APIXABAN DRUG UTILIZATION STUDY IN STROKE PREVENTION IN ATRIAL FIBRILLATION (SPAF)
Conditions: Atrial Fibrillation
Sponsor: Pfizer

Apixaban 
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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
Study information 
Title 
Apixaban drug utilization study in Stroke 
prevention in atrial fibrillation (SPAF) 
Protocol number 
B0661076 
AEMPS Code 
PFI-API-2016-01 
Protocol version identifier 
4.0 – Amendment 1 
Date of last version of protocol 
November 2016 
Active substance 
Apixaban B01AF02 
Medicinal product 
Eliquis® 
Research question and objectives 
Evaluate the apixaban utilization according 
to the approved SPAF indication and 
recommendations by EMA. 
The study objectives are: 
Objective 1: To characterise patients using 
apixaban according to demographics, 
comorbidity, risk of thromboembolic events 
(CHADS2 and CHA2DS2-Vasc scores), risk 
of bleeding events (HAS-BLED score), 
comedications and compare it with the 
profile of patients treated with VKA, 
dabigatran and rivaroxaban. 
Objective 2: Describe the level of 
appropriate usage according to the posology 
recommended in the apixaban SmPC. 
Objective 3: Describe the potential 
interactions with other drugs prescribed 
concomitantly according with the SmPC 
recommendations. 
Objective 4: Estimate the level of apixaban 
adherence by the medication possession ratio 
(MPR) and discontinuation rates and 
compare it with VKA, dabigatran and 

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rivaroxaban cohort.  
Objective 5: To analyze INR (International 
Normalized Ratio) values during the last 12 
months and to obtain TTR (Time in 
Therapeutic Range) values in patients 
previously treated with VKA and, during the 
whole study period for those in the cohort 
treated with VKA 
Author 
, IDIAP Jordi Gol 
, IDIAP Jordi Gol 
, IDIAP Jordi Gol 
, SIDIAP 
, SIDIAP 
, Pfizer SLU 
Sponsor 
Pfizer S.L.U 
Avda. Europa, 20 B 
Parque Empresarial La Moraleja 
28108 Alcobendas (Madrid) 
Contact: 
 (Medical Affairs, 
Pfizer) 
Ethical Committee 
CEIC IDIAP Jordi Gol 
 
 
 
 
. 
PPD
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ...........................................................................................................3 
1. LIST OF ABBREVIATIONS ................................................................................................5 
2. RESPONSIBLE PARTIES ....................................................................................................6 
3. ABSTRACT ...........................................................................................................................7 
4. AMENDMENTS AND UPDATES .....................................................................................10 
5. MILESTONES .....................................................................................................................10 
6. RATIONALE AND BACKGROUND ................................................................................11 
7. RESEARCH QUESTION AND OBJECTIVES .................................................................12 
8. RESEARCH METHODS ....................................................................................................12 
8.1. Study design ............................................................................................................12 
8.2. Setting ......................................................................................................................14 
8.2.1. Inclusion criteria .........................................................................................14 
8.2.2. Exclusion criteria ........................................................................................15 
8.3. Variables ..................................................................................................................15 
8.4. Data sources ............................................................................................................20 
8.5. Study size ................................................................................................................20 
8.6. Data Management ...................................................................................................21 
8.7. Data analysis ...........................................................................................................21 
8.8. Quality control .........................................................................................................23 
8.9. Limitations of the research methods .......................................................................23 
8.10. Other aspects .........................................................................................................23 
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................23 
9.1. Patient Information and Consent .............................................................................23 
9.2. Patient withdrawal ...................................................................................................24 
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............24 
9.4. Ethical Conduct of the Study ..................................................................................24 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................24 
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........25 

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12. REFERENCES ..................................................................................................................26 
13. LIST OF TABLES .............................................................................................................27 
14. LIST OF FIGURES ...........................................................................................................27 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................28 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................28 
ANNEX 3. ADDITIONAL INFORMATION .........................................................................28 
 
 

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1. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ATC 
Anatomical Therapeutic Chemical classification 
system 
AF 
atrial fibrillation 
BMI 
body mass index 
DDD 
defined daily dose 
DOAC 
direct oral anticoagulant 
DUS 
drug utilization study 
DVT 
deep vein thrombosis 
EMA 
European Medicine Agency 
FDA 
Food and Drug Administration 
HR 
hazard ratio 
ICD-10 
International Statistical Classification of Diseases 
and Related Health Problems 10th Revision 
ICS 
Institut Català de la Salut 
INR 
International normalized ratio 
ISPE 
International Society for Pharmacoepidemiology 
MPR 
medication possession ratio 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
NVAF 
non-valvular atrial fibrillation 
PASS 
Post-Authorisation Safety Study 
PE 
pulmonary embolism 
P-gp 
P-glycoprotein 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
SPAF 
Stroke prevention in atrial fibrillation 
TIA 
transient ischemic attack 
TTT 
Time in a therapeutic range 
VKA 
vitamin K antagonists 
VTE 
venous thromboembolic events 

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2. RESPONSIBLE PARTIES 
 
Principal Investigator(s) of the Protocol 
Name, degree(s) 
Title 
Affiliation 
Address 
, 
MD, Clinical 
pharmacologist 
Principal Investigator 
 
 
 
 (IDIAP Jordi Gol) 
 
 
 
, 
PharmD, PhD 
 
Co-investigator 
 
 
 
 (IDIAP Jordi Gol) 
 
 
 
,  
MSc, Statistician 
 
Data analysis 
 
 
 
 (IDIAP Jordi Gol) 
 
 
 
 
, 
MSc, Information 
System from SIDIAP 
Data management  
 
 
 
 (IDIAP Jordi Gol) 
 
 
 
, 
MSc, Information 
System from SIDIAP 
Data management  
 
 
 
 (IDIAP Jordi Gol) 
 
 
 
, 
PhD 
NI Study Lead 
Pfizer 
Parque empresarial La 
Moraleja. Av. Europa 
20 B, Alcobendas 
(Madrid) 
 
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3. ABSTRACT 
Title 
Apixaban drug utilization study for Stroke prevention in atrial fibrillation (SPAF). 
Rationale and background 
Apixaban is a direct oral anticoagulant, which inhibits the factor Xa. Its clinical efficiency in 
prevention of stroke and systemic embolism in adult patients with NVAF (non-valvular atrial 
fibrillation) was demonstrated as well as has shown better safety profile compared with 
warfarin. A Drug Utilization study will evaluate whether this drug has been used in 
accordance with the approved indication and recommendations described in the summary of 
product characteristics (SmPC) and estimate possible misuse or overuse apixaban. 
Research question and objectives 
The primary research question is to evaluate the apixaban utilization according to the 
approved SPAF indication and recommendations by EMA. 
In addition a comparison with a cohort of NVAF patients treated with VKA, dabigatran and 
rivaroxaban for the SPAF indication will also be performed. 
Objective 1: To characterize patients using apixaban according to demographics, 
comorbidity, risk of thromboembolic events (CHADS2 and CHA2DS2-Vasc scores), risk of 
bleeding events (HAS-BLED score), comedications and compare it with the profile of 
patients treated with VKA, dabigatran and rivaroxaban. 
Objective 2: Describe the level of appropriate usage according to the posology 
recommended in the apixaban SmPC. 
Objective 3: Describe the potential interactions with other drugs prescribed concomintatly 
according with the SmPC recommendations. 
Objective 4: Estimate the level of apixaban adherence by the medication possession ratio 
(MPR) and discontinuation rates and compare it with VKA, dabigatran and rivaroxaban 
cohort.  
Objective 5: To analyze INR (International Normalized Ratio) values during the last 12 
months and to obtain TTR (Time in Therapeutic Range) values in patients previously treated 
with VKA, and during the whole study period for those in the cohort treated with VKA. 

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Study design 
Retrospective cohort study using data from the SIDIAP database (
 
 
) in Catalonia, Spain. The observational study period will 
be from August 2013 until December 2015. 
Population  
The study population for this cohort include all eligible subjects from the source population 
with a first –recorded prescription of apixaban, VKA, dabigatran or rivaroxaban registered in 
SIDIAP database and prior diagnosis of NVAF for study period.  
Variables:  
Sociodemographic characterization of the patients in both groups of drugs will be assessed 
for each variable (age, sex, toxic habits, MEDEA index, BMI). 
Comorbidity: Apixaban, VKA, dabigatran and rivaroxaban users will be characterized 
according to presence of comorbidity at the baseline period (12 months prior to the initial 
prescription) before the start date. Comorbidity will be assessed for each disease/condition 
detailed.  
Concomitant treatments at the index date will be identified. Concurrent use of potentially 
interacting medications will be assessed for the months during follow-up period of the study.  
Apixaban dose will be assessed during the study period for each patient at two different 
doses 2.5mg BID and 5mg BID.  
Thromboembolic risk characterization in patients with NVAF and bleeding risk will be 
assessed at the start date for each risk score CHADS2, CHA2DS2Vasc and HAS-BLED. 
INR and TTR estimations would be done for current apixaban users which previously have 
been treated with VKA drugs and for current VKA users and its measurement would be done 
by data of prothrombin time. 
Apixaban, VKA, dabigatran and rivaroxaban adherence will be measured by MPR 
(medication possession ratio) and by discontinuation rates, identified from pharmacy invoice 
data prescriptions during the study period. 
Data sources 
The data source is SIDIAP database, which contains anonymized clinical information that 
originates from different data sources: 1) eCAP™ (electronic medical records in Primary 
Care of the Institut Català de la Salut [ICS]); which includes information since 2006 on 
sociodemographic characteristics, health conditions registered as ICD10 codes, General 
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Practitioners’ prescriptions, clinical parameters and toxic habits. 2) Laboratory data. 3) 
Prescriptions and their corresponding pharmacy invoice data; available since 2005: 
information on all pharmaceutical products dispensed by community pharmacies with 
Catalan Health System prescriptions, by ATC codes. 
Study size 
The sample size is driven by the prescription of apixaban in source population of database. 
According to previous data, we estimate that we would have approx. 2000 patients treated 
with apixaban, 14000 with VKA (warfarina 2000, acenocumarol 12000), 4000 with 
dabigatran and 500 with rivaroxaban. 
Data analysis 
The analysis will be performed using SAS software, version 9.4 (SAS Institute). The use and 
patterns of use of Apixaban and VKA will be summarised by the total number of users, 
prescriptions, and number of defined daily doses (DDDs), and by the number of users 
according to daily dose and duration of use. Characteristics of users, comorbidity, 
comedications, use of interacting drugs will be described as number and percentage of 
patients with each condition. The number and percentage of all variables will be calculated 
by apixaban VKA, dabigatran and rivaroxaban group. In general, frequencies will be used to 
describe the study sample characteristics and characteristics of each category group. Chi-square 
tests and ANOVA will be utilized to compare categorical and continuous variables, respectively, 
across the category groups. 

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4. AMENDMENTS AND UPDATES 
Amendment 
number 
Date 
Substantial or 
administrative 
amendment 
Protocol 
section(s) 
changed 
Summary of 
amendment(s) 
Reason 
1 
Nov 
2016 
Administrative 
change 
2. 
Responsible 
parties 
 is no longer the 
Principal investigator.  
 is no 
longer responsible of data 
management. 
 is now 
de Principal investigator.  
 is a 
new co-investigator of the 
team 
 and 
 
 are now responsible 
of data management.  
 
and 
 are 
not currently working at 
IDIAP Jordi Gol.  
 
 
5. MILESTONES 
 
Milestone 
Planned date 
Drafting of the Protocol, AEMPS classification, Research 
Ethics Committee evaluation 
November 2015-January 2016 
Start of data collection, study variables operational definition 
April 2016 
End of data collection (data management and extraction) 
June 2016 
Statistical analysis 
July-September 2016 
Interim report  
November 2016 
Final study report. 
December 2016 
 
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6. RATIONALE AND BACKGROUND 
We present a non-interventional post authorization study on the use of apixaban in Catalonia 
–Spain public health care population. 
Apixaban was authorized in 2011 by European Medicines Agency (EMA) for prevention of 
venous thromboembolic events (VTE) in adult patients who have undergone elective hip or 
knee replacement surgery, prevention of stroke and systemic embolism in adult patients with 
non-valvular atrial fibrillation (NVAF), with one or more risk factors, and treatment and 
prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE).1 
The apixaban SPAF indication was commercialized in Spain for the first time in August 2013 
as Eliquis, 5 mg BID film-coated tablets.1 
Apixaban is a direct oral anticoagulant (DOAC), which inhibits factor Xa. Its clinical 
efficiency in prevention of stroke and systemic embolism in adult patients with NVAF was 
demonstrated by clinical trial: CV185030 (ARISTOTLE), where it demonstrated superior 
efficacy compared to warfarin in the primary composite endpoint of stroke or systemic 
embolism: 1.27 % / year with apixaban vs. 1.60% / year with warfarin (hazard ratio [HR], 
0.79; 95 % confidence interval [CI], 0.66 to 0.95). While in the primary endpoint for safety it 
showed better safety profile compared with warfarin in severe bleeding: 2.13 % / year 
apixaban vs 3.09 % / year warfarin (HR, 0.69; 95 %, CI: 0.60 to 0.80).2  
Until now, most of the observational studies for apixaban were about cost-effectiveness, 
which is explained due to the relatively high price of this new drug. According to the study 
"Patterns of initiation of oral anticoagulants in patients with atrial fibrillation (AF) - quality 
and cost implications” the patients were characterized by prescription and comparing 
apixaban with other DOAC in the treatment of NVAF and the authors found that DOACs are 
being incorporated quickly into clinical practice, especially among patients with low values 
of CHADS2 score and HAS-BLED score.3 
It is a relatively new drug, recently launched on the Spanish market and according to the 
detailed 
bibliographic 
review 
and 
database 
of 
registered 
clinical 
trials, 
www.clinicaltrialsregister.eu; there are no drug utilization studies (DUS) of apixaban in 
Spanish population. EMA recommends additional monitoring for this drug and 
pharmacovigilance plan which includes performing drug utilization and post marketing 
studies. 
This DUS protocol will evaluate whether this drug has been used properly and in accordance 
with the approved indications and recommendations described in the summary of product 
characteristics (SmPC) and estimate possible misuse or overuse of apixaban. 

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7. RESEARCH QUESTION AND OBJECTIVES 
The primary research question is to evaluate the apixaban utilization according to the 
approved SPAF indication and recommendations by EMA. 
In addition a comparison with a cohort of NVAF patients treated with VKA, dabigatran and 
rivaroraban for the SPAF indication will also be performed. 
Objective 1: To characterise patients using apixaban according to demographics, 
comorbidity, risk of thromboembolic events (CHADS2 and CHA2DS2-Vasc scores) 4, risk of 
bleeding events (HAS-BLED score) 5, comedications and compare it with the profile of 
patients treated with VKA, dabigatran and rivaroxaban. 
Objective 2: Describe the level of appropriate usage according to the posology 
recommended in the apixaban SmPC. 
Objective 3: Describe the potential interactions with other drugs prescribed concomitantly 
according with the SmPC recommendations. 
Objective 4: Estimate the level of apixaban adherence by the medication possession ratio 
(MPR) and discontinuation rates and compare it with the VKA, dabigatran and rivaroxaban 
cohort.  
Objective 5: To analyze INR (International Normalized Ratio) values during the last 12 
months and to obtain TTR (Time in Therapeutic Range) values in patients previously treated 
with VKA, and during the whole study period for those in the cohort treated with VKA. 
 
8. RESEARCH METHODS  
8.1. Study design  
This DUS is a retrospective, observational and cohort study. The users of apixaban are 
patients identified in the primary health care database SIDIAP (
 
 
) in Catalonia, Spain. 
Study cohort  
The study cohort includes all individuals diagnosed with NVAF from source population who 
had a new prescription for apixaban, VKA (warfarin or acenocoumarol), dabigatran or 
rivaroraban from August 2013 until December 2015 and a previously recorded diagnostic of 
NVAF. All the patients enrolled in the cohort will be subdivided in four main groups.  
Group 1: Patients who are on treatment with apixaban, this group will have two subgroups, 
 
1a: patients who have initiated with apixaban as treatment naïve (no prior prescription 
 
of VKA previous to the 12 months before index date), 
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1b: patients who previously have been treated with VKA in the 12 months before 
 
index date. 
Group 2: Patients who are on treatment with VKA, this group will have two subgroups, 
2a: patients who have initiated with VKA as treatment naïve (no prior prescription of 
VKA previous to the 12 months before index date), 
 
2b: patients who previously have been treated with VKA in the 12 months before 
 
index date. 
Group 3: Patients who are on treatment with dabigatran, this group will have two subgroups, 
 
3a: patients who have initiated with dabigatran as treatment naïve (no prior 
prescription of VKA previous to the 12 months before index date), 
3b: patients who previously have been treated with VKA in the 12 months before 
 
index date. 
Group 4: Patients who are on treatment with rivaroxaban, this group will have two 
subgroups, 
 
4a: patients who have initiated with rivaroxaban as treatment naïve (no prior 
prescription of VKA previous to the 12 months before index date), 
4b: patients who previously have been treated with VKA in the 12 months before 
 
index date. 

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Figure 1. Overview of Study Design 
 
 
 
 
       Before start date (Baseline period)  
After start date 
 
 
 
12 months 
 
Follow -up 
1 month  
˃1 month  
Comorbidity 
 
 
 
Co-medication  
 
 
 
Medicine adherence 
 
 
 
INR for VKA 
 
 
VKA: vitamin K antagonists 
   
8.2. Setting 
SIDIAP currently collects information from 274 primary health care centers, including more 
than 5.8 million patients, about 80 % of the Catalonia population, or more than 10 % of the 
Spanish population covered by the Catalan Institute of Health. 
The study population for these cohorts includes all eligible subjects from the source 
population with a first –recorded prescription of apixaban VKA, dabigatran or rivaroxaban 
for the SPAF indication, registered in SIDIAP database and diagnosis of NVAF for study 
period.  
The study period is defined as the time between the dates when apixaban became 
commercialized for the SPAF indication, which in Spain was since August 2013 until latest 
date of interest for our study which is December 2015. 
8.2.1. Inclusion criteria 
1. Patients more than 18 years-old 
2. Patients diagnosed with NVAF registered in primary care according to ICD-10. 
3. Patients initiating apixaban (naïve or VKA experienced), VKA (naïve or VKA 
experienced), dabigatran or rivaroxaban for the SPAF indication 
Start date-first prescription of 
apixaban or VKA (Index date) 

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4. Continuous enrolment in the 12 months pre-index.  
8.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
1. Patients with valvular heart disease (ICD 10: I05.0-I05.09, I08.0-I08.9) including patients 
with mitral prosthetic valves. 
2. Lost to follow-up (e.g. transfer to primary care center non-ICS) 
8.3. Variables 
Sociodemographic: age, sex, socioeconomic index,6 toxic habits (alcohol and smoking), and 
BMI (see Table below). 
Table 1. Sociodemographic characteristics 
Variable 
Role 
Data source 
Operational definition 
Age 
Baseline characteristics  
SIDIAP 
birth date (month/year) 
Sex 
Baseline characteristics 
SIDIAP 
male or female 
Socioeconomic index 
Baseline characteristics 
SIDIAP 
MEDEA index 
Smoking habits 
Baseline characteristics 
SIDIAP 
smoker, non-smoker and 
ex-smoker 
Alcoholic habits 
Baseline characteristics 
SIDIAP 
No intake, moderate intake, 
risk consumption 
Body mass index 
Baseline characteristics 
SIDIAP 
Kg/m2 (two prior year) 
SIDIAP: 
 
 
Comorbidity: heart failure, peripheral artery disease, ischemic heart disease, myocardial 
infraction, hypertension, diabetes mellitus, DVT, PE, liver disease, renal disease, 
cerebrovascular disease, cancer and chronic obstructive pulmonary disease. Diagnoses will 
be identified for the ICD-10 (International Statistical Classification of Diseases and Related 
Health Problems 10th Revision) codes.7 Serum creatinine (to estimate glomerular filtration 
rate [GFR] using the Modification of Diet in Renal Disease [MDRD] formula) (see table 
below). These variables are obtained from the 12 months prior to enrollment in the study and 
12 months of inclusion. 
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Table 2. Comorbidity 
Variable 
Role 
Data source(s) 
Operational definition** 
Heart failure 
Comorbidity 
SIDIAP 
I50 
Peripheral artery disease 
Comorbidity 
SIDIAP 
I73.8, I73.9 
Ischemic heart disease 
Comorbidity 
SIDIAP 
I20*-I25* 
Acute myocardial infarction 
Comorbidity 
SIDIAP 
I21* 
Hypertension 
Comorbidity 
SIDIAP 
I10*-I15* 
Diabetes mellitus 
Comorbidity 
SIDIAP 
E10*-E14*, R73* 
Deep Vein Thrombosis and 
Pulmonary Embolism 
Comorbidity 
SIDIAP 
I26*, I74* 
Liver disease 
Comorbidity 
SIDIAP 
K70*-K77* 
Renal disease 
Comorbidity 
SIDIAP 
N17*-N19* 
Cerebrovascular disease 
Comorbidity 
SIDIAP 
I60*-I69* 
Cancer 
Comorbidity 
SIDIAP 
C00*-D48* 
Chronic 
obstructive 
pulmonary disease 
Comorbidity 
SIDIAP 
J40-J45* 
Creatinine clearance 
Comorbidity 
SIDIAP LAB 
ml/min/1.73m2 (MDRD) 
**ICD-10: International Classification of Diseases 10th Revision; SIDIAP: 
 
, MDRD: Modification of Diet in Renal Disease 
 
Medication  
The drug dispensing will be identified from the invoicing database of CatSalut. ATC code8 
will be used to identify the medication (see table 3). The patients will be followed up to the 
prescription other anticoagulant 
Two groups of doses will be established according to the apixaban SmPC; 5mg/BID or 2.5 
mg/BID in the SPAF indication. 
The co-medications will be identified from prescription data at the index date and collected 
from the inclusion in the study and up to one month after.  
For each user of apixaban, there will be search for concurrent use of other drugs as follows: 
 
Concurrent use at the start date: 
- 
patients who have at least one prescription for potentially interacting 
medication recorded at the start date, 
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- 
patients who have at least one prescription for potentially interacting 
medication recorded during the time of current use of apixaban. 
Table 3.Medication 
ATC 
Drugs description  
A02BC  
Proton pump inhibitors  
A10  
Drugs used in diabetes  
A10A  
Insulins  
A10B, A10X  
Blood glucose lowering drugs  
B01  
Antithrombotic agents  
B01AC  
Platelet aggregation inhibitors  
B01AC04  
Clopidogrel  
B01AC06, B01AC30, B01AC56  
Acetylsalicylic acid  
B01AC01-B01AC03, 
B01AC05, 
B01AC07-B01AC22, B01AC24  
Other platelet aggregation inhibitors  
B01AA  
Vitamin K antagonists  
B01AB  
Heparins  
B01AD, B01AE, B01AF01, B01AX 
Other antithrombotic agents  
B01AF02 
Apixaban 
B03A  
Iron preparations  
C  
Cardiovascular medications  
C01A  
Cardiac glycosides  
C01B  
Antiarrhythmics, Class I and III  
C01C  
Cardiac stimulants excluding cardiac glycosides  
C01D  
Vasodilators used in cardiac diseases  
C01E  
Other cardiac preparations  
C03  
Diuretics  
C04  
Peripheral vasodilators  
C04AD03  
Pentoxifylline  
C07  
Beta blocking agents  
C08  
Calcium channel blockers  
C02  
Antihypertensives  
C09  
Agents acting on the renin-angiotensin system  
C09A, C09B  
Angiotensin-converting-enzyme inhibitors  
C09C, C09D  
Angiotensin II receptor antagonists  
C09X 
Renin-inhibitors  
C10  
Lipid-modifying agents  
C10AA  
Statins  
C10AB, C10AC, C10AD, C10AX, 
C10BA  
Other lipid-modifying agents 
G03C, G03D, G03F 
Hormone replacement therapy 
H02 
Systemic corticosteroids 
L04  
Immunosuppressants  
M01A, N02BA, M01B, M01C  
Drugs for musculoskeletal system  
M01A  
Non-steroidal anti-inflammatory drugs  
N02BA  
Acetylsalicylic 
acid 
(other 
analgesics 
and 
antipyretics)  
M01B-M01C  
Other antirheumatic agents  
N06A  
Antidepressants  
N06AB  
Selective serotonin reuptake inhibitors  
R03  
Drugs for obstructive airway diseases  
ATC: Anatomical therapeutic chemical 

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The co-medications may interact with apixaban.  
Apixaban is metabolized mainly via cytochrome P450 3A4/5 (CYP3A4/5) with minor 
contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Apixaban is a substrate of transport 
proteins, P-glycoprotein (P-gp) and breast cancer resistance protein. Medications potentially 
interacting with apixaban are listed in the risk management plan and in the SmPC and 
include (see table 4): 
- 
Interaction with strong inhibitors of both CYP450 3A4 and P-gp such as azole-
antimycotics (e.g., ketoconazole). 
- 
Interaction with strong inducers of both CYP3A4 and P-gp such as rifampicin, 
phenytoin, carbamazepine, phenobarbital or may lead to a ~50% reduction in 
apixaban exposure. 
Table 4. Medications potentially interacting with apixaban 
Medication  
Substrates 
Inhibitors 
Inducers 
P-gp/CYP3A4 
CYP3A4 
CYP3A4  
Calcium channel blockers  
 
 
 
Diltiazem  
X 
X 
 
Statins  
 
 
 
Simvastatin  
X 
 
 
Antimycotics  
 
 
 
Itraconazole  
 
X 
 
Antimycobacterials  
 
 
 
Rifampin  
 
 
X 
Antipsychotics  
 
 
 
Pimozide  
X 
 
 
Macrolide antibiotics 
 
 
 
Clarithromycin 
X 
X 
 
Erythromycin 
X 
X 
 
Antiepileptics 
 
 
 
Phenytoin 
 
 
X 
Carbamazepine 
 
 
X 
P-gp: P-glycoprotein; CYP3A4: cytochrome P450 3A4. 
Potential pharmacodynamics interactions due to an increased bleeding risk by concomitant 
use any other anticoagulants, platelet aggregation inhibitors and NSAIDs. 
Coagulation variables  
The INR will be collected from SIDIAP database for each patient. 
The TTR of INR is the time in which INR is maintained between 2 and 3. The values will be 
calculated by INR (Roosendaal algorithm) for patients previously treated with VKA or who 
are currently on treatment with VKA. (see data analysis) 
This variable will be obtained from the 12 months prior to enrollment in the study and 12 
months of inclusion. 

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Thomboemblolic risk and bleeding risk assessment: 
 CHADS2: this score helps to estimate the risk of stroke in patients with NVAF and to 
determine which antithrombotic treatment is most appropriate. Its values will be 
calculated with SIDIAP data, which include presence of congestive heart failure 
history, hypertension history, age ≥ 75, diabetes mellitus history, stroke or TIA for 
each patient enrolled in the study. 
 CHA2DS2Vasc: this is another type of score to estimate, in a relatively simple way 
the risk of cerebrovascular accident in the case of patients with AF. The values of this 
variable would be calculated with SIDIAP data, which include presence of congestive 
heart failure history, hypertension history, age ≥ 75, diabetes mellitus history, stroke 
or TIA, vascular disease and gender for each patient enrolled in the study. 
 HAS-BLED: this rating score measures the risk of occurrence of major hemorrhage 
in a year, it includes several factors such as hypertension (systolic blood pressure > 
160 mmHg), impaired renal function, impaired liver function; prior stroke; prior 
major bleeding; Labile INR (less than 60% of the time in therapeutic range); over 65 
years of age, medication usage predisposing to bleeding (antiplatelet agents, NSAIDs) 
and, moderate use and overuse of alcohol. Values of this variable will be calculated 
by SIDIAP patient data. 
Medication adherence outcome 
Definition of the therapeutic adherence: medication possession ratio (MPR), defined daily 
dose (DDD), TTR and accumulative discontinuation rate. 
The therapeutic adherence will be assessed through pharmacy invoice data (drug dispensing) 
from the pharmacies for patients who initiate treatment between August 2013 and 2014. For 
each patient with prescription of apixaban, VKA, dabigatran and rivaroxaban we will 
determine two dates. First invoice date (index date - when the patient took the drug for the 
first time), and date of the last invoicing. MPR will be calculated using variable medication 
possession ration calculation (VMPR), DDD and TTR. The calculations will be performed as follows: 
 
“All days’ supply”=sum of days’ supply between the index date and last prescription dispensed 
(inclusive of the last prescription) and “elapsed days”=number of days between the index date and the 
last prescription dispensed (inclusive of days’ supply) during the 12-month observation period (last 
date of service minus first date of service plus 1). Any prescription days’ supply that spanned the 12-
month end date was truncated at 12 months.9  
MPR will be evaluated for patients receiving medication for at least 12 months during the 
period between the first and the last prescription.  There will be two categories of adherence, 

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good adherence with at least 80% of MPR and poor therapeutic adherence with less than 
80% MPR. 
Additionally, we will use the WHO defined daily dose (DDD) methodology to evaluate drug 
utilization,8 in order to calculate utilization of VKA anticoagulants medications using 
invoicing data. The DDD values will be obtained from the WHO ATC/DDD index to derive 
DDDs for each medication. DDD is a measure that represents that average daily maintenance 
dose for the main indication of a drug. We will use to aggregate data on different doses and 
formulations to enable comparisons of utilization across different VKA . For NOACs use the 
package size to derive days of supply (Rivaroxaban once daily, Dabigatran and Apixaban 
twice daily) as the WHO DDD does not separate between standard and low dose. 
 
The adherence to VKA is evaluated by TTR of INR, which is the time in which INR is 
maintained between 2 and 3. The primary health care centers covered by ICS accounting 
70% of the Catalonia population treated with VKA. 
In addition, accumulative discontinuation rates will be analyzed. Discontinuation rates will 
be defined by lack of subsequent prescription of the index drugs within 2 months after last 
supply day of the last prescription and will be analyzed by calculating the accumulative 
discontinuation (treatment withdrawal or switch) rate.   
8.4. Data sources  
To investigate the use of apixaban, this DUS requires an efficient means to identify sufficient 
number of patient taking this drug. At present, the largest and most readily accessible drug 
utilization data come from automated databases that record prescriptions, diagnoses, and 
procedures on an individual-patient basis. Such databases accumulate records longitudinally 
so that patient experience can be observed before and after prescription of a drug of interest. 
The data source is SIDIAP database, which contains anonymized clinical information that 
originates from different data sources: 1) eCAP™ (electronic medical records in Primary 
Care of the Institut Català de la Salut [ICS]); which includes information since 2006 on 
sociodemographic characteristics, health conditions registered as ICD10 codes, General 
Practitioners’ prescriptions, clinical parameters and toxic habits. 2) Laboratory data. 3) 
Prescriptions and their corresponding pharmacy invoice data; available since 2005: 
information on all pharmaceutical products dispensed by community pharmacies with 
Catalan Health System prescriptions, by ATC codes. 
8.5. Study size 
There will be no calculation of sample size. The sample size is driven by the prescription of 
apixaban in source population of database. According to previous data, we estimate that we 
would have approx. 2000 patients treated with apixaban, 14000 with VKA (warfarina 2000, 
acenocumarol 12000), 4000 with dabigatran and 500 with rivaroxaban. 

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8.6. Data Management 
Routine procedures will include checking electronic files, maintaining security and data 
confidentiality, following analysis plans, and performing quality-control checks of all 
programs. SIDIAP database will maintain any patient-identifying information securely on 
site according to internal standard operating procedures. 
Security processes will be in place to ensure the safety of all systems and data. Every effort 
will be made to ensure that data are kept secure so that they cannot be accessed by anyone 
except select study staff. 
Appropriate data storage and archiving procedures will be followed (i.e., storage on CD-
ROM or DVD), with periodic backup of files to tape. Standard procedures will be in place at 
each research Centre to restore files in the event of a hardware or software failure. 
8.7. Data analysis  
This section provides an overview about the statistical methods that will be applied in order 
to answer each research questions. The core statistical elements (analysis populations, 
definition and measurement of endpoints and other key variables and statistical 
methodology) are adequately detailed. 
Sociodemographic characteristics for the four groups (apixaban, dabigatran, rivaroxaban and 
VKA) at the start date will be provided: (1) for all variables, number and percentage of 
missing data; (2) for categorical variables (sex, toxic habits and MEDEA index), number and 
percentage for each category; (3) for continuous variables (age, BMI), mean, standard 
deviation, median, interquartile range, minimum and maximum.  
Comorbidities at the start date will be identified by codes in table 2. The total number of 
patients with at least one disease and the number and percentage of patients with each 
specific condition will be provided for all groups (apixaban, dabigatran, rivaroxaban and 
VKA).  
Concurrent use of medications listed in table 3 at the start date for apixaban will be 
quantified by the number and percentage of users.  
Risk of stroke and major hemorrhage event will be assessed at the start date with CHADS2, 
CHA2DS2Vasc and HAS-BLED. For each scale, number and percentage of each category for 
four groups (apixaban, dabigatran and rivaroxaban, VKA) will be provided. 
Appropriate use of apixaban during the study period will be assessed for two groups of 
patients depending on the recommended daily dose: 5 or 2.5 mg twice daily. Mean, standard 
deviation, median, interquartile range, minimum and maximum of the estimated daily dose 
will be calculated in each group. Lower dose of apixaban (2.5 mg twice daily) is 
recommended in these situations: 
- 
Patients with at least two of the following characteristics: (1) serum creatinine ≥ 1.5 
mg/dL (133 micromole/L) (2) age ≥ 80 years and (3) body weight ≤ 60 kg. 

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- 
Patients with severe renal impairment (creatinine clearance below 30 mL/min) 
Number of patients receiving an inappropriate dose will be provided: those taking high dose 
that met these criteria and patients taking lower dose outside these criteria. 
 
Potential pharmacokinetic and pharmacodynamic interactions with apixaban will be assessed 
according to comedications at the start date. Number and percentage of each interaction listed 
in table 4 will be reported. 
Apixaban, VKA, dabigatran and rivaroxaban user adherences will be assessed during the 
study period through the MPR. The number of days of supply will be estimated based on the 
number and the size of the packages between the index date and last prescription dispensed.   
Values above 80% will be considered as good adherence. For each group, number and 
percentage of users with good adherence and summary statistics as mean, standard deviation, 
median, interquartile range, minimum and maximum for MPR will be provided. In addition, 
monthly discontinuation rates for all groups during the first year of treatment will be 
calculated. Median and interquartile range for the time to discontinuation and a graph 
representing the accumulative discontinuation rates over time will be provided. 
Additionally, in order to compare drug utilization DDD will be used in the VKA and package 
size in NOACs. We calculate mean, standard deviation, median, interquartile range, 
minimum and maximum in terms of DDD for each drug. 
For VKA users, INR registered during at least one year (i.e, only applicable to patients with 
first prescription prior to January 2015) will be collected. INR will be categorized according 
to the risk level: risk for coagulation (INR<2); optimal range (2<INR<3); and risk of 
hemorrhages (INR>3). Median and interquartile range for INR and number of percentage for 
each category of the categorized INR will be provided. 
TTR well be  calculated according to F.R. Roosendaal's algorithm with linear interpolation.10 
Between two INR determinations, TTR was estimated as the number of days that the patient 
remains into the optimal range assuming that the changes in INR occurs in a linear way. For 
each patient, the total TTR is defined as the sum of estimated TTRs between each couple of 
INR determinations.  Median and standard deviation of total TTR for VKA will be provided.  
For categorical variables, comparisons between groups will be performed with a chi-square 
test or a Fisher test as appropriate. P-values resulting from those tests will be reported. Odds 
ratios for each group relative to apixaban will be estimated with their 95% confidence 
interval.  
For numerical variables, comparisons between groups will be carried out through a one-way 
anova or a Kruskal-Wallis test as appropriate. P-values resulting from those tests will be 
reported. Mean differences relatives to apixaban will be estimated with their 95% confidence 
intervals. 
Analysis will be performed using SAS software, version 9.4 (SAS Institute). 

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In addition, detailed methodology for summary and statistical analyses of data collected in 
this study will be documented in a Statistical Analysis Plan (SAP), which will be dated, filed 
and maintained by the sponsor. The SAP may modify the plans outlined in the protocol; any 
major modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment. 
8.8. Quality control 
IDIAP Jordi Gol will be in charge of implementing their standard operating procedures to 
guide the conduct of the study. These procedures include internal quality audits, rules for 
secure and confidential data storage, methods to maintain and archive project documents, 
quality control procedures for programming, standards for writing analysis plans, and 
requirements for senior scientific review. All programming written by one study analyst will 
be reviewed independently by a different analyst, with oversight by a senior statistician. All 
key study documents, such as the analysis plan, abstraction forms, and study reports, will 
undergo quality-control review, senior scientific review, and editorial review. 
8.9. Limitations of the research methods 
DUS conducted in automated health databases allow identification of patients who are 
prescribed or dispensed the drugs of interest and characterization of these patients according 
to prior medical history, use of medications, and patterns of use of medications. Health care 
databases have become a useful tool for conducting research to study the safety of drugs as 
information on diagnoses and treatments is recorded on an ongoing basis.  
 
However, the use of automated health databases for research has some limitations, mainly 
related to the type and completeness of the recorded information. Regarding prescription 
data, databases provide detailed information on prescribed and/or dispensed medications but 
not on the actual use of the medications by patients. Overall, this can result in 
misclassification of drug exposure. Another limitation on the assessment of medication use in 
databases is that over-the-counter medications are usually not recorded. Therefore, we are not 
able to ascertain the concomitant use of apixaban and non-prescribed NSAIDs. The use of 
external data (e.g., health surveys), when available, might help to quantify the use of over-
the-counter medications. 
8.10. Other aspects 
Not applicable. 
 
9. PROTECTION OF HUMAN SUBJECTS 
9.1. Patient Information and Consent 
In this study the data records of patients who are totally anonymous will be used. In 
accordance with national law, it is not necessary to ask participants for their informed 
consent. Confidentiality rules provided by law 15/1999 (
 
) will be respected. 
PPD

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9.2. Patient withdrawal 
Not Applicable. 
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents, (e.g., 
recruitment advertisements), if applicable, from the IRB/IEC. All correspondence with the 
IRB/IEC should be retained in the Investigator File. Copies of IRB/IEC approvals should be 
forwarded to Pfizer. 
9.4. Ethical Conduct of the Study 
The protocol is presented to the 
 Jordi Gol for 
approval. 
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 issued by the 
International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practice 
guidelines issued by the International Epidemiological Association, Good Practices for 
Outcomes Research issued by the International Society for Pharmacoeconomics and 
Outcomes Research, International Ethical Guidelines for Epidemiological Research issued by 
the Council for International Organizations of Medical Sciences, EMA, European Network 
of Centres for Pharmacoepidemiology and Pharmacovigilance Guide on Methodological 
Standards in Pharmacoepidemiology, and FDA (Food and Drug Administration) 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 includes structured data in an electronic database. In these data sources, it is not 
possible to link (i.e. identify a potential association between) a particular product and 
medical event for any individual. Thus, the minimum criteria for reporting an adverse event 
(i.e., identifiable patient, identifiable reporter, a suspect product, and event) are not available 
and adverse events (AE) are not reportable as individual AE reports. 
 
 
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11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
COMMUNICATION OF ISSUES 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.   
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NI study protocol that the investigator becomes aware. 
The results of this study will be comprehensively summarized in a final report. It is 
furthermore planned to publish the findings in a peer-reviewed journal.  
The IDIAP may independently prepare publications based on the study results irrespective of 
data ownership and publish the results accordance with the principles of scientific 
independence and transparency and respecting the criteria established in the Code of Conduct 
ENCePP. The marketing authorisation holder will be entitled to view the results and 
interpretations included in the manuscript and provide comments prior to submission of the 
manuscript for publication (EMA, 2012, Section VIII.B.7; module VIII). 
 

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12. REFERENCES 
1. Summary 
of 
Product 
Characteristics 
Eliquis. 
Available 
at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002148/WC500107728.pdf. Accessed September 18, 
2015. 
2. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M et al. 
Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 
981-92. 
3. Desai NR, Krumme AA, Schneeweiss S, Shrank WH, Brill G, Pezalla EJ et al. 
Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality 
and cost implications. Am J Med 2014; 127: 1075-82. 
4. Lip GY, Frison L, Halperin JL, Lane DA. Identifying patients at high risk for stroke 
despite anticoagulation: a comparison of contemporary stroke risk stratification 
schemes in an anticoagulated atrial fibrillation cohort. Stroke 2010; 41: 2731-8. 
5. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-
friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with 
atrial fibrillation: the Euro Heart Survey. Chest 2010; 138: 1093-100 
6. Domínguez-Berjón MF, Borrell C, Cano-Serral G, Esnaola S, Nolasco A, Pasarín MI 
et al. Construcción de un índice de privación a partir de datos censales en grandes 
ciudades españolas (Proyecto MEDEA). Gac Sanit 2008; 22: 179-87. 
7. International Statistical Classification of Diseases and Related Health Problems 10th 
Revision. Available at: http://apps.who.int/classifications/icd10/browse/2016/en. 
Accessed October 01, 2015. 
8. WHO Collaborating Centre for Drug Statistics Methodology. Norwegian Institute of 
Public Health. The Anatomical Therapeutic Chemical (ATC) classification system. 
Available at: http://www.whocc.no/atc_ddd_index/. Accessed October 01, 2015. 
9. Kozma CM, Dickson M, Phillips AL, Meletiche DM. Medication possession ratio: 
implications of using fixed and variable observation periods in assessing adherence 
with disease-modifying drugs in patients with multiple sclerosis. Patient Prefer 
Adherence 2013; 7: 509-16. 
10. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the 
optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993;69:236-239 
 
 

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13. LIST OF TABLES  
TABLE 1. Sociodemographic characteristics...……………………………………….15 
TABLE 2. Comorbidity.…………………………………………………………….…16 
TABLE 3. Medication…………………………………...…………………………….17 
TABLE 4. Medications potentially interacting with apixaban………………………..18 
 
 
14. LIST OF FIGURES 
FIGURE 1. Overview of study design……………………………………...…………14 
 

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ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None.  
 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Not required. 
ANNEX 3. ADDITIONAL INFORMATION 
Not applicable