed for collecting the clinical data will 
be identified.  
In order to ensure protection of the patient’s personal data and maintain high confidentiality 
and protection of the personal data according to the corporative policy 404 on Protecting the 
Privacy of Personal Data, the vendor will not transfer the collected database.  
Pfizer will monitor the vendor to ensure the protection of the patient’s personal data. 
7.6.5 Database Retention 
The Principal Investigator will store the database, adverse event reports and relevant 
correspondence securely to prevent unauthorized personnel from accessing the information. 
7.7 Data Analysis 
This type of analysis is descriptive and explanatory, as it depends largely on the sample size. 
Continuous variables will be presented as means, standard deviation or other measures of 
central tendency or position, while categorical variables will be presented as frequencies and 
percentages. 
Regarding bivariate analyses of continuous variables with normal behavior, the Student's t test 
will be performed. In case of presenting non-normal behavior, the Mann-Withney test will be 
used. For variables that are continuous with several categories, analysis of variance (ANOVA) 
will be assessed. In the event of presenting a non-normal behavior, the multivariate analysis of 

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As for the claim database, a limitation is that prescription does not indicate whether the patient 
actually took the therapy as prescribed in both dosage and frequency.  
On the other hand, this study will not obtain information related to hospitalizations of patients 
during the follow-up period; therefore, in the event of having any during this period it will not 
be known if the patient continued therapy. It is worth noting that these types of limitations are 
not differential among the cohorts of therapies to assess.  
In spite of the limitations previously described, this information is very valuable, especially 
because it allows linking the claim information of medications with the medical records of 
each patient, providing a large sample size with a significant number of variables. 
7.10 Other aspects 
Not applicable 
8 
PROTECTION OF STUDY SUBJECTS 
8.1 Patient Information 
All parties will comply with all applicable laws, including those relating to the implementation 
of organizational and technical measures to ensure the protection of patients' personal data. 
Such measures will include the omission of the patient's name, or other directly identifiable 
data in reports, publications or other means of dissemination, except when required by the 
current legislation.  
Patient personal data will be stored in the third party research location in an encrypted 
electronic form and will be password protected to ensure that only authorized study personnel 
have access. Audifarma will implement the appropriate technical and organizational measures 
to ensure that personal data may be recovered in the event of a disaster. In the event of a 
possible violation of personal data, Audifarma will be responsible for determining if there has 
been a violation of personal data and, if so, providing notifications of violation as required by 
law.  
To protect the rights and freedoms of natural persons with respect to the processing of personal 
data, when the study data is compiled to be transferred to Pfizer and other authorized parties, 
any patient´s name will be removed and replaced by a unique and specific numerical code. All 
other identifiable data transferred to Pfizer or other authorized parties will be identified with 
this unique and specific patient´s code. In the event of data transfer, Pfizer will maintain high 
standards of confidentiality and protection of patients' personal data in accordance with the 
applicable Audifarma and privacy laws. 
8.2 Patient Consent 
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required. 

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8.3 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the Investigator to have a prospective approval of the study protocol, 
the protocol amendments, and other relevant documents (for example, recruitment 
advertisements), if applicable, from the IRB/IEC. All correspondence with the IRB/IEC must 
be kept in the Investigator's file. Copies of IRB/IEC approvals must be sent to Pfizer.  
The study will be evaluated by the Bioethics Committee of the Technological University of 
Pereira in the category of risk-free research. The principles of confidentiality of the information 
established by the Declaration of Helsinki will be followed, in accordance with Resolution No. 
8430 of 1993 of the Ministry of Health of Colombia. Once you have the support from the 
committee, the HMO will give authorization to access the medical records. 
8.4 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). 

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9 MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
The safety reporting language below is applicable to Research staff with oversight of electronic 
medical records in this study (Human review of unstructured data):  
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 reviewer is obligated to report AE with explicit 
attribution to any Pfizer drug that appear in the reviewed 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 ECR 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 adverse events with an explicit attribution or scenarios involving exposure to a Pfizer 
product, the safety information identified in the unstructured data reviewed is captured in the 
Event Narrative section of the report form, and constitutes all clinical information known 
regarding these AEs. No follow-up on related AEs will be conducted.  
All research staff members must complete the following Pfizer training requirements:  
“YRR Training for Vendors Working on Pfizer Studies (excluding interventional clinical 
studies and non-interventional primary data collection studies with sites/investigators)”.  
These trainings 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. 

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10 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.  
The results will be published in an indexed journal and presented at an international congress 
according to the availability of the results. 
 

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11. REFERENCES 
1.  
Molteni M, Polo Friz H, Primitz L, Marano G, Boracchi P, Cimminiello C. The 
definition of valvular and non-valvular atrial fibrillation: results of a physicians’ survey. 
Europace. 2014;16:1720–5.  
2.  
Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Refining Clinical Risk 
Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using 
a Novel Risk Factor-Based Approach. Chest [Internet]. 2010 Feb 1 [cited 2019 Jun 
25];137(2):263–72. 
Available 
from: 
https://linkinghub.elsevier.com/retrieve/pii/S0012369210600670 
3.  
Olesen J, Lip G, Lindhardsen J, Lane D, Ahlehoff O, Hansen M, et al. Risks of 
thromboembolism and bleeding with thromboprophylaxis in patients with atrial 
fibrillation: A net clinical benefit analysis using a ‘real world’ nationwide cohort study. 
Thromb Haemost [Internet]. 2011 Nov 29 [cited 2019 Jun 25];106(10):739–49. 
Available from: http://www.thieme-connect.de/DOI/DOI?10.1160/TH11-05-0364 
4.  
Hernández Olmedo M, Suárez Fernández C. Avances en el tratamiento anticoagulante 
de la fibrilacion auricular. Med Clin (Barc). 2014 Sep;En prensa.  
5.  
Banerjee A, Lane DA, Torp-Pedersen C, Lip GYH. Net clinical benefit of new oral 
anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a ‘real world’ 
atrial fibrillation population: A modelling analysis based on a nationwide cohort study. 
Thromb Haemost [Internet]. 2012 Nov 22 [cited 2019 Jun 25];107(03):584–9. Available 
from: http://www.thieme-connect.de/DOI/DOI?10.1160/TH11-11-0784 
6.  
Aurachán Torres SA, Ayala Copete AM, Patiño Hermández D, Rios Zuluaga JD, García 
Peña ÁA, Cano Gutiérrez CA. Riesgo diferencial de hemorragia intracraneana en 
pacientes con fibrilación auricular no valvular con el uso de nuevos anticoagulantes 
orales vs. warfarina. Revisión sistemática de la literatura y análisis de subpoblaciones. 
Univ Médica [Internet]. 2017 Aug 31 [cited 2019 Jun 25];58(2). Available from: 
http://revistas.javeriana.edu.co/index.php/vnimedica/article/view/19887 
7.  
Pinto DA, Sánchez-Vallejo CA, López Pedraza A, Vergara EP, Sáenz ÓA, González F, 
et al. Descripción de los pacientes con fibrilación auricular no valvular que ingresan al 
servicio de urgencias. Rev Colomb Cardiol [Internet]. 2016 Jul 1 [cited 2019 Jun 
25];23(4):270–6. 
Available 
from: 
https://www.sciencedirect.com/science/article/pii/S0120563315001989 
8.  
Nguyen TN, Hilmer SN, Cumming RG. Review of epidemiology and management of 
atrial fibrillation in developing countries. Int J Cardiol. 2013 Sep;167(6):2412–20.  
9.  
Rosselli D, Rodríguez AJ, García ÁA, Rueda JD. Prevalencia de fibrilación auricular 
en un hospital universitario colombiano. Rev Colomb Cardiol. 2013;20(6):383–5.  
 
 

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8.
LIST OF TABLES
Table 1. Table of Variables ...................................................................................................18 
Table 2. Baseline variables or possible confounders...........................................................41 
9.
LIST OF FIGURES
Figure 1. Study Design ...........................................................................................................15 
Figure 2. Inclusion of Patients ..............................................................................................16 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Not applicable.  
ANNEX 3. ADDITIONAL INFORMATION 
Not applicable.